Bradykinin and related peptides in central control of the cardiovascular system

Peptides. Vol. 6, Suppl. 2, pp. 57-64, 1985. AnkhoInternationalInc. Printedin the U.S.A.

0196-9781/85 $3.00 + .00

Bradykinin and Related Peptides in Central Control of the Cardiovascular System D E B R A I. D I Z

Section o f Cardiovascular Neurobiology, D e p a r t m e n t o f Cardiovascular Research Cleveland Clinic Foundation, 9500 Euclid A v e n u e , Cleveland, O H 44106

DIZ, D. 1. Bradykinin and related peptides in central control of the cardiovascular system. PEPTIDES 6: Suppl. 2, 57-64, 1985.--The evidence for a brain kallikrein-kinin system and for the possible role for kinins in brain control of the cardiovascular system are reviewed. All components of the kallikrein-kinin system are present in brain and kinins have a variety of cardiovascular actions of central origin following peripheral, intracerebroventricularor brain parenchymal administration. How components of the brain kallikrein-kinin system are regulated or even whether they function as a system remains to be established. However, bradykinin does fulfill several of the criteria necessary for establishing a substance as a neurotransmitter and these are discussed. Bradykinin

Cardiovascular regulation

Kallikrein

Autonomic nervous system

KININS are local tissue hormones that are generated by the actions of kallikreins (more generally termed kininogenases) on the substrate, kininogen [19]. The two most common kinins, bradykinin and kallidin, are formed by the actions of plasma and glandular (renal, salivary) kallikreins, respectively and are depicted in Fig. 1. While the plasma and renal kallikrein-kinin systems are most often discussed (see reviews [1 I, 19, 23, 42, 51]), the observations that all components of a kinin-generating and kinin-metabolizing system are present in the brain strongly suggest that a kallikrein-kinin system endogenus to the brain exists. Since systemic or central administration of bradykinin and related kinins produce cardiovascular effects of central origin, a physiological role for this system in the regulation of cardiovascular function has been proposed. The present paper is a review of the evidence for a brain kallikrein-kinin system and an evaluation of its possible role in cardiovascular regulation.

Brain sites of action

similar to glandular kallikrein [ 12]. Powers and Nasjletti have recently reported the existence of kinin-forming activity in the porcine anterior pituitary [49] and in the anterior and neurointermediate lobes of the rat pituitary [50]. The anterior pituitary enzyme resembles rat plasma kininogenase in some but not all properties. For instance, the preferred substrate of this enzyme is high molecular weight (plasma) kininogen and the primary kinin generated is bradykinin rather than the tissue kinin, kallidin [49]. In contrast, the rat pars intermedia kininogenase resembles glandular (rat urinary) kallikrein which also releases bradykinin from kininogen [50]. In further support for the existence of brain kallikrein, a recent study demonstrated that brain mRNA generates a kallikrein-like immunoreactive substance in a cell free system [12]. However, since kallikrein-like activity has been described in mesenteric vasculature [44], a brain source of kallikrein separate from brain vessels needs to be demonstrated to rule out a vascular rather than neural origin of the kininogenase activity in brain. In addition to kinin-like material and kinin-generating activity in brain tissue, kinin-inactivating activity is also present. Early studies reported bradykinin metabolizing enzymes in rabbit brain [8,28]. Further characterization of the enzymes indicated the presence of both a kininase which inactivates met-lys- and lys-bradykinin as well as bradykinin and an arylamidase (also termed a "kinin converting enzyme") which generates bradykinin from the met-lys and lys- forms [9]. Subsequent studies by several authors revealed a variety of enzyme systems derived from neural tissue sources that are capable of metabolizing kinins [30, 31, 33, 34] including angiotensin converting enzyme or kininase II [64]. The disappearance rate of bradykinin immunoreactivity in brain following intraventricular administration is quite rapid (<30 sec). The half-life of the peptide is prolonged by

EVIDENCE FOR COMPONENTSOF A KININ SYSTEM IN BRAIN All components necessary for the formation and metabolism of bradykinin and other related kinins have been described in brain. As early as 1961, kinin-like substances were reported in brain and spinal cord extracts or brain synaptosomal fractions from carp, bull frog, chicken, rat, guinea pig, rabbit and cattle [28,29]. Several different bioassay tissues as well as paper electrophoresis were used to identify the peptide [28,29]. The presence of kininogen or some other kinin precursor and kinin-forming activity were also reported in these early studies [29,56]. The strongest evidence for a brain kallikrein was recently provided in experiments by Chao et al. in which an immunoaffinity column with a monoclonal antibody against rat urinary kallikrein was used to isolate and purify a brain enzyme with properties

VIhis paper was presented as part of a symposium entitled "Neuropeptides and central cardiovascular control.

