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The renin-angiotensin system (RAS) generates, maintains, and makes worse hypertension and cardiovascular diseases (CVDs) through its biologically active component angiotensin II (Ang II), that causes vasoconstriction, sodium retention, and structural alterations of the heart and the arteries. A few endogenous vasodilators, kinins, natriuretic peptides, and possibly angiotensin (1-7), exert opposite actions and may provide useful therapeutic agents. As endothelial autacoids, the kinins are potent vasodilators, active natriuretics, and protectors of the endothelium. Indeed, the kallikrein-kinin system (KKS) is considered the dominant mechanism for counteracting the detrimental effects of the hyperactive RAS. The 2 systems, RAS and KKS, are controlled by the angiotensin-converting enzyme (ACE) that generates Ang II and inactivates the kinins. Inhibitors of ACE can reduce the impact of Ang II and potentiate the kinins, thus contributing to restore the cardiovascular homeostasis. In the last 20 years, ACE-inhibitors (ACE-Is) have become the drugs of first choice for the treatments of the major CVDs. ACE-Is not only reduce blood pressure, as sartans also do, but by protecting and potentiating the kinins, they can reduce morbidity and mortality and improve the quality of life for patients with CVDs. This paper provides a brief review of the literature on this topic. Key words: cardiovascular diseases, kinins, angiotensins, natriuretic peptides, angiotensin-converting enzyme inhibitors. Le systeme renine-angiotensine (SRA) engendre, maintient et aggrave l'hypertension et les maladies cardiovasculaires (MCV) par l'angiotensine II (Ang II), sa composante biologiquement active, qui cause une vasoconstriction, une retention sodique et des modifications structurelles du creur et des arteres. Quelques substances vasodilatatrices, les kinines, les peptides natriuretiques et peut-etre l'angiotensine (1-7), exercent des actions opposees et pourraient permettre d'obtenir des agents therapeutiques utiles. En tant qu'autacoides endotheliaux, les kinines sont des vasodilatateurs puissants, actifs sur le plan de la natriurese et protecteurs de l'endothelium. De fait, on considere que le systeme kallicreine-kinines (SKK) correspond au mecanisme qui domine l'antagonisme du SRA hyperactif dans ses effets deleteres. Le SRA et le SKK sont tous deux sous l'emprise de l'enzyme de conversion de l'angiotensine (ECA), qui entraine la production d'Ang II et l'inactivation des kinines. Les inhibiteurs de l'ECA (IECA) peuvent attenuer les effets de l'Ang II et potentialiser ceux des kinines, ce qui contribue a retablir l'homeostasie cardiovasculaire. Au cours des 20 dernieres annees, les IECA sont devenus les medicaments de premier choix dans le traitement des MCV majeures. En plus d'entrainer, tout comme les sartans, une diminution de la tension arterielle en protegeant et en potentialisant les effets des kinines, les IECA peuvent entrainer une reduction des taux de morbidite et de mortalite, ainsi qu'ameliorer la qualite de vie des patients atteints de MCV. Cet article offre une breve synthese de la litterature portant sur le sujet. [Traduit par la Redaction] Mots-cles: maladies cardiovasculaires, kinines, angiotensines, peptides natriuretiques, inhibiteurs de l'enzyme de conversion de l'angiotensine., Introduction For years, the experts of cardiovascular diseases (CVDs) have focussed on the detrimental roles of the renin-angiotensin system (RAS) and have neglected the protective and beneficial functions of the [...]

