Subject(s)
Amino Acid Chloromethyl Ketones/pharmacology , Antithrombins/pharmacology , Fibrinolytic Agents/pharmacology , Thrombocytopenia/chemically induced , Thrombosis/prevention & control , Amino Acid Chloromethyl Ketones/adverse effects , Amino Acid Sequence , Animals , Antithrombins/adverse effects , Fibrinolytic Agents/adverse effects , Male , Molecular Sequence Data , RabbitsABSTRACT
The purpose of this study was to determine if significant relationships exist between plasma and aortic cyclic GMP (cGMP) levels and pharmacodynamic effect after the i.v. administration of the cGMP-selective phosphodiesterase inhibitor zaprinast to conscious, spontaneously hypertensive rats. Zaprinast dose-dependently increased plasma and aortic cGMP levels at 10, 18 and 30 mg/kg and decreased mean arterial blood pressure (MAP) at 18 and 30 mg/kg. The concentrations of cGMP in the plasma and in the aorta were significantly correlated (r = 0.765, P < 0.0001). The changes in MAP were significantly correlated to aortic (r = -0.750, P < 0.0001) and plasma (r = -0.762, P < 0.0001) cGMP levels. We conclude that plasma cGMP may be an index of cGMP-selective phosphodiesterase inhibition in vivo.
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Aorta, Abdominal/metabolism , Cyclic GMP/blood , Cyclic GMP/metabolism , Purinones/pharmacology , Analysis of Variance , Animals , Blood Pressure/drug effects , Dose-Response Relationship, Drug , Hypertension/physiopathology , Injections, Intravenous , Male , Purinones/administration & dosage , Radioimmunoassay , Rats , Rats, Inbred SHRABSTRACT
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 less than 0.3 mg/kg and decreased to levels equal to or significantly less than control values at doses greater than 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 dF/dtmax to a lesser extent than nitrendipine (-5 +/- 36 and 390 +/- 46 ml/s/s, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Alkaloids/pharmacology , Hemodynamics/drug effects , Kidney/drug effects , Protein Kinase C/antagonists & inhibitors , Animals , Cardiac Output/drug effects , Male , Nitrendipine/pharmacology , Rats , Rats, Sprague-Dawley , Regional Blood Flow/drug effects , Staurosporine , Vascular Resistance/drug effectsABSTRACT
Selective inhibition of either the low Km cyclic AMP (cAMP) or low Km cyclic GMP (cGMP) phosphodiesterase (PDE) promotes vasorelaxation and, consequently, produces depressor effects. To evaluate the systemic and regional hemodynamic effects of selective inhibitors of these PDE isozymes, CI-930 (0.1-10 mg/kg), an inhibitor of low Km cAMP PDE, or zaprinast (3-30 mg/kg), an inhibitor of low Km cGMP PDE, was given i.v. to conscious, normotensive rats. The rats were chronically instrumented with vascular catheters and either an ultrasonic transit-time flow probe around the ascending aorta or miniaturized pulsed Doppler flow probes around the superior mesenteric and left renal arteries and the abdominal aorta. CI-930 and zaprinast, at cumulative doses of 3 and 30 mg/kg, respectively, produced comparable reductions in mean arterial pressure (-22 +/- 3 and -19 +/- 4 mm Hg, respectively) and total peripheral resistance (-0.41 +/- 0.07 and -0.42 +/- 0.06 mm Hg/ml/min, respectively) but affected other hemodynamic variables differently. CI-930 at 3 mg/kg increased the heart rate (HR), maximal aortic flow acceleration (dF/dt), and peak aortic flow and decreased the stroke volume (SV). Cardiac output (CO) was not affected by CI-930. Zaprinast at 30 mg/kg increased the CO, dF/dt, and peak aortic blood flow. The HR and SV were unaffected by zaprinast. Although both CI-930 and zaprinast increased the dF/dt and peak aortic flow, these parameters were affected more by CI-930 than by zaprinast. CI-930 decreased hindquarter, mesenteric, and renal vascular resistances in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)