Role of substance P in the cardiovascular system

YNPEP-01690; No of Pages 11 Neuropeptides xxx (2015) xxx–xxx

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Role of substance P in the cardiovascular system Eliska Mistrova a,b, Peter Kruzliak c,d,⁎, Magdalena Chottova Dvorakova a,b a

Department of Physiology, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic c Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic d nd 2 Department of Internal Medicine, Faculty of Medicine, Masaryk University, Brno, Czech Republic b

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 20 August 2015 Received in revised form 7 December 2015 Accepted 7 December 2015 Available online xxxx

This article provides an overview of the structure and function of substance P signalling system and its involvement in the cardiovascular regulation. Substance P is an undecapeptide originating from TAC1 gen and belonging to the tachykinin family. The biological actions of substance P are mainly mediated through neurokinin receptor 1 since substance P is the ligand with the highest affinity to neurokinin receptor 1. Substance P is widely distributed within the central and peripheral nervous systems as well as in the cardiovascular system. Substance P is involved in the regulation of heart frequency, blood pressure and in the stretching of vessels. Substance P plays an important role in ischemia and reperfusion and cardiovascular response to stress. Additionally, it has been also implicated in angiogenesis, pain transmission and inflammation. The substance P/neurokinin receptor 1 receptor system is involved in the molecular bases of many human pathological processes. Antagonists of neurokinin receptor 1 receptor could provide clinical solutions for a variety of diseases. Neurokinin receptor 1 antagonists are already used in the prevention of chemotherapy induced nausea and vomiting. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Substance P NK1 receptor Cardiovascular regulation Antagonist

Contents 1.

Introduction . . . . . . . . . . . . . 1.1. Synthesis of SP . . . . . . . . 1.2. Localization of SP . . . . . . . 1.3. SP receptors . . . . . . . . . 1.4. Principal physiological functions 2. Substance P in the heart . . . . . . . 2.1. Location and function . . . . . 2.2. SP and heart ischemia . . . . . 2.3. SP and other heart diseases . . 3. Substance P in the vascular system . . 3.1. Location and function . . . . . 3.2. SP and neurogenic inflammation 3.3. SP and angiogenesis . . . . . . 3.4. SP and brain ischemia . . . . . 4. Substance P and cardiovascular control 5. NK1 receptor antagonists . . . . . . . 6. Conclusion . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . References . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Odborarov 10, 832 32, Bratislava, Slovak Republic. E-mail address: [email protected] (P. Kruzliak).

http://dx.doi.org/10.1016/j.npep.2015.12.005 0143-4179/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article as: Mistrova, E., et al., Role of substance P in the cardiovascular system, Neuropeptides (2015), http://dx.doi.org/10.1016/ j.npep.2015.12.005

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1. Introduction Substance P (SP) is an undecapeptide belonging to the tachykinin family of neuropeptides that are evolutionarily the oldest neurotransmitters, perhaps even older than acetylcholine and catecholamines. The first reference comes from 1931, when SP was isolated as a crude extract from equine brain and intestine (Von Euler and Gaddum, 1931). This newly discovered matter was named as SP referring to the powder obtained after the extraction procedure (Gaddum and Schild, 1934). In the early seventies, pure form of SP was isolated from bovine hypothalamus and the amino acid structure has been identified (Chang et al., 1971). The tachykinin peptide family certainly represents one of the largest peptide families described in animal organisms, including members occurring in different animal species from low invertebrates to mammals. So far, more than 40 tachykinins have been isolated from invertebrate and vertebrate tissues. But until the end of the last century, only three tachykinins have been isolated and sequenced from mammalian tissues: SP, neurokinin A (NKA) and neurokinin B (NKB) (Pennefather et al., 2004). NKA could be present also in two elongated forms called neuropeptide K (NPK) and neuropeptide γ (NPγ) (Kage et al., 1988, Tatemoto et al., 1985). Since the discovery of a new preprotachykinin gene in year 2000, the number of known tachykinins rapidly increased. These newly described peptides are called endokinins and include hemokinin-1 in mouse, rat and human, endokinin-1 in rabbit, and endokinin A and B in humans (Page, 2006). SP was one of the most extensively studied active substance during the half-century since its discovery, and for many years, it was believed to be the only mammalian tachykinin considered as a neuropeptide. This opinion was resolutely reversed with discovery of NKA and NKB, that differ from SP in their pharmacological activity and in their preference for different tachykinin receptor subtypes (Kangawa et al., 1983). 1.1. Synthesis of SP Mammalian SP derives from the TAC1 (preprotachykinin A, PPT-A) gene, which encodes the sequence of NKA, neuropeptide K and neuropeptide-γ (Nawa et al., 1983, Kotani et al., 1986, Krause et al., 1987). The TAC3 gene (preprotachykinin B, PPT-B) encodes precursor molecule only for NKB (Bonner et al., 1987). The human gene consists of seven exons and the sequences encoding SP and NKA are contained in exon 3 and exon 6, respectively (Fig. 1). Transcription of the TAC1 gene generates a pre-messenger ribonucleic acids that could be alternatively spliced giving a results in four distinct messenger ribonucleic acids (mRNA) isoforms: α, β, γ and δ. Individual mRNA isoforms differ only in a number of exons. Beta mRNA includes all 7 exons of the TAC1 gene, while mRNA α lacks exon 6 and mRNA γ lacks exon 4 (Carter and Krause, 1990). SP results from all of them, while mRNAs β and γ additionally encode NKA (Pennefather et al., 2004, Page, 2004). This indicates that SP could be expressed without NKA, but synthesis of NKA is always accompanied with SP. Both, SP and NKA are frequently synthesized, stored and released collectively (Pennefather et al., 2004). After the synthesis, SP is packed into vesicles and transported to both, the central and peripheral endings of primary sensory neurons for final processing (Nakanishi, 1987, Otsuka and Yoshioka, 1993). Quantity of SP in the central level, in dorsal root ganglia (DRG), is four times lower compared to peripheral nerve endings (Harmar et al., 1980). 1.2. Localization of SP SP is widely distributed throughout the mammalian central and peripheral nervous systems (CNS, PNS) and the enteric nervous system (Pernow, 1983, Mai et al., 1986, Hokfelt et al., 1982). Nervous tissue represents by far the most important localization of the tachykinins. Data on the distribution and localization of neuronal tachykinins in the CNS and periphery have been originally obtained mainly by a combination

Fig. 1. Schematic diagram of synthesis of SP and characteristic steps from transcription to translation, axonal transport and final enzymatic processing. Mammalian SP derives from the TAC1 gene, which encodes the sequence of neurokinin A, neuropeptide K and neuropeptide-γ. Gen TAC3 encodes precursor molecule only for NKB. The human gene consists of seven exons and the sequences that encode SP and NKA are contained in exon 3 and exon 6, respectively. Transcription of the TAC1 gene generates pre-messenger ribonucleic acids that could be alternatively spliced resulting in four distinct mRNA isoforms: α, β, γ and δ. SP results from all of them, while mRNAs β and γ encode just NKA. Translation of the mature mRNA from TAC1 gene generates a large polypeptide in ribosomes of neuronal bodies. This polypeptide is designed as pre-propeptide consisting of signal peptide; one or several copies of a neuropeptide and spacer parts. Pro-peptide form is transported to the Golgi apparatus, where the spacer parts are split off. Subsequently, it is packed into vesicles and axonally transported to both, the central and peripheral endings of primary sensory neurons for final processing. By the activity of peptidase, precursor molecule is enzymatically converted into active form and stored in vesicles ready to release.

of high-performance liquid chromatography with radioimmunoassay and/or by immunohistochemistry (Pernow, 1983, Hokfelt et al., 1977, Hokfelt et al., 1975). In the condition of using regional specific antisera directed against the C-terminal region of the tachykinins, the discrimination between the various tachykinins is not exact (Maggio, 1988). The low specificity of antisera and the different tissue extraction methods (Lindefors et al., 1985, Brodin et al., 1986) may explain some differences on the localization of mammalian tachykinins confronted in the literature. Subsequent studies already used antibodies recognizing only SP and showed that most of the localizations originally described really contains SP immunoreactivity (Ribeiro-da-Silva and Hokfelt, 2000). Distribution of the tachykinins in the CNS has been extensively studied mainly in the rat (Otsuka and Yoshioka, 1993). As expected, SP is generally co-synthesized, co-localized, and co-secreted with NKA.

Please cite this article as: Mistrova, E., et al., Role of substance P in the cardiovascular system, Neuropeptides (2015), http://dx.doi.org/10.1016/ j.npep.2015.12.005

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Immunoreactive SP nerve cell bodies and/or nerve fibers are present in various regions of the CNS including the olfactory tubercle, hippocampus, basal ganglia, ventral pallidum, amygdala, hypothalamus, caudate nucleus, ventral tegmental area, superior colliculus, inferior colliculus, locus coeruleus, reticular formation of the pons, thalamic nuclei, substantia nigra, periaqueductal central gray, parabranchial nuclei, medulla oblongata and dorsal and ventral horn of the spinal cord (Kanazawa and Jessell, 1976, Douglas et al., 1982). More details about this you can find in papers mapping localization of SP and its receptor in the CNS (Ribeiro-da-Silva and Hokfelt, 2000, Nakaya et al., 1994). In certain cerebral areas, the concentration of tachykinins may be in the order of nanomoles and the amount of SP seems to be more abundant in the grey matter compared to white matter (Ebner and Singewald, 2006). In rats, both the density and the distribution of SP-containing neurons change significantly during the life periods reaching the maximum level between postnatal days 5 and 15 and decreasing density afterwards (Inagaki et al., 1982, Sakanaka et al., 1982). In the PNS, the expression of SP and its mRNA is widely abundant in the peripheral components of the autonomic nervous systems. Nerve fibres containing SP are present in majority of autonomic ganglia, with the highest concentration found in both mesenteric ganglia and celiac ganglion (Hokfelt et al., 1977). SP-immunoreactivity has been observed also in pseudounipolar somatosensory neurons localized in the trigeminal, nodose and DRG, where it is released from both, central, dorsal spinal cord, and peripheral tissue terminals (Harrison and Geppetti, 2001). Primary afferent SP-immunoreactive fibers are found around the blood vessels, in the gall bladder and bile duct, in the pancreas, and in lymphoid organs of the immune system, such as bone narrow, thymus, spleen, and lymph nodes. Their localization is mostly perivascular, but some fibers could penetrate within the follicles (Geppetti et al., 1987). 1.3. SP receptors The biological actions of SP and other tachykinins on the target tissue are mediated by neurokinin (NK) receptors, which belong to the family of (rhodopsin-like) G-protein-coupled receptors (Gerard et al., 1993). There are three known types of NK receptors, NK1, NK2 and NK3, exhibiting different preferences to endogenous tachykinins (Page and Bell, 2002, Picard et al., 1994). SP binds preferentially to NK1 receptors (Mantyh, 2002), whereas NKA and NKB display highest affinity for the NK2 and NK3 receptors, respectively (Kerdelhue et al., 1997, Stahl,

