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

Raij L, Chiou XC, Owens R, Wrigley B.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2996345&dopt=Abstract hydrochlorothiazide Microzide



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Use of the converting enzyme inhibitor enalapril in renovascular hypertension. Effect on blood pressure, renal function, and the renin-angiotensin-aldosterone system.

Reams GP, Bauer JH, Gaddy P.

Thirteen patients were entered into a protocol to assess the safety and efficacy of enalapril (MK 421), 5 to 20 mg b.i.d., and hydrochlorothiazide, 50 to 100 mg daily, for the treatment of renovascular hypertension. Specifically monitored were the effects of therapy on blood pressure and pulse, renal function, and the renin-angiotensin-aldosterone axis. Enalapril and hydrochlorothiazide therapy produced excellent control of blood pressure with no adverse side effects. After approximately 8 weeks of therapy, renal vascular resistance was decreased and no adverse effects on glomerular filtration rate or renal blood flow were noted, except in one patient with a functional unilateral stenotic kidney. Patients receiving enalapril and hydrochlorothiazide showed stimulation of plasma renin activity and suppression of plasma angiotensin II, although the initial degree of suppression was not sustained in all patients during prolonged therapy. Although plasma aldosterone concentration was initially suppressed, the degree of suppression was not sustained. Nine patients have been followed for an additional 6 months; none have experienced further progression of renal disease, as assessed by repeated measurements of glomerular filtration and effective renal plasma flow. These results suggest that combined enalapril and hydrochlorothiazide therapy is safe and effective in the medical management of renovascular hypertension and that blood pressure control may be achieved in the absence of sustained interruption of the renin-angiotensin-aldosterone system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3007351&dopt=Abstract hydrochlorothiazide Microzide



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Long-term effects of enalapril monotherapy and enalapril/hydrochlorothiazide combination therapy on blood pressure, renal function, and body fluid composition.

Reams GP, Bauer JH.

Enalapril, a potent long-acting angiotensin-converting enzyme inhibitor, was prescribed either alone (n = 9) or in combination (n = 20) with hydrochlorothiazide for 96 weeks in essential hypertensive subjects. Blood pressure was well controlled following both monotherapy or combination therapy. Plasma renin activity was stimulated in all subjects; plasma aldosterone concentration was stimulated only in subjects receiving combination therapy. Glomerular filtration rate (assessed by inulin clearance) was unchanged in subjects with initial clearances greater than 80 ml/min/1.73 m2 but was significantly improved (55%) following either form of therapy in subjects with initial clearances less than or equal to 80 ml/min/1.73 m2. Neither monotherapy nor combination therapy adversely affected 24-hour urinary protein excretion, sodium excretion, or body fluid composition. These results suggest that enalapril, either alone or in combination with hydrochlorothiazide, is effective therapy for mild to moderate hypertension. There are no adverse effect on renal function; indeed, enalapril has the capability of improving renal function in those subjects whose renal function was initially impaired from long-standing hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3014081&dopt=Abstract hydrochlorothiazide Microzide



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Congenital nephrogenic diabetes insipidus-vasopressin and prostaglandins in response to treatment with hydrochlorothiazide and indomethacin.

Rascher W, Rosendahl W, Henrichs IA, Maier R, Seyberth HW.

Universitat-Kinderklinik, Heidelberg, Federal Republic of Germany.

In four boys with congenital nephrogenic diabetes insipidus, plasma arginine-vasopressin (AVP) and urinary excretion of prostaglandins were studied in response to treatment with hydrochlorothiazide and indomethacin. An abnormal relationship between AVP and urine osmolality was demonstrated in all patients. In the first patient, treatment with indomethacin (3 mg/kg per day) resulted in a drop of the insulin and paraminohippurate clearances. In the other three patients urinary excretion of PGE2 was raised, and fell during treatment with hydrochlorothiazide (2 mg/kg per day) and indomethacin (2 mg/kg per day). Urine flow, free water clearance and osmolar clearance decreased during treatment. A combination of both drugs is more effective than hydrochlorothiazide alone and the effect appears to be additive.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3153321&dopt=Abstract hydrochlorothiazide Microzide



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Hyperglycemic effects of hydrochlorothiazide and propranolol. A biochemical and ultrastructural study.

Papaccio G, Esposito V.

Istituto di Anatomia Umana Normale, I Facolta di Medicina e Chirurgia, Universita di Napoli, Italy.

The authors studied the glycemic disturbances provoked by two antihypertensive drugs, propranolol and hydrochlorothiazide, administered alone or in combination to normal and diabetic rats, using biochemical and ultrastructural parameters. It was found that hydrochlorothiazide raised fasting glucose concentration significantly; propranolol alone caused an insignificant rise of glucose, but significantly aggravated the effect of hydrochlorothiazide with an additive interaction. The ultrastructural findings, as well as the urinary C-peptide excretion, confirmed that the glycemic effects should not be thought to be due to a direct action of the drugs used on the endocrine pancreas.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3326381&dopt=Abstract hydrochlorothiazide Microzide