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

Abstract

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...

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

“…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). Exaggerated response of SHR aortas in [Ca 2+ ]j and tension development in response to CGP-28392 was also normalized by chronic inhibition of ACE.…”

Involvement of Endothelium-Derived Factors in Controlling the Active Tone of Smooth Muscle in Aorta from Hypertensive Rats.

“…The aortic smooth muscles of spontaneously hypertensive rats, however, have the active tone (Noon et al, 1978;Lindner and Heinle, 1987;Fitzpatrick and Szentivanyi, 1980 ;Sada et al, 1989 ;Sunano et al, 1992 ;Sasaki et al, 1993 ;Sunano et al, 1996). The active tone of these smooth muscles are sensitive to extracellular Ca2+ and abolished by the removal of Ca2+ from incuba tion medium or by the application of Ca antagonists Sada et al, 1989 ;Fitzpatrick and Szentivanyi, 1980 ;Lindner and Heinle, 1987 ;Noon et al, 1978).…”

“…In the spontaneously hypertensive rats, however, it has been known that the aortic smooth muscle exhibits the active tone (Sada et al, 1989 ;Fitzpatrick and Szentivanyi, 1980 ;Lindner and Heinle, 1987 ;Noon et al, 1978 ;Sunano et al, 1992 ;Sasaki et al, 1993 ;Sunano et al, 1996). We have observed using various strains of spontaneously hypertensive rats that the amplitude of the active tone of aorta became greater as the blood pressure of the rats increased (Sasaki et al, 1993 ;Sunano et al,1996).…”

“…We have observed using various strains of spontaneously hypertensive rats that the amplitude of the active tone of aorta became greater as the blood pressure of the rats increased (Sasaki et al, 1993 ;Sunano et al,1996). It has been established that the active tone of aortic smooth muscle is sensitive to extracellular Ca2+ and is thought to be induced by influx of Ca2+ through voltage-dependent Ca2+ channels (Sasaki et al, 1993 ;Sada et al, 1989 ;Fitzpatrick and Szentivanyi, 1980 ;Noon et al, 1978 ;Sunano et al, 1996).…”

Effects of Dietary Salt on Inhibition of Norepinephrine-Induced Contraction by Ryanodine and Verapamil in Isolated Aortic Rings from Dahl Rats.

“…Several investigators also reported that voltage-dependent Ca channels are altered in the vascular smooth muscle of SHR (36)(37)(38). There are also several reports that suggest that there is a defect of SR Ca uptake or release in vascular smooth muscle of SHR (39-42).…”