The pharmacology of α1-adrenoceptor subtypes

European Journal of Pharmacology 855 (2019) 305–320

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The pharmacology of α1-adrenoceptor subtypes James R. Docherty

T

Department of Physiology, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland

ARTICLE INFO Keywords: α1-adrenoceptors α1A-adrenoceptors α1B-adrenoceptors α1D-adrenoceptors Vascular contractions Blood pressure control Vas deferens

This review examines the functions of α1-adrenoceptor subtypes, particularly in terms of contraction of smooth muscle. There are 3 subtypes of α1-adrenoceptor, α1A- α1B- and α1D-adrenoceptors. Evidence is presented that the postulated α1L-adrenoceptor is simply the native α1A-adrenoceptor at which prazosin has low potency. In most isolated tissue studies, smooth muscle contractions to exogenous agonists are mediated particularly by α1A-, with a lesser role for α1D-adrenoceptors, but α1B-adrenoceptors are clearly involved in contractions of some tissues, for example, the spleen. However, nerve-evoked responses are the most crucial physiologically, so that these studies of exogenous agonists may overestimate the importance of α1A-adrenoceptors. The major α1adrenoceptors involved in blood pressure control by sympathetic nerves are the α1D- and the α1A-adrenoceptors, mediating peripheral vasoconstrictor actions. As noradrenaline has high potency at α1D-adrenceptors, these receptors mediate the fastest response and seem to be targets for neurally released noradrenaline especially to low frequency stimulation, with α1A-adrenoceptors being more important at high frequencies of stimulation. This is true in rodent vas deferens and may be true in vasopressor nerves controlling peripheral resistance and tissue blood flow. The αlA-adrenoceptor may act mainly through Ca2+ entry through L-type channels, whereas the α1D-adrenoceptor may act mainly through T-type channels and exhaustable Ca2+ stores. α1-Adrenoceptors may also act through non-G-protein linked second messenger systems. In many tissues, multiple subtypes of α-adrenoceptor are present, and this may be regarded as the norm rather than exception, although one receptor subtype is usually predominant.

1. Introduction This review examines the functions of α1-adrenoceptor subtypes, particularly in terms of contraction of smooth muscle, and follows on from previous reviews (Docherty, 1998a, 2010). 1.1. History of adrenoceptors Adrenoceptors or adrenergic receptors (Chiefly US) or even adrenoreceptors, are members of the seven transmembrane spanning Gprotein-linked superfamily of receptors, and respond to the physiological agonists noradrenaline (NA) (norepinephrine) and adrenaline (epinephrine) by producing a response in the cell, mediated by an intermediary G protein linked to second messenger systems or ion channels, although non-G-protein linked pathways may also be involved. The traditional starting point in the subclassification of adrenoceptors is the conceptual breakthrough by Ahlquist (1948), who described two types of adrenoceptor in studies investigating the actions of agonists and the antagonistic actions of ergot alkaloid drugs. The receptor termed β was mainly inhibitory, except in the heart, and the receptor termed α was mainly excitatory, except in the intestine

(Fig. 1). The Ahlquist classification was further expanded by the subdivision of β-adrenoceptors into 2 subtypes, mainly on the affinities of adrenaline and noradrenaline: β1-and β2-adrenoceptors (Lands et al., 1967) (see Fig. 1). The next major expansion in α-adrenoceptor subclassification came when α2-adrenoceptors were identified, initially as presynaptic or prejunctional inhibitory receptors (see Langer, 1974; Starke, 1977), and subsequently also as postjunctional receptors on smooth muscle (Berthelsen and Pettinger, 1977) (see Fig. 1). In hindsight, we can see that Ahlquist's classification already pointed to the division of α-adrenoceptors into α1- (excitatory) and α2-adrenoceptors (inhibitory to intestine by prejunctional actions) (see Fig. 1). New methodologies advanced the study of adrenoceptors. The radioligand binding assay, beginning in the mid-1980's, produced evidence, supported by functional studies, that there were subtypes of α1adrenoceptors (see Morrow and Creese, 1986; Han et al., 1987) and α2adrenoceptors (see Bylund, 1988), and a β3-adrenoceptor (Bylund et al., 1994; Emorine et al., 1989). Subsequently, molecular biological techniques definitively identified receptors as gene products: 9 adrenoceptor genes were sequenced (α1A, α1B, α1D; α2A, α2B, α2C; β1, β2, β3) and identification of species orthologues allowed reduction in subtypes

E-mail addresses: [email protected], [email protected]. https://doi.org/10.1016/j.ejphar.2019.04.047 Received 7 February 2019; Received in revised form 17 April 2019; Accepted 29 April 2019 Available online 05 May 2019 0014-2999/ © 2019 Elsevier B.V. All rights reserved.

European Journal of Pharmacology 855 (2019) 305–320

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2. α1-adrenoceptor subtype selective drugs A number of drugs show selectivity for α1-adrenoceptors over α2adrenoceptors, but the most widely used is prazosin. Prazosin shows high selectivity for α1-adrenoceptors but higher concentrations (above 100 nM) will block α2-adrenoceptors (Ho et al., 1998). Prazosin does not show selectivity between α1-adrenoceptor ligand binding sites (Table 2), although this review will show that prazosin shows selectivity in functional studies. Phenylephrine is a selective α1-adrenoceptor agonist, but NA acts on both α1-and α2-adrenoceptors, and this may be problematic in studies of tissues containing both α1-and α2-adrenoceptors, e.g. rat spleen. A number of selective α1A-adrenoceptor antagonists are available including RS100329 (5-Methyl-3-[3-[3-[4-[2-(2,2,2,-trifluroethoxy) phenyl]-1-piperazinyl]propyl]-2,4-(1H,3H)-pyrimidinedione hydrochloride)(Williams et al., 1999) and silodosin (KMD-3213) (Murata et al., 1999). Silodosin and RS100329 show high affinity for α1Aadrenoceptor ligand binding sites, and low affinity for α1B- and α1Dadrenoceptor sites (Table 2). 5-Methyl-urapidil is also α1A-adrenoceptor selective in ligand binding studies (Perez et al., 1991). A61603 (N-[5(4,5-Dihydro-1H-imidazole-2-yl)-2-hydroxy-5,6,7,8-1-yl]methanesulfonamide hydrobromide) is a potent α1A-adrenoceptor selective agonist (Knepper et al., 1995) (see Table 1). Currently, there is no widely trusted selective antagonist for α1Badrenoceptors. Risperidone, AH11110A (4-Imino-1-(2-phenylphenoxy)4-piperidinebutan-2-ol hydrochloride), and cyclazosin, and the irreversible antagonist Chloroethylclonidine have been employed, particularly in ligand binding studies, but their selectivities are often less clear in functional studies (see Docherty, 2010 for references). BMY 7378 (8-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride) is a selective antagonist at α1D-adrenoceptors (Goetz et al., 1995) and shows high affinity for α1Dadrenoceptor ligand binding sites (Table 2 and Fig. 2). However, BMY 7378 also shows potency as an α2C-adrenoceptor antagonist (pA2 of 6.48 in human saphenous vein: Cleary et al., 2005). Hence, employing a non-selective antagonist (prazosin), an α1Aadrenoceptor (RS100329/silodosin) and an α1D-adrenoceptor (BMY7378) antagonist, we can characterize α1-adrenoceptors ligand binding sites as follows (see Fig. 2, top): α1A-site: high affinity: prazosin/RS100329/silodosin. α1B-site: high affinity: prazosin only. α1D-site: high affinity: prazosin/BMY7378.

Fig. 1. Historical development of the subclassification of adrenoceptors since 1948. Abbreviations: s.m, smooth muscle. It will be argued in this review that the α1L-adrenoceptor is simply the α1A-adrenoceptor at which prazosin has low potency. Hence, there are three subtypes of α1-adrenoceptors: α1A, α1B and α1D. See text for details and references.

