Fridolin Hefti

Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats.

The function of the endothelium is impaired in hypertension. In spontaneously hypertensive rats (SHR), acetylcholine-induced relaxation is decreased and serotonin-induced constriction is increased. The goal of our study was to evaluate the effect of a long-term treatment with cilazapril, a new angiotensin converting enzyme inhibitor, or hydralazine, a vasodilator, on the endothelium-dependent responses in aorta of SHR. Wistar-Kyoto rats were used as normotensive reference. Isolated aortic rings with or without endothelium were suspended in organ chambers. The rings with intact endothelium were contracted with norepinephrine. Acetylcholine-induced relaxation was markedly enhanced by cilazapril treatment. The tension achieved at maximal relaxation was 8 +/- 4% of norepinephrine contraction in the cilazapril-treated SHR versus 55 +/- 5% in the untreated SHR (p less than 0.001). Hydralazine had no significant effect. The effect of serotonin was also markedly modified by cilazapril. In untreated SHR, serotonin induced the release of a vasoconstrictor substance by the endothelium as assessed by the ratio of maximal tension induced by serotonin in rings with endothelium over maximal tension in rings without endothelium, which was greater than 1. This ratio was reversed in cilazapril-treated SHR but not in hydralazine-treated SHR. Captopril had effects similar to cilazapril. Finally, evaluation of carotid arteries showed that cilazapril also prevented morphological changes of the intima in SHR (i.e., infiltration by mononuclear cells). We conclude that angiotensin converting enzyme inhibitors prevent the functional and morphological alterations in endothelium that are found in hypertension and speculate that this action might participate in their antihypertensive effect.

Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting enzyme inhibition.

Hypertension is associated with an impairment of endothelium-dependent relaxation. The angiotensin converting enzyme inhibitors captopril and cilazapril can prevent this endothelial dysfunction. We recently observed that long-term treatment with cilazapril could also prevent subendothelial infiltration by mononuclear cells in spontaneously hypertensive rats. This prompted us to examine whether, in spontaneously hypertensive rats, endothelial dysfunction and subendothelial infiltration by mononuclear cells are associated. These cells were characterized as monocyte macrophages. Infiltration by monocyte macrophages was quantified by morphometry. Endothelial function was estimated by calculating serotonin ratio (maximal contraction to serotonin on isolated arterial rings with endothelium over maximal contraction on paired rings without endothelium). The regional distribution of endothelial dysfunction and subendothelial monocyte macrophages was similar. Both were maximal in the carotid artery, less in the aorta, and nonexistent in the renal artery. A 2-week treatment with cilazapril decreased both endothelial dysfunction (serotonin ratio decreased by 32%) and the number of subendothelial monocyte macrophages in the aorta, which decreased by 38%. We conclude that in spontaneously hypertensive rats, endothelial dysfunction and subendothelial monocyte macrophage infiltration are associated and that cilazapril can decrease both. The observation that angiotensin converting enzyme inhibitors affect subendothelial accumulation of monocyte macrophages may lead to a better understanding of the mechanism of action of this class of drugs.

Effects of chronic ACE inhibition on cardiac hypertrophy and coronary vascular reserve in spontaneously hypertensive rats with developed hypertension.

Left ventricular hypertrophy due to hypertension is associated with a decrease of coronary vascular reserve. We have previously shown that chronic angiotensin converting enzyme (ACE) inhibition prevents cardiac hypertrophy and improves coronary vascular reserve when the treatment is started before appearance of hypertension in spontaneously hypertensive rats (SHR). However, the effects of starting chronic ACE inhibition when hypertension was already developed is not known. The goal of the present study was to assess the effects of chronic ACE inhibition on coronary vascular reserve and on the morphology of the coronary microvasculature when treatment was started after hypertension had developed. For this purpose, one group of SHR was treated from 3-8 months of age with cilazapril, a new ACE inhibitor, and compared with a group treated by placebo. At the end of treatment, cardiac hypertrophy, coronary vascular reserve, density and cross-sectional surface area of the myocardial capillaries (normalized for the myocardial mass) and wall/lumen ratio of the coronary arterioles were determined. Chronic ACE inhibition with cilazapril reduced cardiac hypertrophy and improved by more than 50% coronary vascular reserve in the left and right ventricles. In the left ventricle, the improvement was more pronounced in the subendocardium than in the subepicardium. Cilazapril increased the density and the cross-sectional surface area of the myocardial capillaries and decreased the wall/lumen ratio of the arterioles of the left ventricle. We conclude that chronic ACE inhibition can improve coronary vascular reserve, increase capillary density and capillary cross-sectional surface area and decrease the thickness of the media of coronary arterioles in SHR even when treatment is started after development of hypertension.

