Pharmacological Profiles of CS-622, a Novel Angiotensin Converting Enzyme Inhibitor

Oizumi, Kiyoshi; Koike, Hiroyuki; Sada, Toshio; Miyamoto, Masaaki; Nishino, Hiroshi; Matsushita, Youichi; Iijima, Yasuteru; Yanagisawa, Hideyoshi

doi:10.1254/jjp.48.349

Cited by 39 publications

(22 citation statements)

References 8 publications

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“…CS-622 diacid was used in vitro because CS-622 is converted to the active diacid in vivo. As described elsewhere, 22 CS-622 diacid at a concentration of 3xlO~8 M completely abolished the contraction induced by angiotensin I (3xlO~8 M) in rat aorta. Therefore, 10~5 M of CS-622 diacid was considered sufficient to inhibit ACE of the aortic smooth muscle.…”

Section: Contractile Responses To Cgp-28392 In the Isolated Aortassupporting

confidence: 55%

Long-term inhibition of angiotensin converting enzyme suppresses calcium channel agonist-induced contraction of aorta in hypertensive rats.

1989

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To elucidate functional changes in the vascular smooth muscle of spontaneously hypertensive rats (SHR) after chronic inhibition of angiotensin converting enzyme, we examined the contractile responses to different pharmacological interventions in the isolated aortas from SHR treated with a novel angiotensin converting enzyme inhibitor, CS-622 (10 mg/kg/day) for 20 weeks. In normal K + medium, a marked contraction was elicited by increasing Ca 2+concentration from 0 to 3 mM in aortas from a control group of SHR, but not in aortas from SHR treated with CS-622. In 60 mM K + medium, however, the sensitivity of aorta to Ca 2+ was almost the same in the two groups. A calcium channel activator, CGP-28392 (10~7 to 10"' M), induced a marked contraction in the aortas from control SHR, but not in the aortas from CS-622-treated SHR. When slightly depolarized in 10 or 12 mM K + solution, the aortas from CS-622-treated SHR contracted in response to CGP-28392. The aortic sensitivity to KC1 contraction was much lower in CS-622-treated SHR than in untreated SHR, whereas the sensitivity to phenylephrine contraction was little different in the two groups. These contractile profiles of aortas from CS-622-treated SHR were very similar to those from normotensive Wistar-Kyoto rats but not to those from hydralazine-treated SHR. These data suggest that contractions due to Ca 2+ through voltage-dependent calcium channels are exaggerated in SHR aorta and that long-term treatment with angiotensin converting enzyme inhibitor suppresses the abnormal contractility of SHR vascular smooth muscle, probably through alterations of voltage-related functions of calcium channels. (Hypertension, 1989;14:652-659) A ntihypertensive effects of acute inhibition of angiotensin converting enzyme (ACE) depend on the status of the renin-angiotensin system: acute ACE inhibition produces a marked hypotension in renovascular hypertensive rats and a moderate hypotension in spontaneously hypertensive rats (SHR), whereas it is totally ineffective in reducing blood pressure of deoxycorticosterone acetate-salt hypertensive rats. 1 * 2 However, chronic ACE inhibition has been shown to lower blood pressure of SHR to levels of normotensive Wistar-Kyoto (WKY) rats, which is never accomplished by acute inhibition of ACE.3 These facts suggest that antihypertensive mechanisms underlying chronic ACE inhibition differ from those of acute ACE inhibition. Angiotensin II From the Cardiovascular Division, Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.Address for reprints: Hiroyuki Koike, PhD, Biological Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawaku, Tokyo 140, Japan.Received January 31, 1989; accepted in revised form Jury 24, 1989. (Ang II), when infused chronically at a dose below the threshold of the acute pressor effect, does not increase blood pressure initially, but increases blood pressure gradually over several days.4 -6 Thus, Ang II has a slow pressor action that is different from its acute pressor action. A recent report...