57

58

D1Z me t - l y s - b r a d y k i n l n lys-bradykinln -bradykinln

kJninogen

• . . - A r g - I ~ t iLYI .Arg-Pro-Pro-Gly-Phe-ger-Pro~Phe~Arg

.Ser-Val-..•

-plasma k a l l i k r e i n glandular kalJikrein kinlnase muinopeptidases

I

angiotensln I eonverting enzyme ( k i n i n a s e I I )

FIG. 1. Partial amino acid sequence of kininogen indicating cleavage points of plasma and glandular kallikreins (solid lines with arrows) and structures for the common kinin end products bradykinin, lysbradykinin (kallidin) and met-lys-bradykinin. Dotted lines depict cleavage sites for kinin-inactivating enzymes (kininases 1 and II) and aminopeptidases which can convert met-lys and lys-bradykinins to the nonapeptide, or further metabolize bradykinin to inactive forms.

intraventricular pretreatment with the kininase inhibitors o-phenanthroline, SQ 14225 and bradykinin potentiator B, indicating that rapid inactivation is due to the actions of specific kininases [33]. It has been suggested that the relatively high doses of bradykinin (1-5 Ixg) required to produce cardiovascular and other central nervous system effects are a result of the rapid degradation of the peptide by this kininase system in brain. More recently, the immunohistochemical distribution of bradykinin was determined in rat brain• Correa et al. found bradykinin-like immunoreactive fibers in the periaqueductal gray, hypothalamus, perirhinal and cingulate cortices, ventral caudate putamen and the lateral septal area [17]. Cells bodies were found exclusively in the hypothalamus [17]. While the antibodies employed for immunocytochemical mapping studies cross-react significantly (20-50%,) with metlys-bradykinin and kallidin, the presence of one or more forms of kinin in brain is likely. However, despite this and earlier observations of kinins in brain, little evidence has been obtained for release ofkinins from neural tissue in vivo. Recently, Thomas et al. used a ventriculo-cisternal perfusion technique in anesthetized dogs to determine both basal and stimulated release of immunoreactive kinins 161l. Immunoreactive kinin levels in cerebrospinal fluid are 13±3 pg/ml and remain constant over a four hour period of perfusin. Addition to the perfusion solution of melittin, a bee venom component that activates membrane bound kallikrein [43], results in a tenfold elevation of immunoreactive kinins. These data are the first to demonstrate that kinins are indeed produced in brain and released into the cerebrospinal fluid• Exogenously administered kinins are known to have a variety of central effects, therefore, it is surprising that few reports exist on receptor binding of bradykinin in the central nervous system. Receptor binding has only been reported in spinal cord and sensory ganglia [41] and in a neuroblastoma cell line [57]. There are no data available on bradykinin binding in hypothalamic or cortical areas which are reported to contain immunohistochemical evidence for the peptide. The limited advances in this area may reflect problems associated with the rapid degradation of kinin-like peptides (and thus their relative instability in binding preparations) and the lack of suitable receptor antagonists. While the above information indicates that all compo-

nents of the kinin system are present within the central nervous system, to date there is no definitive proof that these components actually function as a system. Given the fact that kallikreins and kininases have been suggested to participate in the formation and metabolism of other peptides in the central nervous system [50], it remains to be established that these components work or exist together in a given brain area to generate kinins exclusively or even preferentially. For instance, kallikrein is reportedly similar to several nerve growth factor-binding proteases and tonin [5,38] and therefore may be involved in activation of other proteins. In addition, kallikrein is found primarily in cortex while kininogen is found primarily in brainstem and cerebellum [56]. Certainly the low kininogen present in cortex may reflect the active utilization of the substrate by kallikrein in this region. However, immunoreactive bradykinin is located primarily in the hypothalamus (cells and fibers) with only a small amount of fibers in the cortex [17] and bradykinin receptors have only been reported in spinal cord and sensory ganglia [41]. Therefore, the information at present suggests that substrate, processing enzyme, product and receptors are not within the same brain region. It will be necessary to demonstrate how these components interact before the concept of a functional brain kinin system is fully established. Another gap in our knowledge of the endogenous brain kallikrein-kinin system concerns the ability to regulate components of the system. Attempts to investigate differences in acUvity of the various components during experimental perturbation or in different physiological situations are few. The limited data available include: (1) kininogen, but not kininase or kinin-forming activity, decreases following convulsions induced by pentylenetetrazol but not strychnine [56]; (2) perfusion of the brain ventricles with artificial cerebrospinal fluid containing melittin results in an increase in kinin levels 1611; and (3) the kallikrein activity in female rat anterior pituitary is 18 times greater than that in male rats [48]. The significance of these independent observations and their relation to regulation of the system especially with respect to cardiowtscular function, remains to be elucidated. CENTRAL

CARDIOVASCULAR ACTIONS OF PERIPHERALLY ADMINISTERED KININS

Peripherally administered, bradykinin is a potent vasodilator and depressor agent [54]. However, high doses of the peptide have been reported to produce both pressor and depressor responses when given intravenously [37, 46, 55], leading early investigators to propose a central action of the peptide. Indeed, a number of central actions tbr systemically administered bradykinin have been demonstrated and are summarized in Table 1. As early as 1960, Rocha e Silva eta[. suggested that systemic bradykinin exhibits central cardiovascular actions since the peptide produced hypotension and respiratory stimulation when injected into the carotid artery of anesthetized cats at a dose that had no effect when given intravenously [55J. Subsequent studies using crosscirculation experiments in dogs and rats [6, 7, 59] or intracarotid injections [4, 10. 37, 45] determined that bradykinin (1-5 ~g) produces biphasic cardiovascular effects. In addition to the cardiovascular effects of bradykinin, profuse salivation, respiratory stimulation and electroencephalographic changes are also observed in anesthetized animals [6, 10, 45, 55]. Several mechanisms have been proposed to contribute to the cardiovascular effects of peripherally administered bradykinin. First, despite early reports that denervation of