The Proliferative Response to Vascular Injury Is Suppressed by Angiotensin-Converting Enzyme Inhibition

Smooth muscle cell (SMC) proliferation and formation of extracellular matrix in the intima of muscular arteries are major processes that can lead to vascular stenosis in arteriosclerosis or after coronary angioplasty. These processes are also seen in the proliferative response to balloon catheter-induced vascular injury of the rat carotid artery, and result in marked neointima formation by 14 days after catheterization. We have shown recently that the angiotensin-converting enzyme (ACE) inhibitor cilazapril strongly suppressed this development of neointima. In this report, we show that the beneficial effects on neointima formation persist for at least 8 weeks after stopping treatment with cilazapril, and that continuous treatment may have additional inhibitory effects during the late phases of vascular remodeling after injury. To investigate further the possible mechanisms, we examined several vasoactive compounds in this model. Another ACE inhibitor of a different chemical class, captopril, reduced neointima formation as strongly as cilazapril (67 and 78%, respectively), but the calcium antagonist verapamil was not active as an inhibitor of neointima formation, despite similar lowering of blood pressure. Hydralazine and a new calcium antagonist, Ro 40-5967, partially suppressed neointima formation (36%, p less than 0.005 and 33%, p less than 0.05, respectively). In vitro, neither cilazapril nor its active metabolite, cilazaprilate, had any effect on SMC proliferation in response to serum or PDGF. To characterize further the role of angiotensin II (Ang II), we tested in cell culture the effects of Ang II and cilazaprilate on mRNA levels of several proteins potentially involved in regulating the SMC response.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreases of vascular hypertrophy in four different types of arteries in spontaneously hypertensive rats

The goal of the present study was to describe the relative extent of vascular hypertrophy in four different types of arteries (coronary, renal, carotid, and mesenteric) of spontaneously hypertensive rats (SHR) and to evaluate the effects of long-term treatment with cilazapril, a new long-acting angiotensin-converting enzyme inhibitor on this vascular hypertrophy. For this purpose, a group of spontaneously hypertensive rats treated for four months with cilazapril (10 mg/kg orally) was compared with a group of spontaneously hypertensive rats treated with placebo. Another group of Wistar Kyoto (WKY) rats treated with placebo was used as a reference. At the end of the treatment period, the rats were perfused-fixed and morphometry of the carotid, renal, mesenteric and coronary arteries was performed. Vascular hypertrophy (increase of the thickness of the medial layer) was present in the four different types of arteries in a similar extent. Cilazapril normalized completely the arterial wall thickness:diameter ratio in the four different types of arteries. Further studies are required to determine whether this effect of cilazapril was due to the decrease of arterial blood pressure or to an effect of cilazapril on growth factors such as angiotensin II.

Effects of cilazapril on the cerebral circulation in spontaneously hypertensive rats.

&NA; Chronic hypertension is associated with a lower cerebral vascular reserve due to thickening of the media of cerebral vessels. The goal of the present study was to determine if long‐term inhibition of angiotensin converting enzyme with cilazapril, a new long‐acting angiotensin converting enzyme inhibitor, could improve cerebral vascular reserve. For this purpose, two groups of 12 spontaneously hypertensive rats were compared. One group was treated with 10 mg/kg/day cilazapril from 14 weeks to 33 weeks of age and was compared with a group treated with placebo. A third group of 12 Wistar‐Kyoto rats treated with placebo was used as reference. At the end of the treatment period, cerebral vascular reserve was evaluated by measuring cerebral blood flow (radioactive microspheres) at rest and during maximal vasodilation induced by seizures provoked by bicuculline. Then, the rats were perfusion‐fixed, and morphometry of the cerebral vasculature was performed. Cerebral vascular reserve was severely impaired in the spontaneously hypertensive rats since their maximal cerebral blood flow was decreased by 52% compared with the Wistar‐Kyoto rats. Cilazapril normalized cerebral blood flow reserve. This normalization was associated with a decreased thickness of the medial layer in the carotid artery, the middle cerebral artery, and in the pial arteries larger than 100 &mgr;m. Further studies are required to determine whether this decreased medial thickness is due to the normalization of blood pressure induced by cilazapril or to the reduction of trophic factors such as angiotensin II. (Hypertension 1989;14:645‐651)

