title: 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(-4) M nitroprusside (NP) and inhibiting cGMP hydrolysis with 10(-8)-10(-4) M 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 x 10(-6) M and 3.6+/-0.1 x 10(-6) M; for coronary sinus pO2 IC50 values were 0.7+/-0.1 x 10(-6) M and 3.7+/-0.1 x 10(-6) M. CF increased by 13+/-2% with 10(-6) NP, and by 12+/-2% with 10(-5) M ZAP; percentage O2 extraction (%O2E) decreased by 17+/-3% with NP and 28+/-4% with ZAP. Together, 10(-6) M NP + 10(-5) M 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 x 10(-6) M NP and 6.1+/-0.1 x 10(-6) M ZAP. NP given with ZAP gave a logarithmic relation so that IC50 [NP] = -(57 log10 [ZAP]) + 416; R2 = 0.95. NP, 3 x 10(-7) M; ZAP, 3 x 10(-6) M; 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.
authors.affiliation: Department of Anesthesiology, Cardiovascular Research Center, Medical College Wisconsin, and Veterans Affairs Medical Center, Milwaukee 53226, USA. dfstowe@mcw.edu
authors.forename: F
authors.initials: F
authors.lastname: Stowe
authors.forename: E
authors.initials: E
authors.lastname: Novalija
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D006152:Cyclic GMP / Q000096:biosynthesis; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004347:Drug Interactions; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011688:Purinones / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D014665:Vasodilator Agents; D009599:Nitroprusside; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C011145:zaprinast; D006152:Cyclic GMP