COMPARATIVE HEMODYNAMIC AND RENAL EFFECTS OF THE LOW KM CGMP PHOSPHODIESTERASE INHIBITORS CICLETANINE AND ZAPRINAST IN ANESTHETIZED DOGS

Cicletanine, a vasorelaxant/natriuretic agent, inhibits low K(m) cGMP-phosphodiesterase (PDE) (IC50 = 300-mu-M). The objectives of this study were to compare the cardiovascular and renal effects of cicletanine with another cGMP-PDE inhibitor, zaprinast (IC50 = 0.3-mu-M), at intravenous dosages of 0.3-3 mg/kg, and to examine the influence of beta-adrenoreceptor blockade (nadolol, 1 mg/kg, i.v.) upon the responses to cicletanine in anesthetized dogs. Cicletanine (3 mg/kg) and zaprinast (0.3-3 mg/kg) decreased mean arterial pressure (-21.2 +/- 3.9 mm Hg [mean +/- SEM, max. change] at 3 mg/kg and -64.7 +/- 4.8 mm Hg at 0.3 mg/kg, respectively). The response curve of zaprinast was negatively related to the dosages. Cardiac output was increased or tended to increase by approximately 0.3 liter/min by both cicletanine and zaprinast at 3 mg/kg. Renal, but not femoral, blood flow was increased by both cicletanine and zaprinast (18.8 +/- 3.7 ml/min at 3 mg/kg and 17.0 +/- 4.6 ml/min at 1 mg/kg, respectively). These agents did not have major effects upon heart rate, left ventricular end diastolic pressure, and maximum rates of rise and decline in left ventricular pressure. These agents also did not affect pulmonary systolic, mean and diastolic arterial pressures, nor arterial blood pO2, pCO2, and pH. Both cicletanine and zaprinast increased or tended to increase urinary output (0.66 +/- 0.05 and 0.43 +/- 0.22 ml/min, respectively, both at 3 mg/kg) and urinary Na+ excretion (150.4 +/- 19.7 and 67.0 +/- 30.9-mu-Eq/min, respectively, both at 3 mg/kg). Neither agents affected urinary K+ excretion. None of the responses to cicletanine were altered by beta-blockage, suggesting that beta-adrenoreceptors were not involved in mediating the effects of cicletanine. In conclusion, the cGMP-PDE inhibitors cicletanine and zaprinast vasodilate, increase renal blood flow, and induce diuresis and natriuresis in anesthetized dogs. However, the differences in the natriuretic and vasodilator effects of these agents cannot be explained by the difference in their potencies in PDE inhibition, suggesting that their effects in these dogs may involve additional mechanisms of action.