SMOOTH-MUSCLE APOPTOSIS DURING VASCULAR REGRESSION IN SPONTANEOUSLY HYPERTENSIVE RATS

We previously reported that apoptosis is increased in smooth muscle ce lls cultured from the aorta of spontaneously hypertensive rats versus normotensive controls. As an initial in vivo exploration, we now exami ned smooth muscle cell apoptosis regulation during the regression of v ascular hypertrophy in the thoracic aorta media of spontaneously hyper tensive 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 hydrochlorothiazide (75 mg . kg(-1). d(-1)) for 1 to 4 weeks starting at 10 to 11 weeks of age. Three criteria were use d to evaluate smooth muscle cell apoptosis: (1) oligonucleosomal fragm entation of the extracted aortic DNA, (2) reduction in aortic DNA cont ent, and (3) depletion of smooth muscle cells in the arterial media. A rterial DNA synthesis was evaluated by [H-3]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. Howe ver,these agents affected vascular growth and apoptosis differently. L osartan, enalapril, and nifedipine stimulated smooth muscle cell apopt osis 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 ce ll number as measured at 4 weeks by the three-dimensional disector met hod. Losartan and nifedipine stimulated smooth muscle cell apoptosis b efore reducing blood pressure. In contrast, hydralazine did not affect vascular mass, apoptosis, or DNA synthesis, although blood pressure w as lowered. Propranolol or hydrochlorothiazide failed to affect hypert ension or vascular growth. Thus, smooth muscle cell apoptosis represen ts a novel therapeutic target for the control of hypertensive vessel r emodeling in response to therapeutic agents.