Premium
Pharmacological and biochemical effects of the cardiotonic agent Org10325 in isolated cardiac and vascular tissue preparations
Author(s) -
Shahid M.,
Martorana M.G.,
Cottney J.E.,
Marshall R.J.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb14084.x
Subject(s) - chronotropic , isoprenaline , inotrope , milrinone , medicine , endocrinology , phenylephrine , chemistry , contractility , phosphodiesterase , pharmacology , biology , biochemistry , enzyme , heart rate , stimulation , blood pressure
1 The pharmacological and biochemical effects of a novel cardiotonic agent, Org10325 have been studied in isolated cardiac and vascular tissue preparations. 2 Org10325 produced concentration‐dependent (0.15–4.8 m m ) positive inotropic, positive chronotropic and vascular relaxant responses in rabbit isolated papillary, atrial and aortic preparations, respectively. The maximal chronotropic effect (45%) was significantly less than the isoprenaline maximum. The inotropic effects of Org10325 were not modified by α‐ or β‐adrenoceptor blockade or by pretreatment with reserpine. Org10325 was at least 23 times more potent at relaxing aortic strips pre‐contracted with phenylephrine than with KCl. 3 Org10325 (74 μ m ) potentiated (10–14 fold) the positive inotropic effects of isoprenaline in rabbit isolated papillary muscles. Carbachol inhibited the positive inotropic effect of Org10325. Both the positive inotropic and vasorelaxant effects of Org10325 were accompanied by increases in cyclic AMP but not cyclic GMP. 4 In rat perfused heart preparation Org10325 increased phosphorylase a , cyclic AMP‐dependent protein kinase activities and stimulated phosphorylation of contractile proteins (troponin‐I and C‐protein). 5 Org10325 selectively inhibited the cyclic AMP hydrolytic activity of cyclic AMP high affinity cyclic nucleotide phosphodiesterase (PDE) isoenzymes, PDE III (IC 50 65 μ m ) and PDE IV (IC 50 71 μ m ), from rabbit cardiac ventricle. Weak inhibition (IC 50 > 250μ m ) of PDE I and PDE II was observed. 6 The results show that the cardiac and vascular effects of Org10325 are mediated by an increase in cellular cyclic AMP due to inhibition of PDE III and PDE IV activities. However, in contrast to other PDE‐inhibitors Org10325 produced a marked increase in relaxation time of isolated papillary muscle suggesting the involvement of additional cyclic AMP‐independent mechanisms of action.