Thus, PGI(2) analogs potently inhibit proliferation of human pulmonary artery, probably via a cAMP-dependent pathway, although cAMP elevation in itself is not a good predictor of antiproliferative potency. UT-15 produced a significantly larger and more sustained increase in cAMP compared with other analogs, with iloprost being the weakest elevator. Phosphc,rylase activation in smooth muscle is accelerated by cyclic AMP (145), apgarently by a mechanism similar to that which occurs in skeletal muscle (35. Experimental evidence suggests that each of these messenger molecules exerts regulatory influences. The production and metabolism of these cyclic nucleotides and the regulation of intracellular concentrations of Ca 2+ are highly interdependent. Intracellular cyclic AMP (cAMP) was elevated by all analogs and inhibited by DDA, although SQ22536 was a highly variable inhibitor, suggesting that different pathways might mediate cAMP generation. Smooth muscle relaxation is mediated by the intracellular second messengers cyclic AMP and cyclic GMP. Active glycogen phosphorylase then catalyzes the breakdown of glycogen to glucose1phosphate. Effects were reversed by the adenylyl cyclase inhibitor, 2,5'dideoxyadenosine (DDA) but not SQ22536. In this study we determined whether cAMP is metabolized to adenosine in vascular smooth muscle cells and whether cAMP-derived adenosine modulates vascular. Cyclic AMP binds to protein kinase A, which then catalyzes the transfer of phosphate from ATP to a serine residue on a second enzyme, phosphorylase kinase, which itself transfers a phosphate to glycogen phosphorylase. smooth muscle cell line is regulated by beta2 - adrenergic CAMP analogues. Serum-induced proliferation, as assessed by thymidine incorporation (30 h) or cell number (48 h), was significantly inhibited with a 10-fold difference in potency, ranking in effectiveness UT-15 > iloprost > cicaprost > beraprost. staurosporine and cyclic AMP : methods for assessing a The mechanism of cAMP. We therefore investigated the antiproliferative activity of several prostacyclin (PGI(2)) analogs on human pulmonary arterial smooth muscle cells, including UT-15 and iloprost, analogs that have recently completed successful clinical trials. Stable analogs are increasingly being used to treat this disease, although no data exists comparing their effects on proliferation. The principal determinant of smooth muscle contraction is the intracellular free Ca2 + concentration, and phosphorylation of myosin light chain (MLC) by activated myosin light chain kinase (MLCK) in response to increased Ca 2 + is the main pathway by which vasoconstrictor stimuli induce crossbridge cycling of myosin and actin filaments. 246, 177–185 (1971).Primary pulmonary hypertension is characterized by increased pulmonary vascular resistance and smooth muscle proliferation. Instead, cyclic AMP stimulates a protein kinase cascade that ultimately leads to a cellular response. in Colloquium on Smooth Muscle, Pharmacology and Physiology (eds Worcel, M. Cyclic AMP doesnt act directly on its target enzymes for example, glycogen phosphorylase and glycogen synthase. Cyclic AMP (cAMP) mediates relaxation by beta-adrenergic agonists as well as other activators of adenylate cyclase. in Excitation–Contraction Coupling in Smooth Muscle (eds Casteels, R., Godfraind, T. Towards an understanding of the mechanism of action of cyclic AMP and cyclic GMP in smooth muscle relaxation Cyclic GMP (cGMP) mediates the relaxing action of a variety of vasodilator drugs and endogenous vasodilator substances. & Brown, B.) (Plenum, New York, 1975).Īndersson, R. Beta2-adrenoceptor agonists such as epinephrine stimulate. Anti-Actin, Anti-Smooth Muscle, Antibodies, Anti-Cyclic Citrullinated Peptide (Ccp). in Regulation of Function and Growth of Eukaryotic Cells by Intracellular Cyclic Nucleotides (eds Dumont, J. NO and cGMP together comprise an especially wide-ranging signal transduction system when one considers the many roles of cGMP in physiological regulation, including smooth muscle relaxation. Cyclic-AMP also plays an important role in regulating the contraction of vascular smooth muscle. 5-Amp-Phosphate Release (Colorimetric Test), 5-Nucleotidase.
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