Dose-dependent effects of perindopril on blood pressure and small-artery structure.

Abstract

Long-term treatment of young spontaneously hy-pertensive rats (SHR) with angiotensin-converting enzyme (ACE) inhibitors has a persistent effect on blood pressure when treatment is withdrawn. The aim of the present study was to determine whether this effect could be mediated by the effect of treatment on resistance-artery structure. We determined the dose dependence of ACE-inhibitor therapy on blood pressure and small-artery structure during treatment and on the recovery of blood pressure when treatment was withdrawn. SHR (40 per group) were treated from age 4 to 24 weeks with one of three doses of perindopril (0.4, 0.8, or 1.5 mg/kg per day). Control groups were untreated SHR and Wistar-Kyoto rats. At 24 weeks, treatment was stopped and small arteries were taken from half of the rats from the mesenteric, femoral, cerebral, and coronary vascular beds for morphological and functional measurements. The blood pressure of the other half of the rats was followed until 36 weeks of A lthough modern antihypertensive treatment is in / \ general able to control blood pressure, it is _Z \. almost invariably found that withdrawal of treatment results in blood pressure returning to original hypertensive levels in both essential hypertensive patients 13 and animal models of hypertension. 46 A notable exception to this rule concerns treatment of young spontaneously hypertensive rats (SHR) with angioten-sin-converting enzyme (ACE) inhibitors, in which, after treatment is discontinued, blood pressure remains at a level below that of control SHR. 610 This persistent effect of ACE inhibitor treatment seems to be mediated through the ability of ACE inhibitors to reduce angio-tensin II levels, for similar results are obtained with the angiotensin II receptor inhibitor losartan. 11 There is also evidence that the effect is only seen if the treatment is performed while animals are young. 7 Given the fact that the pathogenesis of hypertension in SHR might have relevance for some forms of human essential hypertension, it is clear that elucidation of the mechanism of the persistent effect could provide an interesting new therapeutic approach. One possible mechanism concerns vascular structure because, on the basis that an increased media-lumen ratio of resistance vessels could be a factor that maintains hyperten-sion, 1213 reduction of the media-lumen ratio could maintain low pressure levels. This possibility has been age. During treatment, perindopril caused a dose-dependent reduction in blood pressure and in the media-lumen ratio and media area of the small arteries, whereas there was a dose-dependent increase in lumen diameter. The effect of treatment on the structure of arteries from the different vascular beds was homogeneous. Compared with values from Wistar-Kyoto rats, blood pressure normalization in SHR was not associated with full normalization of structure. After withdrawal of treatment, there was an inverse relation between perindopril dose and the persistent effect. The results suggest that although treatment of SHR has a unif...

Antihypertensive Treatment and the Responsiveness to Glutamate in Ventrolateral Medulla

“…A decrease in body weight as the result of treatment with enalapril 13,14 or other ACE inhibitors 15,16 has also been reported by other investigators. The mechanism of body weight reduction is not fully understood but may be explained in part by the natriuresis produced by ACE inhibitors, as has been suggested by Clozel et al 17 Because we did not measure sympathetic nerve activity in this study, we cannot exclude the possibility that the difference in pressor response evoked by microinjection of EAA into the RVLM may be due to the responsiveness of peripheral vessels rather than a difference in the sympathetic outflow.…”

Responses of the ambulatory arterial stiffness index and other measures of arterial function to antihypertensive drugs

“…Furthermore, under treatment with angiotensinconverting enzyme inhibitors, in particular PER, but not under treatment with AT, the structural arteriolar abnormalities associated with hypertension regress. 28,29 The ensuing reduction of the reflection coefficients likely reduces the amplitude of the backward pressure wave and promotes a decrease of systolic BP and PP in the brachial artery.…”

Time Course of Vascular Structural Changes During and After Short-Term Antihypertensive Treatment

“…[1][2][3]8,9 The concept that the persistent reduction in MAP and the regression of vascular structure are linked mechanistically has also been widely discussed, although without resolution. 1-4,10 -14 Further, the vascular structural changes that persist off-treatment have been proposed to result from extended inhibition of the trophic actions of angiotensin II, 8,15,16 prolonged reduction in arterial pressure, 16 -18 or from the combined effects. Regardless of the mechanism of action, the result is a reduced thickness of the medial layer and an increase in the lumen size of the vessels 4,6,19 that lasts long after the cessation of therapy.…”