Froldi G, Ragazzi E, Caparrotta L
Department of Pharmacology, University of Padova, Largo E. Meneghetti 2, 35131 Padua, Italy.
Comp Biochem Physiol C Toxicol Pharmacol. 2001 Feb;128(2):265-74. doi: 10.1016/s1532-0456(01)00203-4.
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.
ATP和UTP对大鼠左心房产生双重变力作用：首先观察到收缩张力降低，随后升高。PPADS是P2X受体拮抗剂，可抑制ATP和α,β- meATP诱导的正性肌力作用。主要地，我们研究了负责正性肌力作用的细胞内机制。我们分别测试了ATP敏感性钾通道的激活剂克罗卡林和抑制剂格列本脲。这些化合物不影响ATP的作用。磷酸二酯酶抑制剂IBMX以及蛋白激酶C和cAMP依赖性蛋白激酶的抑制剂H-7，均未改变ATP的变力作用。相反，cAMP和cGMP依赖性蛋白激酶的抑制剂H-8强烈抑制ATP和UTP的正性作用，提示cGMP可能参与了变力作用。此外，cGMP生成抑制剂LY 83583可降低α,β- meATP、ATP和UTP引起的正性肌力作用。而且，cGMP的稳定类似物8-溴-cGMP（50 microM）可抑制所有核苷酸引起的正性肌力作用。最后，我们通过放射免疫分析法测定细胞内cGMP水平；在ATP和UTP诱导的正性肌力作用期间，环核苷酸增加。关于正性肌力作用的结果表明：(a) ATP通过P2X受体起作用，而UTP可能通过P2X起作用，但也可通过对PPADS不敏感的受体起作用；(b) 细胞内cGMP浓度的变化参与了这种变力作用。
