Apoptosis during regression of cardiac hypertrophy in spontaneously hypertensive rats - Temporal regulation and spatial heterogeneity

We previously reported that increased apoptosis participates in the regress ion of aortic hypertrophy in spontaneously hypertensive rats. To further do cument the potential role of apoptosis in cardiovascular therapy, we examin ed apoptosis during regression of hypertrophy in the heart 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 hydr ochlorothiazide (75 mg.kg(-1).d(-1)) for 1 to 4 weeks, starting at 10 to 11 weeks of age. Systolic blood pressure and heart rate were measured by the tail-cuff method. Markers of apoptosis included oligonucleosomal DNA fragme ntation in extracted cardiac DNA or in situ in ventricular cross sections l abeled with terminal deoxynucleotidyl transferase. Cardiac DNA synthesis wa s evaluated by [H-3]-thymidine incorporation in vivo. All drugs reduced car diac workload, defined as the product of blood pressure and heart rate, by >20% at 4 weeks. However, only nifedipine, enalapril, losartan, and propran olol reduced cardiac mass (>19%) within 4 weeks. Regression of cardiac hype rtrophy was accompanied by a 50% to 300% increase in DNA fragmentation and a >20% reduction in DNA synthesis, resulting in a >20% reduction in cardiac DNA content after 4 weeks. Apoptosis induction occurred early and was tran sient within 4 weeks of nifedipine, enalapril, or losartan administration. With all regression-inducing drugs, the increase in DNA fragmentation occur red mainly in the subepicardium. Thus, transient induction of apoptosis in the subepicardium appears to be a characteristic feature of the early respo nse to drug-induced regression of cardiac hypertrophy in spontaneously hype rtensive rats.