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Section: Contractile Responses To Cgp-28392 In the Isolated Aortassupporting

confidence: 55%

Long-term inhibition of angiotensin converting enzyme suppresses calcium channel agonist-induced contraction of aorta in hypertensive rats.

1989

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“…Drugs CS-866 (20), a selective non-peptide angiotensin AT1 receptor antagonist, and temocapril hydrochloride (21), an angiotensin-converting enzyme (ACE) inhibitor, were synthesized by Sankyo Co., Ltd. (Tokyo, Japan). These drugs were suspended in 0.5% carboxymethylcellulose (CMC).…”

Section: Methodsmentioning

confidence: 99%

Effects of Angiotensin AT1 Receptor Antagonist on Volume Overload-Induced Cardiac Gene Expression in Rats.

et al. 1997

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The present study was undertaken to examine the effects of volume overload on cardiac gene expression and the possible role of angiotensin ATl receptor in such expression. Cardiac volume overload was prepared by abdominal aortocaval shunt in rats. Rats with aortocaval shunt were treated with 1) vehicle, 2) an angiotensin ATi receptor antagonist, CS-866 (10 mg/kg/d), or 3) an angiotensin-converting enzyme inhibitor, temocapril (10 mg/kg/d), for 7 days. Cardiac tissue mRNA was measured by Northern blot analysis with specific probes. Aortocaval shunt not only caused cardiac hypertrophy but also upregulated the gene expression of atrial natriuretic polypeptide, collagen III, and downregulated Cat+. ATPase expression in the left ventricle. These changes were prevented by treatment with CS-866, while temocapril failed to normalize left ventricular Cat+-ATPase expression. Unlike the left ventricle, the significant downregulation of a-myosin heavy chain and transforming growth factor-i93 by aortocaval shunt was observed in the right ventricle, and CS-866 normalized this decreased expression of transforming growth factor-/93. The left and right atria showed increased expression of collagen type I as well as of collagen type III and atrial natriuretic polypeptide, and these increases were more effectively prevented by CS-866 than by temocapril. Thus, the effects of cardiac volume overload on cardiac performance-related gene expression differ between the ventricles and atria. Our results suggest that ATi receptor partially contributed to volume overload-induced changes in cardiac gene expression and that ATi receptor antagonists and angiotensin-converting enzyme inhibitors have different effects in this model of cardiac hypertrophy. (Hypertens Res 1997; 20: 133-142)

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“…CS-622 is a selective ACE inhibitor that does not have any other pharmacological actions. 40 Our previous studies showed that long-term administration of CS-622 suppressed the increased Ca 2+ -dependent resting tone and CGP-28392-induced contraction in SHR aorta and that these suppressions were never achieved by either long-term treatment with hydralazine or acute inhibition of aortic ACE in vitro. 15 - 35 In the present study, long-term treatment with CS-622 (10 mg/kg/ day) lowered blood pressure of SHR to the same level as that of WKY rats (Table 1) and lowered both [Ca 2+ ], and resting tone in SHR aortas to levels in WKY rat aortas (Figure 2).…”

Section: Effects Of Nicardipine On Basal Calcium Level and Basal Tensmentioning

confidence: 97%

Cytosolic free calcium of aorta in hypertensive rats. Chronic inhibition of angiotensin converting enzyme.

et al. 1990

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Pharmacological Profiles of CS-622, a Novel Angiotensin Converting Enzyme Inhibitor

Abstract: Abstract-CS-622is a prodrug type ACE inhibitor with a thiazepin ring.

Cited by 39 publications

References 8 publications

Long-term inhibition of angiotensin converting enzyme suppresses calcium channel agonist-induced contraction of aorta in hypertensive rats.

Long-term inhibition of angiotensin converting enzyme suppresses calcium channel agonist-induced contraction of aorta in hypertensive rats.

Effects of Angiotensin AT1 Receptor Antagonist on Volume Overload-Induced Cardiac Gene Expression in Rats.

Cytosolic free calcium of aorta in hypertensive rats. Chronic inhibition of angiotensin converting enzyme.

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