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1999). The rank order potency of tachykinins is SP N NKA N NKB for the NK1 receptor, NKA N NKB N SP for the NK2 receptor and NKB N NKA N SP for the NK3 receptor (Guard and Watson, 1991, Maggi, 1995). The structural unit of NK1 receptor is formed by seven hydrophobic transmembrane domains, extracellular and intracellular loops. Three loops denoted as EL1, EL2, and EL3 and the unique amino-tail are localized extracellularly. On the cytoplasmic side, there are situated three loops C1, C2, and C3 and the conserved carboxyl terminal. The second and third membrane-spanning domains are involved in binding of agonists or antagonists, while the third intracellular loop is responsible for G protein interaction (Fig. 2) (O'Connor et al., 2004, Steinhoff et al., 2014). Cloned NK1 receptor shows very high degree of sequence homology between man, mouse, rat and guinea pig (Gerard et al., 1993), e.g. human and rat NK1 receptor shows more than 90% sequence homology (Gerard et al., 1991, Takeda et al., 1991). Despite this very high sequence homology and similar affinity to endogenous SP, the NK1 receptor affinity to non-peptide antagonists differs significantly between species (Beresford et al., 1991, Gitter et al., 1991). Such effect is probably caused by different binding epitopes on the NK1 receptor for SP and antagonists (Gether et al., 1993). The biological action of SP is mainly mediated by the NK1 receptor, since SP is the natural ligand with the highest affinity for the NK1 receptor. The NK1 receptor mediates also the effect of NKA and NKB (Pennefather et al., 2004), but the affinity of SP to NK1 receptor is about 100 and 500 times higher than those of NKA and NKB, respectively (Gerard et al., 1991). The NK1 receptor has two naturally occurring forms that differ in the length of their carboxyl-terminal cytoplasmic tails. Due to alternative splicing mechanisms or posttranslational modification, tachykinin receptor 1 gene can produce a full length receptor consisting of 407 amino acids and/or a truncated NK1 (NK1-Tr) receptor isoform lacking 96 C-terminal amino acid residues, thus has 311 amino acids (Caberlotto et al., 2003, Fong et al., 1992). This shorter isoform is generated when the intron located between exons 4 and 5 is not removed and the premature stop codon is identified before starting exon 5. Differential RNA splicing alters the structural, physiological and pharmacological properties of both forms of the NK1 receptors. The truncated NK1 receptor isoform has up to 10 times lower affinity for SP than its fulllength counterpart and does not undergo a rapid desensitization and internalization suggesting a need for a longer responsiveness in these

Fig. 2. Schematic diagram of human neurokinin 1 receptor. Neurokinin 1 receptor is a glycoprotein belonging to a family 1 of (rhodopsin-like) G-protein coupled receptors. The structural unit of NK1 receptor is formed by seven hydrophobic transmembrane domains, extracellular and intracellular loops. Extracellularly are localized three loops denoted as EL1, EL2, and EL3 and the unique amino-tail. On the cytoplasmic side are situated three loops C1, C2, and C3 and the conserved carboxyl terminal. The second and third membrane-spanning domains are involved in binding of agonists or antagonists, while the third intracellular loop is responsible for G protein interaction.

Please cite this article as: Mistrova, E., et al., Role of substance P in the cardiovascular system, Neuropeptides (2015), http://dx.doi.org/10.1016/ j.npep.2015.12.005

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regions (Li et al., 1997, Fong et al., 1992). This shorter isoform could also mediate distinct biological effects, while in cells expressing full-length NK1 receptor, SP stimulated phosphorylation of PKCδ but inhibited phosphorylation of PKCδ in cells expressing truncated NK1 receptor (Lai et al., 2008). So far the truncated isoform of NK1 receptor has been detected in the brain, and also in the bone and spleen. The intracellular signalling pathways are diverse for these two NK1 receptor isoforms, e.g. phosphorylation of the Erk via the long isoform was faster, from 1 to 2 min, and in contrast, cells transfected with truncated isoform have not been phosphorylated even 20 min after the exposure to SP (Lai et al., 2008). Besides these variation modifications, another important phenomenon is involved in the receptor signalling. The amino terminal end has two glycosylated N-sites and these glycosylation can influence the functional level of the receptors (Tansky et al., 2007). They discovered that nonglycosylated NK1 receptor showed lower affinity for SP, approximately 50%, and the receptor was internalized faster compared to glycosylated form. This detection also suggests the possibility that glycosylation may be a feature in the stabilization of the receptor in the plasma membrane (McGillis et al., 1990, Friess et al., 2003). NK1 receptor is found on neurons and glia in the CNS, smooth muscle cells, endothelial cell, fibroblast and various circulating immune and inflammatory cells (Schaffer et al., 1998). On unstimulated neurons, NK1 receptors are localized to the plasma membrane of both the cell body and dendrites. Interestingly, SP binding is followed by rapid internalization into the cytoplasm via endosomes and complete return of internalized receptors to the surface proceeds in 30 min (Mantyh, 2002). Several studies suggest that both forms of the NK1 receptor are expressed in vivo in animals and human beings with distinct tissue distributions. In the human brain, the full-length NK1 receptor isoform is more abundant than the short with the exception of selected sites: the substantia nigra and cerebellum. Truncated form seems to be the most prevalent in several peripheral tissues such as heart, lung, liver, spleen and bone, in which it makes about 80 or more percent of total amount of NK1 receptors. Various tissues express different ratios of the two isoforms of the NK1 receptor and the distinct expressions provide the theoretical basis for tissue specific pharmacological targeting of the NK1 receptors (Caberlotto et al., 2003). Further studies are needed to map prevalence of the short isoform in the peripheral tissues and assess its functional implications. The intracellular signalling pathways activated by NK1 receptor seem to be system and cell-dependent. In the cells such as astrocytes and microglia, SP binding to NK1 receptor leads to activation of phospholipase C, which results in a transient increase of inositol1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). In contrast, in the vascular smooth muscle, stimulation of NK1 receptor activates adenylyl cyclase producing cyclic adenosine monophosphate, which activates calcium ATPase, reducing intracellular calcium levels and promoting relaxation and dilation of vascular smooth muscle (Maggi, 1995). In the endothelial cells, NK1 stimulation promotes phosphorylation of myosin by myosin light chain kinase, which assist the interaction of actin and myosin, leading to cell retraction and the formation of gaps between endothelial cells (van Hinsbergh and van Nieuw Amerongen, 2002). Consequence of that is flux of plasma proteins from the vascular lumen into the interstitial space. Throughout NK1 receptor, SP can modulate its own release, while NK1 receptors act as autoreceptors. Several studies have demonstrated that this regulation could have a character of negative feedback due to blocking potassium channels or stimulatory effect via production of IP3 (Harrison and Geppetti, 2001). 1.4. Principal physiological functions After more than 80 years of research, it is fully recognized that the physiological role of SP is very considerable; ubiquitous in the rodents as well as in the humans. Initially, the hypotensive and smooth muscle

contraction effect on the gastrointestinal tract was described (Von Euler and Gaddum, 1931). Research done by Lembeck lead to the proposal that SP is a neuronal sensory mediator associated with pain transmission, due to high concentrations of this peptide located in dorsal roots of the spinal cord (Lembeck, 1953). Besides these activities, SP participates on a wide spectrum of biological processes: growth and development of neuronal tissue (Park et al., 2007), stimulation of cells growth in vitro (Reid et al., 1993), wound healing (Brain, 1997), stabilization of the memory trace (Huston et al., 1993), regulation of circulatory and respiratory mechanisms on the central and peripheral level (Bonham, 1995), an influence on the secretion of salivary glands (Ekstrom, 1989, Suzuki et al., 2013), and inflammation (Katsanos et al., 2008). In addition to that, SP regulates many other functions in the CNS, such as emotional behaviour, stress, anxiety and depression (Kormos and Gaszner, 2013). SP is involved in the integration of emotional responses to stress suggesting that the pathogenesis of depression and anxiety could also be due to an alteration of the SP signalling pathway (Ebner and Singewald, 2006). SP can induce mitogenesis by autocrine, paracrine, endocrine, and/or neuroendocrine mechanisms (Munoz and Covenas, 2013a). 2. Substance P in the heart 2.1. Location and function SP containing nerve fibres were identified in both, atrial and ventricular myocardium, where nerve endings are localized more endocardially than epicardially with higher concentration close to basis compared to apex (Wharton et al., 1981). These nerve fibres occur mainly around neural cell bodies in the intrinsic cardiac ganglia and closely to arterioles, capillaries and veins, but do not appear to terminate in the myocardium (Weihe and Reinecke, 1981, Wharton et al., 1981, Weihe et al., 1981). The intrinsic cardiac nervous system is a complex neural network composed of ganglionated plexuses, which is modulated by extrinsic control via the sympathetic and parasympathetic component of autonomic nervous system. Afferent sensory nerves carry nerve impulses from the heart toward the CNS. Pseudounipolar cell bodies of the cardiac afferent sensory fibres are located in the DRG in the range of C8–Th9 (Kuo et al., 1984, Vance and Bowker, 1983) and nodose ganglion. The peripheral branch of the pseudounipolar neurons (Fig. 3) innervates heart and coronary arteries. Afferent, sensory functions are mediated by tachykinins and calcitonin gene-related peptide (CGRP) that are released from nerve processes terminating in CNS. Efferent, motor functions are exerted by the same neuropeptides released from the peripheral processes. These neurons are activated by nociceptive stimuli and exhibit both afferent and efferent functions (Reinecke et al., 1980). Receptors respond to stimulation and excitation elicits pain, activate protective reflexes, and regulate cardiac function (Brown and Malliani, 1971). Peripheral processes of SP containing neurons were also identified between cardiomyocytes but still there are limited information concerning to presence of NK receptors on the surface of cardiomyocytes (Walsh et al., 1996, Sternini et al., 1995, Goldstein et al., 2001). Recent functional study demonstrated the presence of NK1 receptors on the surface of cardiomyocytes from 7 week old rats (Jubair et al., 2015). On the other hand, isolated cardiomyocytes of newborn rats possess genes for NK1 and NK3 receptors, but not for NK2 receptor (Church et al., 1996). The possible elucidation for this observation could be the fact that attributes of cardiomyocytes significantly vary during postnatal development. Binding sites for SP are localized in connective tissue surrounding coronary arteries, on the cardiac fibrous and on mitral and tricuspid valves (Walsh et al., 1996). Removal of sympathetic stellate ganglion on both sides and selective degeneration of vagal sensory afferents lead to conspicuous (app. 60%) decrease of SP in the right atrium (Dalsgaard et al., 1986). This finding suggests existence of additional, non-neuronal source of SP in the

Please cite this article as: Mistrova, E., et al., Role of substance P in the cardiovascular system, Neuropeptides (2015), http://dx.doi.org/10.1016/ j.npep.2015.12.005

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Fig. 3. Sensory afferents of the heart and vessels. Sensory afferent nerves transmit visceral sensation and nociception and are part of the cardiac nerve plexus. Cell bodies of the cardiac afferent sensory fibres are located in the nodose ganglion (NG) and the dorsal root ganglia (DRG) in the range of C8–Th9. Cardiac vagal afferents make their primary synapse in the nucleus tractus solitarii (NTS). This nucleus initiates a variety of cardiovascular reflexes and also conveys cardiovascular receptor information to the cardiovascular centrum (CVC) in the medulla oblongata. The cardiovascular centrum is formed by the rostral ventrolateral pressor area and the caudal ventrolateral depressor area. Bulbospinal SP-positive fibres originate in pressor area and travel to the spinal cord to the intermediolateral cell column (IML). Sensory innervation of arteries consists predominantly of C fibres and lesser of Aδ fibres. Sensory terminals are localized in perivascular connective tissue and the irritation of receptors on these endings generates action potentials that are transmitted through dorsal root ganglia to the spinal cord and medulla. ICG—intrinsic cardiac ganglion.

