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Vascular protection with cilazapril
J P Clozel1, J S Powell, H Kuhn
1Department of Pharmaceutical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Insights
Cilazapril effectively reduced cardiac hypertrophy and improved blood flow in hypertensive rats. This hypertension drug also prevented blood vessel narrowing after injury, suggesting potential for preventing restenosis after angioplasty.
Area of Science:
- Cardiovascular Pharmacology
- Hypertension Research
- Vascular Biology
Background:
- Hypertension-induced medial hypertrophy of coronary arteries reduces vascular reserve.
- Vascular injury, such as from angioplasty, can lead to restenosis due to myointimal proliferation.
Purpose of the Study:
- To investigate the effects of cilazapril on cardiac hypertrophy and coronary vascular resistance in spontaneously hypertensive rats (SHR).
- To evaluate cilazapril's impact on vascular reserve in cerebral, mesenteric, and renal arteries of SHR.
- To assess cilazapril's preventive effect on myointimal proliferation in a rat model of vascular injury.
Main Methods:
- Administration of cilazapril (10 mg/kg daily) to SHR at the onset and after the development of hypertension.
- Measurement of cardiac hypertrophy, coronary vascular resistance, and maximal coronary blood flow in isolated perfused hearts.
- Assessment of cerebral, mesenteric, and renal vascular reserve in SHR.
- Induction of vascular injury using ballooning in rats and evaluation of myointimal proliferation with and without cilazapril treatment.
Main Results:
- Cilazapril decreased cardiac hypertrophy and minimal coronary vascular resistance by 40% in SHR.
- In established hypertension, cilazapril normalized arterial pressure, increased maximal coronary blood flow by 96%, and reduced medial hypertrophy.
- Cilazapril improved cerebral vascular reserve and significantly prevented myointimal proliferation post-vascular injury, an effect independent of blood pressure reduction.
Conclusions:
- Cilazapril effectively mitigates cardiac hypertrophy and improves coronary and cerebral vascular function in hypertensive rats.
- The drug demonstrates a significant preventive effect against neointima formation, suggesting a potential role in preventing restenosis after angioplasty.
- Ongoing clinical trials are evaluating cilazapril's efficacy in preventing restenosis post-coronary angioplasty.
Abstract:
The 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.