BRAIN KININS AND THE CARDIOVASCULAR SYSTEM

59

TABLE 1 CENTRAL ACTIONS OF PERIPHERALLY ADMINISTERED KININ

Response hypotension initial depressor, then pressor

tachypnea changes in EEG increased cerebral blood flow increased salivation

Kinin

Species present

Anesthesia

Dose

Route

Reference

yes yes, no

10 units 0.1-0.5/zg

IC IC

55 4, 6, 10, 46

BK BK,ELE

cat dog

BK,KAL BK BK BK,ELE BK

cat rat dog, cat cat goat

yes yes yes yes no

10/zg 10/xg 10/xg 10/~g 150-750 ng/min

IC IC IC IC IC

37 7,59 6,55 10,45 27

dog

yes

10 ~ g

IC

6

BK

Abbreviations: BK, bradykinin; ELE, eledoisin; KAL, kallidin; [C, intracarotid.

the carotid sinus had no effect on the response [6,551, in other studies carotid sinus denervation was found to enhance the pressor responses to bradykinin [4,37]. Since bradykinin and kallidin both cause a fall in blood pressure by directly stimulating the carotid sinus, the depressor component of the response may be related to this effect [37]. However, the pressor effect is thought to be of central origin unrelated to stimulation of the carotid sinus [37]. In fact, the pressor response to bradykinin and kallidin in anesthetized cats is abolished by hexamethonium and reduced with adrenalectomy, suggesting that central activation of the sympathetic nervous system including the adrenal occurs [37]. Consistent with this finding, Bunag and Takahashi recorded increases in sympathetic (splanchnic) nerve activity during the pressor phase of the response [7,59]. Since responses are strictly depressor following bradykinin injections into the carotid artery of decerebrate or spinal cats a rostral pathway is suggested as necessary Ibr the peptides" effects on sympathetic outflow [37]. Interestingly, central catecholamines are proposed to contribute to the initial depressor phase of the response as intraventricular 6-hydroxydopamine pretreatment abolishes this effect [7,59]. On the other hand, central prostaglandins may be involved in the increased sympathetic nervous activity (pressor phase) since pretreatment with indomethacin by the intraventricular route antagonizes this response [59]. Baertschi et al. described actions of bradykinin on the neurohypophysis suggesting that vasopressin release may occur following peripheral administration of the peptide [2,3]. Whether this release is triggered by the initial fall in blood pressure or is a direct central action was not clearly demonstrated. Finally, since intra-arterial administration of bradykinin has been reported to evoke a pain response, the central cardiovascular effects of bradykinin are suggested to be a result of stimulation of pain receptors [25]. However, Buckley et al. indicated that the central actions of bradykinin were not dependent upon the depth of anesthesia [6]. Subsequent studies by Pearson and Lang [47] demonstrated that aspirin or morphine actually enhance the peak pressor response to intracarotid bradykinin. Thus, the centrally mediated cardiovascular effects produced by systemic administration of bradykinin are not likely to be the result of a pain reflex. The physiological significance of the above central cardiovascular actions of bradykinin given peripherally is not

known at present. While these responses are most likely due to actions of the peptide at blood-brain barrier deficient areas, definitive proof of kinin's actions (or entry into brain) at these sites has not been provided. Circulating bradykinin is rapidly destroyed and thus levels required peripherally to produce central effects may not be attained under normal circumstances. Whether bradykinin participates in the cardiovascular changes that occur in pathophysiological states such as hypertension remains to be determined. CARDIOVASCULAR ACTIONS OF CENTRALLY ADMINISTERED KINiNS

The effects of centrally administered kinins are summarized in Table 2. Intraventricular injections of bradykinin produce cardiovascular effects that are similar to those observed when the peptide is given into the carotid arteries. For example, intraventricular bradykinin produces hypotension of longer duration than that observed following intravenous injections in anesthetized cats [55]. The mechanism responsible for this effect was not determined. Later studies in anesthetized rats or conscious rabbits reported an initial depressor effect followed by a pressor effect, again similar to that seen with intracarotid administration of bradykinin [24,45]. In rats, hexamethonium blocks both phases of the response indicating a central origin of the effects [45]. Phentolamine (intravenous) was found to block the initial depressor component of the response which suggested that withdrawal of sympathetic tone is responsible for the hypotensive actions [45]. Intravenous atropine had no effect in this study [45]. The secondary pressor effects were blocked by intravenous propranolol; thus selective activation of the cardiac sympathetic nerves was considered to be responsible for this component of the response [45]. In contrast to these findings in rats, in rabbits atropine reduced the initial hypotension and bradycardia and enhanced the hypertensive effects suggesting that activation of the vagus occurred during the response to bradykinin in this species [24]. Finally, in conscious rats, the pressor effect predominated [7, 16, 36, 59]; phentolamine blocked this response while propranolol had no effect, contrasting with the above findings in anesthetized rats [45]. Interestingly, increases in blood pressure and heart rate were associated with the increase in cerebrospinal fluid kinins during ventriculocisternal perfusion with melittin in dogs [61]. Collectively,