heart including subpopulation of endothelial cells. In the coronary arteries, it was established the presence of small cell population, approximately around 10% of endothelial cells that release SP under the hypoxic conditions. These cells are lying in isolation, surrounded by non-positive SP cells (Milner et al., 1989). The influence of SP on cardiovascular system is connected with many of physiological processes. SP increases the activity of cholinergic neurons, with negative chronotropic and inotropic effect of parasympathetic component of autonomic nervous system on the heart innervation (Hoover et al., 2000). The slowing of the heart rate consequently increases the force of contraction (Walsh and McWilliams, 2006). It has been demonstrated that intravenous infusion of SP induces a dose-dependent increase of cardiac output mostly due to a larger stroke volume (Burcher et al., 1977). Besides this, SP has a strong vasodilatory effect on the coronary vascular bed, which is endothelium dependent and mediated by (Loesch and Burnstock, 1988). Sources of SP are ideally localized for immediate regulation of coronary blood flow in the heart. Vasodilation is stronger due to higher amount of NO released from endothelial cells of coronary arteries (Bossaller et al., 1992). 2.2. SP and heart ischemia Myocardial ischemic episodes are associated with an imbalance between myocardial oxygen and glucose supply and demand. The sources of myocardial ischemia are acute myocardial infarction or unstable angina. In the affected area, blood flow fall causes rapid cell death due to the insufficient supply of substrate to maintain cellular energy production. The amount of death cell is dependent upon the severity and duration of the resultant ischemia (Chiao and Caldwell, 1996). The primary injury mechanisms lead to activation of molecular and cellular responses that result in secondary injury: increase in extracellular levels of glutamate, leading to release of numerous chemical mediators, including serotonin, histamine, thromboxane A, bradykinin, ROS,

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followed by the onset of oxidative stress, inflammation, all of which exacerbate injury and tissue damage. Chemical mediators either individually, or frequently in combination, interact with specific receptor most commonly on chemically sensitive terminals that lead to the depolarization of the cardiac afferent fibres (Fu and Longhurst, 2009).Of particular interest is the role that inflammation can play in this secondary injury cascade and whether modification of this inflammatory process has the potential to improve outcome. Several ischemia–reperfusion experiments focussing to role of SP in this process have been done (Zhong and Wang, 2007, Zhang et al., 2012, Wang et al., 2011). One group of experiments includes capsaicin administration prior to ischemia reperfusion, which caused sensory denervation of the heart including also depletion of SP and calcitonin generelated peptide. In comparison to non-capsaicin treated heart, capsaicin-treated heart had higher size of infarction, myocyte apoptosis, reduced recovery of heart rate, coronary flow and left ventricular developed pressure. Replacement of SP restored contractile function and coronary flow (Ustinova et al., 1995, Zhang et al., 2012). Experimental conditions of other ischemia–reperfusion experiments varied significantly therefore also results are not consistent. Additionally, experiments showing e.g. levels of SP in the heart after myocardial infarction or in the plasma during longer period after ischemia–reperfusion injury are missing. Nevertheless the obtained data indicate the protective effect of SP after ischemia–reperfusion injury, at least in acute phase (Dehlin and Levick, 2014). This effect is probably mainly due to its vasodilatory effect on coronary vessels. 2.3. SP and other heart diseases The impact of SP in the aetiology of several heart pathologies has been studied. Diabetes mellitus is associated with abnormal SP signalling system, while SP gene and protein expression is significantly reduced in the heart of diabetic patients. Additionally, down regulation of NK1 receptor was detected in the right atrium of STZ-treated rats. These changes occur probably due to cardiac autonomic neuropathy and imply that SP signalling system could be involved in pathogenesis of the diabetic cardiomyopathy, although the exact mechanism remains to be discovered. Contrarily, a dramatic increase in myocardial SP levels has been detected in the hearts with viral or parasitic infection (Dvorakova et al., 2014). Such infection is often associated with cardiomyocyte hypertrophy and apoptotic cytokine induced apoptosis (D'Souza et al., 2007). SP stimulates the production of proinflammatory cytokines such as IL-6, and tumor necrosis factor (TNF)α (Cuesta et al., 2002, Fiebich et al., 2000). TNFα activates death-domain pathways leading to necrosis and apoptosis in the heart (Ankersmit et al., 2002). Interestingly, transfected mice missing TAC1 gene were protected against cardiac hypertrophy and dilatation of the left ventricle (Melendez et al., 2011). SP may also be operative in modulating the inflammation in hypertensive heart disease (Levick et al., 2010). SP probably plays an important role in the cardiac fibrosis, where it induces adverse myocardial remodelling via a mechanism involving cardiac mast cells (Melendez et al., 2011). Additionally, SP enhances soluble ICAM-1 release from adult rat cardiac fibroblasts by a p42/44 MAPK- and PKC-mediated mechanism (Sapna and Shivakumar, 2007). SP can stimulate cardiac fibroblast proliferation through calcium and superoxide anion-mediated mechanisms (Kumaran and Shivakumar, 2002). SP may also affect myocardial fibrosis via up-regulation of endothelin-1 (Dehlin and Levick, 2014). 3. Substance P in the vascular system 3.1. Location and function The majority of SP-containing nerve fibres are located around the vessels not only in the heart, but also in the gut and skin. Terminal tissue endings of C- and A-delta fibres serve as nociceptors and are capsaicin-

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sensitive (Lin et al., 2000). Capsaicin is used as the stimulant to activate and desensitize sensory nerve fibres, whereas pre-treatment with a neurotoxic dose of capsaicin causes the depletion of them and prevents neurogenic changes in vascular function. To obtain data about the conditions of release and the effect of tachykinins, recent investigators are using different provocation tests including intradermal capsaicin application (Serra et al., 1998). NK1 receptors responsible for the effect of SP on vessels have been localized to the vascular endothelium on most arteries, arterioles, capillaries and post-capillary venules. Venous endothelium may display a low expression of NK1 receptors (Walsh and McWilliams, 2006). The occurrence of short NK1 receptor variant in the vessels was not established yet. Peptides released from sensory afferents act on the blood vessels either indirectly through vasodilator agents from the endothelium or directly on the vascular smooth muscle causing generally constriction. The response of blood vessels to SP is dependent not only on the characteristic and localization of vascular beds but also on animal species (Walsh and McWilliams, 2006). The relaxing effect of the tachykinins could be obtained only when the endothelium is intact. This clearly indicated that the site of action of the tachykinins (like that of acetylcholine, bradykinin, neurotensin, and bombesin) is not the smooth muscle cell, as formerly believed, but the endothelium. Thus, the tachykinins may act to promote the release of endogenous factors (prostacyclins, endothelium-delivered relaxing factors, and nitrous oxide) from the endothelium that is able to reduce the tone of the arterial smooth muscle fibers (Tanaka and Grunstein, 1985, Severini et al., 2002). Vasodilation is dominant vasomotor action of SP in intact blood vessels, although the removal of endothelium or blockade of NO systems reveals its direct vasoconstrictor effects on vascular smooth muscle (Walsh and McWilliams, 2006). Predominant vasodilatory effect in vivo has been demonstrated, although such effect is not inducible in normotensive animals or in man. Application of NK1 receptor antagonists to normotensive animals does not substantially increase blood pressure (Newby et al., 1999). This indicates that SP is not essential for the maintenance of normal systemic blood pressure. SP may contribute to the control of vascular tone of the cutaneous vessels. Primary afferent neuron innervation of the skin can serve as vasodilator neuron and regulator of cutaneous flood flow. Antidromic vasodilation and hyperemia arise from axon reflex that takes place entirely between the arborizing collaterals of single sensory neuron's fibers without entering the nerve cell body (Wardell et al., 1993). The release of vasoactive transmitters from varicosities of afferent neurons may be associated with an increase in vascular permeability, plasma extravasation and recruitment of leukocyte (Jancso et al., 1967).

3.2. SP and neurogenic inflammation Injury or application of capsaicin to the human skin leads to release of vasoactive neuropeptides, including SP and CGRP, from peripheral terminals of primary sensory neurons. Such stimulation can be caused by a large number of exogenous and endogenous substances such as serotonin, histamine and leukotrienes, as well as changes in pH, extremes of temperature and mechanical injury and lead to blood vessel dilatation and hyperaemia, plasma extravasation, tissue swelling, activation of immune cells and mast cell degranulation. This process is called neurogenic inflammation and under some circumstances may be accompanied by pain and nociceptive responses (Severini et al., 2002). SP is thought to be the most potent initiator of neurogenic inflammation due to its association with increased vascular permeability and subsequent plasma protein extravasation (Holzer, 1998). The involvement of SP in this process has been demonstrated on mutant mice with disrupted TAC1 gene, in which topical application of capsaicin does not induce neurogenic inflammation. However in non-neurogenic paw oedema produced by complete Freund's adjuvant,

neurogenic inflammation was the same in wild-type and mutant mice (Cao et al., 1998). Nevertheless, there is some doubt about the fact that SP is the unique direct or indirect (through release of histamine from the mast cells) agent responsible for the vasodilation and plasma extravasation seen in neurogenic inflammation. Two points deserve attention. The first is that SP is co-stored and co-released from sensory nerve endings with CGRP, which displays a potent edema producing activity; the second is that the histamine-releasing activity of SP, which remarkably contributes to plasma extravasation and edema, has been attributed not to the intact SP molecule but to its N-terminal fragment (1–7) (Geppetti et al., 1991, Hua and Yaksh, 1993). There is also evidence, that endogenously released tachykinins realize some of the actions on pro-inflammatory cells (Mousli et al., 1990). These include plasma protein extravasation evoked by activation of NK1 receptors on endothelial cells of postcapillary venules, contraction of iris and bronchial smooth muscle, and secretion from seromucous gland. SP has also been proposed to accumulate neutrophils, activate macrophages throughout NK2 receptor and stimulate mast cells (Baluk et al., 1995, Brunelleschi et al., 1990). In rodents, SP mediates the plasma protein extravasation, and CGRP is responsible for most of the vasodilatory component of the inflammatory response evoked by stimulation of sensory nerve endings in peripheral tissues (Geppetti et al., 2012). In humans, CGRP antagonist telcagepant particularly reduced the increased skin blood flow evoked by application of capsaicin in forearm, which points the CGRP as a mediator of the neurogenic dilator response (Sinclair et al., 2010). It is of great interest that intradermal injection of SP induced a dosedependent edema on wild-type mice, whereas in NK1 receptor knockout mice, the peptide was inactive. The reaction in wild mice was reduced by the histamine antagonist mepyramine, indicating that edema induced by the tachykinin, although totally dependent on NK1 receptor-mediated mechanism, contains a mast cell-dependent component (Cao et al., 1998). It has been suggested that tachykinin release is co-involved in the pathogenesis of flushing episodes without occurring in the carcinoid disease (Severini et al., 2002). Participation of NO in the neurogenic inflammation reaction has been demonstrated by topical application of mustard oil on the rat hind paw skin. It leads to vasodilatation and increased skin temperature accompanied by plasma protein extravasation and edema. Neurogenic origin of the mustard oil-induced increase was demonstrated by the finding that both responses were absent in adult rats treated with a neurotoxic dose of capsaicin as neonates (Lippe et al., 1993).The classical endogenous inflammatory mediators liberated in inflamed tissue, bradykinin, serotonin, and histamine, show direct excitatory and/or sensitizing effects on nociceptive primary afferents (Kress and Reeh, 1996) and induce neuropeptide secretion. The incubation of rat skin in vitro by the triple combination of inflammatory mediators caused significant release of the two neuropeptides, CGRP and SP (Averbeck and Reeh, 2001). SP introduced in the mouse pleural cavity caused a long-lasting recruitment of leukocytes and a small but evident exudation. These effects were partially inhibited by NK1 receptor antagonists and were mediated by NO (Frode-Saleh et al., 1999). 3.3. SP and angiogenesis SP plays an important role in the initiation of angiogenesis, while it belongs amongst the first angiogenic factors to be released following tissue injury. Several studies, where destruction of afferent nerve fibers from certain part of the body has been done, demonstrated affected ability of wound healing in denervated area. Contrary, stimulation of sensory nerve fibers leads to endothelial cell proliferation and capillary growth. SP enhances proliferation and migration of endothelial cells throughout NK1 receptor and that whole process is mediated by NO. Additionally, SP stimulates angiogenesis indirectly due to stimulation

