Differential Hemodynamic Responses to Selective Inhibitors of Cyclic Nucleotide Phosphodiesterases in Conscious Rats

Summary: 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. Since the doses of zaprinast at which significant reductions in hindquarter, mesenteric, and renal vascular resistances first occurred were 10,18, and 30 mg/kg, respectively, these vascular beds may be differentially sensitive to the vasorelaxant effects of zaprinast. It is concluded that, although selective inhibitors of either low Km cGMP or low Km cAMP PDE decrease blood pressure by lowering the total peripheral resistance in conscious rats, the accompanying hemodynamic patterns for each agent are different.