(the rat α2D-adrenoceptor was a species orthologue of the human α2A and is now termed α2A: see Bylund et al., 1994). Molecular cloning techniques initially indicated that there were four subtypes of α1adrenoceptor (Cotecchia et al., 1988; Lomasney et al., 1991; Schwinn et al., 1990; Perez et al., 1991). However, the α1C-clone correlated well with the α1A-ligand binding site, and the α1A- and α1D-clones were found to represent the same subtype: α1D. The result of this initial classification is the historical anomaly that explains why there is no α1C-adrenoceptor, despite there being only three subtypes (Fig. 1) (see Docherty, 1998a; 2010). 1.2. Function of α1-adrenoceptors The moment by moment level of vasoconstriction in the vascular system is controlled by the sympathetic innervation. Widespread sympathetic activation, such as in the “Fight or Flight” reaction, will cause α1-adrenoceptor mediated vasoconstriction in less vital vascular beds, particularly splanchnic and skin (although the skin vasculature may dilate later to dissipate heat), to divert blood to skeletal muscle. Sympathetic activation also mobilises blood from the venous reservoir by constriction of the large veins and inhibits digestion. Ocular effects involve α1-adrenoceptor mediated dilatation of the pupil by contraction of the dilator pupillae muscle, allowing more light to reach the retina, leading to greater alertness. α1-Adrenoceptor agonists as vasoconstrictors can be used to treat hypotension, as nasal decongestants and reduce intraocular pressure, and α1-adrenoceptor antagonists lower blood pressure in hypertension. α1-Adrenoceptors also have major contractile function in non-vascular tissues of the gastrointestinal and urinary tracts, including bladder, prostate and vas deferens. α1-Adrenoceptors contribute to the hypophagic actions of (−)-ephedrine (Wellman et al., 2003), and MDMA (3,4-Methylenedioxy methamphetamine) can cause hyperthermia at least partly by peripheral α1-adrenoceptor actions (Bexis and Docherty, 2006) and α1adrenoceptors contribute to the cognitive enhancing effects of modafinil in man (Winder-Rhodes et al., 2010). There is evidence that the α1-adrenoceptor antagonist prazosin reduces nightmares and overall Post Traumatic Stress Disorder (PTSD) symptoms (Singh et al., 2016) and improves behavioural symptoms in patients with Alzheimer's disease (Wang et al., 2009), and may reduce alcohol intake in patients with alcohol dependence (Kenna et al., 2016). Table 1 lists some of the major characteristics of the α1-adrenoceptor subtypes, and aspects of these will be explained at relevant points in this review.

3. α1A-adrenoceptors: are there high (α1A-) and low (α1L-) affinity ligand binding sites for prazosin? Although prazosin is non-selective in most ligand binding studies of α1-adrenoceptors, a small number of studies suggest that there are high and low affinity ligand binding sites for prazosin. Employing [3H]-silodosin, but not [3H]-prazosin, as radioligand, two sites could be demonstrated in some circumstances. [3H]-Silodosin binds at low concentrations (300 pM) largely to α1A-adrenoceptors. In ligand binding studies of intact segments of rat cerebral cortex and rabbit ear artery, but not in membranes of cerebral cortex and rat tail artery, prazosin displaced [3H]-silodosin binding from two sites with high (9.9) and low (7.8) affinity (see Table 3). There are also reports of a low affinity prazosin sites in rabbit iris dilator and prostate (Table 3). Nishimune et al. (2010) reported that a protein, CRELD1α (Cysteine-rich epidermal growth factor-like domain 1alpha) downregulates α1A-adrenoceptors in Chinese hamster ovary (CHO) cells and increases the proportion of low affinity receptors, although the prazosin pKi was extremely low (6.9) (Table 3) and CRELD1α caused a fall in specific binding of approximately 10 fold (Table 3). Hence, two α1A-adrenoceptor ligand binding sites can be demonstrated under certain intact cell conditions, but only one site in membranes. The second site may represent internalization/modulation of 306

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Table 1 Summary of α1-adrenoceptor subtype characteristics. Receptor Subtype

α1A

α1B

α1D

Functional responses vascular contraction non-vascular contraction Blood pressure control Nerve-mediated responses

smooth muscle contraction: rat mesenteric artery (major). rat vas deferens (tonic) role in control of blood pressure less rapid response high frequency responses peri- & para-junctional?

role in contraction:

smooth muscle contraction: rat aorta rat vas deferens (phasic) role in control of blood pressure. rapid response low frequency responses peri- & para-junctional?

LOW A61603

LOW

HIGH

high affinity low potency RS 100329 high silodosin high BMY 7378 low

high affinity high potency RS100329 low silodosin low BMY7378 low more sensitive to CEC?

high affinity high potency RS100329 low silodosin low BMY7378 high

Gq/11 IP3, DAG β-arrestin Rho L-type Ca2+channels

Gq/11 IP3, DAG β-arrestin Rho Ca2+channels/Ca2+sensitization?

Gq/11 IP3, DAG β-arrestin Rho T-type Ca2+channels/Ca2+ stores

Agonist selectivity NA potency Selective agonists Prazosin selectivity prazosin (binding) prazosin (function) Selective antagonists Sensitivity to other agents Post-receptor mechanisms G protein Second messenger Non-G protein Possible major contractile effect:

rat spleen Regulatory

Table 2 Comparison of ligand binding affinities (-log M) of prazosin, silodosin, RS100329 and BMY738 at α1A, α1B and α1D-adrenoceptor ligand binding sites. Tissue and selectivity

α1A-

α1B

α1D

reference

Prazosin Non-selective (in ligand binding)

9.23 9.57 10.1 9.95 9.73 9.7 9.3 9.39 9.17 9.57 10.44 10.7 9.8 9.36 9.69 10.0 9.60 9.56 9.58 6.1 6.6 7.0 6.1 6.8 6.62 6.54

9.26 9.72 10.1 10.26 10.18 10.3 10.0 9.85 9.96 9.96 7.68 8.12 8.5 7.99 8.29 8.12 7.5 8.07

9.48 9.49 9.9 10 9.71 9.2 9.1 9.47

Forray et al. (1994) Kenny et al. (1994) Blue et al. (1995) Buckner et al. (1996) Martin et al. (1997) Sathi et al. (2008) Sathi et al. (2008) Sato et al. (2012) Docherty & Bexis (unpub)

MEAN Silodosin α1A-selective

MEAN RS 100329 α1A-selective MEAN BMY7378 α1D-selective

MEAN

9.54 8.7 8.64 8.1 8.06 8.29 8.36 7.9 7.78 8.2 9.4 8.2 9.0 9.2

6.2 7.2 6.2 6.7 7.0 7.5 6.80

8.80

notes

intact cells

Shibata et al. (1995) Murata et al. (1999) Piao et al. (2000) Ishiguro et al. (2002) Sato et al. (2012) Williams et al. (1999) Docherty & Bexis (unpub) (7.9) Goetz et al. (1995) Goetz et al. (1995) Yoshio et al. (2001) Sathi et al. (2008) Sathi et al. (2008) Docherty & Bexis (unpub)

Bovine/hamster/rat Human intact cells

Abbreviations: unpub, unpublished. Functional potencies are shown in Tables 4 and 5

the functional receptor by the internal cellular environment, although this remains to be established.

adrenoceptors (Figs. 1 and 2), but the α1L-adrenoceptor did not appear to fit this classification. A large number of vascular and non-vascular tissues were reported to contain α1L-adrenoceptors in multiple studies by Muramatsu and Co-workers (see Tables 4 and 5). Studies by other authors have also confirmed the presence of α1-adrenoceptors with low potency for prazosin, although not all authors have used the term α1Ladrenoceptor to describe them (see e.g. Marshall et al., 1996). Genetic polymorphism of α1A-adrenoceptors does not explain α1Ladrenoceptors, since human α1A-adrenoceptor splice variants (Shibata et al., 1996) and homo- and heterodimers of human α1A-adrenoceptor variants (Ramsay et al., 2004) have been found to have similar pharmacological characteristics. It has been suggested that the α1A- and α1Ladrenoceptors may be different affinity/conformational states of the

4. Prazosin potency in functional studies 4.1. α1L-adrenoceptors Functional receptors will now be considered. Prior to the definitive classification of α1-adrenoceptors (Fig. 1), an alternative classification was proposed subdividing α1-adrenoceptors in smooth muscle based on their affinities particularly for prazosin into α1H (high affinity for prazosin) and α1L (low affinity)(Muramatsu et al., 1990). α1H-Adrenoceptors appeared to match the current classification of α1A-, α1B-, α1D307

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potency, usually obtained from the effects of a single antagonist concentration). If there is a single receptor population, a pA2 is the most reliable indicator of antagonist potency, being based on the effects of several antagonist concentrations, but often a pKB from a single antagonist concentration is used. A pKB obtained may be dependent on the choice of antagonist concentration: if multiple subtypes of receptor are present, the first concentration to produce a significant shift in agonist potency should be used. 4.3. Aorta In rat aorta, prazosin exhibits high potency (pA2/pKB: mean of 9.61) and the α1D-adrenoceptor antagonist BMY 7378 also exhibits high potency (8.56), suggesting the predominant receptor is an α1D-adrenoceptor (Table 4A). In mouse aorta, prazosin had high potency (mean of 9.68) but BMY 7378 had high potency in the upper (suggesting α1D) and low potency in the lower (suggesting α1B) abdominal aorta, (Table 4A). From Table 5, it can be seen that both silodosin and RS100329 have low potency in rat aorta, ruling out an α1A-adrenoceptor as the predominant receptor. These results suggest that prazosin has high potency at α1D-adrenoceptors. In contrast, prazosin has low potency in rabbit (mean of 8.73) and guinea-pig (mean of 8.37) aorta (Table 4A). However, BMY7378 had low potency in the lower abdominal aorta, but high potency in the thoracic and upper abdominal aorta of the guinea-pig (Table 4A). Silodosin had high potency (9.36) in rabbit aorta (Yamagishi et al., 1996). Pharmacologically, the data would suggest the predominant receptor is α1A-in rabbit aorta, but that α1D-adrenoceptors are also present at least in the upper abdominal aorta of the guinea-pig.

