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Dundore Ronald L.; Brousseau, Armand C.; Habeeb, Peter G.; Pratt, Phillip F.; Becker, Lynn T.; Clas, Dawn M.; Silver, Paul J.; Buchholz, R. Allan
Journal of Cardiovascular Pharmacology: October 1992
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To evaluate the pattern of hemodynamic responses produced by an inhibitor of protein kinase C (PKC), staurosporine 0.03–0.55 mg/kg was administered intravenously (i.v.) to conscious, normotensive rats chronically instrumented with vascular catheters for direct measurement of blood pressure (BP) and i.v. administration of drugs and either an aortic flow probe for measurement of cardiac output (CO) or miniaturized pulsed Doppler flow probes for measurement of hindquarter, renal, and mesenteric vascular resistances. Staurosporine decreased mean arterial pressure (MAP) and total peripheral resistance (TPR) and increased heart rate (HR) in a dose-dependent manner. Because staurosporine decreased resistance in all three vascular beds monitored (hindquarter, renal, and mesenteric), staurosporine is probably a nonselective vasodilator that decreases MAP by decreasing resistance in a number of peripheral vascular beds. Staurosporine produced biphasic effects on CO, dF/dtmaX and peak aortic blood flow; these parameters were significantly increased at doses <0.3 mg/kg and decreased to levels equal to or significantly less than control values at doses >0.3 mg/kg. In comparison, the calcium channel blocker nitrendipine decreased MAP and TPR and increased HR, CO, dF/dtmax, and peak aortic flow in a dose-dependent manner over the entire dose range (0.01–1 mg/kg i.v.). Staurosporine (0.3 mg/kg) and nitrendipine (1 mg/kg) produced similar changes in MAP (-44 ± 3 and −33 ± 2 mm Hg, respectively), yet staurosporine affected dFldtMAX to a lesser extent than nitrendipine (-5 ± 36 and 390 ± 46 ml/s/s, respectively). These data may indicate that the reflex increase in contractility produced by lower doses of staurosporine is limited by a negative inotropic effect of staurosporine which predominates at higher doses. The renal effects of staurosporine were assessed in conscious, hydrated rats. Staurosporine (0.1 mg/kg) significantly decreased urinary potassium excretion and increased the ratio of sodium to potassium, thereby promoting selective excretion of sodium. Staurosporine (0.3 mg/kg) had significant antinatriuretic and antidiuretic effects, however. We conclude that although staurosporine produced a pattern of hemodynamic and renal effects that may be desirable for new antihypertensive agents, it may be cardiotoxic at higher doses. Because staurosporine inhibits other protein kinases, a definitive evaluation of PKC inhibition as a potential method for treating hypertension requires development of more specific PKC inhibitors.

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