EFFECTS OF NUCLEOTIDE CYCLASE ACTIVATORS ON THE DEPRESSOR RESPONSE TO SELECTIVE LOW KM CYCLIC-AMP PHOSPHODIESTERASE INHIBITORS IN RATS

The potential interaction between agents which promote vasodilation through cyclic AMP (cAMP)- and cyclic GMP (cGMP)-dependent mechanisms was examined in conscious, spontaneously hypertensive rats (SHR). Selective inhibitors of low Km cAMP phosphodiesterase (PDE), Cl-930 (0.1-10 mg/kg) and milrinone (0.03-3 mg/kg), were administered i.v. to SHR during a steady-state i.v. infusion of either the guanylate cyclase activator sodium nitroprusside (SNP, 5 or 15-mu-g/kg/min) or the adenylate cyclase activator fenoldopam (20-mu-g/kg/min). The depressor responses to Cl-930 and milrinone were significantly attenuated in the presence of SNP. This attenuation of the depressor response to Cl-930 was apparently not due to a hemodynamic floor effect since an equihypotensive dose of the calcium channel blocker verapamil (20-mu-g/kg/min infusion preceeded by a loading dose of 1.2 mg/kg i.v.) did not alter the response to Cl-930. The depressor response to Cl-930 was also attenuated during an infusion of fenoldopam, although this interaction was dependent upon the order of administration of these agents since pretreatment with Cl-930 (0.3 mg/kg, i.v.) potentiated the depressor response to infusions of fenoldopam (10 and 20-mu-g/kg/min). These data suggest that activation of either adenylate or guanylate cyclase may alter the intrinsic activity of low Km cAMP PDE and functionally impair the ability of inhibitors of this PDE isozyme to lower blood pressure. Furthermore, the interactive effects of fenoldopam and Cl-930 on blood pressure are dependent upon the order of administration.