Showing papers by "Mark E. Cooper published in 1990"

Glomerular Filtration Rate in Streptozocin-Induced Diabetic Rats: Role of Exchangeable Sodium, Vasoactive Hormones, and Insulin Therapy

Abstract: The interrelationships of sodium and volume status, atrial natriuretic peptide (ANP), plasma renin activity (PRA), insulinlike growth factor I (IGF-I), and kidney weight and their influence on glomerular filtration rate (GFR) were investigated in rats during the first 4 wk of streptozocin-induced diabetes (STZ-D). In each of three experiments, untreated diabetic rats were compared with nondiabetic control rats and rats with varying degrees of glycemic control during insulin therapy. The first experiment evaluated exchangeable sodium, plasma volume, and GFR. In untreated diabetic rats, exchangeable sodium and plasma volume, but not GFR, were increased by approximately 25% compared with control rats. Insulin-treated diabetic rats with plasma glucose levels ranging from 12 to 30 mM had increased GFR, whereas exchangeable sodium and plasma volume were reduced toward control values. Daily insulin therapy, titrated to maintain euglycemia, further reduced exchangeable sodium and plasma volume and decreased but did not normalize GFR. The second experiment evaluated the relationship between vasoactive hormones and GFR. In untreated diabetic rats, plasma ANP levels increased 89% and urinary cyclic GMP (cGMP) excretion increased 94%, with an 85% decrease in PRA, whereas GFR was unchanged. Moderate hyperglycemia (plasma glucose 12-30 mM) was associated with normalized plasma ANP levels and urinary cGMP excretion, a 52% decrease in PRA, and a 13% increase in GFR. The third experiment studied serial changes in food and water intake and vasoactive hormones and end-point measurement of kidney weight, GFR, and plasma IGF-I. In the untreated diabetic group, urinary cGMP excretion was significantly elevated after 3 wk, whereas the reduction in PRA levels was apparent after 1 wk.(ABSTRACT TRUNCATED AT 250 WORDS)

Nephropathy in model combining genetic hypertension with experimental diabetes. Enalapril versus hydralazine and metoprolol therapy.

Abstract: We compared the effects of the angiotensin-converting enzyme inhibitor enalapril and a conventional antihypertensive regimen (hydralazine and metoprolol) on kidney function, albuminuria, and glomerular ultrastructure in hypertensive diabetic and nondiabetic rats. Diabetes was induced with streptozocin at 8 wk of age in spontaneously hypertensive (SHR) rats. Antihypertensive drugs were administered in drinking water from the time of induction of diabetes in all groups. Blood pressure reduction was equal in the diabetic and nondiabetic SHR rats receiving either enalapril or hydralazine plus metoprolol. In diabetic SHR rats, there was a rise in serum creatinine after 32 wk, which did not occur in diabetic rats treated with either antihypertensive regimen or in nondiabetic rats. Both drug regimens reduced albuminuria in diabetic and nondiabetic SHR rats to a similar degree. Enalapril and the combination of hydralazine and metoprolol were associated with decreased glomerular basement membrane thickness and glomerular volume in diabetic and nondiabetic SHR rats without significant effect on fractional mesangial volume. Thus, antihypertensive therapy retards the development of albuminuria, glomerular basement membrane thickening, and glomerular hypertrophy in the rat in the presence or absence of diabetes. No specific benefit of angiotensin-converting enzyme inhibition was observed in these hypertensive models of nephropathy. Human studies comparing the effects of different classes of antihypertensive drugs on kidney function, proteinuria, and glomerular morphology are warranted.

Comparison of simvastatin and cholestyramine in the treatment of primary hypercholesterolaemia.

Abstract: The effects of simvastatin, a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on plasma lipid levels were compared with those of the bile acid sequestrant cholestyramine in a randomized parallel study of 60 subjects with primary hypercholesterolaemia After a 12-week direct comparison period 37 subjects with inadequate cholesterol reduction received a combination of both drugs and all subjects were followed for a further 40 weeks Simvastatin was more effective than cholestyramine in lowering total and LDL cholesterol levels and the LDL/HDL ratio (-317% v -197% [P less than 001], -410% v -318% [P less than 005] and -467% v -336% [P less than 001], respectively at Week 12) Only simvastatin significantly increased the HDL cholesterol concentration (+133% [P less than 001] v +64%) Cholestyramine increased plasma triglyceride levels by 375% (P less than 001) whereas simvastatin caused a slight non-significant reduction Combined therapy produced a further decrease in total and LDL cholesterol levels, and in the LDL/HDL ratio, which was sustained for the duration of the study Simvastatin was better tolerated than cholestyramine (P less than 001), and combining the two drugs enhanced efficacy without increasing the frequency of side effects

The Use of Simvastatin, an HMG CoA Reductase Inhibitor, in Older Patients with Hypercholesterolemia and Atherosclerosis

Abstract: Epidemiological evidence suggests that elevated serum cholesterol, especially the low density lipoprotein (LDL) fraction, the total/high density lipoprotein (HDL)-cholesterol ratio, and the LDL/HDL-cholesterol ratio, remains a risk factor for atheromatous disease up to the age of 79 years. We studied the efficacy and tolerability of simvastatin, an HMG CoA reductase inhibitor, in 20 patients aged 65 to 75 years with clinical evidence of atheromatous disease. After four weeks of treatment, there was a 29% fall in LDL-cholesterol levels (P less than .01 vs placebo) with low dose simvastatin and a 38% fall with high dose simvastatin (P less than .001 vs placebo). Similar falls were seen in total cholesterol levels and the LDL/HDL-cholesterol and total/HDL-cholesterol ratios. Apoprotein B levels decreased by approximately 20% with both doses (P less than .05 vs placebo). In an open extension of the study, the decreases in lipid parameters were sustained for a further 48 weeks of treatment with doses of simvastatin ranging from 10 to 40 mg. Two patients required the addition of cholestyramine. Although a small study like this cannot establish safety and tolerance, side effects were minor and did not require stopping therapy in any patient. Simvastatin is an effective cholesterol lowering agent in older patients.

Hyperlipidaemia increases albuminuria in hypertensive and normotensive rats.

Abstract: 1. The effects of a high cholesterol diet on urinary albumin excretion were examined in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats over 36 weeks. 2. Cholesterol feeding resulted in an increase in total-cholesterol and a decrease in HDL-cholesterol without influencing triglyceride levels in both strains. 3. Urinary albumin excretion was significantly elevated in cholesterol-fed SHR and WKY rats. 4. These results suggest that hyperlipidaemia may be important in acceleration of experimental nephropathy.