Apoptosis During Regression of Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Abstract

Abstract-We previously reported that increased apoptosis participates in the regression of aortic hypertrophy in spontaneously hypertensive rats. To further document the potential role of apoptosis in cardiovascular therapy, we examined apoptosis during regression of hypertrophy in the heart of spontaneously hypertensive rats receiving the antihypertensive drug enalapril (30 mg ⅐ kg) 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 fragmentation in extracted cardiac DNA or in situ in ventricular cross sections labeled with terminal deoxynucleotidyl transferase. Cardiac DNA synthesis was evaluated by [ 3 H]-thymidine incorporation in vivo. All drugs reduced cardiac workload, defined as the product of blood pressure and heart rate, by Ͼ20% at 4 weeks. However, only nifedipine, enalapril, losartan, and propranolol reduced cardiac mass (Ͼ19%) within 4 weeks. Regression of cardiac hypertrophy was accompanied by a 50% to 300% increase in DNA fragmentation and a Ͼ20% reduction in DNA synthesis, resulting in a Ͼ20% reduction in cardiac DNA content after 4 weeks. Apoptosis induction occurred early and was transient within 4 weeks of nifedipine, enalapril, or losartan administration. With all regression-inducing drugs, the increase in DNA fragmentation occurred mainly in the subepicardium. Thus, transient induction of apoptosis in the subepicardium appears to be a characteristic feature of the early response to drug-induced regression of cardiac hypertrophy in spontaneously hypertensive rats. (Hypertension. 1999;34:229-235.)Key Words: ␤-adrenergic antagonist Ⅲ calcium channel blocker Ⅲ AT 1 antagonist Ⅲ ACE inhibitor A lthough cardiac hypertrophy is an independent risk factor for cardiovascular morbidity and mortality, the mechanisms regulating cardiac mass remain poorly defined. Different classes of antihypertensive drugs are not equally effective at reducing left ventricular mass, suggesting a blood pressure-independent regulation. 1 Cardiac hypertrophy involves both cellular hyperplasia (mainly in nonmyocytes) and hypertrophy (mainly in myocytes). 2 A potential mechanism contributing to the suppression of cardiac hypertrophy is the gene-regulated process of physiological cell self-destruction called apoptosis. 3 Cardiac apoptosis has been documented during normal neonatal maturation, 4,5 aging, 6 hypertension, 7-10 ischemia, and failure. 11 The spontaneously hypertensive rat (SHR) is a model of genetically determined cardiac hypertrophy with increased cardiac mass and DNA content at birth, 12 further suggesting blood pressure-independent regulation. In this model, cardiac alterations evolve from concentric hypertrophy to dilated cardiomyopathy and heart failure. 13 Results from our group suggest that neonatal cardiac hypertrophy in SHRs might be due in part to an imbalance between cell growth and apoptosis favoring DNA accumulation. 5 As the heart of untreated adult SHRs adapts to hyperte...

Stimulation of Cardiac Apoptosis in Essential Hypertension

“…Nifedipine was shown to block calcium-mediated apoptosis in isolated chick cardiomyocytes. 24 In contrast, Tea et al 25 reported that cardiac apoptosis transiently increased in SHR chronically treated with nifedipine but returned to baseline values at the end of the treatment period. Thus, our data in amlodipine-treated hypertensives would suggest that dihydropyridines do not exert long-term effects on cardiac apoptosis in hypertension.…”

Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

“…These include an ACE inhibitor (enalapril), an angiotensin II receptor blocker (losartan), and a diuretic (furosemide) that have all been shown to be very effective in preventing or reversing LVH in animals including mice (37,(51)(52)(53)(54)(55)(56)(57)(58). Thus, in Npr1 -/-mice BP independent stimuli contribute to the development of LVH.…”

Cardiomyocyte Apoptotic Cell Death in Arterial Hypertension

“…17,21,22 Other groups 18,20 have confirmed these effects in adult SHR and failing aged SHR. In the same experimental model, Tea et al 47 recently analyzed the effects that a 4-week administration of different antihypertensive drugs had on cardiac hypertrophy regression and on the DNA fragmentation index. Basically, they showed that renin-angiotensin system intervention and ␤-adrenergic blockade produced an increment of apoptosis in parallel to cardiac hypertrophy regression; calcium channel antagonists produced a time window of apoptosis after the first week of administration, whereas hydralazine and hydrochlorothiazide did not modify either cardiac hypertrophy or DNA fragmentation.…”