Concentration and time-dependent relationships between isosorbide dinitrate-induced relaxation and formation of cyclic GMP in coronary arterial smooth muscle.

This study is based on the hypothesis that isosorbide dinitrate (ISDN)-induced relaxation of coronary arterial smooth muscle is causally linked to formation of cyclic (c) GMP. The hypothesis requires the extent of relaxation to be correlated to both time-and concentration-dependent increases in coronary content of cGMP. Accordingly, studies were performed with bovine coronary arterial strips to determine the relationships among isometric force and coronary content of cGMP and cAMP with respect to time of exposure to and concentration of ISDN. Cyclic nucleotide levels were determined by radioimmunoassay. No change in cAMP levels was observed during ISDN-induced relaxation of KCl contracted strips. In sharp contrast, cGMP levels increased significantly with time of exposure and concentration of ISDN stimulation. Moreover, the addition of methylene blue, a reported inhibitor of guanylate cyclase, to the bathing medium significantly inhibited the relaxation and cGMP increase during ISDN stimulation. In addition, prolonged exposure to ISDN resulted in a redevelopment of force with a parallel decrease in cGMP content. The increase in cGMP during ISDN stimulation also occurs in the absence of depolarization by KCl and in an essentially Ca++-free medium. These data support the hypothesis that the relaxation of coronary arterial strips in response to ISDN stimulation is causally linked to cGMP.