Effects of different antihypertensive treatments on morphologic progression of diabetic nephropathy in uninephrectomized dogs. Survival after myocardial infarction in the rat. Role of tissue angiotensin-converting enzyme inhibition. Inhibition of kinin degradation on the luminal side of renal tubules reduces high blood pressure in deoxycorticosterone acetate salt-treated rats. Rx drugs

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Kidney Int. 1994 Jul;46(1):161-9.
Effects of different antihypertensive treatments on morphologic progression of diabetic nephropathy in uninephrectomized dogs.

Gaber L, Walton C, Brown S, Bakris G.

Department of Pathology, University of Tennessee Medical Center, Memphis.

We previously reported the renal hemodynamic effects of different antihypertensive regimens in uninephrectomized, alloxan-induced, diabetic (DM) beagle dogs following one year of treatment. Dogs were prospectively randomized to one of five groups (N = 26): nondiabetic controls, Group I; dogs with DM on no antihypertensive drugs, Group II; dogs on a converting enzyme inhibitor, lisinopril (L), Group III; dogs on a calcium antagonist, TA3090 (diltiazem-like), Group IV; and dogs on a combination of each drug, in reduced doses, Group V. The current paper extends our previous studies by describing the morphologic changes that occurred within each group of dogs studied. More than 100 glomeruli from the renal cortex of each dog were evaluated for increases in mesangial volume fraction (Vv), glomerulosclerosis (GS) and ateriolar hyalinosis. The interstitium was also evaluated for associated changes. Increases in Vv were attenuated in all treated groups (0.28 +/- 0.04, DM alone versus 0.16 +/- 0.05 L; 0.21 +/- 0.07, TA-3090; 0.19 +/- 0.06 micron 2/micron 2, L+TA 3090; P < 0.05) compared to untreated DM. An attenuated increase in Vv also correlated with a blunted rise in proteinuria in Groups III (r = 0.79) and V (r = 0.81) but not Group IV (r = 0.29). Development of focal GS was blunted in all treated groups; however, global GS was fourfold greater in Group IV compared to untreated DM. The degree of interstitial fibrosis also correlated with the degree of global GS. These data support the concept that both a converting enzyme inhibitor and heart rate lowering calcium antagonist attenuate morphologic progression of diabetic renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)

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Circulation. 1994 Nov;90(5):2457-67.
Survival after myocardial infarction in the rat. Role of tissue angiotensin-converting enzyme inhibition.

Wollert KC, Studer R, von Bulow B, Drexler H.

Medizinische Klinik III, Universitat Freiburg, Germany.

BACKGROUND--Chronic treatment with high doses of angiotensin-converting enzyme (ACE) inhibitors prolongs survival after myocardial infarction. Since the plasma renin-angiotensin system (RAS) is not consistently activated in the chronic phase after myocardial infarction, the beneficial effects of ACE inhibition have been attributed, in part, to inhibition of an activated tissue RAS. However, a relation between tissue ACE inhibition and long-term efficacy (ie, concerning left ventricular [LV] hypertrophy and survival) has not been established. The present study was designed to evaluate the impact of low-dose ACE inhibition (predominant inhibition of plasma ACE) and high-dose ACE inhibition associated with substantial tissue ACE inhibition) on reversal of LV hypertrophy and 1-year mortality after myocardial infarction in the rat. METHODS AND RESULTS--Infarcted rats were randomized to placebo, low-dose lisinopril, or high-dose lisinopril (each, n = 80) and compared with sham-operated animals (n = 40). In a separate group of animals, tissue ACE activity was determined after 6 weeks of therapy, demonstrating that both regimens were effective with regard to both plasma and pulmonary ACE inhibition; however, only high-dose lisinopril inhibited renal ACE. Neither dose affected LV ACE activity and ACE mRNA levels as determined by competitive polymerase chain reaction, whereas LV ANF mRNA levels were significantly reduced by high-dose lisinopril. High-dose lisinopril reduced arterial blood pressure and normalized right ventricular and LV weight and resulted in a substantial reduction of 1-year mortality, whereas the low dose did not (1 year mortality: placebo, 56.3%; low dose, 53.3%; high dose, 22.9%, P < .0001 versus low dose and versus placebo). CONCLUSIONS--Hemodynamically effective ACE inhibition is required for reduction of LV hypertrophy and long-term mortality after myocardial infarction in the rat. Sustained inhibition of renal ACE during long-term therapy may contribute to the beneficial effect of high-dose lisinopril. Low-dose lisinopril, although exerting sustained inhibition of the plasma ACE, does not improve survival after myocardial infarction.

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Clin Exp Pharmacol Physiol. 2000 Jan-Feb;27(1-2):80-7.
Inhibition of kinin degradation on the luminal side of renal tubules reduces high blood pressure in deoxycorticosterone acetate salt-treated rats.

Nakajima S, Ito H, Hayashi I, Kuribayashi Y, Okumura T, Yajima Y, Katori M, Majima M.

Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.

1. To determine whether the antihypertensive response in deoxycorticosterone acetate (DOCA) salt-treated rats was mediated by kinins on the luminal side of renal tubules or in the circulation, selective urinary kininase inhibitors were administered to normal Brown Norway Kitasato (BN-Ki) rats and kininogen-deficient Brown Norway Katholiek (BN-Ka) rats. 2. Kinins were degraded by neutral endopeptidase (NEP) and carboxypeptidase Y-like kininase (CPY) in urine, but were inactivated mainly by angiotensin-converting enzyme (ACE) in the plasma. 3. Ebelactone B inhibited CPY, while poststatin inhibited CPY and NEP. 4. Daily administration of poststatin (5 mg/kg per day, s.c.) for 3 days reduced blood pressure (BP) in DOCA salt-treated BN-Ki rats, but not in BN-Ka rats. 5. Ebelactone B (5 mg/kg per day, s.c.) also reduced BP in BN-Ki rats, which was accompanied by increased urinary sodium excretion, but had no effect on BP in BN-Ka rats. 6. Lisinopril (5 mg/kg per day, s.c.) had no effect on BP in either rat strain. 7. Arterial kinin levels in BN-Ki rats increased significantly (2.2-4.6 pg/mL) with captopril (10 mg/kg, s.c.). However, arterial kinin levels that induced hypotension following the infusion of bradykinin (1000 ng/kg per min, i.v.) were 110-fold higher than endogenous arterial kinin levels attained following captopril. 8. These results suggest that inhibition of kinin degradation on the luminal side of the renal tubules may effectively attenuate hypertension.

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