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of non-endothelial cells, which finally leads to release of angiogenic factors such as IL-1, IL-6, IL-8, IL-10, TNFα and histamine (Walsh and McWilliams, 2006). Additionally, SP is probably involved in the maintenance and organization of mature vascular beds (Smith and Wolpert, 1975), although experiments with knock out animals missing the TAC1 or TACR1 genes develop apparently normal vasculatures, suggesting that this system is not essential for normal angiogenesis (Walsh and McWilliams, 2006). 3.4. SP and brain ischemia Ischemic stroke is often caused by atherothrombosis of cerebral vessels or emboli and is associated with a sudden and extreme reduction of blood flow to an area of the brain (Hademenos and Massoud, 1997). Consequent cell death is caused by the initial insult but also by cascade of secondary reactions including also neurogenic inflammation where SP is involved. Role of SP in this pathologic process is critical and it has been recently reviewed in detail (Corrigan et al., 2015). 4. Substance P and cardiovascular control Several lines of evidence indicate that SP is involved in central regulation of cardiovascular system both at spinal and supraspinal levels. It modulates heart rate and blood pressure on the central level: through actions on the CNS and on the periphery: due to postganglionic sympathetic efferents and parasympathetic neurones. SP-IR neurons and/or a high density of SP-IR nerve terminals and SP-binding sites have been reported in several cardiovascular centres localized in the brain and spinal cord, which are known to be involved in the regulation of cardiovascular functions including nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM), rostral ventromedial medulla (RVMM), caudal raphe nuclei, paraventricular nucleus of the hypothalamus (PVN), dorsal motor nucleus of vagus and intermediolateral cell column (IML) (Nakaya et al., 1994, Ribeiro-da-Silva and Hokfelt, 2000). NTS represents the site of termination of primary visceral sensory fibres, which convey information from cardiac vagal receptors, baroreceptors, and chemoreceptors. SP serves as a putative neurotransmitter and neuromediator in the NTS (Helke et al., 1980), while its presence as well as presence of specific binding sites for SP was detected there (Nakaya et al., 1994, Ribeiro-da-Silva and Hokfelt, 2000). Additionally, SP-LI was found in the nodose and petrosal ganglia (Gillis et al., 1980). Injection of SP into the NTS of conscious rats increases blood pressure and heart rate (Abdala et al., 2003), while similar dose of SP, when applied into the NTS of anesthetized rats, caused hypotension and bradycardia (Feldman, 1995, Kubo and Kihara, 1987). The different cardiovascular responses to microinjections of SP into the NTS may be related to the differences in experimental conditions used in each laboratory, namely different anaesthetic or even no anaesthetic. This would play an important role, while it has been demonstrated, that urethane or chloralose anaesthesia produced a major effect on the cardiovascular responses to microinjection of l-glutamate into the NTS (Machado and Bonagamba, 1992). Selective destruction of NK1 receptor neurons in the NTS leads to chronic lability of arterial pressure (Riley et al., 2002, Abdala et al., 2006). While NK1 receptors are colocalized with ionotropic glutamate receptors in NTS neurones (Lin et al., 2008), functional changes observed after destruction of the neurons would be caused not only by damage to SP signalling pathway but also or even only by loss of the glutamate receptors. Additionally, the toxin (stabilized substance P conjugated with saporin) used in these experiments has been shown to decrease GABA synthesizing enzyme. GABA is involved in baroreceptor signal processing (Tsukamoto and Sved, 1993), so, its affection in the experiment would also play an important role. That's why it could not be postulated that all reported cardiovascular changes associated with application of the toxin are related just to an effect on the NK1 receptor itself. Such doubts are in agreement with the recent study published by Talman and Lin (2013).

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Another part of brain, which is involved in the cardiovascular control, is the PVN of the hypothalamus. It contains a population of “pre-autonomic neurones”, which project to the IML, exerting a powerful modulatory influence on the cardiovascular system including blood pressure, heart rate and volume regulation, circadian regulation of the cardiovascular system, stress response, and heart failure (Lovick et al., 1993, Cui et al., 2001, Jansen et al., 1995, Patel, 2000, Coote, 2007). These neurones express SP receptors and modulate the cardiovascular system (Womack et al., 2007). PVN has been shown to be central to the HPA component of the stress response (Herman and Cullinan, 1997, Herman et al., 2002, Tavares et al., 2009), while inhibition of SP signal transmission in the brain suppresses the induction of c-Fos in corticotrophin-releasing hormone neurones in the PVN (Culman et al., 2010) leading to inactivation of neural circuits linked to the control of the complex response pattern to stress. Several lines of evidence support the theory that these processes are mediated by neurones of PVN, which express NK1 receptor (Culman et al., 2010, Womack and Barrett-Jolley, 2007, Womack et al., 2007, Feetham and Barrett-Jolley, 2014). Periaqueductal grey is another target region for the NK1 receptor antagonist to inhibit the cardiovascular responses to stress, while its SP concentration increased after stress (Rosen et al., 1992). A number of studies indicate that SP in the hypothalamus might be involved in the generation of central responses to stress (Herman and Cullinan, 1997). Deeper and more detailed information concerning the role of SP in stress response could be found in a review written by Ebner and Singewald (2006). The VTA, part of the midbrain implicated also in cardiovascular regulation, contains SP as well as NK1 receptor (Tamiya et al., 1990, Lejeune et al., 2002). Application of NK1 receptor agonist into the VTA increases the firing rate of A10 dopamine cells (Overton et al., 1992), which are engaged in diurnal blood pressure and heart rate regulation (Sakata et al., 2002). Dopamine involvement in this process has been proven by an application of DA receptor antagonist, which blocks the effect of SP or NK1 agonists on neurones in VTA (Elliott et al., 1992, Kelley et al., 1979). Further study demonstrated that dopaminergic receptors responsible for the effect are of type D1 (Deschamps and Couture, 2005). Sympathetic preganglionic neurones localised in the IML could be modulated by neurons localised in different parts of the brain, e.g. PVN, but also by spinal and primary sensory C-fibers which can release SP in the vicinity of sympathetic preganglionic neurons (Couture et al., 1995, Tan et al., 1996). Intrathecal application of SP causes dosedependent increases in mean arterial pressure and heart rate mediated by NK1 receptors in the spinal cord and, additionally, by sympathoadrenal activation (Couture et al., 1995). However, injection of NK1 receptor antagonist into the spinal cord does not alter resting blood pressure and heart rate, which suggests that SP does not play an important role in maintaining resting heart rate and mean arterial pressure (Swiatkowski et al., 1999). Expression of the NK1 receptor is different in the spinal cord of Wistar–Kyoto rats and spontaneously hypertensive rats (Chen et al., 1990, Cloutier et al., 2006). 5. NK1 receptor antagonists According to the data obtained from basic research and clinical practice, several human pathologies, including emotional stress, viral myocarditis, migraine, emesis, and thrombotic disease, are associated with upregulation of the SP/NK1 receptor system (Munoz and Covenas, 2014). These findings suggest that the administration of NK1 receptor antagonists can be used as potential therapeutic tools for the treatment of such diseases. In SP/NK1 signalling system, a series of agonists and antagonists have already been described. They were used for study of this signalling system and help to describe its functions in different organs and body systems. Several working groups have produced structurally diverse, highly selective antagonist. This created the opportunity to investigate

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whether selective blockade of central and peripheral NK1 receptor is capable of modifying the cardiovascular system (Zhang et al., 2000, Lessard and Couture, 2001, Deschamps and Couture, 2005, Culman et al., 2010). The NK1 receptor antagonists show different chemical compositions, but their activity is linked to their affinity for the NK1 receptor and they act in a concentration-dependent manner. There are two groups of NK1 receptor antagonists: peptide NK1 receptor antagonists (SP antagonists or SP receptor antagonists) and nonpeptide NK1 receptor antagonists (Munoz et al., 2010). These two types of antagonists differ in binding sites to NK1 receptor. SP and peptide NK1 receptor antagonists bind at the extracellular ends of the transmembrane helices, in the extracellular loops of the receptor, whereas the small hydrophobic, nonpeptide antagonists are binding more deeply in between the transmembrane segments (Hokfelt et al., 2001). Most work carried out on the design and preparation of peptide NK1 receptor antagonists has focused on the introduction of D-amino acids. However, the lower affinity of these antagonists than that of natural agonists, the metabolic instability of the peptides and their inability to gain access to the CNS through the blood–brain barrier limit their usefulness for in vivo studies. In addition, after administration in the CNS, these peptide substances induce neurotoxicity (Munoz et al., 2010). First non-peptide NK1 antagonist (CP-96, 345) was reported in 1991 by Snider (Snider et al., 1991). In a review from 1997, Betancur listed more than 20 non-peptide NK1 antagonists (Betancur et al., 1997), and since then many more compounds have been developed within the framework of the pharmaceutical industry. Currently there are more than 300 NK1 receptor antagonists. In this sense, benzylether piperidines (L-733,060, L-741,671,L-742,694); perhydroisoindolones (P67,580, RP-73,467, RPR-100,893); steroids (WIN-51,708); tryptophanbased (L-732,138); benzylamino piperidines (CP-99,994, CP-122,721, GR-203,040, GR-205,171), benzylamino and benzylether quinuclidine (CP-96,345, L-709,210) NK1 receptor antagonists have been reported (Munoz and Covenas, 2014). Non-peptide antagonists can be administered orally and are able to cross the blood–brain barrier. SP stimulates production of proinflammatory cytokines such as IL1β, TNFα, and IL-6 and these cytokines have been implicated in the pathogenesis of myocarditis caused by encephalomyocarditis virus (EMCV) (Cuesta et al., 2002, Robinson et al., 2009, Kahler et al., 1993). EMCV infection is commonly used as an experimental model to study viral myocarditis (Kanda et al., 2004, Matsumori and Kawai, 1982). It has been reported that EMCV-infected mice have 51% mortality at 14 days accompanied by cardiac inflammation and necrosis along with cardiomyocytes apoptosis and hypertrophy of surviving cells (Robinson et al. 2009). In contrast, SP precursor knockout mice were completely protected from EMCV mortality, cardiac inflammation and necrosis as well as from cardiomyocyte apoptosis and hypertrophy (Robinson et al., 2009). These results indicate that SP is essential in the pathogenesis of EMCV myocarditis. As it has been mentioned above, SP is responsible for the regulation of heart rate and mean arterial pressure. Application of SP agonist induces rapid increases of mean arterial pressure as well as heart rate, although different agonist induces a bit different time-course effects on these parameters (Itoi et al., 1992, Cellier et al., 1999). In clinical practice it would be useful to have available some substance, which is able to decrease blood pressure. That is why the effect of several NK1 receptor antagonists on the CNS has been tested on different animal models. Dose dependent inhibition of the heart rate and mean arterial pressure increase caused by NK1 receptor agonists has been detected for LY303870 and RP67580, whereas SR140333 inhibits only the increase of mean arterial pressure (Cellier et al., 1999). The pressor and tachycardiac responses evoked by SP or its agonists were attributed to the stimulation of sympathetic preganglionic neurones, which could occur on the spinal level or due to stimulation from upper centres. In spontaneously hypertensive rats, NK1 receptor is upregulated in the spinal cord (Cloutier et al., 2006), suggesting an important role of SP