Fig. 2. Diagrammatical representation of classification of α1-adrenoceptors based on high and low affinity (ligand binding studies) or potency (functional studies) of prazosin, the α1A-adrenoceptor selective antagonists RS100329 or silodosin, and the α1D-adrenoceptor antagonist BMY7378 (see text and Tables). There are clear patterns of affinity/potency that allow receptor characterization using 3 antagonists, in the absence of a useful selective α1B-adrenoceptor antagonist. Note that prazosin has high potency at α1A-sites in ligand binding studies but low potency in functional studies. Abbreviations: High, high antagonist affinity or potency; Low, low antagonist affinity or potency; RS, RS100329.

α1A-adrenoceptor (Ford et al., 1997; Williams et al., 1999). Knock-out of the α1A-adrenoceptor in mouse prostate abolishes α1L-adrenoceptor pharmacology, suggesting that the α1L-adrenoceptor is a functional phenotype of the α1A-adrenoceptor (Gray et al., 2008).

4.4. Spleen In rat spleen, high prazosin potency (mean of 9.56; Table 4A) and low potency of silodosin (Table 5) was found especially when the α1adrenoceptor agonist phenylephrine was employed and there is evidence for an α1B-adrenoceptor involved in splenic smooth muscle contraction (Burt et al., 1995; Docherty and Daly, 2014). These results suggest that prazosin has high potency at α1B-adrenoceptors.

4.2. Prazosin potency in comparison to potency of the α1D-adrenoceptor antagonist BMY7378 in functional studies To identify the receptors at which prazosin has low potency, it is necessary to systematically look at the potency of prazosin in a number of tissues, and this is done in Tables 4 and 5. In these Tables, antagonist potency is expressed as a pA2 (the negative logarithm of the molar concentration of an antagonist that produces a 2 fold shift in agonist potency, obtained from the effects of several antagonist concentrations, employing a Schild plot), or pKB (the negative logarithm of the molar concentration of an antagonist that produces a 2 fold shift in agonist

4.5. Rat and mouse vas deferens A wide range of pA2 values have been obtained for prazosin against NA in rat vas deferens, ranging from 8.32 to 9.59 (see Table 4A).

Table 3 Comparison of ligand binding affinities (-log M) of prazosin (praz) and silodosin (silod) employing prazosin or silodosin as radioligand. Also shown is affinity of BMY 7378 (BMY). Tissue Rat tail artery Rat aorta Rat cerebral cortex segments CHO cells CHO cells CRELD1α Rabbit ear artery Rabbit iris dilator: iris (albino) membranes iris (albino) segments iris (pigmented) segments Rabbit prostate membranes Rabbit prostate segments

Radio-ligand 3

Praz high

[ H]-praz [3H]-praz [3H]-silod [3H]-praz

9.4 9.9 9.8 9.9

[3H]-praz [3H]-silod [3H]-praz [3H]-silod [3H]-silod [3H]-praz [3H]-silod

9.9 9.9

[3H]-silod [3H]-silod [3H]-silod [3H]-praz [3H]-silod

9.28 9.5

9.7 10.2 9.3 9.9

9.8 8.8

Praz low

7.8 8.7

Silod high

Silod Low

BMY

reference

9.7 10.0 9.9 7.1

7.5

Sathi et al. (2008) Morishima et al. (2008)

9.9 9.8

7.9

6.4 6.4 6.3 8.8 6.1 6.2 6.3

9.6 9.6 9.7 9.5

6.9 8.3 7.6 6.3 7.1

Abbreviations: high: high affinity (> 9.00); low: low affinity (< 9.00). 308

6.7

Sathi et al. (2008) Morishima et al. (2008) Williams et al. (1999) Nishimune et al. (2010) Hiraizumi-Hiraoka et al. (2004)

10.3

6.91

9.0 10.1 9.5

6.2

Nakamura et al. (1999) Muramatsu et al. (2008) Su et al. (2008)

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Table 4A Prazosin potency (-log M) in comparison to potency of the α1D-adrenoceptor antagonist BMY7378 in functional studies of aorta, spleen and vas deferens. Section

Species and Tissue

Praz high

4.3.

Rat aorta: α1D (Prazosin high potency: 9.59; BMY7378 high potency: 8.60.)

9.42 9.6 9.89 9.45 9.4 9.8 9.35 9.69 9.17

4.3.

MEAN (rat aorta) Mouse aorta: (prazosin high potency)

4.3.

Rabbit aorta: α1A (prazosin low potency)

4.3.

Guinea-pig aorta: α1A (prazosin low potency)

4.4.

Rat spleen: α1B (prazosin high potency: 9.56)

4.5.

9.9 9.38 9.84 9.6 9.63 9.7 9.59 9.65 9.34 10.04

9.56 9.45 9.2 10.02

MEAN (rat spleen) Rat vas deferens: α1D plus α1A (prazosin two potencies: 9.24 + 8.54)

9.56 9.26 9.21 9.2 9.59 9.34 9.2 9.35 9.01 9.12 9.24

MEAN (rat vas deferens)

Praz Low

BMY

8.3 8.39 8.95 9.0 8.39 8.64 8.5 8.60 8.53 6.00 8.59 8.45 8.82 9.05 8.56 8.65 8.45 7.83

8.91 8.32

8.78

8.43 8.53 6.00 5.73 7.4 7.24 6.56 7.07

6.7 5.98

8.59 8.66

6.48

8.64

6.3 6.64 7.05 5.8 7.48

8.26 8.50 8.54

6.55

Reference

Notes

Digges & Summers (1983) Beckeringh et al. (1984) Muramatsu et al. (1990) Aboud et al. (1993) Testa et al. (1995) Kenny et al. (1995) Buckner et al. (1996), 2001 Yamagishi et al. (1996) Tatemichi et al. (2006) Fagura et al. (1997) Hussain and Marshal, 1997 Castillo et al. (1997) Maruyama et al. (1998) Williams et al. (1999) Lima et al. (2005) Sathi et al. (2008) Yamamoto and Koike (2001) Yamamoto and Koike (2001) Tanaka et al., 2005 Cavero et al. (1978) Docherty et al. (1982) Muramatsu et al. (1990) Yamagishi et al. (1996) Chuliá et al., 1996 Beckeringh et al. (1984) Muramatsu et al. (1990) Yamamoto & Koike (1999) Aboud et al. (1993) Teng et al. (1994) Burt et al. (1995) Buckner et al. (1996), 2001 Lima et al. (2005) Ohmura et al. (1992) Aboud et al. (1993) Teng et al. (1994) Burt et al. (1995) Buckner et al. (1996), 2001 Pupo (1998) Honner and Docherty (1999) Amobi et al. (1999) Lima et al. (2005) cocaine Docherty (2013) Docherty (2014)

Upper abd a Lower abd a

Thorac a Upp. Abdom Low abdom Thorac a Phe Phe

NA NA cocaine NA A61603 Methox Longt m Circ m Vehicle Cocaine Tonic Phasic

Potency of prazosin: praz high (high potency > 9.00); praz low (low potency < 9.00). Abbreviations; abd a, abdominal aorta; BMY, BMY7378 potency; circ m, circular muscle; longt m, longitudinal muscle; methox, methoxamine; phe, phenylephrine; praz, prazosin.

