Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) demonstrate elevated blood pressure, cardiac hypertrophy, glucose intolerance, and insulin resistance compared with age-matched Wistar-Kyoto rats (WKY). We investigated concurrent effects of captopril on blood pressure, cardiac mass, myocardial enzyme activities, glucose tolerance, and insulin action in young male SHR. At 10 weeks of age, SHR were randomized into two groups, one receiving distilled water, the other a captopril solution (50 mg/kg body weight/day). We also examined age-matched WKY receiving distilled water. Blood pressure was measured by tail-cuff during the 4-week treatment period and oral glucose tolerance was tested at the end of treatment. Hearts were weighed and ventricular tissue was assayed for activities of 3-hydroxyacyl-CoA dehydrogenase, citrate synthase, and hexokinase. Growth rates were similar between captopril-treated and control SHR, but less than those of WKY. Captopril reduced blood pressure (134 +/- 8 v 177 +/- 8 mm Hg, P < .05) and left ventricular mass (-18%, P < .05) in SHR. Cardiac enzyme activities also changed with captopril treatment, reflecting an increased capacity for beta-oxidation of fatty acids and reduced potential for glucose phosphorylation in the left ventricle of SHR. Serum concentrations of glucose, insulin, and free fatty acids after a brief fast and in response to oral glucose were not different after captopril treatment, suggesting no improvement in insulin action or glucose tolerance. In summary, treatment of young male SHR with captopril reduces blood pressure and cardiac mass, and promotes a small but significant increase in cardiac capacity for oxidation of fatty acids and reduction of glucose phosphorylation. In contrast, metabolic effects of captopril on oral glucose tolerance and insulin action were not evident.

Insulin resistance and hypertension: in vivo and in vitro insulin action in skeletal muscle in spontaneously hypertensive and Wistar-Kyoto rats.

The spontaneously hypertensive rat (SHR) has been reported to be insulin-resistant compared to the Wistar-Kyoto (WKY) parent strain. Because insulin resistance usually reflects a defect in insulin action at the muscle, we compared the ability of muscle (gastrocnemius) to store glycogen in response to a standard oral glucose challenge in SHR to that in WKY. As a control, we examined the glycogen response in liver in these two rat strains. However, in vivo insulin action reflects both tissue responsiveness as well as substrate and hormone availability at the tissue level. To evaluate tissue responsiveness in vitro, we examined two parameters of insulin action: 1) muscle glycogen synthesis using 3H-glucose and 2) muscle glucose transport using 3H-2-deoxy-glucose (3H-2-DG). Thirteen-week-old male rats were studied after overnight fasting. Liver glycogen increased similarly (mean +/- SD shown) in response to glucose gavage feeding in both groups [WKY: 15.2 +/- 6.9 to 50.6 +/- 17.9 micromol/g wet wt (P < .05); SHR: 30 +/- 18 to 63.5 +/- 33.3 micromol/g wet wt (P < .01)]. On the other hand, muscle glycogen increased in WKY [13.7 +/- 2 to 17.8 +/- 1.1 micromol/g wet wt (P < .05)], whereas in SHR there was no significant change [14.6 +/- 2.1 to 15.3 +/- 2.99 micromol/g wet wt P = NS)]. Results of in vitro studies demonstrated that glycogen synthesis increased from 377 +/- 120 to 439 +/- 175 disintegrations per minute (dpm) 3H-glucose/mg extensor digitorum longus (EDL) in WKY when insulin increased from 0 to 1000 microU/mL (P < .05), whereas SHR the increase was from 289 +/- 89 to 565 +/- 187 (P < .05). Glucose transport increased from 483 +/- 74 to 785 +/- 369 dpm 3H-2-DG/mg EDL in WKY when insulin was increased from 0 to 500 microU/mL (P < .03), whereas in SHR the increase was 516 +/- 61 to 997 +/- 347 (P < .001). In summary, liver glycogen increased in response to feeding in a similar manner in both WKY and SHR, whereas muscle glycogen increased only in WKY. We conclude that in vivo muscle glycogen accumulation may represent an index of insulin resistance in SHR. In contrast, in vitro data suggest that both muscle glucose transport and glycogen synthesis were stimulated to a comparable degree by insulin in EDL strips from WKY and SHR; there were no significant differences between WKY and SHR. Further studies are needed to clarify these differences.

Postmarketing analysis of lovastatin use in the VA Northern California System of Clinics: a retrospective, computer-based study.

Prevention of coronary heart disease is a major public health goal. The efficacy of lovastatin in lowering serum cholesterol has been proven in research studies, but its efficacy in practice is unclear. To evaluate our practice patterns and outcome in the Veterans Administration Northern California System of Clinics, we reviewed computer-based records of 203 unselected patients issued lovastatin; 193 (95%) were men, and the average patient age was 66 +/- 9 years. The average daily dose of lovastatin was 24 +/- 10 mg, and average duration of therapy was 22 +/- 11 months. Only 72 patients (35%) were instructed on the prescription to take their medication with the evening meal, and only 59 patients (29%) had seen a dietitian during the observed (1 to 3 years) treatment period. Nevertheless, among the 124 patients with pretreatment lipid data, total serum cholesterol decreased by 18% from 271 +/- 45 to 221 +/- 41 mg/dL (P < 0.001), and low density lipoprotein (LDL)-cholesterol decreased by 23% from 185 +/- 43 to 143 +/- 37 (P < 0.001) mg/dL. High density lipoprotein-cholesterol and triglycerides were unchanged. Of the 168 patients with LDL-cholesterol data during the treatment period, only 74 (44%) achieved an LDL-cholesterol level of less than 130 mg/dL, the minimum goal for a population of older males with a high incidence of other cardiac risk factors. Safety surveillance with liver function testing was performed at least once in 192 patients (95%), but with creatine phosphokinase (CPK) testing in only 123 patients (61%) during the survey period. Enzyme elevations were minor, but occurred at least intermittently in approximately one quarter of patients. Only 5.7% of patients on lovastatin manifested an increase in transaminases on therapy. Due to incomplete baseline data, it is unclear how many patients had elevated CPK as a result of lovastatin. We conclude that: (1) lovastatin is effective in lowering total and LDL-cholesterol in practice, but is often used in dosage insufficient to lower LDL-cholesterol to goal levels; (2) patients are not being adequately educated on dosing schedules; (3) toxicity may be underestimated by infrequent and inconsistent surveillance; and (4) nonpharmacologic therapy is underutilized.