signalling system in the regulation of sympathetic activity on the spinal level. This is important to mention that intracerebral or i.t. injection of NK1 receptor antagonists failed to affect baseline arterial blood pressure and heart rate, suggesting that this peptide do not exert a tonic control of cardiovascular function (Picard et al., 1994). It is known that both SP and the NK1 receptor are upregulated during the inflammation processes and that, in rats, NK1 receptor antagonists exert an anti-inflammatory action (Munoz and Covenas, 2013b), however this beneficial effect was often not found in human clinical trial. These findings could be partially dependent on the species used in studies, due to different affinities of their NK1 receptor to the tested antagonists (Gether et al., 1993). The successful therapeutical use of tachykinins antagonists in humans is limited e.g. by the brain permeability and heterogeneity of all NK receptors occurring in the different human organs and tissues. Moreover, it is known that SP stimulates platelet aggregation, while platelets express both SP and NK1 receptors, and that NK1 receptorblocking antibodies inhibit platelet aggregation. These data imply that SP regulates platelet function and that NK1 receptor antagonists could inhibit platelet aggregation and therefore regulate thrombus formation (Graham et al., 2004). These findings increase our understanding of thrombotic diseases and suggest possible therapeutic interventions using NK1 receptor antagonists to improve the treatment of this disease. In general, NK1 receptor antagonists are safe and well tolerated. Many clinical trials have reported the absence of serious side effects when NK1 receptor antagonists were administered to humans, even at high doses (300 mg/day) (Kramer et al., 1998). Results obtained in a double-blind study using NK1 receptor antagonists showed no signal of any effect on atrioventricular conduction, cardiac depolarization, heart rate or cardiac morphology (Spinelli et al., 2014). Most adverse events are generally mild or moderate, a.g. fewer or headache (Munoz and Covenas, 2013b). NK1 receptor antagonists have many promising therapeutic indications; however, the only NK1 receptor antagonist available commercially and used in clinical practice is the drug aprepitant (Emend, MK-869, L-754,030) and its intravenously administered prodrug, fosaprepitant (Ivemend, MK-0517, L-758,298). Fosaprepitant is rapidly converted to aprepitant via the action of phosphatases (Saito et al., 2013). These antagonists are indicated for the treatment of acute and delayed emesis and vomiting in chemotherapy treated patients and are used for the prevention post-operative nausea and vomiting. Aprepitant is an excellent candidate for testing antiangiogenic action since safety and characterization studies have been already carried out (Munoz and Covenas, 2013b).

6. Conclusion SP/NK1 receptor system is widely distributed throughout whole cardiovascular system and is involved in the molecular bases of many physiological processes including increasing the activity of cardiac cholinergic neurons, vasodilation, and plasma extravasation, but also in several pathologies. Although probably the more important function of SP concerning the cardiovascular system is its involvement in the central regulation. Rigorous knowledge of the structure and biochemical features of SP signalling system is needed for a better understanding and management of those pathologies. Creation of synthetic SP agonists and antagonists would be one way to improve treatment of the disease as well as their prognosis. Valuable therapeutic interventions already take place in the treatment of emesis and vomiting (Kerdelhue et al., 1997, Wang et al., 2014), migraine (Tajti et al., 2015), viral infection (Robinson et al., 2015), chronic pruritus (Mollanazar et al., 2015) and cancer (Munoz et al., 2015). Sadly many of the hopes raised by pre-clinical studies concerning cardiovascular disease treatment have not led to new therapeutic method in man.

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Conflict of interest Authors declare no conflict of interest. Acknowledgements This work was supported by the Charles University Research Fund (project number P36) and by the National Sustainability Program I (NPU I) Nr. LO1503 provided by the Ministry of Education Youth and Sports of the Czech Republic. References Abdala, A.P., Haibara, A.S., Colombari, E., 2003. Cardiovascular responses to substance P in the nucleus tractus solitarii: microinjection study in conscious rats. Am. J. Physiol. Heart Circ. Physiol. 285, H891–H898. Abdala, A.P., Schoorlemmer, G.H., Colombari, E., 2006. Ablation of NK1 receptor bearing neurons in the nucleus of the solitary tract blunts cardiovascular reflexes in awake rats. Brain Res. 1119, 165–173. Ankersmit, H.J., Moser, B., Zuckermann, A., Roth, G., Taghavi, S., Brunner, M., Wolner, E., Boltz-Nitulescu, G., 2002. Activation-induced T cell death, and aberrant T cell activation via TNFR1 and CD95-CD95 ligand pathway in stable cardiac transplant recipients. Clin. Exp. Immunol. 128, 175–180. Averbeck, B., Reeh, P.W., 2001. Interactions of inflammatory mediators stimulating release of calcitonin gene-related peptide, substance P and prostaglandin E(2) from isolated rat skin. Neuropharmacology 40, 416–423. Baluk, P., Bertrand, C., Geppetti, P., McDonald, D.M., Nadel, J.A., 1995. NK1 receptors mediate leukocyte adhesion in neurogenic inflammation in the rat trachea. Am. J. Physiol. 268, L263–L269. Beresford, I.J., Birch, P.J., Hagan, R.M., Ireland, S.J., 1991. Investigation into species variants in tachykinin NK1 receptors by use of the non-peptide antagonist, CP-96,345. Br. J. Pharmacol. 104, 292–293. Betancur, C., Azzi, M., Rostene, W., 1997. Nonpeptide antagonists of neuropeptide receptors: tools for research and therapy. Trends Pharmacol. Sci. 18, 372–386. Bonham, A.C., 1995. Neurotransmitters in the CNS control of breathing. Respir. Physiol. vol. 101 pp. 219–230. Bonner, T.I., Affolter, H.U., Young, A.C., Young 3rd, W.S., 1987. A cDNA encoding the precursor of the rat neuropeptide, neurokinin B. Brain Res. 388, 243–249. Bossaller, C., Reither, K., Hehlert-Friedrich, C., Auch-Schwelk, W., Graf, K., Grafe, M., Fleck, E., 1992. In vivo measurement of endothelium-dependent vasodilation with substance P in man. Herz 17, 284–290. Brain, S.D., 1997. Sensory neuropeptides: their role in inflammation and wound healing. Immunopharmacology 37, 133–152. Brodin, E., Lindefors, N., Dalsgaard, C.J., Theodorsson-Norheim, E., Rosell, S., 1986. Tachykinin multiplicity in rat central nervous system as studied using antisera raised against substance P and neurokinin a. Regul. Pept. 13, 253–272. Brown, A.M., Malliani, A., 1971. Spinal sympathetic reflexes initiated by coronary receptors. J. Physiol. 212, 685–705. Brunelleschi, S., Vanni, L., Ledda, F., Giotti, A., Maggi, C.A., Fantozzi, R., 1990. Tachykinins activate guinea-pig alveolar macrophages: involvement of NK2 and NK1 receptors. Br. J. Pharmacol. 100, 417–420. Burcher, E., Atterhog, J., Pernow, B., Rosell, S., 1977. Cardiovascular effects of substance P: effects on the heart and regional blood flow in the dog. Raven Press, New York, pp. 261–268. Caberlotto, L., Hurd, Y.L., Murdock, P., Wahlin, J.P., Melotto, S., Corsi, M., Carletti, R., 2003. Neurokinin 1 receptor and relative abundance of the short and long isoforms in the human brain. Eur. J. Neurosci. 17, 1736–1746. Cao, Y.Q., Mantyh, P.W., Carlson, E.J., Gillespie, A.M., Epstein, C.J., Basbaum, A.I., 1998. Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392, 390–394. Carter, M.S., Krause, J.E., 1990. Structure, expression, and some regulatory mechanisms of the rat preprotachykinin gene encoding substance P, neurokinin a, neuropeptide K, and neuropeptide gamma. J. Neurosci. 10, 2203–2214. Cellier, E., Barbot, L., Iyengar, S., Couture, R., 1999. Characterization of central and peripheral effects of septide with the use of five tachykinin NK1 receptor antagonists in the rat. Br. J. Pharmacol. 127, 717–728. Chang, M.M., Leeman, S.E., Niall, H.D., 1971. Amino-acid sequence of substance P. Nat. New. Biol. 232, 86–87. Chen, J., Gao, J., Xue, H., Liu, Y., Xu, C., 1990. The role of substance P of the central nervous system in the pathogenesis of spontaneously hypertensive rats. Proc. Chin. Acad. Med. Sci. Peking Union Med. Coll. 5, 153–156. Chiao, H., Caldwell, R.W., 1996. The role of substance P in myocardial dysfunction during ischemia and reperfusion. Naunyn Schmiedeberg's Arch. Pharmacol. 353, 400–407. Church, D.J., Arkinstall, S.J., Vallotton, M.B., Chollet, A., Kawashima, E., Lang, U., 1996. Stimulation of atrial natriuretic peptide release by neurokinins in neonatal rat ventricular cardiomyocytes. Am. J. Physiol. 270, H935–H944. Cloutier, F., Ongali, B., Deschamps, K., Brouillette, J., Neugebauer, W., Couture, R., 2006. Upregulation of tachykinin NK-1 and NK-3 receptor binding sites in the spinal cord of spontaneously hypertensive rat: impact on the autonomic control of blood pressure. Br. J. Pharmacol. 148, 25–38. Coote, J.H., 2007. Landmarks in understanding the central nervous control of the cardiovascular system. Exp. Physiol. vol. 92 pp. 3–18.

