Degradation of Atrial Natriuretic Peptide

Rl, Webb; Gd, Yasay; McMartin, Colin; Rb, McNeal; Mb, Zimmerman

doi:10.1097/00005344-198908000-00015

Cited by 44 publications

(7 citation statements)

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“…A clear distinction between the ®rst and the second phase of the hypotensive response to adenosine was supported by the drastic bradycardic activity that was contemporaneous with the second phase. A hypotensive response closely linked to an action of adenosine at the cardiac level has been already reported in the rat (Webb et al (1990)). A variety of evidence demonstrates the presence of adenosinic receptors responsible both for the negative chronotropic and the inotropic and dromotropic e ects on cardiac function; they are mostly described as belonging to the A1 subtype in experiments in di erent mammals including humans (Belardinelli et al, 1989;Pelleg & Belardinelli, 1993;Olsson & Pearson, 1990; Linden, 1991); these receptors represent the basis for the therapeutic use of adenosine in the treatment of supraventricular tachycardia, and for the use of adenosine receptor antagonists in the treatment of bradyarrhythmias (Ralevic & Burnstock, 1998).…”

Section: Discussionmentioning

confidence: 69%

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Nieri¹,

Martinotti²,

Calderone³

et al. 2001

British J Pharmacology

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1 Adenosine produced a biphasic lowering of the mean BP with a drastic bradycardic e ect at the highest doses. The ®rst phase hypotensive response was signi®cantly reduced by the nitric oxide (NO) synthase inhibitor L-NAME. 2 The A 2a /A 2b agonist NECA produced hypotensive and bradycardic responses similar to those elicited by adenosine, which were not signi®cantly modi®ed by the A 2b antagonist enprofylline. 3 The A 2a agonist CGS 21680 did not signi®cantly in¯uence basal HR while induced a hypotensive response antagonized by the A 2a selective antagonist ZM 241385, and reduced by both L-NAME and the guanylate cyclase inhibitor methylene blue. 4 The A 1 agonist R-PIA showed a dose-dependent decrease in BP with a drastic decrease in HR at the highest doses. The A 1 selective antagonist DPCPX signi®cantly reduced the bradycardic activity and also the hypotensive responses obtained with the lowest doses while it increased those obtained with the highest ones. 5 The A 1 /A 3 agonist APNEA, in the presence of the xanthinic non-selective antagonist 8-pSPT, maintained a signi®cant hypotensive, but not bradycardic, activity, not abolished by the histamine antagonist diphenhydramine. 6 The selective A 3 agonist IB-MECA revealed a weak hypotensive and bradycardic e ect, but only at the highest doses. 7 In conclusion, in the systemic cardiovascular response to adenosine two major components may be relevant: an A 2a -and NO-mediated hypotension, and a bradycardic e ect with a consequent hypotension, via atypical A 1 receptors. Finally, an 8-pSPT-resistant hypotensive response not attributable to A 3 receptor-stimulation or to release of histamine by mastocytes or other immune cells was observed. IntroductionFour classes of membrane surface adenosine receptors are described, de®ned A 1 , A 2a , A 2b and A 3 , through which the nucleoside in¯uences many functions in humans and other animals (Ralevic & Burnstock, 1998). As far as the cardiovascular system is concerned, adenosine slows heart rate (HR) and atrioventricular conduction and antagonizes the cardio-stimulatory e ects of catecholamines via cardiac A 1 receptors in di erent mammals (Belardinelli et al., 1989;Olsson & Pearson, 1990). An increase in blood pressure (BP) and HR has been described in rats and in cats via central A 1 receptors (St Lambert et al., 1994; SilvaCarvalho et al., 1993). In contrast, a dose-related decrease in BP and HR is observed after microinjection of adenosine into the caudal nucleus of tractus solitarii in the rat (Lo et al., 1998).As regards a direct e ect on blood vessels, A 1 purinoceptors mediate vasodilation in the porcine coronary artery (Merkel et al., 1992) but they are involved, on the contrary, in vasoconstrictor responses, i.e. in the rat kidney (Jackson, 1991), in guinea-pig pulmonary artery and aorta (Biaggioni et al., 1989;Stoggall & Shaw, 1990) and in hamster skin (Stojanov & Proctor, 1990;Proctor & Stojanov, 1991).Moreover, a signi®cant role of A 1 receptors in the regulation of BP also appears to be linked to a prejunction...