60

DIZ TABLE 2 ACTIONS OF CENTRALLY ADMINISTEREDKININS

Response hypotension initial depressor, then pressor pressor

Kinin

Anesthesia

Dose

Route

Reference

cat rat

yes yes

10 units 1 /xg

IVT IVT

55 45

rabbit rat

no no

I-5/xg I-5/xg

IVT IVT

rat

yes

0.5/.tg

cat rabbit rat rabbit rat, rabbit

no no yes no no

I ~g 1-5/zg I /zg 1-5 tzg 1-5 gg

lateral septum IVT IVT IVT IVT IVT

24 7, 16, 32, 36, 39, 59 15 10 24 45 24 24, 32, 36

BK BK

rat rabbit

no no

0.5-2/~g I- I0/xg

IVT l VT

53 I

BK

rat

no

I-5 ttg

IVT

26

BK BK,ELE BK,ELE BK,ELE,KAL BK

desynchronized EEG biphasic EEG changes tachypnea behavioral exitation, then sedation antinociception increased rectal temperature antidiuresis

Species present

BK BK BK,ELE BK BK,ELE

Abbreviations: BK, bradykinin; ELE, eledoisin; KAL, kallidin: IVT, intraventricular.

these data clearly show that bradykinin has cardiovascular actions at sites reached by the ventricular route. However, the effects of the peptide appear to differ both with respect to species studied and presence of anesthesia. Therefore, as is true for any cardiovascular study, data obtained in anesthetized animals must be interpreted with caution as the mechanism of action observed under such conditions may reflect characteristics of the anesthetic agent rather than the peptide itself. Several central neurotransmitter systems are proposed to contribute to the pressor response to intraventricular bradykinin. Phentolamine, 6-hydroxydopamine or the antihistamines, pyrilamine and diphenhydramine, injected into the lateral ventricle of rats antagonizes the response [7, 16, 36, 59]. These data suggest that central alpha-adrenergic receptors and brain histamine are involved in the response. Graeff et al. reported a reduction in brain stem norepinephrine after intraventricular bradykinin which further supports an involvement of central noradrenergic systems [24]. Since intraventricular administration of indomethacin also attenuates the pressor action of bradykinin [32, 35, 40], central prostaglandins probably mediate this response as was shown for intracarotid administration of the peptide [59]. In attempts to determine other central neurotransmitter systems involved in the expression of the cardiovascular actions of centrally administered bradykinin, intraventricular capsaicin, propranolol, hexamethonium, or methysergide were found to have no effect on the response [16]. Lesions of the median eminence do not affect the pressor response to the peptide, suggesting that vasopressin is not involved in this effect [26]. On the other hand, the angiotensin II receptor antagonist, saralasin, potentiates the pressor response to bradykinin [40]; the significance of this finding remains to be demonstrated. In contrast to the peripheral pain-evoking effects of the peptide [6,17], intraventricular administration of bradykinin

is reported to have an antinociceptive action similar to that of morphine [53]. However, when morphine is administered peripherally to rats, the pressor responses to intraventricular bradykinin have been reported to be abolished [36] or enhanced [16]. The reason for these discrepancies is not apparent and a pain-reflex involvement in the cardiovascular actions of kinin-like peptides cannot be completely excluded. That bradykinin may have effects on central regulation of fluid balance is also indicated [26]. Intraventricular injections of bradykinin produce antidiuretic effects, indicative of vasopressin release. These actions appear to be separate from the pressor effects of the peptide because lesions of the median eminence block only the antidiuretic actions of bradykinin [26]. From these data, the authors inferred that vasopressin release mediates the antidiuresis but not the pressor response [26]. Since the pressor and thermogenic actions of bradykinin appear to be mediated by central prostaglandin release, it is possible that PGE~ mediates the bradykinin-induced vasopressin release also. In other studies, ventriculo-cisternal perfusion with PGE., has been reported to cause vasopressin release [63]. Few studies have addressed the cellular mechanism through which bradykinin acts to produce its various central nervous system effects. However, bradykinin has been reported to increase both cyclic AMP and cyclic GMP in a number of peripheral tissues [13,58] and may regulate cyclic GMP levels in certain neural cell lines [52,57]. In lung, the increases in cAMP may be secondary to bradykinin-induced prostaglandin relase as it is blocked following indomethacin [58]. Increases in cyclic GMP are not affected by indomethacin and are therefore considered to be a direct effect of bradykinin [58]. Whether these findings will hold true for brain tissue is not known. The similarities in cardiovascular responses between intracarotid and intraventricular injections of bradykinin suggest that common brain areas mediate the actions of the

BRAIN KININS AND THE CARDIOVASCULAR

SYSTEM

61

TABLE 3 C A R D I O V A S C U L A R E F F E C T S O F I N T R A H Y P O T H A L A M I C A N D PREOPTIC I N J E C T I O N S O F 5 N M O L B R A D Y K I N I N IN H A L O T H A N E A N E S T H E T I Z E D RATS

Blood Pressure (mm Hg)

Heart Rate (beats/min)

N

Pre-injection

Maximal Change

Pre-injection

Maximal Change

8

85 _+ 3

5 +- 3

345 _+ 18

50 +- lOt

10

86_+ 1

2 +- 2

348_+ 7

34 +- 7+

4

87 _+ I

7 + 2*

354 +- 7

47_+ 6t

8

8 8 -+ 1

0 _+ 1

338--

6

87-+2

2 _+ 1

340 +_ 13

8_+ 5

5

87 ± 3

- 4 +- 4

355 -+ 12

-18 + 9

8

91 _+ 2

2 +- 2

355 +- 15

-41 +- 9t

18

89-+ 1

10 +- 2t

346 + 8

57 + 5t

4

86 _+ 2

5 +- 1"