However, it can be seen that two distinct potency values for prazosin were obtained in rat vas deferens, a high potency of mean of 9.24, and a low potency of mean of 8.54 (Table 4A). The potencies of the subtype selective antagonists RS100329 and BMY7378 against tonic and phasic contractions are consistent with the presence of α1A- and α1D-adrenoceptors, respectively (Docherty, 2013, 2014), and ligand binding studies of rat vas deferens from sympathectomised rats also confirm the presence of α1A- and α1D-adrenoceptors (Cleary et al., 2004). mRNA for all α1-adrenoceptors is expressed in rat vas deferens (Yono et al., 2004), and the α1D-adrenoceptor has a role secondary to the α1A-adrenoceptor in terms of protein expression (Perez et al., 1991). In mouse vas deferens, the predominant receptor mediating contractions to exogenous agonists is an α1A-adrenoceptor based on high potency of silodosin (and low potency of prazosin) (Muramatsu et al., 2008). From this it would seem that the low potency site for prazosin is an α1A-adrenoceptor, and

the high potency site an α1D-adrenoceptor. In human vas deferens, prazosin potency of 8.6 against contractions to phenylephrine is consistent with predominantly α1A-adrenoceptors (Davis et al., 2015). Studies may differ in the reported potency of prazosin in rat vas deferens due to a number of factors: 1. Phasic contractions are predominantly α1D-adrenoceptor mediated and tonic contractions are predominantly α1A-adrenoceptor mediated (see Docherty, 2013). 2. Use of cocaine to block the NA transporter (NET) increases the phasic α1D-adrenoceptor mediated component of the contraction (see Docherty, 2013). 3. Use of desipramine, which has α1-adrenoceptor antagonist actions, to block NET may result in lower prazosin potency (see Docherty, 2013, 2014). 309

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Table 4B Prazosin potency (-log M) in comparison to potency of the α1D-adrenoceptor antagonist BMY7378 (BMY) in functional studies of genito-urinary and vascular tissues. Section

Species and Tissue

4.6. α1A

Human LUT tissue

4.6. α1A

Praz high

Human bldr neck Rabbit bldr neck Rat bldr neck Mouse ureter Rat urethra Pig anal sphincter Human prostate 9.29 Mouse prostate Rabbit prostate

4.7. 4.7.

4.7.

Rat portal vein Rabbit mes a Human subcut art Rat fem rest art Human skel rest art Human mes art Rat small mes art

9.2 9.4 9.6 9.18 9.1 9.9

Rabbit pulm art 9.4

4.7.

Dog pulm art Hum int mam art Humun mam art

9.8* 9.56 9.36 9.29 9.65 9.2

Praz Low 8.70 8.5 8.2 8.3 8.4 8.6 8.55 8.2 8.15 8.5 8.70

BMY

6.59 6.06

8.23 8.12

6.57 6.28

8.3 8.39

6.5

8.65

7.1 7.2 6.52 8.8 6.16

8.64 8.76 8.37

Reference Williams et al. (1999) Kava et al. (1998) Yoshiki et al. (2013) Williams et al. (1999) Kava et al. (1998) Yoshiki et al. (2013) Kobayashi et al. (2009a) Yoshiki et al. (2013) Mills et al. (2008) Marshall et al. (1996) Kenny et al., 1995 Teng et al. (1994) Takahashi et al. (1999) Gray & Ventura (2006) Delaflotte et al. (1996) Yamagishi et al. (1996) Digges & Summers (1983) Marshall et al. (1996) Muramatsu et al. (1990) Jarajapu et al. (2001a) Jarajapu et al. (2001b) Jarajapu et al. (2001c) Yoshiki et al. (2013) Hussain and Marshal, 1997 Stam et al. (1999) Docherty & Starke (1981) Vizi et al. (1986) Holck et al. (1983)

8.65 8.78 8.4*

Docherty (1988b) 6.1

Flavahan et al. (1998) Docherty and Ruffolo, 1989

8.5 8.4

6.88 7.00 < 6.00

Sohn et al. (2005) Giessler et al. (2002) Rudner et al. (1999)

Notes

Methoxamine Clonidine phe clonidine Phe (*2 sites) phe Methoxamine Phe

Potency of prazosin: praz high (high potency > 9.00); praz low (low potency < 9.00). Abbreviations; art, artery; bldr bladder; int, internal; mam, mammary,; mes, mesenteric; phe, phenylephrine; praz, prazosin; pulm, pulmonary; rest, resistance; skel, skeletal; subcut subcutaneous.

4.6. Genitourinary tract Prazosin potency tended to be low in a wide range of genito-urinary tissues, including bladder neck and prostate, suggesting mainly α1Aadrenoceptors (Table 4B). Prazosin tended to have high potency in resistance arteries, suggesting a major role for α1D-adrenoceptors (Table 4B).

adrenoceptor. In particular, both silodosin and RS100329 had low potency in rat aorta, in contrast to prazosin, and silodosin had high potency in bladder neck and lower urinary tract (LUT) where prazosin has low potency (Table 5). However, there are some exceptions: rabbit ear artery, rat tail artery and prostate and CHO cells (Table 5), where both prazosin and α1A-adrenoceptor selective antagonists have high potency, but these will be considered in more detail below.

4.7. Pulmonary artery and other blood vessels

5.2. Does prazosin have low functional potency at all α1A-adrenoceptors?

In a number of blood vessels, prazosin shows high potency, or has high and low potency receptors. In rabbit and dog pulmonary arteries a wide range of potencies for prazosin are reported, suggesting perhaps a mixture of α1A- and α1D-adrenoceptors, although some α1B-adrenoceptors cannot be ruled out (Table 4B). Low potency of BMY7378 coupled with high potency of prazosin may suggest α1B-adrenoceptors.

As the α1L-adrenoceptor is thought to be a low affinity state of the α1A-adrenoceptor, prazosin should have low potency at α1L-adrenoceptors (around 8.5) and higher potency at α1A-adrenoceptors (around 9.5) in functional and ligand binding studies and the two sites might be expected in the same tissue. Some ligand binding studies, especially of whole cells, may suggest the presence of high and low affinity sites. Therefore, where are the α1A-adrenoceptors at which prazosin has high functional potency? In many tissues more than one subtype of α-adrenoceptor may be involved in responses. Indeed, the involvement of multiple receptor subtypes in responses may be the norm rather than the exception. In some tissues both α1-and α2-adrenoceptors play a role in contraction: In rat tail artery, prazosin has high potency (9.2) against contractions to clonidine (Kennedy et al., 2006), but very low potency (6.8) against admittedly small contractions to UK14,304 (5-Bromo-6-(2-imidazolin2-ylamino)quinoxaline)(Jantschak et al., 2010), and yohimbine had high potency against UK14,304 (8.45). Hence, very low potency of prazosin (< 7.0) may indicate α2-adrenoceptors. Similarly, in rat

5. Prazosin potency at α1A-adrenoceptors 5.1. Prazosin potency in comparison to potency of α1A-adrenoceptor antagonists in functional studies From Table 4, it is clear that prazosin has low potency in some functional studies. Table 5 relates prazosin potency to the potency of α1-adrenoceptor antagonists in a number of tissues. It can be seen in general that prazosin has low potency where α1A-adrenoceptor selective antagonists (silodosin or RS100329) have high potency and vice versa, suggesting that this low potency receptor for prazosin is the α1A310

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Table 5 Prazosin potency in comparison to potency of α1A-adrenoceptor antagonists in functional studies.

5.1.

Tissue

Praz high

Rat aorta

9.69

Praz low

Silod high

5.1.

5.3

Rabbit aorta Rat spleen Human bldr neck Rat bladder neck Rabbit bldr neck Rabbit bldr trigone Dog ureter Mouse ureter Rat urethra Rabbit urethra Human ureter Human LUT Human int anl sph Pig int anl sphinct Human renal art Rabbit penile art Pig prostatic art Rat tail art

5.4.

Rat vas deferens

5.4.

Rabbit prostate

5.4.

Rat prostate

5.5.

Rabbit iris dilator (albino) Rabbit iris dilator (pigmented)

5.6.

Rabbit ear artery

5.7.

