Phosphodiesterase inhibitors induce endothelium-dependent relaxation of rat and rabbit aorta by potentiating the effects of spontaneously released endothelium-derived relaxing factor.
The selective cyclic GMP phosphodiesterase inhibitor M&B 22948 and the less selective phosphodiesterase inhibitors papaverine and isobutylmethylxanthine (IBMX) each induced a component of relaxation of rat aortic rings that was endothelium-dependent. The most selective agent at inducing endothelium-dependent relaxation was M&B 22948, which caused little relaxation of endothelium-denuded rings at concentrations that produced almost complete relaxation of endothelium-containing rings. Although endothelium-dependent components of relaxation induced by papaverine and IBMX were clearly present, they were less well separated from the endothelium-independent components of relaxation. In the aorta of the rabbit, M&B 22948 and papaverine were less affective at inducing an endothelium-dependent component of relaxation than in the aorta of the rat, and IBMX produced no discernible endothelium-dependent component. The endothelium-dependent components of relaxation induced by M&B 22948, papaverine and IBMX on rat and rabbit aorta were probably dependent on endothelium-derived relaxing factor (EDRF), because they were associated with concomitant endothelium-dependent rises in cyclic GMP, and these components of relaxation as well as the rises in cyclic GMP were completely blocked by the EDRF-blocking agent hemoglobin. The action of hemoglobin was entirely specific, as none of the endothelium-independent components of relaxation induced by any of the phosphodiesterase inhibitors was affected by this hemoprotein. It is likely that the phosphodiesterase inhibitors induce their endothelium-dependent components of relaxation by inhibiting the hydrolysis of cyclic GMP formed in response to EDRF released spontaneously from endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
W
W
Martin
R F
RF
Furchgott
G M
GM
Villani
D
D
Jothianandan
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000032:analysis / Q000187:drug effects; D006152:Cyclic GMP / Q000032:analysis; D004357:Drug Synergism; D004727:Endothelium / Q000502:physiology*; D006454:Hemoglobins / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide; D005996:Nitroglycerin / Q000494:pharmacology; D010208:Papaverine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000502:physiology
D006454:Hemoglobins; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D010208:Papaverine; D005996:Nitroglycerin; C011145:zaprinast; D006152:Cyclic GMP; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine