title: Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle.
abstract: Activation of 5-HT(4) receptors in failing ventricles elicits a cAMP-dependent positive inotropic response which is mainly limited by the cGMP-inhibitable phosphodiesterase (PDE) 3. However, PDE4 plays an additional role which is demasked by PDE3 inhibition. The objective of this study was to evaluate the effect of cGMP generated by particulate and soluble guanylyl cyclase (GC) on the 5-HT(4)-mediated inotropic response. Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats, exhibiting heart failure 6 weeks after surgery. Contractility was measured in left ventricular preparations. Cyclic GMP was measured by EIA. In ventricular preparations, ANP or BNP displayed no impact on 5-HT(4)-mediated inotropic response. However, CNP increased the 5-HT(4)-mediated inotropic response as well as the β(1)-adrenoceptor (β(1)-AR)-mediated response to a similar extent as PDE3 inhibition by cilostamide. Pretreatment with cilostamide eliminated the effect of CNP. Inhibition of nitric oxide (NO) synthase and soluble GC by L-NAME and ODQ, respectively, attenuated the 5-HT(4)-mediated inotropic response, whereas the NO donor Sin-1 increased this response. The effects were absent during PDE3 inhibition, suggesting cGMP-dependent inhibition of PDE3. However, in contrast to the effects on the 5-HT(4) response, Sin-1 inhibited whereas L-NAME and ODQ enhanced the β(1)-AR-mediated inotropic response. cGMP generated both by particulate (NPR-B) and soluble GC increases the 5-HT(4)-mediated inotropic response in failing hearts, probably through inhibition of PDE3. β(1)-AR and 5-HT(4) receptor signalling are subject to opposite regulatory control by cGMP generated by soluble GC in failing hearts. Thus, cGMP from different sources is functionally compartmented, giving differential regulation of different G(s)-coupled receptors.
authors: Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316, Oslo, Norway.
authors: Faraz
authors: F
authors: Afzal
authors: Eirik
authors: E
authors: Qvigstad
authors: Jan Magnus
authors: JM
authors: Aronsen
authors: Lise Román
authors: LR
authors: Moltzau
authors: Ivar
authors: I
authors: Sjaastad
authors: Tor
authors: T
authors: Skomedal
authors: Jan-Bjørn
authors: JB
authors: Osnes
authors: Finn Olav
authors: FO
authors: Levy
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006333:Heart Failure / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000503:physiopathology; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D006152:Cyclic GMP; D019205:GTP-Binding Protein alpha Subunits, Gs; D006162:Guanylate Cyclase; D020098:Natriuretic Peptide, C-Type; D018342:Receptors, Adrenergic, beta-1; D017461:Receptors, Atrial Natriuretic Factor; D018160:Receptors, Cytoplasmic and Nuclear; D044422:Receptors, Serotonin, 5-HT4; D000071756:Soluble Guanylyl Cyclase; D000099242:Atrial Natriuretic Factor Receptor B