CHO cells CHO cells CREld1a MEAN (ALL)

9.4 9.2 9.2 9.1 9.8

9.9 9.19

9.3 9.1 9.39

RS high

8.13 8.3 8.2 7.88

9.7 9.17 9.6 9.28 9.3 9.05 9.34

Silod low

9.36 8.2 8.6 8.3 8.1 8.16 8.55 8.2 7.96 8.64 8.7 8.89 8.58 8.7 8.42 8.4

8.93 8.97 8.06 9.01 8.3 7.91 8.2

9.7 10.3 9.45 9.32 9.1 9.72

7.15 9.2 9.35

10.1 9.5 9.77

6.78 6.06

8.71

7.04

9.2 9.01 9.2 9.1

9.89 9.6 9.84

10.0 9.6 9.7 11.5+

9.3

8.54

8.3

10.0 9.9

7.9 8.7 7.8 8.40

7.9 8.1

9.8 10.4

9.84 9.5 9.0

BMY

8.5

9.36

8.08 7.8 6.7 8.7

RS low

7.28 6.59 8.8

7.69

< 5.0 8.3

6.81 7.0

7.3

<6 9.6 9.40

Yamagishi et al. (1996) Murata et al. (1999) Sathi et al. (2008) Tatemichi et al. (2006) Williams et al. (1999) Docherty (2011) Docherty&Bexis (2013) Gómez-Zamudio and Villalobos-Molina, 2009 Yamagishi et al. (1996) Tatemichi et al. (2006) Yoshiki et al. (2013) Yoshiki et al. (2013) Williams et al. (1999) Tatemichi et al. (2006) Kobayashi et al., 2009b Kobayashi et al. (2009c) Yoshiki et al. (2013) Tatemichi et al., 2006 Sasaki et al. (2011) Williams et al. (1999) Owaki et al. (2015) Mills et al. (2008) Williams et al. (1999) Morton et al. (2007) Recio et al. (2008) Yoshiki et al. (2013) Kava et al. (1998) Murata et al. (1999) Sathi et al. (2008) Parés-Hipólito et al., 2006 Docherty (2013) Yamagishi et al. (1996) Tatemichi et al. (2006) Yoshiki et al. (2013)

5.9 <6 <6

7.95

Reference

Maruyama et al. (1998) Nakamura et al. (1999) Muramatsu et al. (2009) Leonardi et al. (1997) Hiraizumi-Hiraoka et al., 2004 Williams et al. (1999) Nishimune et al. (2010)

Agonist

Phe NA Ro meth A616 Phe Veh Cocn NA Ro NA NA des NA NA NS-49

8.15

Comparison of potencies of prazosin (praz), silodosin (silod) and RS100329 (RS) (high potency > 9.00; low potency < 9.00) in functional, mostly contractile, studies of a number of smooth muscle tissues. Also shown for comparison is potency of BMY7378 (BMY). Abbreviations: A616, A61603; art, artery; bldr, bladder; cocn, cocaine present; des, desipramine present; int anl, internal anal; meth, methoxamine; Ro, Ro 115–1240; sph, sphinct, sphincter; veh, vehicle (cocaine absent). See Fig. 3. + Quoted as 10.3, but looks > 11.5 from graph.

spleen, prazosin (10 nM) produces a marked shift in the potency of the α1-adrenoceptor agonist phenylephrine, but only a small shift in the potency of NA due to the presence of α2-adrenoceptors (Alsufyani and Docherty, unpublished). In Fig. 3, prazosin potency is plotted in relation to the potency of the α1A-adrenoceptor antagonists RS100329 and silodosin. For RS100329, 2 groups of points are clearly discernible, presumably α1A- and nonα1A-adrenoceptors (but some overlap of prazosin potency may mean that some of the points in the α1A-adrenoceptor group may represent tissue with both α1A- and non-α1A-adrenoceptors (mixed). For silodosin, the same pattern is seen if 6 outliers are omitted (shown by red triangles in Fig. 3). These outliers are: 1, rat tail artery; 2, rat prostate (Ro 115–1240 as agonist, 2a as published, 2b, reinterpreted); 3, rabbit iris (pigmented). These outliers will be discussed below.

5.3. Rat tail artery In rat tail artery (see Table 5), in the presence of rauwolscine (100 nM) to block α2-adrenoceptors, prazosin had high potency against both NA and the α1A-adrenoceptor-partial agonist Ro 115–1240 (9.4 and 9.2, respectively) (Yoshiki et al., 2013), with silodosin also showing high potency (9.8 and 10.4, respectively). BMY7378 had high potency (8.3) (Yoshiki et al., 2013). This was interpreted as demonstrating an α1Aadrenoceptor at which prazosin had high potency. The concentrationresponse curves suggest that low concentrations of NA were resistant to silodosin and high concentrations resistant to prazosin (see Fig. 4E of Yoshiki et al., 2013). In contrast, Parés-Hipólito et al. (2006) found that prazosin had low potency against both A61603 and phenylephrine but that RS100329 had a low potency receptor only with phenylephrine as 311

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suggesting contractile responses involve mainly α1A-adrenoceptors (Table 5). Hence, responses in rat prostate are consistent with an α1Aadrenoceptor at which prazosin has low potency. 5.5. Rabbit iris dilator muscle In rabbit iris dilator muscle, prazosin potency was 8.6 (in absence of desipramine: Ishikawa et al., 1996) and 8.08 or 7.79 (in presence of desipramine 100 nM: Nakamura et al., 1999; Konno and Takatyanagi, 1986) and 7.8 (desipramine 300 nM: Muramatsu et al., 2009). In a study in rat vas deferens of the effects of different blockers of NET on potency of prazosin, prazosin pKB was 9.12 in the presence of cocaine (10 μM), but 8.42 in the presence of desipramine (300 nM) (Docherty, 2014). α1-Adrenoceptor blockade by desipramine can shift prazosin potency markedly. Even lower prazosin potency of around 7.5 has been reported against contractions in mouse vas deferens and mouse and rabbit prostate, again in the presence of desipramine (HiraizumiHiraoka et al., 2004; Muramatsu et al., 2008; Yoshiki et al., 2013). However, in pigmented rabbit iris, as compared to albino, with desipramine (300 nM), prazosin potency fell from 7.8 to 6.7 (Muramatsu et al., 2009) or 6.4 (Ishikawa et al., 1996), silodosin potency fell from 9.5 to 9.0 (Muramatsu et al., 2009: desipramine 300 nM), and 5-methylurapidil potency fell from 8.3 (albino) to 6.4 (Ishikawa et al., 1996: no desipramine) or 7.6 (albino) to 6.8 in pigmented iris dilator (Muramatsu et al., 2009). Results suggest that the rabbit iris dilator (albino) has mainly α1A-adrenoceptors but iris dilator (pigmented) has receptors at which α1A-adrenoceptor antagonists have low potency, but prazosin also has very low potency. Prazosin has actions at α2-adrenoceptors in this range with a pKB at α2C-adrenoceptors in human saphenous vein of 6.62 (Gavin et al., 1997). If there is an α1A-adrenoceptor present, then a number of antagonists have lower potency due perhaps to some confounding factor (e.g. multiple receptors, perhaps including an α2-adrenoceptor). If there is not an α1A-adrenoceptor present, it is also not an α1L-adrenoceptor as α1A-adrenoceptor antagonists have high potency at α1L-adrenceptors, and a prazosin potency of 6.5–6.7 is too low. This remains uncertain. Two other tissues must be considered in relation to silodosin, not because they are outliers in Fig. 3, but because 2 prazosin potencies were obtained, reportedly α1A- and α1L-adrenoceptors. These are rabbit ear artery and CHO cells.

Fig. 3. Relationship between prazosin potency and potency of the α1A-adrenoceptor selective aagonists RS100329 or silodosin (Data points taken from Table 5). RS100329 (blue open circles); silodosin (black filled circles); silodosin outliers (red filled triangles). Dashed ovals enclose presumed α1A- (top left), non-α1A-adrenoceptors (bottom right) and a mixture of subtypes (mixed) (top right). An inner oval is also shown for the α1A-adrenoceptor as some of the points outside this but within the outer oval may represent a mixture of α1Aand non-α1A-adrenoceptors. Silodosin outliers are: 1, rat tail artery (4 points); 2, rat prostate (Ro 115–1240 as agonist); 3 rabbit iris (pigmented)(see text).

Fig. 4. Effects of α1-adrenoceptor-KO on baseline blood pressure (BP) in conscious mice (data from all studies combined). Values are the change in BP from WT value expressed as the mean (and s.e. mean) of all mean values shown in parentheses in Table 6 (α1A-: n = 5; α1B- and α1D-: n = 6). α1A- or α1D-Adrenoceptor KO produced significant falls in baseline blood pressure (**P < 0.01, Anova).

