An unexpected potent positive chronotropic effect of (15s)-15-methyl-prostaglandin E1 in the isolated guinea-pig right atria

Background Although both positive chronotropic and inotropic effects of beta-adrenergic stimulation are thought to be mediated by cyclic adenosine 3'5'-monophosphate, phosphodiesterase III inhibitors such as amrinone and milrinone potentiate the positive inotropic effect of catecholamines with minimum influence on the heart rate in clinical setting. The aim of the current study was to compare the positive chronotropic effect of norepinephrine with that of forskolin to elucidate whether cyclic adenosine monophosphate is relevant to the chronotropic effect of norepinephrine. Methods Concentration-response curves for the positive chronotropic effects of norepinephrine and forskolin on the spontaneously beating right atria of guinea pigs were determined in the absence and presence of phosphodiesterase inhibitors or ion channel inhibitors. In some experiments, the left atria driven electrically were used to determine the positive inotropic effect of norepinephrine. Results Norepinephrine and forskolin increased the beating rate in a concentration-dependent manner. The positive chronotropic effect of forskolin was potentiated by amrinone and 3-isobutyl-1-methylxanthine, whereas the positive chronotropic effect of norepinephrine was not potentiated by the phosphodiesterase inhibitors. In contrast, the positive inotropic effect of norepinephrine was potentiated by amrinone. The hyperpolarization-activated inward current inhibitor cesium chloride and L-type voltage-dependent Ca2+ current inhibitor verapamil suppressed the chronotropic effect of norepinephrine, whereas these inhibitors did not affect the chronotropic effect of forskolin. Conclusion Norepinephrine increases the spontaneously beating rate by a different mechanism from that of forskolin, suggesting that cyclic adenosine monophosphate is causally unrelated to the positive chronotropic effect of norepinephrine in the guinea pig heart.

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Positive chronotropic effect of ouabain on the isolated guinea pig atrium (Ger.)

Journal of Electrocardiology ◽

10.1016/s0022-0736(69)80072-5 ◽

1969 ◽

Vol 2 (1) ◽

pp. 88

Author(s):

E. Lepeschkin

Keyword(s):

Guinea Pig ◽

Chronotropic Effect ◽

Guinea Pig Atrium ◽

Positive Chronotropic Effect

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α1a-Adrenergic receptor mediated positive chronotropic effect in right atria isolated from rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y94-226 ◽

1994 ◽

Vol 72 (12) ◽

pp. 1574-1579 ◽

Cited By ~ 16

Author(s):

Anthony P. Williamson ◽

Ernst Seifen ◽

Jon P. Lindemann ◽

Richard H. Kennedy

Keyword(s):

Adrenergic Receptor ◽

Response Curve ◽

Male Rats ◽

Chronotropic Effect ◽

Rightward Shift ◽

Spontaneous Rate ◽

Negative Chronotropic Effect ◽

Right Atria ◽

Concentration Response Curve ◽

Positive Chronotropic Effect

Experiments in right atria isolated from adult male rats were designed to determine which of the α1-adrenergic receptor (α1-AR) subtypes are involved in the positive chronotropic effect of phenylephrine, an α1-AR agonist. Chloroethylclonidine (CEC), an irreversible α1b-, α1c-, and α1d-AR antagonist, did not alter the efficacy or potency of phenylephrine; however, CEC did elicit a concentration-dependent negative chronotropic effect and reduce the absolute maximum spontaneous rate observed in the presence of phenylephrine. WB4101, a competitive α1a- and α1c-AR-selective antagonist, did not alter basal spontaneous rate or the efficacy of phenylephrine, but it did produce a significant rightward shift of the phenylephrine concentration–response curve. Phenoxybenzamine, an irreversible nonselective α-AR antagonist, elicited a concentration-dependent negative chronotropic effect, a significant rightward shift of the phenylephrine concentration–response curve, and a reduction in the efficacy of phenylephrine. The chronotropic action of the β-adrenergic agonist isoproterenol was not affected by CEC, WB4101, or phenoxybenzamine. These data suggest that the positive chronotropic effect of α1-adrenergic agonists in rat right atria is mediated via stimulation of α1a-ARs.Key words: α1-adrenergic receptor subtypes, chloroethylclonidine, WB4101, phenylephrine, right atria (rat).

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