PHOSPHODIESTERASE INHIBITORS INDUCE ENDOTHELIUM-DEPENDENT RELAXATION OF RAT AND RABBIT AORTA BY POTENTIATING THE EFFECTS OF SPONTANEOUSLY RELEASED ENDOTHELIUM-DERIVED RELAXING FACTOR

  • 1 May 1986
    • journal article
    • research article
    • Vol. 237  (2) , 539-547
Abstract
The selective cyclic GMP phosphodiesterase inhibitor M and 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 and 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 and B 22948 and papaverine were less effective 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 and 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. The more profound degree of endothelium-dependent relaxation in the rat aorta than in the rabbit is consistent with our previous reports that the aorta of the rat is under the tonic influence of spontaneously released EDRF to a greater extent than that of the rabbit. Additional evidence that the phosphodiesterase inhibitors can selectively potentiate the actions of agents which act through guanylate cyclase was obtained with M and B 22948: this agent potentiated the relaxation of endothelium-denuded rings of rat and rabbit aorta induced by glyceryl trinitrate, which increases cyclic GMP levels, but did not potentiate the relaxation induced by isoproterenol, which has no effect on cyclic GMP content.