Enhancement of amrinone-induced positive inotropy in rabbit papillary muscles with depressed contractile function: effects on cyclic nucleotide levels and phosphodiesterase isoenzymes.
The inotropic activity of amrinone and its effects on cyclic nucleotide levels in rabbit papillary muscles with normal and depressed contractile function have been compared. The effects of amrinone on the cyclic (c) AMP hydrolytic activity of cyclic nucleotide phosphodiesterase (PDE) isoenzymes were also examined. Amrinone (2.4 x 10(-4) - 1.2 x 10(-3) M) produced a relatively weak (maximal increase 11%) positive inotropic effect in papillary muscles stimulated at the near optimal stimulation frequency of 1 Hz. In contrast, large positive inotropic responses (maximal 138-200%) were obtained with amrinone in papillary muscles in which contractile force had been depressed by: (a) lowering stimulation frequency to 0.4 Hz, (b) reducing extracellular Ca2+ concentration from 2.5 x 10(-3) M to 6.3 x 10(-4) M, (c) prior addition of sodium pentobarbitone (6.5 x 10(-4) M). The EC50 values for amrinone under conditions (a), (b), and (c) were 3.0 x 10(-3), 2.6 x 10(-3), and 2.8 x 10(-3) M, respectively. Force-frequency curves in rabbit papillary muscles were compared at normal (2.5 x 10(-3) M) and low (6.3 x 10(-4) M) extracellular Ca2+ concentration. Contractions at low frequencies of stimulation (less than 0.4 Hz) were less sensitive to removal of extracellular Ca2+ than higher stimulation rates indicating that in the former situation, recycling of intracellular Ca2+ is more important for maintaining contractile force.(ABSTRACT TRUNCATED AT 250 WORDS)
Shahid
M
M
Department of Pharmacology, Organon Laboratories Ltd, Newhouse, Lanarkshire, UK.
Rodger
I W
IW
D000676:Amrinone / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011817:Rabbits
D007527:Isoenzymes; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000676:Amrinone