Phosphodiesterase Type 5 Inhibition Enhances Vasorelaxation Caused by Nitroprusside in Guinea Pig Intact Heart and Isolated Aorta

Abstract

Increased vascular smooth muscle cyclic guanine monophosphate (cGMP) results in vascular relaxation. The vascular effects of stimulating cGMP production with 10−8-10−4M nitroprusside (NP) and inhibiting cGMP hydrolysis with 10−8-10−4M zaprinast (ZAP), a selective type V inhibitor of cGMP phosphodiesterase (PDE), were assessed in isolated guinea pig hearts and aortic rings. Coronary flow (CF) IC50 values for NP and ZAP, respectively, were 0.8 ± 0.1 × 10−6M and 3.6 ± 0.1 × 10−6M; for coronary sinus pO2 IC50 values were 0.7 ± 0.1 × 10−6M and 3.7 ± 0.1 × 10−6M. CF increased by 13 ± 2% with 10−6 NP, and by 12 ± 2% with 10−5M ZAP; percentage O2 extraction (%O2E) decreased by 17 ± 3% with NP and 28 ± 4% with ZAP. Together, 10−6M NP + 10−5M ZAP augmented the increased in CF to 23 ± 3% of control, and the decrease in percentage O2 extraction (%O2E) to 40 ± 4% of control. Other cardiac effects of NP and ZAP were minimal. In norepinephrine preconstricted aortic rings, the IC50 for relaxation was elicited at 0.4 ± 0.1 × 10−6M NP and 6.1 ± 0.1 × 10−6M ZAP. NP given with ZAP gave a logarithmic relation so that IC50 [NP] = −(57log10 [ZAP]) + 416; R2 = 0.95. NP, 3 × 10−7M; ZAP, 3 × 10−6M; and NP + ZAP combined increased aortic tissue cGMP by eight-, nine-, and 15-fold, respectively. Inhibiting cGMP hydrolysis may be an effective approach to augment vasorelaxation elicited by cGMP synthesis in the heart.