355 + 14

30 ÷ 8*

8

91 -+ 3

7 +- 2*

344 +- 8

39 +- 7t

pos

(A7250-7000 pom (A6900-6401 nha (A6400-6001 nha (A6000-5801 nha (A5800-5601 nha (A5600-5200 npv (A5600-5200 ndm (A5100-4000

6

- 1 8 _+ 4t

nvm

(A5340-4100 nhp (A3900-3300

Pre-injection values were obtained 1 min prior to 100-300 nl injections of 5 nmol bradykinin and were similar for all groups. A difference in heart rate responses when two adjacent 200/xm sections were compared provided the basis for subdivisions of anatomical nuclei (one way analysis of variance and Duncan's Multiple Range tests). Abbreviations: ndm, nucleus dorsomedialis; nha, nucleus hypothalamicus anterior; nhp, nucleus hypothalamicus posterior; npv, nucleus paraventricularis: nvm, nucleus ventromedialis hypothalamicus; pom, nucleus preopticus medialis; pos, nucleus preopticus suprachiasmaticus. N--Number of animals injected. *Denotes p<0.05 and tp<0.01 when pre- and post-injection values at each site are compared (paired t-tests). (Reprinted with modifications from Diz et al. Br Re s Bull 12: 409-417, 1984, with permission from Ankho International, Inc.)

peptide by either route, h o w e v e r this c o n c e p t has not been evaluated. Precise brain sites responsive to bradykinin have been identified. In 1975, C o r r e a and G r a e f f reported that bradykinin (0.5 ~g) p r o d u c e s hypertensive responses without affecting heart rate w h e n injected into the pars ventralis of the lateral septal area [15]. Lesions of the lateral septal area abolish the actions o f intraventricular bradykinin and therefore, this nucleus was suggested as the site mediating the central responses to the peptide. Specificity of action was d e m o n s t r a t e d for bradykinin since Des-argg-bradykinin and substance P have no effect at this same site. Intraseptal injection of the a l p h a - r e c e p t o r antagonist p h e n t o l a m i n e blocks or e v e n reverses the pressor effects of intraseptal bradykinin [14]. P r e t r e a t m e n t with the antihistamine pyrilamine has no effect. T h e s e data led the authors to conclude that alpha-adrenergic m e c h a n i s m s are responsible for the bradykinin-induced r e s p o n s e in the lateral septal area, a finding consistent with earlier o b s e r v a t i o n s on the r e s p o n s e s to intraventricular and intracarotid bradykinin [16, 36, 59]. While further support for an action o f bradykinin in the lateral septal area was p r o v i d e d by the subsequent d e m o n -

stration that n e r v e fibers containing bradykinin-like imm u n o r e a c t i v i t y are present in this region [17], a more recent study using cold c r e a m plugs to restrict access of the peptide to certain periventricular sites suggested a site of action for the peptide within the third ventricle [39]. In addition, the p r e s e n c e of bradykinin-like i m m u n o r e a c t i v i t y throughout the hypothalamus [17] suggested that actions of the peptide may o c c u r at sites not reached by the intraventricular route. Indeed, a variety of c a r d i o v a s c u l a r effects are p r o d u c e d by microinjections of bradykinin depending upon the particular injection site within the hypothalamus and preoptic area [ 18]. T h e s e data are summarized in Table 3. Additional studies using pharmacological or surgical interruption o f the sympathetic or parasympathetic n e r v o u s systems suggest that the m e c h a n i s m of action for bradykinin's responses differs with respect to the particular nucleus. F o r example, the increase in blood pressure and heart rate o b s e r v e d with injections of the peptide (1-5/~g) into the posterior and dorsomedial hypothalamic nuclei primarily occurs through inhibition of the p a r a s y m p a t h e t i c n e r v o u s system [18]. In contrast, bradycardia occurring following bradykinin injection into the

62

DIZ

paraventricular nucleus is due to activation of the vagus [18]. The increase in heart rate produced by bradykinin in the anterior hypothaIamic and medial preoptic nuclei appears to be due to activation of cardiac sympathetic nerves [18]. In the preoptic suprachiasmatic nucleus, inhibition of the parasympathetic nervous system and adrenal catecholamine release both contribute to the increase in heart rate observed [18]. These data suggest that the cardiovascular actions of bradykinin can be quite complex depending upon the precise brain region studied. Further investigations on the anatomical connections between bradykinin neurons and other neurotransmitter pathways may help clarify the possible physiological role of the peptide at each site. Again, it is important to recognize that the cardiovascular actions of bradykinin at these tissue sites may be mediated by the release of central prostaglandins. Prostaglandins are known to be released from neural tissue [62] and prostaglandins E~, F.2, and I~ have been reported to have different effects on heart rate and blood pressure depending upon the area of injection within the hypothalamus [20-22]. Bradykinin-induced prostaglandin release in the periphery is tissue-specific (i.e., arteries release PGE.., and veins release PGF~,0, a finding which accounts for some of the peptides' diverse peripheral physiological actions [60]. If this is also true in brain tissue, it may account for some of the diverse actions of bradykinin in different brain sites. Therefore, interactions between the central prostaglandin and kinin systems may be as important to blood pressure regulation as those in the periphery. SUMMARY Evidence supports the concept of a kinin-generating system in brain and an activation of this system which results in increases in cerebrospinal fluid kinins is associated with increases in blood pressure. While intraventricular injections of kinins most often produce biphasic cardiovascular effects, injection of bradykinin into certain nuclei of the hypothalamic, preoptic or septal area results in very site specific cardiovascular responses. Whether the complexity of actions demonstrated by microinjection studies represents physiological or pharmacological actions of the peptide is not known and definitive studies will await the availability of a specific receptor antagonist. Kinin-like immunoreactive nerve fibers and/or cell bodies have been localized in brain