9

Corrigan, F., Vink, R., Turner, R.J., 2015. Inflammation in acute CNS injury: a focus on the role of substance P. Br. J. Pharmacol. http://dx.doi.org/10.1111/bph.13155. Couture, R., Picard, P., Poulat, P., Prat, A., 1995. Characterization of the tachykinin receptors involved in spinal and supraspinal cardiovascular regulation. Can. J. Physiol. Pharmacol. 73, 892–902. Cuesta, M.C., Quintero, L., Pons, H., Suarez-Roca, H., 2002. Substance P and calcitonin gene-related peptide increase IL-1 beta, IL-6 and TNF alpha secretion from human peripheral blood mononuclear cells. Neurochem. Int. 40, 301–306. Cui, L.N., Coderre, E., Renaud, L.P., 2001. Glutamate and GABA mediate suprachiasmatic nucleus inputs to spinal-projecting paraventricular neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1283–R1289. Culman, J., Das, G., Ohlendorf, C., Haass, M., Maser-Gluth, C., Zuhayra, M., Zhao, Y., Itoi, K., 2010. Blockade of tachykinin NK1/NK2 receptors in the brain attenuates the activation of corticotrophin-releasing hormone neurones in the hypothalamic paraventricular nucleus and the sympathoadrenal and pituitary-adrenal responses to formalin-induced pain in the rat. J. Neuroendocrinol. 22, 467–476. D'Souza, M., Garza, M.A., Xie, M., Weinstock, J., Xiang, Q., Robinson, P., 2007. Substance P is associated with heart enlargement and apoptosis in murine dilated cardiomyopathy induced by Taenia crassiceps infection. J. Parasitol. 93, 1121–1127. Dalsgaard, C.J., Franco-Cereceda, A., Saria, A., Lundberg, J.M., Theodorsson-Norheim, E., Hokfelt, T., 1986. Distribution and origin of substance P- and neuropeptide Yimmunoreactive nerves in the guinea-pig heart. Cell Tissue Res. 243, 477–485. Dehlin, H.M., Levick, S.P., 2014. Substance P in heart failure: the good and the bad. Int. J. Cardiol. 170, 270–277. Deschamps, K., Couture, R., 2005. The ventral tegmental area as a putative target for tachykinins in cardiovascular regulation. Br. J. Pharmacol. 145, 712–727. Douglas, F.L., Palkovits, M., Brownstein, M.J., 1982. Regional distribution of substance Plike immunoreactivity in the lower brainstem of the rat. Brain Res. 245, 376–378. Dvorakova, M.C., Kruzliak, P., Rabkin, S.W., 2014. Role of neuropeptides in cardiomyopathies. Peptides 61, 1–6. Ebner, K., Singewald, N., 2006. The role of substance P in stress and anxiety responses. Amino Acids 31, 251–272. Ekstrom, J., 1989. Autonomic control of salivary secretion. Proc. Finn. Dent. Soc., 85, 323– 31; (discussion) 361-363. Elliott, P.J., Mason, G.S., Graham, E.A., Turpin, M.P., Hagan, R.M., 1992. Modulation of the rat mesolimbic dopamine pathway by neurokinins. Behav. Brain Res. 51, 77–82. Feetham, C.H., Barrett-Jolley, R., 2014. NK1-receptor-expressing paraventricular nucleus neurones modulate daily variation in heart rate and stress-induced changes in heart rate variability. Physiol. Rep. 2, e12207. Feldman, P.D., 1995. Neurokinin1 receptor mediation of the vasodepressor effects of substance P in the nucleus of the tractus solitarius. J. Pharmacol. Exp. Ther. 273, 617–623. Fiebich, B.L., Schleicher, S., Butcher, R.D., Craig, A., Lieb, K., 2000. The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B. J. Immunol. 165, 5606–5611. Fong, T.M., Anderson, S.A., Yu, H., Huang, R.R., Strader, C.D., 1992. Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor. Mol. Pharmacol. 41, 24–30. Friess, H., Zhu, Z., Liard, V., Shi, X., Shrikhande, S.V., Wang, L., Lieb, K., Korc, M., Palma, C., Zimmermann, A., Reubi, J.C., Buchler, M.W., 2003. Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer. Lab. Investig. 83, 731–742. Frode-Saleh, T.S., Calixto, J.B., Medeiros, Y.S., 1999. Analysis of the inflammatory response induced by substance P in the mouse pleural cavity. Peptides 20, 259–265. Fu, L.W., Longhurst, J.C., 2009. Regulation of cardiac afferent excitability in ischemia. Handb. Exp. Pharmacol. 185-225. Gaddum, J.H., Schild, H., 1934. Depressor substances in extracts of intestine. J. Physiol. 83, 1–14. Geppetti, P., Del Bianco, E., Patacchini, R., Santicioli, P., Maggi, C.A., Tramontana, M., 1991. Low pH-induced release of calcitonin gene-related peptide from capsaicin-sensitive sensory nerves: mechanism of action and biological response. Neuroscience 41, 295–301. Geppetti, P., Maggi, C.A., Zecchi-Orlandini, S., Santicioli, P., Meli, A., Frilli, S., Spillantini, M.G., Amenta, F., 1987. Substance P-like immunoreactivity in capsaicin-sensitive structures of the rat thymus. Regul. Pept. 18, 321–329. Geppetti, P., Rossi, E., Chiarugi, A., Benemei, S., 2012. Antidromic vasodilatation and the migraine mechanism. J. Headache Pain. 13, 103–111. Gerard, N.P., Bao, L., Xiao-Ping, H., Gerard, C., 1993. Molecular aspects of the tachykinin receptors. Regul. Pept. 43, 21–35. Gerard, N.P., Garraway, L.A., Eddy Jr., R.L., Shows, T.B., Iijima, H., Paquet, J.L., Gerard, C., 1991. Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones. Biochemistry 30, 10640–10646. Gether, U., Johansen, T.E., Snider, R.M., Lowe 3rd, J.A., Nakanishi, S., Schwartz, T.W., 1993. Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist. Nature 362, 345–348. Gillis, R.A., Helke, C.J., Hamilton, B.L., Norman, W.P., Jacobowitz, D.M., 1980. Evidence that substance P is a neurotransmitter of baro- and chemoreceptor afferents in nucleus tractus solitarius. Brain Res. 181, 476–481. Gitter, B.D., Waters, D.C., Bruns, R.F., Mason, N.R., Nixon, J.A., Howbert, J.J., 1991. Species differences in affinities of non-peptide antagonists for substance P receptors. Eur. J. Pharmacol. 197, 237–238. Goldstein, D.J., Offen, W.W., Klein, E.G., Phebus, L.A., Hipskind, P., Johnson, K.W., Ryan Jr., R.E., 2001. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia 21, pp. 102–106. Graham, G.J., Stevens, J.M., Page, N.M., Grant, A.D., Brain, S.D., Lowry, P.J., Gibbins, J.M., 2004. Tachykinins regulate the function of platelets. Blood 104, 1058–1065. Guard, S., Watson, S.P., 1991. Tachykinin receptor types: classification and membrane signalling mechanisms. Neurochem. Int. 18, 149–165.

Please cite this article as: Mistrova, E., et al., Role of substance P in the cardiovascular system, Neuropeptides (2015), http://dx.doi.org/10.1016/ j.npep.2015.12.005

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E. Mistrova et al. / Neuropeptides xxx (2015) xxx–xxx

Hademenos, G.J., Massoud, T.F., 1997. Biophysical mechanisms of stroke. Stroke 28, 2067–2077. Harmar, A., Schofield, J.G., Keen, P., 1980. Cycloheximide-sensitive synthesis of substance P by isolated dorsal root ganglia. Nature 284, 267–269. Harrison, S., Geppetti, P., 2001. Substance p. In Int J Biochem Cell Biol. Vol. 33, England, 555–576. Helke, C.J., O'Donohue, T.L., Jacobowitz, D.M., 1980. Substance P as a baro- and chemoreceptor afferent neurotransmitter: immunocytochemical and neurochemical evidence in the rat. Peptides 1, 1–9. Herman, J.P., Cullinan, W.E., 1997. Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci. 20, 78–84. Herman, J.P., Cullinan, W.E., Ziegler, D.R., Tasker, J.G., 2002. Role of the paraventricular nucleus microenvironment in stress integration. Eur. J. Neurosci. 16, 381–385. Hokfelt, T., Elfvin, L.G., Schultzberg, M., Goldstein, M., Nilsson, G., 1977. On the occurrence of substance P-containing fibers in sympathetic ganglia: immunohistochemical evidence.In Brain Res. Vol. 132, Netherlands, 29–41. Hokfelt, T., Kellerth, J.O., Nilsson, G., Pernow, B., 1975. Substance p: localization in the central nervous system and in some primary sensory neurons. Science 190, 889–890. Hokfelt, T., Pernow, B., Wahren, J., 2001. Substance P: a pioneer amongst neuropeptides. J. Intern. Med. 249, 27–40. Hokfelt, T., Vincent, S., Dalsgaard, C.J., Skirboll, L., Johansson, O., Schultzberg, M., Lundberg, J.M., Rosell, S., Pernow, B., Jancso, G., 1982. Distribution of substance P in brain and periphery and its possible role as a co-transmitter. CIBA Found. Symp. 84-106. Holzer, P., 1998. Neurogenic vasodilatation and plasma leakage in the skin. Gen. Pharmacol. 30, 5–11. Hoover, D.B., Chang, Y., Hancock, J.C., Zhang, L., 2000. Actions of tachykinins within the heart and their relevance to cardiovascular disease. Jpn. J. Pharmacol. 84, 367–373. Hua, X.Y., Yaksh, T.L., 1993. Pharmacology of the effects of bradykinin, serotonin, and histamine on the release of calcitonin gene-related peptide from C-fiber terminals in the rat trachea. J. Neurosci. 13, 1947–1953. Huston, J.P., Hasenohrl, R.U., Boix, F., Gerhardt, P., Schwarting, R.K., 1993. Sequencespecific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity. Psychopharmacology 112, 147–162. Inagaki, S., Sakanaka, M., Shiosaka, S., Senba, E., Takatsuki, K., Takagi, H., Kawai, Y., Minagawa, H., Tohyama, M., 1982. Ontogeny of substance P-containing neuron system of the rat: immunohistochemical analysis—I Forebrain and upper brain stem. Neuroscience 7, 251–277. Itoi, K., Tschope, C., Jost, N., Culman, J., Lebrun, C., Stauss, B., Unger, T., 1992. Identification of the central tachykinin receptor subclass involved in substance P-induced cardiovascular and behavioral responses in conscious rats. Eur. J. Pharmacol. 219, 435–444. Jancso, N., Jancso-Gabor, A., Szolcsanyi, J., 1967. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br. J. Pharmacol. Chemother. 31, 138–151. Jansen, A.S., Nguyen, X.V., Karpitskiy, V., Mettenleiter, T.C., Loewy, A.D., 1995. Central command neurons of the sympathetic nervous system: basis of the fight-or-flight response. Science 270, 644–646. Jubair, S., Li, J., Dehlin, H.M., Manteufel, E.J., Goldspink, P.H., Levick, S.P., Janicki, J.S., 2015. Substance P induces cardioprotection in ischemia–reperfusion via activation of AKT. Am. J. Physiol. Heart. Circ. Physiol. 309, H676–H684. Kage, R., McGregor, G.P., Thim, L., Conlon, J.M., 1988. Neuropeptide-gamma: a peptide isolated from rabbit intestine that is derived from gamma-preprotachykinin. J. Neurochem. 50, 1412–1417. Kahler, C.M., Sitte, B.A., Reinisch, N., Wiedermann, C.J., 1993. Stimulation of the chemotactic migration of human fibroblasts by substance P. Eur. J. Pharmacol. 249, 281–286. Kanazawa, I., Jessell, T., 1976. Post mortem changes and regional distribution of substance P in the rat and mouse nervous system. Brain Res. 117, 362–367. Kanda, T., Takahashi, T., Kudo, S., Takeda, T., Tsugawa, H., Takekoshi, N., 2004. Leptin deficiency enhances myocardial necrosis and lethality in a murine model of viral myocarditis. Life Sci. 75, 1435–1447. Kangawa, K., Minamino, N., Fukuda, A., Matsuo, H., 1983. Neuromedin K: a novel mammalian tachykinin identified in porcine spinal cord. Biochem. Biophys. Res. Commun. 114, 533–540. Katsanos, G.S., Anogeianaki, A., Orso, C., Tete, S., Salini, V., Antinolfi, P.L., Sabatino, G., 2008. Impact of substance P on cellular immunity. J. Biol. Regul. Homeost. Agents 22, 93–98. Kelley, A.E., Stinus, L., Iversen, S.D., 1979. Behavioural activation induced in the rat by substance P infusion into ventral tegmental area: implication of dopaminergic A10 neurones. Neurosci. Lett. 11, 335–339. Kerdelhue, B., Gordon, K., Williams, R., Lenoir, V., Fardin, V., Chevalier, P., Garret, C., Duval, P., Kolm, P., Hodgen, G., Jones, H., Jones, G.S., 1997. Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiolinduced LH and FSH surges in the ovariectomized cynomolgus monkey. J. Neurosci. Res. 50, 94–103. Kormos, V., Gaszner, B., 2013. Role of neuropeptides in anxiety, stress, and depression: from animals to humans. Neuropeptides 47, 401–419. Kotani, H., Hoshimaru, M., Nawa, H., Nakanishi, S., 1986. Structure and gene organization of bovine neuromedin K precursor. Proc. Natl. Acad. Sci. U. S. A. 83, 7074–7078. Kramer, M.S., Cutler, N., Feighner, J., Shrivastava, R., Carman, J., Sramek, J.J., Reines, S.A., Liu, G., Snavely, D., Wyatt-Knowles, E., Hale, J.J., Mills, S.G., MacCoss, M., Swain, C.J., Harrison, T., Hill, R.G., Hefti, F., Scolnick, E.M., Hargreaves, R.J., Rupniak, N.M., 1998. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281, 1640–1645. Krause, J.E., Chirgwin, J.M., Carter, M.S., Xu, Z.S., Hershey, A.D., 1987. Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin a. Proc. Natl. Acad. Sci. U. S. A. 84, 881–885. Kress, M., Reeh, P.W., 1996. Chemical Excitation and Sensitization in Nociceptors. Oxford University Press, pp. 258–297.