5.6. Rabbit ear artery In rabbit ear artery, prazosin showed high potency against contractions to NA (9.3) and low potency against contractions to the α1Aadrenoceptor selective agonist NS-49 (7.9) and the reverse was true for silodosin (7.3 and 9.3, respectively) (Hiraizumi-Hiraoka et al., 2004) (see Table 5). However, since NA had a much shallower concentrationresponse curve than NS-49 and prazosin had a Schild slope of 0.69 against NA, this would suggest two receptors (Hiraizumi-Hiraoka et al., 2004), one the α1A-adrenoceptor and the other is probably an α1Dadrenoceptor at which NA has high affinity. Other authors have reported a pKB of 8.7 for prazosin against NA in this tissue, suggesting predominantly α1A-adrenoceptors (Leonardi et al., 1997).

agonist (see Table 5). These results can be re-interpreted as demonstrating the presence of α1D-adrenoceptors (Yoshiki et al., 2013) or α1B-adrenoceptors (Parés-Hipólito et al., 2006) at which prazosin has high potency, in addition to α1A-adrenoceptors, at which prazosin had low potency. 5.4. Prostate In rat prostate, prazosin had low potency, and silodosin high potency, against contractions to NA (pKB of 8.2 and 9.7, respectively), but both had high potency (9.9 and 10.3, respectively) against contractions to the partial agonist Ro115-1240 (1,2-dihydroxybenzene)(Yoshiki et al. (2013) (see Table 5 and point 2A on Fig. 3). This might suggest both α1L- and αlA-adrenoceptors in the same tissue. However, the graph of the data clearly shows that silodosin (1 nM) virtually abolishes contractions to Ro 115–1240, making it much more potent than prazosin, maintaining the potency difference (a suggested pKB for sildosin is around 11.5: Fig. 4C, Yoshiki et al., 2013) (point 2B in Fig. 3). This may suggest that contractions to Ro 115-1240 decline in multiple additions, making it difficult to interpret the results. Certainly, in rabbit prostate, prazosin had low potency and silodosin high potency,

5.7. CHO cells In functional studies of calcium responses of CHO cells, prazosin potency was 9.1, with high potency of silodosin (10.1) (Nishimune et al., 2010) (Table 4). However, in CHO cells overexpressing the protein CRELD1α (reportedly α1L-dominant), prazosin potency fell to 7.8, but this was carried out in the presence of prazosin 10 nM, on the premise that a low concentration of prazosin blocks α1A-adrenoceptors, although it is likely to block non-α1A-adrenoceptors (Table 5). CRELD1α reduced ligand binding site number by 90%, and presumably affected calcium response magnitude. 312

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5.8. α1L-adrenoceptors are α1A-adrenoceptors

Faber, 2001) and in mouse femoral arteries both are required for neointimal formation (Hosoda et al., 2007). Chronic infusion of subvasoconstrictor doses of NA raises blood pressure and causes hypertrophy in wild-type (WT) mice, but not in α1B-adrenoceptor KO mice (Vecchione et al., 2002). This suggests that slowly developing rises in blood pressure, and possible structural changes in blood vessels, are due to α1B-adrenoceptor activation. α1B-Adrenoceptors are expressed in the heart (Lomasney et al., 1991). However, overexpression of α1B-adrenoceptors results in hypotension and cardiac hypertrophy and predisposes to heart failure, suggesting that effects seen in α1B-adrenoceptor knockout mice may not relate to direct blood pressure actions of α1B−adrenoceptors (Zuscik et al., 2001; Woodcock, 2007). α1B-Adrenoceptor overexpression decreases, and α1A-overexpression, increases β-adrenoceptor mediated contractility and improves outcomes (Woodcock, 2007).

Evidence suggests that the receptor at which prazosin has low potency in functional studies previously identified as an α1L-adrenoceptor, is simply the native α1A-adrenoceptor. There is no strong evidence to prove that there are two subtypes of α1A-adrenoceptor in functional studies in terms of prazosin potency The current classification of α1-adrenoceptors into α1A-, α1B-, α1D-adrenoceptors seems to adequately explain the pharmacology, at least in functional studies. Muramatsu and coworkers are to be congratulated as they were first to document a wide number of tissues where prazosin had low potency (α1L-adrenoceptors), but it has taken a long time to realize that these are indeed α1A-adrenoceptors. Hence, given the low functional potency of prazosin at α1A-adrenoceptors, we can characterize α1-adrenoceptors subtypes in functional studies as follows (see Fig. 2). α1A-adrenoceptor: RS100329/silodosin high potency; α1B-adrenoceptor: prazosin high potency; α1D-adrenoceptor: prazosin high potency; BMY7378 high potency.

6.3. Responses mediated by α1D-adrenoceptors

The α1A-adrenoceptor is the most common receptor mediating contractions to exogenous agonists in a wide number of smooth muscle preparations, although this may overestimate its importance, since nerve mediated responses are more important. Contractions are reported to be mediated at least partly by α1A-adrenoceptors in a number of tissues including rabbit and guinea-pig aorta, rat vas deferens (Table 4A), lower urinary tract (LUT) tissues and rabbit and dog pulmonary artery (Table 4B). Contraction of the dilator pupillae muscle (iris dilator) in vitro is mediated by an α1A-adrenoceptor with low prazosin potency in human, rat and rabbit (Ishikawa et al., 1996; Yu and Koss, 2002). mRNA levels show that the α1A-adrenoceptor is predominant in rat tail artery and small mesenteric arteries (Rudner et al., 1999; Martí et al., 2005) and in genitourinary tissues. In rat vas deferens, the α1Aadrenoceptor predominate protein expression (Perez et al., 1991). In terms of cardiac actions, pro-arrthythmic actions of adrenaline, assessed as premature ventricular contractions, were blocked by antagonists with selectivity for α1A-adrenoceptors in rat heart (Pytka et al., 2016).

NA has higher potency at α1D-than at α1A-adrenoceptors or α1Badrenoceptors and this has been confirmed in many pharmacological studies (see Docherty, 2010). Indeed, NA has been reported to have high potency (aorta: pEC50 of 8.15: Cleary et al., 2005) in tissues with a high level of α1D-adrenoceptor mRNA (aorta: 70–80%; Martí et al., 2005) and low potency (pEC50 of 6.32; Stam et al., 1999) in small mesenteric artery, a tissue that has a high level of α1A-adrenoceptor mRNA (75%) (Martí et al., 2005). Contractions are reported to be mediated at least partly by α1Dadrenoceptors in a number of tissues including: rat and mouse aorta (Table 4A) rat tail artery (Table 5), rabbit aorta (Fagura et al., 1997), rat mesenteric, pulmonary, renal and carotid arteries (VillalobosMolina and Ibarra, 1996; Hussain and Marshal, 1997) and mouse carotid (Deighan et al., 2005) and mesenteric arteries (Hosoda et al., 2005b). α1D-Adrenoceptors are reported to mediate endothelium-dependent relaxation in the rat mesenteric bed (Filippi et al., 2001). Rat aorta expresses predominantly α1D- and rat tail and small mesenteric arteries express predominantly α1A- but with significant amounts of α1D-adrenoceptors (Martí et al., 2005; Kamikihara et al., 2005) (see Table 6). In a study of human blood vessels the α1D-adrenoceptor was predominant only in aorta (Rudner et al., 1999). Prazosin has been reported to have high potency (pA2 of 9.68–10.2) in tissues with a high level of α1D-adrenoceptor mRNA (aorta, large mesenteric artery: 70–80%) (Martí et al., 2005; see also Stam et al., 1999).

6.2. Responses mediated by α1B-adrenoceptors

7. Responses mediated by multiple subtypes of α-adrenoceptor

Studies of α1B-adrenoceptors have been hampered by lack of selective antagonists in which investigators could be confident. In rat and mouse spleen, adrenergic contractions are reported to involve both α1Band α2-adrenoceptors (for references, see Docherty, 2010). Knockout (KO) of α1A- and α1D-adrenoceptors does not affect contractions to NA in mouse spleen (Docherty and Daly, 2014). Hence, mouse, and presumably rat, spleen is an example of a tissue in which α1B-adrenoceptors play a major role in contractions, although the predominant receptor is an α2A-adrenoceptor. Although the major subtypes involved in vascular contractions are usually α1A- and α1D-adrenoceptors, KO of α1B-adrenoceptors reveals differences in vascular responsiveness not easily identified in antagonist studies (Daly and McGrath, 2011), and the α1B-adrenoceptor may have a trophic role or be involved in cell surface expression of other subtypes (see Hague et al., 2004) or act through non-G protein linked pathways (Rho A or β-arrestin signaling). Contractions in, for example, tail artery developed more slowly in α1B-adrenoceptor knock-out mice (Daly et al., 2002), and in mouse aorta, contractions to NA and phenylephrine were unaffected by α1B–KO, markedly reduced by α1D-KO, but abolished by combination of α1B/α1D-KO (Hosoda et al., 2005). In rat aorta, both α1A- and α1B−adrenoceptors are involved in trophic effects (Zhang and

