Effect of glucagon on heart.
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Adenine Nucleotides↗
Biomedical subjects
F Murad
Publications and source records attributed to F Murad.
Immunohemolytic anemia during therapy with methyldopa.
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Aged↗
Ca2+/calmodulin-regulated nitric oxide synthases.
NO synthase (NOS) catalyzes the oxidation of L-arginine to L-citrulline and nitric oxide (NO) or a NO-releasing compound. At least three isoforms of NOS exist (types I-III). The activities of the type I isoform purified from brain and the type III isoform purified from endothelial cells are regulated by the intracellular free calcium concentration ([Ca2+]i) and the Ca(2+)-binding protein calmodulin. At resting [Ca2+]i, both isozymes are inactive; they become fully active at [Ca2+]i greater than or equal to 500 nM Ca2+. Longer lasting increases in [Ca2+]i may downregulate NO formation, for in vitro phosphorylation by Ca2+/calmodulin protein kinase II decreases the Vmax of NOS. Besides the conversion of L-arginine, type I NOS, Ca2+/calmodulin dependently, generates H2O2 and reduces cytochrome c/P450. Other redox activities, i.e. the reduction of nitroblue tetrazolium to diformazan (NADPH-diaphorase) or of quinoid-dihydrobiopterin to tetrahydrobiopterin, by NOS appear to be Ca2+/calmodulin-independent.
Amino Acid Oxidoreductases↗
Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation.
The action of some vascular smooth muscle relaxants depends on the presence of the endothelium. We have recently shown that relaxation may be mediated through the formation of cyclic GMP. The nitrovasodilators are another class of relaxants which exert their effects through the formation of cyclic GMP, although their relaxation is independent of the presence of the endothelium. Their relaxant properties seem to depend on free radical formation--specifically, the formation of nitric oxide. The NO-induced smooth muscle relaxation is proposed to occur through activation of guanylate cyclase and the formation of cyclic GMP. Protein phosphorylation is thought to be a common event in the pathway for many biological phenomena. Moreover, sodium nitroprusside and 8-bromo cyclic GMP induce similar patterns of protein phosphorylation in intact rat thoracic aorta. Here we report that the patterns of protein phosphorylation induced by the endothelium-dependent vasodilators and nitrovasodilators were identical. Incorporation of 32P into myosin light chain was decreased by both classes of agents. Removal of the endothelium abolished the changes in phosphorylation with the endothelium-dependent vasodilator (acetylcholine), but not those with the nitrovasodilator (sodium nitroprusside). These results suggest that endothelium-dependent vasodilators and nitrovasodilators induce relaxation through cyclic GMP-dependent protein phosphorylation and dephosphorylation of myosin light chain.
Acetylcholine↗
NO, nitrotyrosine, and cyclic GMP in signal transduction.
Over the past 25 years, the role of nitric oxide (NO) in biology has evolved from being recognized as an environmental pollutant to an endogenously produced substance involved in cell communication and signal transduction. NO is produced by a family of enzymes called nitric oxide synthases (NOSs), which can be stimulated by a variety of factors that mediate responses to various stimuli. NO can initiate its biological effects through activation of the heterodimeric enzyme, soluble guanylyl cyclase (sGC), or through several other chemical reactions. Activation of sGC results in the production of 3',5'-cyclic guanosine monophosphate (cGMP), an intracellular second messenger signaling molecule, which can subsequently mediate such diverse physiological events such as vasodilatation and immunomodulation. Chemically reactive NO can affect physiological changes through modifications to cellular proteins, one of which is tyrosine nitration. The demonstration that NO is involved in so many biological pathways indicates the importance of this endogenously produced substance, and suggests that there is much more to be discovered about its role in biology in years to come.
Animals↗
Endothelium-dependent and nitrovasodilator-induced activation of cyclic GMP-dependent protein kinase in rat aorta.
Cyclic GMP-dependent protein kinase (cyclic GMP-kinase) activity in isolated strips of rat aorta was measured in the absence and presence of exogenous cyclic GMP (2 microM) and expressed as a ratio. This activity ratio represented an estimate of the endogenous activation state of the enzyme. Acetylcholine [10 microM), an endothelium-dependent vasodilator, increased the activity ratio from a control value of 0.42 to 0.71 in aorta with endothelium intact. With endothelium removed, acetylcholine had no effect on cyclic GMP-kinase activity. The nitrovasodilator sodium nitroprusside (50 nM) increased activity ratios in aorta both with (0.42 to 0.54) and without (0.29 to 0.40) endothelium. Since activity ratios were higher in aortas with an intact endothelium, a tonic influence of the endothelium on aorta cyclic GMP-kinase is suggested. The vasodilator isoproterenol (3 microM) had no effect on cyclic GMP-kinase activity ratios. The increases in cyclic GMP-kinase activity caused by sodium nitroprusside and acetylcholine were preserved when aortas were homogenized in buffer containing 3 mg/ml charcoal. Thus, most of the cyclic GMP-kinase activation occurred in the intact tissue and not because of endogenous cyclic nucleotides present during homogenization or assay. The increases in the activity ratio to sodium nitroprusside and acetylcholine correlate with increases in cyclic GMP concentration and with smooth muscle relaxation. It is concluded that cyclic GMP-kinase in rat aorta is activated by acetylcholine in an endothelium-dependent manner and by sodium nitroprusside in an endothelium-independent manner. These data are consistent with the hypothesis that cyclic GMP mediates relaxation of vascular smooth muscle to acetylcholine and sodium nitroprusside by activating cyclic GMP-kinase and consequent protein phosphorylation. The data further illustrate the importance of endothelial cells in vascular responses to acetylcholine.
Acetylcholine↗