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Section: Discussionmentioning

confidence: 69%

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Nieri¹,

Martinotti²,

Calderone³

et al. 2001

British J Pharmacology

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“…These results indicate that the interaction between sialorphin and renal membrane-anchored NEP shown by tissue uptake in vivo could lead to a physiological action, such as the protection of regulatory peptides from breakdown by NEP. The kidney, which contains the highest NEP activity, seems also to be a major site of atrial natriuretic peptide (ANP) metabolism (23). And, as several peripheral effects of circulating ANP are regulated mainly by NEP ectopeptidase, we postulate that sialorphin may help potentiate the physiological actions of ANP at periphery, especially at the renal site (23,24).…”

Section: Resultsmentioning

confidence: 99%

Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity

Rougeot

Messaoudi

Hermitte

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Sialorphin is an exocrine and endocrine signaling mediator, which has been identified by a genomic approach. It is synthesized predominantly in the submandibular gland and prostate of adult rats in response to androgen steroids and is released locally and systemically in response to stress. We now demonstrate that the cell surface molecule to which sialorphin binds in vivo in the rat kidney is the membrane-anchored neutral endopeptidase (neprilysin; NEP, EC 3.4.24.11). NEP plays an important role in nervous and peripheral tissues, as it turns off several peptide-signaling events at the cell surface. We show that sialorphin prevents spinal and renal NEP from breaking down its two physiologically relevant substrates, substance P and Met-enkephalin in vitro. Sialorphin inhibited the breakdown of substance P with an IC50 of 0.4 -1 M and behaved as a competitive inhibitor. In vivo, i.v. sialorphin elicited potent antinociceptive responses in two behavioral rat models of injury-induced acute and tonic pain, the pin-pain test and formalin test. The analgesia induced by 100 -200 g͞kg doses of sialorphin required the activation of -and ␦-opioid receptors, consistent with the involvement of endogenous opioid receptors in enkephalinergic transmission. We conclude that sialorphin protects endogenous enkephalins released after nociceptive stimuli by inhibiting NEP in vivo. Sialorphin is a natural systemically active regulator of NEP activity. Furthermore, our study provides evidence that it is a physiological modulator of pain perception after injury and might be the progenitor of a new class of therapeutic molecules.

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“…Stimulation of the A2,4 receptor by adenosine induces coronary and peripheral vasodilatation (Kusachi et al, 1983;Webb et al, 1990), while the Al receptor mediates cardiac depression (Olsson & Pearson, 1990). During the past few years selective and potent agonists and antagonists have been described for both receptor subtypes (Jacobson et al, 1992;Shimada et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic modelling of the haemodynamic effects of the A_2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

Mathôt

Cleton

Soudijn

et al. 1995

British J Pharmacology

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1 The aim of the present investigation was to determine the relationship between the blood concentration and haemodynamic effects of the adenosine Au receptor agonist, CGS 21680C (the sodium salt of 2-p-(2-carboxyethyl)phenylethylamino-5'-N-ethylcarboxamidoadenosine) in conscious normotensive rats.2 Chronically cannulated rats were randomly assigned to three groups which received 300, 1000 or 3000 jLg kg-' (0.56, 1.9 or 5.6 pmol kg-') of CGS 21680C intravenously over 15 min. The mean arterial blood pressure (MAP) and heart rate (HR) were monitored continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentration. The ratio MAP/HR was also calculated, which may reflect changes in total peripheral resistance on the assumption that no changes in stroke volume occur. 3 For each individual rat the reduction in mean arterial pressure was related to the blood concentration according to the sigmoidal E. model. The concentration-effect relationships were consistent for the different treatment groups. The potency based on free drug concentrations (ECm,u) was 5.8 ng ml' (11 nM) (mean ± s.e.; n = 19) and correlated well with the reported adenosine Au4 receptor affinity (Ki 19 nM). In comparison with the reduction in blood pressure, CGS 21680C exhibited a greater potency for the reduction of the ratio MAP/HR. 4 It is concluded that estimates can be obtained for the potency and intrinsic activity of adenosine Au receptor agonists in vivo by pharmacokinetic-pharmacodynamic analysis of mean arterial pressure data in a rat model. In future studies, total peripheral resistance may also be useful as a pharmacodynamic parameter for A,4 activation, provided that possible changes of the stroke volume are also assessed.

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Degradation of Atrial Natriuretic Peptide

Cited by 44 publications

References 0 publications

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity

Pharmacokinetic modelling of the haemodynamic effects of the A_2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

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Degradation of Atrial Natriuretic Peptide

Cited by 44 publications

References 0 publications

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity

Pharmacokinetic modelling of the haemodynamic effects of the A2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

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Pharmacokinetic modelling of the haemodynamic effects of the A_2a adenosine receptor agonist CGS 21680C in conscious normotensive rats