areas responding to bradykinin, however, it remains to be established that receptor binding sites showing high affinity and specificity for bradykinin exist in these or additional locations. The mechanisms responsible for the cardiovascular effects of centrally administered bradykinin appear to depend upon the site of administration and may include inhibition or activation of the parasympathetic nervous system or activation of the sympathetic nervous system selectively or generally. Bradykinin's actions may be direct or due to the release of other central neurotransmitters or neuromodulators. Certainly the central alpha-adrenergic and prostaglandin systems have been demonstrated to mediate some of the actions of bradykinin. Finally, the specific anatomical pathways involved in the response to bradykinin have not been defined, although numerous connections between the responsive areas and autonomic pathways involved in blood pressure control are well known. In conclusion, information derived from the experimental studies presented in this review clearly indicates that kinins have an influence on central cardiovascular regulation lollowing exogenous administration of kinins or pharmacological activation of the endogenous system. Whether these peptides exert a tonic influence on blood pressure control is not known and further studies utilizing selective bradykinin antagonists are necessary to determine the role of brain kinins in physiological and pathophysiological states. However, several of the criteria necessary for establishing a substance as a neurotransmitter have been fulfilled. First, kinins and their generating and inactivating enzymes have been found in brain tissue by biochemical, immunological and molecular biological techniques. Second, kinins have been demonstrated to be released into the brain ventricular system as a result of a pharmacological stimulus. Third, kinins have been shown to have a variety of actions in the central nervous system following peripheral, ventricular or brain parenchymal injection. It remains to be established that high affinity binding-sites, characteristic of specific bradykinin reception, are present in brain and that electrical stimulation of certain kinin pathways actually releases kinins to produce a response. These studies have been hampered by the lack of stable bradykinin agonists and specific receptor antagonist analogs. Further insights into the physiology and pharmacology of brain, or peripheral, kinin systems awaits the development of such tools.

REFERENCES

1. Almeida e Silva, T. C. and 1. R. Pela. Changes in rectal temperature of the rabbit by intracerebroventricular injection of bradykinin and related kinins. A g e n t s Act 8: 102-107, 1978. 2. Baertschi, A. J. and J. J. Dreifuss. Antidromic compound potentials of the pituitary tract: interactions with systemic bradykinin. Brain Res 149: 530-534, 1978. 3. Baertschi, A. J., H. H. Zingg and J. J. Dreifuss. Enkephalins, substance P, bradykinin and angiotensin ll: differential sites of action on the hypothalamo-neurohypophysial system. Brain Re~ 220: 107-119, 1981. 4. Benetato, G., 1. Haulica, I. Muscalu, E. Butuianu and S. Galesanu. On the central nervous action of bradykinin. Rev R o u m Physiol l: 313-322, 1964. 5. Bothwell, M. A., W. H. Wilson and E. M. Shorter. The relationship between glandular kallikrein and growth factorprocessing proteases of the mouse submaxillary gland..I Biol C h e m 254: 7287-7294, 1979.

6. Buckley, J. P., R. K. Bickerton, R. P. Halliday and H. Kato. Central effects of peptides on the cardiovascular system. Ann N Y A e a d Sei 104: 299-311, 1963. 7. Bunag, R. D. and H. Takahashi. Exaggerated sympathetic responses to bradykinin in spontaneously hypertensive rats. ttypertension 3: 433-440, 1981. 8. Camargo, A. C. M. and F. G. Graeff. Subcellular distribution and properties of the bradykinin inactivation system in rabbit brain homogenates. Bioehem P h a r m a e o l 18: 548-549, 1969. 9. Camargo, A. C. M., F. J. Ramalho-Pinto and L. J. Greene. Brain peptidases: Conversion and inactivation of kinin hor mones. J Nettroehem 19: 37-49, 1972. 10. Capek, R., A. P. Corrado, S. H. Ferreira and M. Rocha e Silva. The effects of bradykinin on the electroencephalogram. Act N e r v Super 8: 41%420, 1966. II. Carretero, O. A. and A. G. Scicli. The renal kallikrein-kinin system. A m J Phvsiol 238: F247-255, 1980.

BRAIN KININS AND THE CARDIOVASCULAR SYSTEM

12. Chao, J., C. Woodley, L. Chao and H. S. Margolius. Identification of tissue kallikrein in brain and in the cell-free translation product encoded by brain mRNA. J Biol Chem 258: 1517315178, 1983. 13. Clyman, R. 1., A. S. Blacksin, J. A. Sandier, V. C. Manganiello and M. Vaughan. The role of calcium in regulation of cyclic nucleotide content in human umbilical artery. J Biol Chem 250: 4718-4721, 1975. 14. Correa, F. M. A. and F. G. Graeff. On the mechanism of the hypertensive action of intraseptal bradykinin in the rat. Neuropharmacology 15:713-717, 1976. 15. Correa, F. M. A. and F. G. Graeff. Central site of the hypertensive action of bradykinin. J Pharmacol Exp Ther 192: 670-676, 1975.