7.1. Pressor responses and resting blood pressure in rat and mouse

6. Responses mediated by α1-adrenoceptor subtypes 6.1. Responses mediated by α1A-adrenoceptors

The predominant α1-adrenoceptors involved in pressor responses of the pithed rat were identified as α1A-adrenoceptors but with an α1Dadrenoceptor component based on the effects of BMY 7378 (Zhou and Vargas, 1996), and both α1A- and α1D-adrenoceptors, and, in addition, α2Aadrenoceptors, were involved in pressor responses to NA (Docherty, 2011, 2012). However, the α1B-adrenoceptor subtype also participates in the response to exogenous agonists in the conscious rat (Piascik et al., 1995). In mice, α1D-adrenoceptor KO consistently reduced pressor responses to NA (Tanoue et al., 2002; Hosoda et al., 2005), but less clearly to phenylephrine, suggesting that the pressor responses to phenylephrine involve mainly α1A-, but those to NA involve both α1A- and α1D-adrenoceptors (Hosoda et al., 2005). In addition, in α1B−adrenoceptor KO mice, pressor responses to NA or phenylephrine were significantly blunted (Cavalli et al., 1997; Vecchione et al., 2002; but see Hosoda et al., 2005). Hence, all subtypes of α1-adrenoceptor are involved in blood pressure responses to exogenous agonists. The most important receptors physiologically in control of vascular neurotransmission can be assessed by the effects of receptor KO on resting blood pressure in mice. In tail cuff measurement, α1A313

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Table 6 Baseline blood pressure (BP) in wild type (WT) and α1-adrenoceptor KO mice in (a) conscious tail cuff systolic (SBP) and (b) conscious invasive mean arterial pressure (MAP) studies, respectively. WT

α1A-KO

α1B–KO

(a) Conscious Tail cuff SBP (mmHg) 114 104 (−10) a 111 102 (−9) 99 99 (0) 109 111 111 120 111 (−9) 105 102 (−3) 104 (−1) 112 (est) 106 (est) 111 (est) 102 (−9) a (b) Conscious Invasive MAP (mmHg) 138 121 (−17) a 119 118 117 130 (est) 95

α1D-KO

93 (−6)a 99 (−10)a a

95 (−10)

118 (−1) 111 (−7) 130 (0)

α1A/α1B–KO

α1B/α1D-KO

92 (−7)

triple KO

a

112 (+1) 111 (0)

Reference

male female

Rokosh & Simpson (2002) Rokosh & Simpson (2002) Hosoda et al. (2005) Tanoue et al. (2002) O'Connell et al. (2003) O'Connell et al. (2003) Townsend et al. (2004) Hosoda et al. (2007) Sanbe et al. (2007) Sanbe et al. (2009) White et al. (2013)

male female

104 (−1)

78 (−27)

109 (−9) a 107 (−10) a 83 (−12)

Notes

a

103 (−15)

75 (−37) 88 (−34)

a

a

a a

Rokosh & Simpson (2002) Cavalli et al. (1997) Hosoda et al., 2005 Tanoue et al. (2002) Vecchione et al. (2002) Chu et al. (2004)

Values in parentheses are differences from WT (see Fig. 4). Adenotes baseline BP in KO significantly different from value in WT in same study (P < 0.05). Abbreviations; est, estimate (from graph in quoted paper).

adrenoceptor KO significantly reduced resting blood pressure in 2 from 4 studies, and combined α1A/α1B-adrenoceptor KO failed to affect basal blood pressure in 2 studies (see Table 7); α1B-adrenoceptor KO did not affect resting blood pressure in 2 from 3 studies; but α1D-adrenoceptor knockout significantly reduced resting blood pressure in 3 from 3 studies (Table 7). In conscious invasive recording of blood pressure, there was a decreased blood pressure in one study of α1A-adrenoceptor knockout, no fall in 3 studies of α1B-adrenoceptor KO, and a large fall in 3 studies of α1D-adrenoceptor KO mice (Table 6). The above individual studies confirm an important role for α1D-adrenoceptors, and a possible role for α1A-adrenoceptors in blood pressure control. However, combining tail cuff and conscious invasive studies, plotting the change in BP in KO from that in WT for each study (the mean of the individual means in Table 6), it can be seen that α1A- or α1D-adrenoceptor KO significantly reduced BP, but α1B-adrenoceptor KO had no effect (Fig. 4). There may be limitations to this analysis, but it does seem to confirm that both α1A- and α1D-adrenoceptors are crucial for blood pressure control, but cannot rule out a central component to the response.

effective (Oelke et al., 2013). α1D-Adrenoceptor blockade may improve BPH treatment by inhibiting prostate cell growth in vitro and in vivo (Kojima et al., 2011), so that additional α1D-adrenoceptor antagonism may be useful, particularly in prostatic hyperplasia (Andersson, 2002). Traish et al. (2000) showed that the predominant adrenoceptors in human corpus cavernosum in terms of mRNA expression were α1D- and α2A-adrenoceptors, and contractions of cavernous artery (Hedlund and Andersson, 1985) and penile veins (Recio et al., 2004) may involve both α1-and α2-adrenoceptors. Since α1-adrenoceptors are involved in reduction of penile blood flow, it is not surprising that α1-adrenoceptor antagonists can be used to treat erectile dysfunction, particularly in patients with LUTS (Carson, 2006). 8. Neurotransmission 8.1. Distribution of α1-adrenoceptors on smooth muscle cells In mouse, not all vascular smooth cells express α1A-adrenoceptors, and this is presumably true for other subtypes (Methven et al., 2009). Cells not close to the neuromuscular junctional area are presumably part of a functional syncytium involving transfer of the signal from muscle cell to muscle cell.

7.2. Pathological changes in adrenoceptors A receptor may have limited expression in a tissue, but may still be important if it is the main peri-junctional receptor at the neuro-effector junction, but also, if one considers a dynamic situation in which receptors may be upregulated in pathophysiological conditions. Benign prostatic hypertrophy (BPH) causes problems with micturition, including increased frequency, due to outflow obstruction that has a dynamic component due to α1-adrenoceptor mediated contraction of the bladder neck, prostate and urethra. Knockout of the α1D-adrenoceptor has been shown to decrease voiding frequency but increase volume per void in mice (Chen et al., 2005), and increased expression of α1D-adrenoceptors mediates bladder overactivity with increased voiding frequency in cold stress in rats (Yamagishi et al., 2015). Human bladder also expresses α1D-adrenoceptors (Malloy et al., 1998), and both the expression and function increase due to bladder outlet obstruction, both in rats and humans (Hampel et al., 2002; Barendrecht et al., 2009). There is also evidence that the prostatic expression of α1Dadrenoceptor mRNA may be increased in BPH (Kojima et al., 2011). α-Adrenoceptor antagonists, particularly α1A-adrenoceptor antagonists, are used to control moderate to severe lower urinary tract symptoms (LUTS)/BPH (Oelke et al., 2013), but may not be fully

8.2. Receptors involved in adrenergic neurotransmission The autonomic neuroeffector junction is much less specialized that the somatic neuromuscular junction. The most important adrenoceptors physiologically must be those peri-junctional receptors situated in the neuroeffector junction. Receptors slightly away from nerve terminals are the target for NA spilling over from the junctional region (parajunctional) and those far from nerve terminals are the target for circulating catecholamines (extrajunctional). Plasma levels of NA in man are around 1.0–1.75 nM (Ziegler et al., 1976) or 2 nM (Kotlyar et al., 2017), with adrenaline levels approximately 10 times lower (0.12–0.2 nM: Kotlyar et al., 2017), but levels of NA rise by about 25% during activities such as speaking (Kotlyar et al., 2017). Plasma levels of NA rise with age (Ziegler et al., 1976), but this may be mainly due to diminished activity of the noradrenaline transporter (NET) (Borton and Docherty, 1989). These levels of NA or adrenaline should be sufficient to produce threshold stimulation of α1D-adrenoceptors at all sites. Adrenaline is about 4 times more potent than NA at α1A-adrenoceptors 314

