Do ATP and UTP involve cGMP in positive inotropism on rat atria?
ATP and UTP induced a dual inotropic effect in rat left atria: first a decrease and then an increase in contractile tension were observed. PPADS, an antagonist of P2X receptors, inhibited positive inotropism induced by ATP and alpha,beta-meATP. Chiefly, we investigated intracellular mechanisms responsible for the positive inotropism. We tested cromakalim and glibenclamide, an activator and an inhibitor, respectively, of ATP-sensitive K(+) channels. These compounds did not influence the effects of ATP. IBMX, a phosphodiesterase inhibitor, and H-7, an inhibitor of protein kinase C and cAMP-dependent protein kinase, did not modify the inotropic effects of ATP. Instead, H-8, an inhibitor of cAMP- and cGMP-dependent protein kinases, strongly inhibited the positive effects of both ATP and UTP, suggesting the possible involvement of cGMP in the inotropism. Also, LY 83583, an inhibitor of cGMP production, reduced positive inotropism by alpha,beta-meATP, ATP and UTP. Moreover, 8-Br-cGMP (50 microM), a stable analogue of cGMP, inhibited positive inotropism by all nucleotides. Lastly, we determined intracellular cGMP levels by RIA; the cyclic nucleotide increased during positive inotropism induced by ATP and UTP. The results regarding positive inotropism suggest that: (a) ATP acts through P2X receptors, while UTP may act by P2X, but also through PPADS-insensitive receptors; and (b) changes in intracellular cGMP concentration are involved in this inotropic effect.
Department of Pharmacology, University of Padova, Largo E. Meneghetti 2, 35131 Padua, Italy. froldi@ux1.unipd.it
G
G
Froldi
E
E
Ragazzi
L
L
Caparrotta
D000255:Adenosine Triphosphate / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D016275:Atrial Function; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015221:Potassium Channels; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D014544:Uridine Triphosphate / Q000502:physiology*
D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D015221:Potassium Channels; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; C117780:mitochondrial K(ATP) channel; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate; D006152:Cyclic GMP; D014544:Uridine Triphosphate