16. Correa, F. M. A. and F. G. Graeff. Central mechanisms of the hypertensive action of intraventricular bradykinin in the unanesthetized rat. Neuropharmacology 13: 65-75, 1974. 17. Correa, F. M. A., R. B. lnnis, G. R. Uhl and S. H. Snyder. Bradykinin-like immunoreactive neuronal systems localized histochemically in rat brain. Proe Natl Acad Sci USA 76: 1489-1493, 1979. 18. Diz, D. 1. and D. M. Jacobowitz. Cardiovascular effects of discrete intrahypothalamic and preoptic injections of bradykinin. Brain Res Bull 12: 409-417, 1984. 19. Erdos, E. G. The kinins: A status report. Bioche,1 Pharmacol 25: 1563-1569, 1976. 20. Feuerslein, G., S. A. Adelberg, I. J. Kopin and D. M. Jacobowitz. Central cardiovascular effects of prostacyclin. Neuropllarmacoh~,y 20: 1085-1090, 1981. 21. Feuerstein, G., S. A. Adelberg. I. J. Kopin and D. M. Jacobowitz. Hypothalamic sites for cardiovascular and sympathetic modulation by prostaglandin E.,. Brain Res 231: 335-342. 1982. 22. Feuerstein, G., C. M. Helke, R. L. Zerbe, D. M. Jacobowilz and 1. J. Kopin. Mechanisms involved in central cardiovascular effects of prostaglandin Fz,~. Am J Phvsiol 242: R545-R551, 1982. 23. Fiedler, F. Enzymology of glandular kallikreins. In: Handbook ~/E.vperinlentttl Pharmacolo~,,y. vol 25, Suppl, edited by E. G. Erdos. Berlin: Springer-Verlag, 1979, pp. 103-161. 24. Graeff, F. G., 1. R. Pela and M. Rocha e Silva. Behavioral and somatic effects of bradykinin injected into the cerebral ventricles of unanesthetized rabbils. Br J Pharmacol 37: 723-732, 1969. 25. Guzman, F., C. Braun and R. A. S. Lira. Visceral pain and the pseudoaffective response to intraarterial injection of bradykinin and other algesic agents. Arch lnt Pharmacodyn Ther 136: 353384, 1962. 26. Hoffman, W. E. and P. G. Schmid. Separation of pressor and antidiuretic effects of intraventricular bradykinin. Neuropharmaeolo~,y 17: 999-1002, 1978. 27. Hoflman. W. E., D. J. Miletich, P. H. Volkman and R. F. Albrecht. Cerebrovascular and metabolic effects of bradykinin, ATP and hypercapnia in the goat. Clin IL~p Pharmacol Phvsiol 10: 115-124, 1983. 28. Hori, S. Zetler's satellite polypeptides of substance P in subcellular particles of bovine peripheral nerves. Jpn J Physiol 18: 746-77 I, 1968. 29. lnouye, A., K. Kataoka and T. Tsujioka. On a kinin-like substance in the nervous tissue extracts treated with trypsin. Jpn J Physiol 11: 319--324, 1961. 30. Iwata, H., T. Shikimi and T. Oka. Pharmacological significances of peptide and proteinase in the brain (Report I). Enzymatic inactivation of bradykinin in the rat brain. Biochem Pharmacol 18: 119-128, 1969. 31. Kariya, K.. R. Kawauchi and H. Okamoto. Regional distribution of kininase in rat brain. J Neurochem 36: 2086-2088, 1981. 32. Kariya, K., A. Yamauchi and Y. Chatani. Relationship between central actions of bradykinin and prostaglandins in the conscious rat. Neuropharmacology 21: 267-272, 1982.