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(Buckner et al., 1996), and plasma levels of adrenaline markedly rise even in handling stress in rats (Bühler et al., 1978). Hence, resting plasma levels of catecholamines, should begin to stimulate α1D-, but higher levels in relatively mild stress should activate α1A-adrenoceptors. However, parajunctional receptors will experience higher concentrations of NA overflowing from the neuro-effector junctions. Sympathetic neurotransmission often involves, in addition to α1adrenoceptors, α2-adrenoceptors or purinergic or other receptors. In rat and mouse vas deferens, the nerve-mediated contraction to a single stimulus has two components: the first purinergic, mediated by a P2X1 purinergic receptor, a ligand-gated cation channel, (see Bültmann et al., 1999); the second is α1D-adrenoceptor mediated, at which NA has high potency, involving T-type Ca2+ channels/calcium stores (Seto et al., 2010). α1A-Adrenoceptors are involved in a slower component especially of responses to trains of pulses that involves Ca2+ entry through L-type channels. α1A-Adrenoceptor KO reduces the maintained contraction to trains of pulses in mouse vas deferens, but even after combined α1A and P2X1 KO, a small portion of the initial spike and later maintained response remains (White et al., 2013) and a α1D-KO reduced responses to low frequency stimulation and low concentrations of NA (Bexis et al., 2008). Studies of knockout mice have given important insights into the importance of various receptors in ejaculation and thus in fertility: α1Aadrenoceptor knockout caused a 50% loss of fertility, triple α1-adrenoceptor knock-out a 92% loss, P2X1-receptor knockout 86% loss (Mulryan et al., 2000), and combined P2X1/α1A-receptor knockout produced 100% loss of fertility (Mulryan et al., 2000; White et al., 2013; Sanbe et al., 2007). These changes were caused by diminished sperm in the ejaculate (Sanbe et al., 2007). The Evidence suggests a major role for α1A-adrenoceptors and a minor role for α1B- and α1Dadrenoceptors in vas deferens function. Many studies suggest that the rat aorta is sparsely innervated (Burnstock et al., 1972; Stassen et al., 1998; Kawamura et al., 1999) and unusually exhibits predominantly α1D-adrenoceptor pharmacology (see Table 5a). Sympathectomy increases the proportion of α1D-adrenoceptors in rat vas deferens (Cleary et al., 2004) and reserpine, which depletes adrenergic neurons of transmitter, increases the proportion of α1D-adrenoceptors and mRNA levels in rat tail artery (Taki et al., 2004; Kamikihara et al., 2005). This may suggest that, in small or densely innervated tissues, nerve activity keeps the α1D-adrenoceptors localized to the junctional region, but in large or poorly innervated vessels such as rat aorta, α1D-adrenoceptors spread out from the junctional region. The alternative view is that in innervated small arteries, the high local concentrations of catecholamines is sufficient to activate the perijunctional α1A-adrenoceptors (Flacco et al., 2013) but large conductance vessels, in which receptors are distant from nerve terminals, may require α1D-adrenoceptors, at which NA has high affinity and potency (Flacco et al., 2013). However, in rat and mouse vas deferens, it is difficult not to think that the α1D-adrenoceptors are perijunctional (see section 8.2, above). Likewise, a component of nerve mediated pressor responses in the pithed rat (Docherty, 2011) and nerve mediated contractions in mouse femoral arteries (Zacharia et al., 2005) involve α1D-adrenoceptors, although the α1A-adrenoceptor predominates. It would seem that the α1Dadrenoceptor, at which NA has high potency, is probably perijunctional, mediates a fast initial response, given that there is no ligandgated receptor for NA, and this is maintained by the slower responding α1A-adrenoceptors. The more numerous α1A-adrenoceptors may be perijunctional and parajunctional.

Fig. 5. Diagrammatical representation of α1-adrenoceptor mediated postreceptor mechanisms involving G protein mediated and non-G protein mediated pathways in smooth muscle. Although all receptor subtypes may activate all pathways, the diagram attempts to suggest major modes of action for α1A- (light blue arrows) and α1D-adrenoceptors (dark blue arrows) as discussed in the text. Abbreviations: Gg/11, G protein Gq/11; MAPK, MAP kinase; MLCK, MLCP, myosin light chain kinase, phosphatase; PKC, protein kinase C; PLC, phospholipase C; TRPC, transient receptor potential channel.

response (Kenakin and Miller, 2010). Different exogenous pharmacological agonists could have different profiles of response simply due to differences in how the binding of the agonist to the receptor affects Gprotein binding (partial agonism) or whether binding of the agonist to the receptor favours G protein, Rho A or β-arrestin binding. This is biased agonism (see Fig. 5). α1-Adrenoceptors are classically coupled to second messenger systems via G-proteins, predominantly to pertussis toxin insensitive Gproteins of the Gq/11 family to phospholipase C (Minneman, 1988; Wu et al., 1992). Activation of the receptor causes binding of the G protein and GDP release. G-protein activation by α1-adrenoceptor subtypes can produce responses via phospholipase C stimulation leading to formation of inositol trisphosphate (IP3) and diacylglycerol (DAG). DAG stimulates protein kinase C and inositol IP3 acts on the IP3 receptor involved in calcium signaling: the net result is increased entry of extracellular Ca2+ and/or release from Ca2+ stores (Minneman, 1988; Wu et al., 1992). On activation, protein kinase C (PKC) locates on the cell membrane, and acts to phosphorylate other proteins. The effects of PKC are cell specific depending on the proteins presented to it (See Fig. 5). α1-Adrenoceptors are also coupled to non-G-protein linked cellular responses: the small GTP binding protein Rho A mediated calcium sensitisation, and β-arrestin-mediated responses include receptor internalization (Kenakin and Miller, 2010). In rat tail artery, α1-adrenoceptor-mediated calcium sensitization is due mainly to the activation of Rho kinase (Mueed et al., 2004), which phosphorylates myosin lightchain phosphatase, causing inhibition of its function and so reducing this inhibitory input (see Somlyo and Somlyo, 2003) (see Fig. 5). βArrestin desensitizes G protein signaling pathways and this targets receptors for internalization and to β-arrestin signaling (Cahill et al., 2017). Rho kinase inhibitors reduce tonic (presumably α1A-adrenoceptor mediated) contractions to NA in rat vas deferens (Amobi et al., 2006), and contractions to methoxamine in particularly immature rat saphenous vein (Mochalov et al., 2018). In contrast, Rho kinase inhibition in pig uterine strips reduced contractions to phenylephrine more in vessels from older animals (Lim et al., 2018). In rat tail artery, Rho kinase inhibitors inhibit prazosin-sensitive nerve-evoked contractions, that given the high potency of prazosin, may be α1D-adrenoceptor mediated (Yeoh and Brock, 2005).

9. Cellular responses mediated by α1-adrenoceptors in smooth muscle Receptor activation/response is not an all-or-none phenomenon, and different agonists can activate different parts of the receptor mediated response and so cause different parts of the second messenger 315

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adrenoceptor usually acts through Ca2+ entry through L-type channels, whereas the α1D-adrenoceptor acts mainly through T-type channels and exhaustible Ca2+ stores (see Fig. 6). α1-Adrenoceptors may also act through second messenger systems leading to Ca2+ sensitization (see Fig. 6). Although a great deal is known about the function of adrenoceptor subtypes, a number of major questions remain to be answered.

• The location and function of α -adrenoceptor subtypes in the neuroeffector junction. The • role of the α -adrenoceptor in relation to the α -adrenoceptor. • The second messenger systems involved in a number of adrenoceptor mediated responses. • The lack of useful selective antagonists for the α -adrenoceptor 1

1D

Fig. 6. Diagram showing a simplified representation of possible major postreceptor mechanisms involving the 3 subtypes of α1-adrenoceptor (from Fig. 5). Although all receptor subtypes may activate all pathways, the diagram attempts to suggest major modes of action for α1A- (light blue arrows) and α1D-adrenoceptors (dark blue arrows) as discussed in the text.

1A

1B

• •

In rat vas deferens, α1A-adrenoceptor mediated contractions largely involve influx of Ca2+ through L-type Ca2+ channels, but the α1Dadrenoceptor mediated component at least partly involves opening of T-type Ca2+ channels (Seto et al., 2010) and may rely on Ca2+ ryanodine-sensitive stores (Burt et al., 1998). Similarly, in guinea-pig vas deferens, there is an early nifedipine resistant T-type Ca2+ channel mediated, and a later L-type Ca2+ channel mediated, α1-adrenoceptor mediated response (Shishido et a., 2009). In human vas deferens, both L-type and T-type Ca2+ channel blockers reduce contractions to NA (Amobi et al., 2010). T-type calcium channel blockers also blocked a component of contractions to α1-adrenoceptor agonists in rat aorta and tail artery (Seto et al., 2010). T-type channel activation by a small degree of depolarisation (Park et al., 2004) will cause rapid entry of calcium and fast contraction, but followed by fast inactivation. Hence, α1A- and α1D-adrenoceptors seem to act via different pathways beyond the level of the G-protein. Biased activation of postreceptor mechanisms, or alternatively cell specific postreceptor environments may explain such differences. It remains to be established whether a specific α1-adrenoceptor acts mainly through Rho A or B-arrestin signaling. The diagram shows a simplified version of possible actions to cause contraction. (Fig. 6).

subtype hinders progress in identifying the physiological role of this receptor and its interaction with other adrenoceptor subtypes. The role of changes in α1-adrenoceptors in pathology of disease. The therapeutic potential of the development of receptor subtype selective agonists and antagonists.

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