Cilazapril Prevents the Development of Cardiac Hypertrophy and the Decrease of Coronary Vascular Reserve in Spontaneously Hypertensive Rats

Cilazapril is a new inhibitor of angiotensin converting enzyme which has been shown to prevent development of high blood pressure and cardiac hypertrophy in spontaneously hypertensive (SHR) rats. The goal of the present experiment was to evaluate the effects of a chronic treatment with cilazapril on the decrease of coronary reserve in SHR rats. For this purpose, a group of 10 SHR rats which received by oral gavage 10 mg/kg/day of cilazapril for 9 weeks was compared with a control group of 9 SHR rats which received distilled water. Coronary reserve was evaluated by measuring coronary blood flow with the radioactive microspheres method before and after a dose of dipyridamole (2 mg/kg/min) which induces maximal coronary vasodilation. The left ventricular weight/body weight ratio was decreased in the cilazapril group compared to the placebo-treated group (p less than 0.001). Moreover, minimal coronary vascular resistance of the left ventricle and the right ventricle were 33% and 39%, respectively, lower in the cilazapril group as compared with the control group (p less than 0.01). We conclude that chronic treatment with cilazapril can prevent the development of left ventricular hypertrophy and the decrease of coronary vascular reserve in the left and right ventricles of spontaneously hypertensive rats.

Effects of chronic therapy with cilazapril, a new angiotensin-converting enzyme inhibitor, on regional blood flows in conscious spontaneously hypertensive rats.

Summary: Cilazapril is a new potent inhibitor of the angiotensin-converting enzyme. The purpose of the present study was to evaluate the effects of chronic treatment with cilazapril on hemodynamics and regional blood flows in spontaneously hypertensive rats. Cilazapril or distilled water was given by gavage for 9 weeks to hypertensive rats at a dose of 10 mg/kg/day, and arterial blood pressure was monitored each week by an indirect method. After the 9 weeks of treatment, blood pressure was measured by a direct method, and regional blood flows, regional vascular resistances, and cardiac output and its distribution were measured with the radioactive microsphere technique. The cilazapril-treated group was compared with the group that received distilled water. Cilazapril had a very pronounced antihypertensive effect which was due to a general peripheral vasodilatation. The regional vascular resistances were decreased in all the organs except the heart. Cardiac output was unchanged, as well as its distribution. Heart rate was lower in the cilazapril-treated group than in the control group. Cardiac hypertrophy was reduced by cilazapril. We conclude that cilazapril is an antihypertensive agent which acts by dilating most of the peripheral vascular beds and which reduces cardiac hypertrophy

Vascular protection with cilazapril in hypertension

Anatomical changes of arteries and arterioles secondary to hypertension explain most of the late complications of this disease. Therefore, a series of experiments was performed to characterize the vascular protective effects of cilazapril in experimental hypertension. These experiments aimed to answer three types of questions: (a) In which vascular bed is cilazapril effective? (b) Are the vascular changes induced by cilazapril associated with functional effects? (c) Is the effect of cilazapril only preventive or can cilazapril also be effective when hypertension is already present? Our results show that cilazapril is acting on nearly every vascular bed. Its vascular morphological effects (decrease of vascular hypertrophy) are associated with functional changes such as improvements of coronary or cerebral vascular reserves. Cilazapril is active either as a preventive treatment or given when hypertension is already present.

Vascular Protection with Cilazapril

SummaryThe hypertrophy of the media of coronary arteries associated with hypertension reduces cross-sectional area and limits vascular reserve. Cilazapril 10 mg/kg daily decreased cardiac hypertrophy, and decreased minimal coronary vascular resistance by 40% when administered to spontaneously hypertensive rats (SHR) at the onset of hypertension. After hypertension had developed, cilazapril restored arterial pressure to normal and increased the maximal coronary blood flow in isolated perfused hearts by 96%, which was probably a result of a marked decrease in medial hypertrophy of the coronary arteries. Similarly, cilazapril improved cerebral vascular reserve in the mesenteric and renal arteries of SHR.In the rat model of vascular injury produced by ballooning, cilazapril 10 mg/kg daily demonstrated a marked preventive effect on the myointimal proliferation that resulted in untreated controls, a phenomenon responsible for restenosis in humans after arterial angioplasty. Although this effect occurred with usual antihypertensive dosages in rats, it appeared to be independent of the decrease in arterial pressure since effective antihypertensive dosages of verapamil did not prevent neointima formation. In view of the clinical potential for preventing restenosis after coronary angioplasty, 2 multicentre trials of cilazapril are ongoing to test this hypothesis.