We have shown that the tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibited endothelin-1 (ET-1)-induced cell proliferation and collagen synthesis in cultured rat cardiac fibroblasts (CFs) and reduced left ventricle collagen deposition in rats with aldosterone (salt)- and ANG II-induced hypertension. However, it is not known whether these effects are mediated by receptor binding sites specific for Ac-SDKP. We hypothesized that Ac-SDKP exerts antifibrotic effects by binding to specific receptor sites in cultured rat CFs, which mediate the inhibitory effects of Ac-SDKP on ET-1-stimulated collagen synthesis. Ac-SDKP binding sites in rat CFs and hearts were characterized by a specific radioligand, [sup.125]I-labeled 3-(p-hydroxyphenyl)-propionic acid (or desaminotyrosine) (Hpp)-Aca-SDKP, a biologically active analog of Ac-SDKP. [sup.125]I-labeled Hpp-Aca-SDKP bound to rat CFs and fractionated membranes with similar affinities and specificity in a concentration- and time-dependent fashion. Scatchard plot analyses revealed a single class of high-affinity Hpp-Aca-SDKP binding sites (maximal binding: 1,704 [+ or -] 198 fmol/mg protein; dissociation constant: 3.3 [+ or -] 0.6 nM). [sup.125]I-labeled Hpp-Aca-SDKP binding in CFs was displaced by unlabeled native peptide Ac-SDKP (inhibition constant: 0.69 [+ or -] 0.15 nM) and the analog Hpp-Aca-SDKP (inhibition constant: 10.4 [+ or -] 0.2 nM) but not the unrelated peptide ANG II or ET-1 (10 [micro]M). In vitro, both Ac-SDKP and Hpp-Aca-SDKP inhibited ET-1-stimulated collagen synthesis in CFs in a dose-dependent fashion, reaching a maximal effect at 1 nM (control: 7.5 [+ or -] 0.4, ET-1: 19.9 [+ or -] 1.2, ET-1+SDKP: 7.7 [+ or -] 0.4, ET-1+Hpp-Aca-SDKP: 9.7 [+ or -] 0.1 [micro]g/mg protein; P < 0.001). Ac-SDKP also significantly attenuated ET-1-induced increases in intracellular calcium and MAPK ERK1/2 phosphorylation in CFs. In the rat heart, in vitro autoradiography revealed specific [sup.125]I-labeled Hpp-Aca-SDKP binding throughout the myocardium, primarily interstitially. We believe that these results demonstrate for the first time that Hpp-Aca-SDKP is a functional ligand specific for Ac-SDKP receptor binding sites and that both Ac-SDKP and Hpp-Aca-SDKP exert antifibrotic effects by binding to Ac-SDKP receptors in rat CFs. collagen synthesis; heart; autoradiography; receptor

It has been recently claimed that the human [B.sub.1] receptors for kinins bind angiotensin-converting enzyme (ACE) inhibitors via a potential zinc-binding domain and are pharmacologically stimulated by these drugs. We verified whether ACE inhibitors stimulate [B.sub.1] receptors in vitro. The isolated rabbit aorta or mouse stomach responded by negligible contractions to the application of captopril, enalaprilat, or zofenoprilat. The human isolated umbilical vein also failed to respond to enalaprilat. All of these preparations were responsive to the [B.sub.1] receptor agonists des-[Arg.sup.9]-bradykinin (BK) or Lys-des-[Arg.sup.9]-BK. Furthermore, enalaprilat applied continuously had no significant interaction with the effects of Lys-des-[Arg.sup.9]-BK on the rabbit aorta. Enalaprilat failed to stimulate [[sup.3]H]arachidonate release, translocate the receptors (confocal microscopy), or stimulate ERK1/2 phosphorylation (immunoblot) in HEK-293 cells stably expressing the rabbit [B.sub.1] receptor conjugated to yellow fluorescent protein. The phospho-ERK1/2 content of arterial smooth muscle cells of human or rabbit origin was increased by treatment with Lys-des-[Arg.sup.9]-BK but not with enalaprilat. ACE inhibitors do not act as bona fide agonists of the kinin [B.sub.1] receptors. enalaprilat; angiotensin II; des-[Arg.sup.9]-bradykinin

With the use of in vitro receptor autoradiography, this study aims at determining whether the higher level of kinin [B.sub.2] receptor density in the spinal cord of the spontaneously hypertensive rat (SHR) is secondary to arterial hypertension and whether chronic treatment with angiotensin I-converting enzyme inhibitors (ACEI) can regulate neuronal [B.sub.1] and [B.sub.2] receptors. SHR received, from the age of 4 wk, one of the two ACEI (lisinopril or zofenopril, 10 mg*[kg.sup.-1]*[day.sup.-1]) or for comparison, the selective [AT.sub.1] antagonist (losartan, 20 mg*[kg.sup.-1]*[day.sup.-1]) in their drinking water for a period of 4, 12, and 20 wk. Age-matched untreated SHR and Wistar-Kyoto rats (WKY) were used as controls. [B.sub.2] receptor binding sites in most laminae were higher in SHR than in WKY from the age of 8 to 24 wk. Whereas [B.sub.1] receptor binding sites were significantly present in young SHR and WKY, they were barely detectable in adult rats. ACEI (16 and 24 wk) and [AT.sub.1] antagonist (24 wk) enhanced the number of [B.sub.2] without changing [B.sub.1] receptor binding sites. However, at 8 wk the three treatments significantly increased [B.sub.1] and decreased [B.sub.2] receptors in lamina I. It is concluded that 1) the higher density of [B.sub.2] receptors in the spinal cord of SHR is not due to hypertension, 2) kinin receptors are regulated differently by ACEI in neuronal and vascular tissues, and 3) aging may have a profound impact on levels of [B.sub.1] and [B.sub.2] receptors in the rat spinal cord. bradykinin; [B.sub.1] receptor; [B.sub.2] receptor; hypertension