Therapeutic implications of hypertension-induced glomerular injury. Comparison of enalapril and a combination of hydralazine, reserpine, and hydrochlorothiazide in an experimental model.

Systemic hypertension does not always reflect concomitant glomerular hypertension. At similar levels of systemic hypertension, glomerular injury occurs only in kidneys that lack protective preglomerular vasoconstriction, which results in glomerular hypertension. indeed, glomerular hypertension and glomerular injury do not develop in rats with spontaneous hypertension that have effective preglomerular vasoconstriction. In the experiments reported herein, the normal adaptive response (afferent arteriolar dilation) to a reduction of one and five-sixths of the renal mass in rats with spontaneous hypertension was examined to ascertain whether that response would expose the remaining nephrons to the injurious effects of high perfusion pressure. In addition, the efficacies of two different antihypertensive regimens were compared. Rats with spontaneous hypertension received either no therapy, or a combination of hydralazine, reserpine, and hydrochlorothiazide, or the angiotensin converting enzyme inhibitor enalapril. Three weeks after ablation of one and five-sixths of the renal mass, blood pressure, glomerular filtration rate, urinary protein excretion, and histologic injury scores for mesangial expansion and glomerulosclerosis were determined. Untreated rats with hypertension had severe glomerulosclerosis and mesangial expansion. Both antihypertensive regimens normalized systemic blood pressure and reduced glomerulosclerosis. However, enalapril was more effective than the combination of hydralazine, reserpine, and hydrochlorothiazide in reducing the exaggerated glomerular filtration rate (0.52 +/- 0.40 versus 0.82 +/- 0.10 ml per minute; p less than 0.05), the injury score for mesangial expansion (79 versus 103; p less than 0.05), and the degree of proteinuria (32 +/- 4 versus 42 +/- 3 mg per 24 hours; p less than 0.05). Persistence of hyperfiltration accompanied by increased mesangial expansion, may lead to progression of glomerular damage despite "adequate" control of systemic hypertension, as observed in rats treated with a combination of hydralazine, reserpine, and hydrochlorothiazide.