PHOSPHODIESTERASE INHIBITION AND MUSCLE CONTRACTION

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The goals of this research program are to elucidate some of the fundamental mechanisms that control contraction of coronary arteries and to gain insights into the mechanisms by which smooth muscle relaxants in general, and the xanthines in particular, can relax smooth muscle. Specifically, we will develop methods to determine the extent of phosphorylation of myosin light chain kinase in intact coronary arteries and use these methods to study the effect of relaxing agents upon the extent of phosphorylation of this enzyme. We will also determine if myosin light chain kinase activity and phosphodiesterase activities are controlled by calmodulin in the intact bovine coronary arteries and determine the effects of various smooth muscle relaxants on the levels of the enzyme-calmodulin complexes. In addition, we will utilize a "skinned" preparation of bovine coronary artery strips that we have recently developed in our laboratory. We will investigate whether the cyclic nucleotide dependent protein kinases will cause relaxation of these preparations that do not have a functional sarcolema to prevent access of large molecules to the contractile system. If the kinases cause relaxation, we will endeavor to identify the substrates involved. We will also use the "skinned" artery strips to attempt to identify smooth muscle relaxing agents that can act on this system in order to identify agents that may act on the contractile system or those control systems that are still functional in the "skinned" preparation.