Kubo, T., Kihara, M., 1987. Blood pressure modulation by substance P in the rat nucleus tractus solitarius. Brain Res. 413, 379–383. Kumaran, C., Shivakumar, K., 2002. Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts. Am. J. Physiol. Heart Circ. Physiol. 282, H1855–H1862. Kuo, D.C., Oravitz, J.J., DeGroat, W.C., 1984. Tracing of afferent and efferent pathways in the left inferior cardiac nerve of the cat using retrograde and transganglionic transport of horseradish peroxidase. Brain Res. 321, 111–118. Lai, J.P., Lai, S., Tuluc, F., Tansky, M.F., Kilpatrick, L.E., Leeman, S.E., Douglas, S.D., 2008. Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor. Proc. Natl. Acad. Sci. U. S. A. 105, 12605–12610. Lejeune, F., Gobert, A., Millan, M.J., 2002. The selective neurokinin (NK)(1) antagonist, GR205,171, stereospecifically enhances mesocortical dopaminergic transmission in the rat: a combined dialysis and electrophysiological study. Brain Res. 935, 134–139. Lembeck, F., 1953. Central transmission of afferent impulses. III. Incidence and significance of the substance P in the dorsal roots of the spinal cord Naunyn. Schmiedebergs. Arch. Exp. Pathol. Pharmakol. 219, 197–213. Lessard, A., Couture, R., 2001. Modulation of cardiac activity by tachykinins in the rat substantia nigra. Br. J. Pharmacol. 134, 1749–1759. Levick, S.P., Murray, D.B., Janicki, J.S., Brower, G.L., 2010. Sympathetic nervous system modulation of inflammation and remodeling in the hypertensive heart. Hypertension 55, 270–276. Li, H., Leeman, S.E., Slack, B.E., Hauser, G., Saltsman, W.S., Krause, J.E., Blusztajn, J.K., Boyd, N.D., 1997. A substance P (neurokinin-1) receptor mutant carboxyl-terminally truncated to resemble a naturally occurring receptor isoform displays enhanced responsiveness and resistance to desensitization. Proc. Natl. Acad. Sci. U. S. A. 94, 9475–9480. Lin, L.H., Taktakishvili, O.M., Talman, W.T., 2008. Colocalization of neurokinin-1, Nmethyl-D-aspartate, and AMPA receptors on neurons of the rat nucleus tractus solitarii. Neuroscience 154, 690–700. Lin, Q., Zou, X., Willis, W.D., 2000. Adelta and C primary afferents convey dorsal root reflexes after intradermal injection of capsaicin in rats. J. Neurophysiol. 84, 2695–2698. Lindefors, N., Brodin, E., Theodorsson-Norheim, E., Ungerstedt, U., 1985. Regional distribution and in vivo release of tachykinin-like immunoreactivities in rat brain: evidence for regional differences in relative proportions of tachykinins. Regul. Pept. 10, 217–230. Lippe, I.T., Stabentheiner, A., Holzer, P., 1993. Participation of nitric oxide in the mustard oilinduced neurogenic inflammation of the rat paw skin. Eur. J. Pharmacol. 232, 113–120. Loesch, A., Burnstock, G., 1988. Ultrastructural localisation of serotonin and substance P in vascular endothelial cells of rat femoral and mesenteric arteries. Anat. Embryol. (Berl) 178, 137–142. Lovick, T.A., Malpas, S., Mahony, M.T., 1993. Renal vasodilatation in response to acute volume load is attenuated following lesions of parvocellular neurones in the paraventricular nucleus in rats. J. Auton. Nerv. Syst. 43, 247–255. Machado, B.H., Bonagamba, L.G., 1992. Microinjection of L-glutamate into the nucleus tractus solitarii increases arterial pressure in conscious rats. Brain Res. 576, 131–138. Maggi, C.A., 1995. The mammalian tachykinin receptors. Gen. Pharmacol. 26, 911–944. Maggio, J.E., 1988. Tachykinins. Annu. Rev. Neurosci. 11, 13–28. Mai, J.K., Stephens, P.H., Hopf, A., Cuello, A.C., 1986. Substance P in the human brain. Neuroscience 17, 709–739. Mantyh, P.W., 2002. Neurobiology of substance P and the NK1 receptor. J. Clin. Psychiatry. 63 (Suppl. 11), 6–10. Matsumori, A., Kawai, C., 1982. An animal model of congestive (dilated) cardiomyopathy: dilatation and hypertrophy of the heart in the chronic stage in DBA/2 mice with myocarditis caused by encephalomyocarditis virus. Circulation 66, 355–360. McGillis, J.P., Mitsuhashi, M., Payan, D.G., 1990. Immunomodulation by tachykinin neuropeptides. Ann. N. Y. Acad. Sci. 594, 85–94. Melendez, G.C., Li, J., Law, B.A., Janicki, J.S., Supowit, S.C., Levick, S.P., 2011. Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells. Cardiovasc. Res. 92, 420–429. Milner, P., Ralevic, V., Hopwood, A.M., Feher, E., Lincoln, J., Kirkpatrick, K.A., Burnstock, G., 1989. Ultrastructural localisation of substance P and choline acetyltransferase in endothelial cells of rat coronary artery and release of substance P and acetylcholine during hypoxia. Experientia 45, 121–125. Mollanazar, N.K., Smith, P.K., Yosipovitch, G., 2015. Mediators of chronic pruritus in atopic dermatitis: getting the itch out? Clin. Rev. Allergy. Immunol. (May 1. [Epub ahead of print]). Mousli, M., Bueb, J.L., Bronner, C., Rouot, B., Landry, Y., 1990. G protein activation: a receptor-independent mode of action for cationic amphiphilic neuropeptides and venom peptides. Trends Pharmacol. Sci. 11, 358–362. Munoz, M., Covenas, R., 2013a. Involvement of substance P and the NK-1 receptor in cancer progression. Peptides 48, 1–9. Munoz, M., Covenas, R., 2013b. Safety of neurokinin-1 receptor antagonists. Expert Opin. Drug Saf. 12, 673–685. Munoz, M., Covenas, R., 2014. Involvement of substance P and the NK-1 receptor in human pathology. Amino Acids 46, 1727–1750. Munoz, M., Covenas, R., Esteban, F., Redondo, M., 2015. The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs. J. Biosci. 40, 441–463. Munoz, M., Rosso, M., Covenas, R., 2010. A new frontier in the treatment of cancer: NK-1 receptor antagonists. Curr. Med. Chem. 17, 504–516. Nakanishi, S., 1987. Substance P precursor and kininogen: their structures, gene organizations, and regulation. Physiol. Rev. 67, 1117–1142. Nakaya, Y., Kaneko, T., Shigemoto, R., Nakanishi, S., Mizuno, N., 1994. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J. Comp. Neurol. 347, 249–274. Nawa, H., Hirose, T., Takashima, H., Inayama, S., Nakanishi, S., 1983. Nucleotide sequences of cloned cDNAs for two types of bovine brain substance P precursor. Nature 306, 32–36.

Please cite this article as: Mistrova, E., et al., Role of substance P in the cardiovascular system, Neuropeptides (2015), http://dx.doi.org/10.1016/ j.npep.2015.12.005

