Cyclic GMP inhibition

Taira M, Hodcman SC, Calvo JC, Taira M, Bdfrage P, Manganidlo VC. Molecular doling of the rat adqNMTte honnone-sensitive cyclic GMP-inhibited cydic nudeotide phosphodiesterase. J Biol Chem 1993 268 18573-18579. 

C.J. Smith, V. Vasta, E. Degerman, P. Belfrage, and V. Manganiello, Hormone-sensitive cyclic GMP-inhibited cyclic AMP phosphodiesterase in rat adipocytes. Regulation of insulin- and cAMP-dependent activation by phosphorylation, J. Biol. Chem., 1991, 266, 13385-13390. 

INAMRINONE AND MILRINONE Parenteral formulations of inamrinone (previous name amrinone) and milrinone are approved for short-term support of the circulation in advanced heart failure. Both drugs are bipyridine derivatives and relatively selective inhibitors of PDE3, the cyclic GMP-inhibited cyclic AMP PDE. These drugs cause direct stimulation of myocardial contractility and acceleration of myocardial relaxation. In addition, they cause balanced arterial and venous dilation with a consequent fall in systemic and pulmonary vascular resistances, and left and right heart filling pressures. Cardiac output increases due to the stimulation of myocardial contractility and the decrease in left ventricular afterload. As a result of this dual mechanism of action, the increase in cardiac output with milrinone is greater than that seen with nitroprusside at doses that comparably reduce systemic resistance. Conversely, the arterial and venous dilator effects of milrinone are greater than those of dobutamine at doses that produce comparable increases in cardiac output. 

Hirata, M., Kohse, K. P., Chang, C-H., Ikebe, T., and Murad, F. (1990). Mechanism of cyclic GMP inhibition of inositol phosphate formation in rat aorta segments and cultured bovine aortic smooth muscle cells. /. Biol. Chem. 265, 1268-1273. 

Cyclic GMP is made from GTP by the enzyme gua-nylyl cyclase, which exists in soluble and membrane-bound forms. Each of these isozymes has unique physiologic properties. The atriopeptins, a family of peptides produced in cardiac atrial tissues, cause natriuresis, diuresis, vasodilation, and inhibition of aldosterone secretion. These peptides (eg, atrial natriuretic factor) bind to and activate the membrane-bound form of guanylyl cyclase. This results in an increase of cGMP by as much as 50-fold in some cases, and this is thought to mediate the effects mentioned above. Other evidence links cGMP to vasodilation. A series of compounds, including nitroprusside, nitroglycerin, nitric oxide, sodium nitrite, and sodium azide, all cause smooth muscle re-... 

Bennett, B. M., MacDonald, B. J., Nigam, R., Long, P. G., Simon, W. C., Inhibition of nitrovasodilator- and acetylcholine-induced relaxation and cyclic GMP accumulation by the cytochrome P450 substrate 7-ethoxyresorufin. Can. J. Physiol. Pharmacol. 70 (1992), p. 1297-1303... 

GEA-3162 spontaneously generates NO when dissolved [93, 94]. GEA-3163 inhibited ADP-induced platelet aggregation and induced a dose-dependent increase in cyclic GMP in platelets. The increase in cGMP was potentiated by phosphodiesterase-5 inhibitor, zaprinast, and inhibited by oxyhemoglobin [94]. 

The enzyme phosphodiesterase (PDE) converts cyclic GMP to GMP. The Pfizer scientists wanted to develop a drug to inhibit PDE so that the level of cyclic GMP remains high, so that the last mechanism step can proceed. 

A further characteristic of this principle is that, if the activity of phosphodiesterase is decreased, the concentration of cyclic GMP will increase to an extent dependent upon the extent of the decrease in activity. This characteristic has been made use of by the pharmaceutical industry. Cyclic GMP has a vasodilatory effect and this is the case for the arterioles that supply blood to the corpus cavemosum in the penis, which controls the erection of the penis. Drugs were developed (e.g. sildenafil) that inhibits cyclic GMP phosphodiesterase and hence increases the cyclic GMP level which resnlts in vasodilation of the arterioles and an increase in the snpply of blood to the spongy tissue of the corpus cavemosum, which expands resulting in erection. This dmg has been found to be effective in some patients snffering from erectile dysfunction. This can be a particular problem in diabetic patients and more elderly men (Chapter 19). 

Gold, M. E., Wood, K. S., Byrns, R. E., Fulcuto, J. M., and Ignarro, L. J. (1990). N°-Methyl-L-arginine causes endothelium-dependent contraction and inhibition of cyclic GMP formation in artery and vein. Proc. Natl. Acad. Sci. U.S.A. 87, 4430-4434. 

Mellion, B. T., Ignarro, L. J., Myers, C. B., Ohlstein, E. H., Ballot, B. A., Hyman, A. L., and Kadowitz, P. J. (1983). Inhibition of human platelet aggregation by S-nitrosothiols. Heme-dependent activation of soluble guanylate cyclase and stimulation of cyclic GMP accumulation. Mol. Pharmacol. 23, 653-664. 

B. Cyclic GMP Is Not Involved in Interleukin 1-Induced Inhibition of Insulin Secretion by Islets... 

Most membrane receptors generate a diffusible intracellular signal called a second messenger. Five intracellular messengers are currently known Cyclic AMP, cyclic GMP, inositol triphosphate, diacylglyc-erol, and calcium. Second messengers usually activate or inhibit the action of one or more enzymes. 

Dipyridamole is a vasodilator that inhibits platelet function by inhibiting adenosine uptake and cyclic GMP phosphodiesterase activity. Dipyridamole by itself has little or no beneficial effect. Therefore, therapeutic use of this agent is primarily in combination with aspirin to prevent cerebrovascular ischemia. It may also be used in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves. A combination of dipyridamole complexed with 25 mg of aspirin is now available for secondary prophylaxis of cerebrovascular disease. 

The approved drugs for erectile dysfunction (ED) all share the same mode of action, which is inhibition of phosphodiesterase type 5 (PDE5). PDE5 hydrolyzes the phosphodi-ester of cyclic GMP (cGMP). Elevated levels of cGMP relax the muscle tissue that lines the blood vessels of the corpus cavernosum in the penis. Blood freely enters the tissue,... 

Hall KU, Collins SP, Gamm DM, Massa E, DePaoli-Roach AA, Uhler MD (1999) Phosphorylation-dependent inhibition of protein phosphatase-1 by G-substrate. A Purkinje cell substrate of the cyclic GMP-dependent protein kinase. J Biol Chem 274 3485-95 Han J, Mark MD, Li X, Xie M, Waka S, Rettig J, Herlitze S (2006) RGS2 determines short-term synaptic plasticity in hippocampal neurons by regulating Gi/o-mediated inhibition of presynap-tic Ca2+ channels. Neuron 51 575-86... 

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