(Hypertension. 1997;29:340.)
© 1997 American Heart Association, Inc.
Arthur C. Corcoran Memorial Lecture |
Smooth Muscle Apoptosis During Vascular Regression in Spontaneously Hypertensive Rats
From the Centre de Recherche de l'Hòtel-Dieu de Montréal, and the Departments of Pharmacology (D.deB., B.-S.T.) and Medicine (J.T., P.H.), Université de Montréal, Québec, Canada. E-mail debloisd{at}ere.umontreal.ca.
Correspondence to Dr Pavel Hamet, Centre de Recherche Hòtel-Dieu de Montréal, 3840 St Urbain St, Montréal, Québec H2W 1T8, Canada
We previously reported that apoptosis is increased in smooth muscle cells cultured from the aorta of spontaneously hypertensive rats versus normotensive controls. As an initial in vivo exploration, we now examined smooth muscle cell apoptosis regulation during the regression of vascular hypertrophy in the thoracic aorta media of spontaneously hypertensive rats receiving the antihypertensive drug enalapril (30 mg·kg-1·d-1), losartan (30 mg·kg-1·d-1), nifedipine (35 mg·kg-1·d-1), hydralazine (40 mg·kg-1·d-1), propranolol (50 mg·kg-1·d-1), or hydrochlo-rothiazide (75 mg·kg-1·d-1) for 1 to 4 weeks starting at 10 to 11 weeks of age. Three criteria were used to evaluate smooth muscle cell apoptosis: (1) oligonucleosomal fragmentation of the extracted aortic DNA, (2) reduction in aortic DNA content, and (3) depletion of smooth muscle cells in the arterial media. Arterial DNA synthesis was evaluated by [3H]thymidine incorporation in vivo. After 4 weeks of treatment, systolic blood pressure was reduced significantly by <42% with losartan, enalapril, and hydralazine, and by 23% with nifedipine, versus control values of 220±5 mm Hg. However, these agents affected vascular growth and apoptosis differently. Losartan, enalapril, and nifedipine stimulated smooth muscle cell apoptosis threefold to fivefold before there was a significant reduction in DNA synthesis (<25%), vascular mass (<19%), or vascular DNA content (<38%), and these treatments markedly reduced (by 38% to 50%) medial cell number as measured at 4 weeks by the three-dimensional disector method. Losartan and nifedipine stimulated smooth muscle cell apoptosis before reducing blood pressure. In contrast, hydralazine did not affect vascular mass, apoptosis, or DNA synthesis, although blood pressure was lowered. Propranolol or hydrochlorothiazide failed to affect hypertension or vascular growth. Thus, smooth muscle cell apoptosis represents a novel therapeutic target for the control of hypertensive vessel remodeling in response to therapeutic agents.
Key Words: apoptosis • smooth muscle cell • angiotensin II • calcium channel antagonist
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