E. Mistrova et al. / Neuropeptides xxx (2015) xxx–xxx Newby, D.E., Sciberras, D.G., Ferro, C.J., Gertz, B.J., Sommerville, D., Majumdar, A., Lowry, R.C., Webb, D.J., 1999. Substance P-induced vasodilatation is mediated by the neurokinin type 1 receptor but does not contribute to basal vascular tone in man. Br. J. Clin. Pharmacol. 48, 336–344. O'Connor, T.M., O'Connell, J., O'Brien, D.I., Goode, T., Bredin, C.P., Shanahan, F., 2004. The role of substance P in inflammatory disease. J. Cell. Physiol. 201, 167–180. Otsuka, M., Yoshioka, K., 1993. Neurotransmitter functions of mammalian tachykinins. Physiol. Rev. 73, 229–308. Overton, P., Elliott, P.J., Hagan, R.M., Clark, D., 1992. Neurokinin agonists differentially affect A9 and A10 dopamine cells in the rat. Eur. J. Pharmacol. 213, 165–166. Page, N.M., 2004. Hemokinins and endokinins. Cell. Mol. Life Sci. 61, 1652–1663. Page, N.M., 2006. Characterization of the gene structures, precursor processing and pharmacology of the endokinin peptides. Vasc. Pharmacol. 45, 200–208. Page, N.M., Bell, N.J., 2002. The human tachykinin NK1 (short form) and tachykinin NK4 receptor: a reappraisal. Eur. J. Pharmacol. 437, 27–30. Park, S.W., Yan, Y.P., Satriotomo, I., Vemuganti, R., Dempsey, R.J., 2007. Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions. J. Neurosurg. 107, 593–599. Patel, K.P., 2000. Role of paraventricular nucleus in mediating sympathetic outflow in heart failure. Heart Fail. Rev. 5, 73–86. Pennefather, J.N., Lecci, A., Candenas, M.L., Patak, E., Pinto, F.M., Maggi, C.A., 2004. Tachykinins and tachykinin receptors: a growing family. Life Sci. 74, 1445–1463. Pernow, B., 1983. Substance P. Pharmacol. Rev. 35, 85–141. Picard, P., Regoli, D., Couture, R., 1994. Cardiovascular and behavioural effects of centrally administered tachykinins in the rat: characterization of receptors with selective antagonists. Br. J. Pharmacol. 112, 240–249. Reid, T.W., Murphy, C.J., Iwahashi, C.K., Foster, B.A., Mannis, M.J., 1993. Stimulation of epithelial cell growth by the neuropeptide substance P. J. Cell. Biochem. 52, 476–485. Reinecke, M., Weihe, E., Forssmann, W.G., 1980. Substance P-immunoreactive nerve fibers in the heart. Neurosci. Lett. 20, 265–269. Ribeiro-da-Silva, A., Hokfelt, T., 2000. Neuroanatomical localisation of substance P in the CNS and sensory neurons. Neuropeptides 34, 256–271. Riley, J., Lin, L.H., Chianca Jr., D.A., Talman, W.T., 2002. Ablation of NK1 receptors in rat nucleus tractus solitarii blocks baroreflexes. Hypertension 40, 823–826. Robinson, P., Garza, A., Moore, J., Eckols, T.K., Parti, S., Balaji, V., Vallejo, J., Tweardy, D.J., 2009. Substance P is required for the pathogenesis of EMCV infection in mice. Int. J. Clin. Exp. Med. 2, 76–86. Robinson, P., Taffet, G.E., Engineer, N., Khumbatta, M., Firozgary, B., Reynolds, C., Pham, T., Bulsara, T., Firozgary, G., 2015. Substance P receptor antagonism: a potential novel treatment option for viral-myocarditis. Biomed. Res. Int. 2015, 645153. Rosen, A., Brodin, K., Eneroth, P., Brodin, E., 1992. Short-term restraint stress and s.c. saline injection alter the tissue levels of substance P and cholecystokinin in the periaqueductal grey and limbic regions of rat brain. Acta Physiol. Scand. 146, 341–348. Saito, H., Yoshizawa, H., Yoshimori, K., Katakami, N., Katsumata, N., Kawahara, M., Eguchi, K., 2013. Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Ann. Oncol. 24, 1067–1073. Sakanaka, M., Inagaki, S., Shiosaka, S., Senba, E., Takagi, H., Takatsuki, K., Kawai, Y., Iida, H., Hara, Y., Tohyama, M., 1982. Ontogeny of substance P-containing neuron system of the rat: immunohistochemical analysis—II Lower brain stem. Neuroscience 7, 1097–1126. Sakata, M., Sei, H., Toida, K., Fujihara, H., Urushihara, R., Morita, Y., 2002. Mesolimbic dopaminergic system is involved in diurnal blood pressure regulation. Brain Res. 928, 194–201. Sapna, S., Shivakumar, K., 2007. Substance P enhances soluble ICAM-1 release from adult rat cardiac fibroblasts by a p42/44 MAPK- and PKC-mediated mechanism. Cell Biol. Int. 31, 856–859. Schaffer, M., Beiter, T., Becker, H.D., Hunt, T.K., 1998. Neuropeptides: mediators of inflammation and tissue repair? Arch. Surg. 133, 1107–1116. Serra, J., Campero, M., Ochoa, J., 1998. Flare and hyperalgesia after intradermal capsaicin injection in human skin. J. Neurophysiol. 80, 2801–2810. Severini, C., Improta, G., Falconieri-Erspamer, G., Salvadori, S., Erspamer, V., 2002. The tachykinin peptide family. Pharmacol. Rev. 54, 285–322. Sinclair, S.R., Kane, S.A., Van der Schueren, B.J., Xiao, A., Willson, K.J., Boyle, J., de Lepeleire, I., Xu, Y., Hickey, L., Denney, W.S., Li, C.C., Palcza, J., Vanmolkot, F.H., Depre, M., Van Hecken, A., Murphy, M.G., Ho, T.W., de Hoon, J.N., 2010. Inhibition of capsaicininduced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974). Br. J. Clin. Pharmacol. 69, 15–22. Smith, A.R., Wolpert, L., 1975. Nerves and angiogenesis in amphibian limb regeneration. Nature 257, 224–225. Snider, R.M., Constantine, J.W., Lowe 3rd, J.A., Longo, K.P., Lebel, W.S., Woody, H.A., Drozda, S.E., Desai, M.C., Vinick, F.J., Spencer, R.W., et al., 1991. A potent nonpeptide antagonist of the substance P (NK1) receptor. Science 251, 435–437. Spinelli, T., Moresino, C., Baumann, S., Timmer, W., Schultz, A., 2014. Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial. 3. Springerplus, p. 389. Stahl, S.M., 1999. Peptides and psychiatry, part 3: substance P and serendipity: novel psychotropics are a possibility. J. Clin. Psychiatry. 60, 140–141.

11

Steinhoff, M.S., von Mentzer, B., Geppetti, P., Pothoulakis, C., Bunnett, N.W., 2014. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol. Rev. 94, 265–301. Sternini, C., Su, D., Gamp, P.D., Bunnett, N.W., 1995. Cellular sites of expression of the neurokinin-1 receptor in the rat gastrointestinal tract. J. Comp. Neurol. 358, 531–540. Suzuki, Y., Itoh, H., Amada, K., Yamamura, R., Sato, Y., Takeyama, M., 2013. Significant increase in salivary substance p level after a single oral dose of cevimeline in humans. Int. J. Pept. 2013, 284765. Swiatkowski, K., Dellamano, L.M., Vissing, J., Rybicki, K.J., Kozlowski, G.P., Iwamoto, G.A., 1999. Differential effects from parapyramidal region and rostral ventrolateral medulla mediated by substance P. Am. J. Physiol. 277, R1120–R1129. Tajti, J., Szok, D., Majlath, Z., Tuka, B., Csati, A., Vecsei, L., 2015. Migraine and neuropeptides. Neuropeptides 52, 19–30. Takeda, Y., Chou, K.B., Takeda, J., Sachais, B.S., Krause, J.E., 1991. Molecular cloning, structural characterization and functional expression of the human substance P receptor. Biochem. Biophys. Res. Commun. 179, 1232–1240. Talman, W.T., Lin, L.H., 2013. Sudden death following selective neuronal lesions in the rat nucleus tractus solitarii. Auton. Neurosci. 175, 9–16. Tamiya, R., Hanada, M., Kawai, Y., Inagaki, S., Takagi, H., 1990. Substance P afferents have synaptic contacts with dopaminergic neurons in the ventral tegmental area of the rat. Neurosci. Lett. 110, 11–15. Tan, C.K., Tang, F.R., Ling, E.A., 1996. Ultrastructural localization of substance P-like immunoreactivity in the intermediolateral column of spontaneously hypertensive rats and Wistar–Kyoto rats. Histol. Histopathol. 11, 303–311. Tanaka, D.T., Grunstein, M.M., 1985. Vasoactive effects of substance P on isolated rabbit pulmonary artery. J. Appl. Physiol. 58, 1291–1297. Tansky, M.F., Pothoulakis, C., Leeman, S.E., 2007. Functional consequences of alteration of N-linked glycosylation sites on the neurokinin 1 receptor. Proc. Natl. Acad. Sci. U. S. A. 104, 10691–10696. Tatemoto, K., Lundberg, J.M., Jornvall, H., Mutt, V., 1985. Neuropeptide K: isolation, structure and biological activities of a novel brain tachykinin. Biochem. Biophys. Res. Commun. 128, 947–953. Tavares, R.F., Pelosi, G.G., Correa, F.M., 2009. The paraventricular nucleus of the hypothalamus is involved in cardiovascular responses to acute restraint stress in rats. Stress 12, 178–185. Tsukamoto, K., Sved, A.F., 1993. Enhanced gamma-aminobutyric acid-mediated responses in nucleus tractus solitarius of hypertensive rats. Hypertension 22, 819–825. Ustinova, E.E., Bergren, D., Schultz, H.D., 1995. Neuropeptide depletion impairs postischemic recovery of the isolated rat heart: role of substance P. Cardiovasc. Res. 30, 55–63. van Hinsbergh, V.W., van Nieuw Amerongen, G.P., 2002. Endothelial hyperpermeability in vascular leakage. Vasc. Pharmacol. 39, 171–172. Vance, W.H., Bowker, R.C., 1983. Spinal origins of cardiac afferents from the region of the left anterior descending artery. Brain Res. 258, 96–100. Von Euler, U.S., Gaddum, J.H., 1931. An unidentified depressor substance in certain tissue extracts. J. Physiol. 72, 74–87. Walsh, D.A., McWilliams, D.F., 2006. Tachykinins and the cardiovascular system. Curr. Drug Targets 7, 1031–1042. Walsh, R.J., Weglicki, W.B., Correa-de-Araujo, R., 1996. Distribution of specific substance P binding sites in the heart and adjacent great vessels of the Wistar white rat. Cell Tissue Res. 284, 495–500. Wang, L.L., Guo, Z., Han, Y., Wang, P.F., Zhang, R.L., Zhao, Y.L., Zhao, F.P., Zhao, X.Y., 2011. Implication of substance P in myocardial contractile function during ischemia in rats. Regul. Pept. 167, 185–191. Wang, S.Y., Yang, Z.J., Zhang, Z., Zhang, H., 2014. Aprepitant in the prevention of vomiting induced by moderately and highly emetogenic chemotherapy. Asian Pac. J. Cancer Prev. 15, 10045–10051. Wardell, K., Naver, H.K., Nilsson, G.E., Wallin, B.G., 1993. The cutaneous vascular axon reflex in humans characterized by laser Doppler perfusion imaging. J. Physiol. 460, 185–199. Weihe, E., Reinecke, M., 1981. Peptidergic innervation of the mammalian sinus nodes: vasoactive intestinal polypeptide, neurotensin, substance P. Neurosci. Lett. 26, 283–288. Weihe, E., Reinecke, M., Opherk, D., Forssmann, W.G., 1981. Peptidergic innervation (substance P) in the human heart. J. Mol. Cell. Cardiol. 13, 331–333. Wharton, J., Polak, J.M., McGregor, G.P., Bishop, A.E., Bloom, S.R., 1981. The distribution of substrate P-like immunoreactive nerves in the guinea-pig heart. Neuroscience 6, 2004–2193. Womack, M.D., Barrett-Jolley, R., 2007. Activation of paraventricular nucleus neurones by the dorsomedial hypothalamus via a tachykinin pathway in rats. Exp. Physiol. 92, 671–676. Womack, M.D., Morris, R., Gent, T.C., Barrett-Jolley, R., 2007. Substance P targets sympathetic control neurons in the paraventricular nucleus. Circ. Res. 100, 1650–1658. Zhang, C., Bonagamba, L.G., Machado, B.H., 2000. Blockade of NK-1 receptors in the lateral commissural nucleus tractus solitarii of awake rats had no effect on the cardiovascular responses to chemoreflex activation. Braz. J. Med. Biol. Res. 33, 1379–1385. Zhang, R.L., Guo, Z., Wang, L.L., Wu, J., 2012. Degeneration of capsaicin sensitive sensory nerves enhances myocardial injury in acute myocardial infarction in rats. Int. J. Cardiol. 160, 41–47. Zhong, B., Wang, D.H., 2007. TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am. J. Physiol. Heart Circ. Physiol. 293, H1791–H1798.

Please cite this article as: Mistrova, E., et al., Role of substance P in the cardiovascular system, Neuropeptides (2015), http://dx.doi.org/10.1016/ j.npep.2015.12.005