Cyclic AMP-dependent and -independent effects of beta-adrenergic stimulation on the contraction-relaxation cycle of spontaneously beating rat atria.
The effects of isoproterenol (ISO, 1 X 10(-7) M) and phenylephrine (beta-PHEN, 5 X 10(-5) M, in the presence of 5 X 10(-6) M phentolamine) as well as the effect of hypercalcemia (5.7 X 10(-3) M instead of 1.9 X 10(-3) M) on the kinetics of changes in developed tension (DT) and its second derivative (T") and on cAMP level and 45Ca uptake were studied in spontaneously beating rat atria. Both the effects of ISO and the beta-adrenergic effect of PHEN on amplitude were equipotent 15 and 60 sec after administration. However, the ISO response developed faster, and the amplitude at 30 sec was significantly higher in the ISO than in the PHEN response. The effects of ISO on the ratio of the amplitudes of the first maximum and the minimum of T" (T"max/T"min) as well as on the duration of the contraction-relaxation cycle (CRC) were biphasic. At 15 sec, it first produced increases, and subsequently, 60 sec after the drug, these parameters decreased below the control. beta-Phenylephrine produced a similar biphasic response in the ratio T"max/T"min, but the duration of CRC appeared only to decrease 60 sec after the drug. The durations of the contraction phases of T" were reduced both by ISO (30 and 60 sec) and beta-PHEN (60 sec) after administration. All of the effects of beta-PHEN on T" were weaker than those induced by ISO. Furthermore, the ability of PHEN to stimulate the formation of cAMP was also poorer. The inhibition of phosphodiesterase by methylisobutylxanthine enhanced, dose dependently, the increase in the relaxing components of CRC. However, the amplitude response of ISO was antagonized by this drug. The time course effects of ISO on the amplitude and cAMP were parallel. beta-Phenylephrine stimulated first contractility and much later an increase in cAMP. Uptake of 45Ca was stimulated equally by ISO and beta-PHEN. Hypercalcemia produced increases in amplitude, in the ratio T"max/T"min, and in the duration of CRC but no change in the level of cAMP. The data suggest that the beta-adrenergic response is at the outset qualitatively similar to the response of hypercalcemia and that the typical changes in CRC for beta stimulation take place only secondly. Thus, even though cAMP is involved in beta-adrenergic stimulation, it may not be the main cause of positive inotropism. The qualitative changes in CRC, i.e., the increase in the relaxing components and the decrease in time to peak tension, could be responsible for the faster increase in amplitude to the steady-state level.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D006325:Heart Atria / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010646:Phentolamine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000318:Adrenergic beta-Agonists; D007473:Ion Channels; D010656:Phenylephrine; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; D010646:Phentolamine