Differential effects of (-)-norepinephrine and of (+/-)-isoproterenol on cardiac contraction, an uptake phenomenon.
Concentration-dependent inotropic effects of (-)-norepinephrine and of (+/-)-isoproterenol were compared in isometrically contracting guinea pig papillary muscles stimulated at a frequency of 0.2 Hz. (-)-Norepinephrine (0.1-100 mumol/l) elicited a positive inotropic effect that was not antagonized by carbachol, failed to produce a positive inotropic staircase after resumption of stimulation and shortened relaxation time in a concentration-dependent fashion.(+/-)-Isoproterenol had a dual action: at low and moderately effective concentrations (1-30 nmol/l), the positive inotropic effect was antagonized by carbachol, a positive inotropic staircase was elicited and time to peak force was shortened. At (+/-)-isoproterenol concentrations exceeding an EC80 for the positive inotropic effect (greater than 30 nmol/l), relaxation time became shorter, staircase and carbachol-induced antagonism became less pronounced until at 300 nmol/l inotropic effects of (+/-)-isoproterenol resembled closely those of (-)-norepinephrine. Cyclic AMP derivatives and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine mimicked (+/-)-isoproterenol in their inotropic actions. Impairment of neuronal uptake caused (-)-norepinephrine 1) to produce (+/-)-isoproterenol-like effects on the isometric contraction, 2) to induce a positive inotropic staircase and 3) to become sensitive to carbachol-induced antagonism. The results are compatible with the concept that neuronal uptake produces a distribution of (-)-norepinephrine within the papillary muscle which allows predominantly high concentrations of (-)-norepinephrine to become effective in the receptor compartment.(ABSTRACT TRUNCATED AT 250 WORDS)
Korth
M
M
Institut für Pharmakologie und Toxikologie der Technischen Universität München, Federal Republic of Germany.
Schmied
R
R
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology*; D010210:Papillary Muscles / Q000378:metabolism; D010766:Phosphorylation; D013237:Stereoisomerism
D002217:Carbachol; D000242:Cyclic AMP; D003042:Cocaine; D007545:Isoproterenol; D002118:Calcium; D009638:Norepinephrine