63

33. Kariya, K., A. Yamauchi, S. Hattori, Y. Tsuda and Y. Okada. The disappearance rate of intraventricular bradykinin in the brain of the conscious rat. Biochem Biophys Res Commun 107: 1461-1466, 1982. 34. Kariya, K., H. lwaki, A. Yamauchi, M. Okamoto, Y. Tsuda and Y. Okada. Central action of bradykinin (II). Separation of bradykinin degrading enzymes from the rat brain. Jpn ,! Pharmacol 31: 613-619, 1981. 35. Kondo, K., T. Okuno, K. Konishi, T. Sawta and E. Kato. Central and peripheral effects of bradykinin and prostaglandin E2 on blood pressure in conscious rats. Naunyn Schmiedebergs Arch Pharmacol 308:111-115, 1979. 36. Lambert, G. A. and W. J. Lang. The effects of bradykinin and eledoisin injected into the cerebral ventricles of conscious rats. Eur J Pharmacol 9: 383-386, 1970. 37. Lang, W. J. and L. Pearson. Studies on the pressor responses produced by bradykinin and kallidin. Br J Pharmacol Chemother 32: 330-338~ 1968. 38. Lazure, C., N. G. Seidah, G. Thibault, R. Boucher, J. Genest and M. Chretien. Sequence homologies between tonin, nerve growth factor c~ subunit, epidermal growth factor-binding protein and serine proteases. Nature 292: 383-384, 1981. 39. Lewis, R. E. and M. 1. Phillips. Localization of the central pressor action of bradykinin to the cerebral third ventricle. Am J Physiol 247: R63-R68~ 1984. 40. Lewis, R. E., W. E. Hoffman and M. 1. Phillips. Angiotensin II and bradykinin: interaction between two centrally active peptides. Am J Physiol 244: R285-R291, 1983. 41. Manning, D. C. and S. H. Snyder. :~H-Bradykinin receptor localization in spinal cord and sensory ganglia-evidence for a role in primary afferent function. Soc Neurosci Abstr 9: 590, 1983, 42. Nasjletti, A. and K. U. Malik. Relationships between the kallikrein-kinin and prostaglandin systems. Lift, Sci 25:99-110, 1979. 43. Nishimura, K., F. Alhenc-Gelas, A. White and E. G. Erdos. Activation of a membrane-bound kallikrein and renin in the kidney. Proc Ntttl Acad Sci USA 77: 4975-4978, 1980. 44. Nolly, H. and M. C. Lama. "Vascular kallikrein': a kallikreinlike enzyme present in vascular tissue of the rat. Clin Sci 63: 249s-251 s, 1982. 45. Pearson, L., G. A. Lambert and W. J. Lang. Centrally mediated cardiovascular and EEG responses to bradykinin and eledoisin. Eur J Pharmacol 8: 153-158, 1%9. 46. Pearson, L. and W. J. Lang. A comparison in conscious and anaesthetized dogs of the effect on blood pressures of bradykinin, kallidin, eledoisin and kallikrein. EurJ Pharmacol 2: 83-87, 1967. 47. Pearson, L. and W. J. Lang. Effect of acetylsalicylic acid and morphine on pressor responses produced by bradykinin. Eur J Pharmacol 6: 17-23, 1969. 48. Powers, C. A. and A. Nasjletti. A major sex difference in kallikrein-like activity in the rat anterior pituitary. Endocrinology !i4: 1841-1844, 1984. 49. Powers, C. A. and A. Nasjletti. A novel kinin-generating protease (kininogenase) in the porcine anterior pituitary. J Biol Chem 257: 5594-5600, 1982. 50. Powers, C. A. and A. Nasjletti. A kininogenase resembling glandular kallikrein in the rat pituitary pars intermedia. Endocrinolo~,y 112:1194--1200, 1983. 51. Regoli, D. and J. Barabe. Pharmacology of bradykinin and related kinins. Pharmacol Rev 32: 1-46, 1980. 52. Reiser, G., U. Walter and B. Hamprecht. Bradykinin regulates the level of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in neural cell lines. Brain Res 290: 369-371, 1984. 53. Ribeiro, S. A., A. P. Corrado and F. G. Graeff. Antinociceptive action of intraventricular bradykinin. Neuropharmacology 10: 725-731, 1971. 54. Rocha e Silva, M., W. T. Beraldo and G. Rosenfeld. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am J Physiol 156: 261-273, 1949. -

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55. Rocha e Silva, M., A. P. Corrado and A. O. Ramos. Potentiation of duration of the vasodilator effect of bradykinin by sympatholytic drugs and by reserpine. J Pharmacol Exp Ther 128: 217-226, 1960. 56. Shikimi, T., R. Kima, M. Matsumoto, Y. Hamahata and S. Miyata. Studies on kinin-like substances in brain. Biochem Pharmacol 22: 567-573, 1973. 57. Snider, R. M. and E. Richelson. Bradykinin receptor binding and biological activity in murine neuroblastoma clone NIE-115 cells. Sot: Neurosci Abstr 9: 172, 1983. 58. Stoner, J., V. C. Manganiello and M. Vaughan. Effects of bradykinin and indomethacin on cyclic GMP and cyclic AMP in lung slices. Proc Natl Acad Sci USA 70: 3830-3833, 1973. 59. Takahashi, H. and R. D. Bunag. Centrally induced cardiovascular and sympathetic nerve response to bradykinin in rats. J Pharmacol Exp Ther 216: 192-197, 1981.

DIZ

60. Terragno, D. A., K. Crowshaw, N. A. Terragno and J. C. McGiff. Prostaglandin synthesis by bovine mesenteric arteries and veins. Circ Res 36: Suppl 1, 1-76-I-80, 1975. 61. Thomas, G. R., H. Thibodeaux, H. S. Margolius and P. J. Privitera. Cerebrospinal fluid kinins and cardiovascular function. Effects of cerebroventricular melittin. Hypertension 6: Suppl 1, 1-46-1-50, 1984. 62. Wolfe, L. S., K. Rostworowski and H. M. Pappius. The endogenous biosynthesis of prostaglandins by brain tissues in vitro. Can J Biochem 54" 62%640, 1975. 63. Yamamoto, M., L. Shane and R. E. Shade. Vasopressin release during ventriculocisternal perfusion with prostaglandin E~ in the dog. J Endocrinol 71" 325-331, 1976. 64. Yang, H. Y. T. and N. H. Neff. Distribution and properties of angiotensin converting enzyme of rat brain. J Neurochem 19" 2443-2450, 1972.