Α‐sympathomimetic Amines and Calcium‐mediated Action Potentials in Guinea‐pig Ventricular Muscle

Ledda, F.; Mantelli, Laura; Mugelli, Alessandro

doi:10.1111/j.1476-5381.1980.tb07905.x

Cited by 34 publications

(8 citation statements)

References 29 publications

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“…Again these properties are shared by isoprenaline [17] and are in good agreement with the hypothesis of a cAMPmediated inotropic effect: more particularly, the increase in the rate of relaxation and the ability of the inotropic effect to follow high frequencies of stimulation can be adequately explained by a cAMP-stimulated calcium uptake by the sarcotubular system [28]. With regard to the characteristics of the Hi-receptor-mediated inotropie effect it is apparent that, owing to the lack of specificity of PEA at high doses [23], they must be inferred from the effects induced by PEA concentrations up to 10-5-3 x 10 -5 M. Our findings interestingly indicate that PEA, at these concentrations, showed properties very similar to those previously demonstrated with alpha tamine H t receptors is chiefly due to an enhanced adl"enoceptor agonists [17,29,30] which also are release of calcium from the sarcotubular system. known to be capable of inducing a cAMP-…”

Section: Discussionsupporting

confidence: 81%

Some characteristics of the inotropic effects of histamine H1- and H2-receptor agonists in comparison with those of alpha- and beta-adrenoceptor agonists

et al. 1982

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The positive inotropic effects of 2-pyridyl-ethylamine (PEA) and of 4-methylhistamine (4MeH) were studied in isolated guinea-pig ventricular strips electrically stimulated at a rate of 60 and 150/min. The increase in contractile tension induced by PEA (10(-7)-3 X 10(-4) M) in the presence of cimetidine (10(-5) M) was associated with a slight increase in time to peak tension and with a lengthening of the relaxation phase; the positive inotropic effect of PEA was significantly higher at a frequency of 60/min than at 150/min. Conversely, the inotropic response to 4MeH (10(-8)-3 X 10(-6) M) was not frequency dependent, and was associated with an evident decrease in relaxation time. Moreover, 4MeH consistently antagonized, in dose-dependent manner, the negative inotropic effects induced by the calcium antagonistic drug D600 and by lowering calcium concentration in the medium, and was able to restore the contractility abolished by treatment of preparations with a high K+ medium. On the other hand PEA, in the presence of cimetidine, scarcely antagonized the negative inotropic effects induced either by D600 or by low calcium solution, and was unable to restore the contractility of K+-depolarized preparations. The characteristics of the inotropic response of the H1-receptor agonist were very similar to those of the alpha-adrenoceptor agonist phenylephrine. This observation suggests that a common mechanism is probably involved in the inotropic effects mediated by H1 and by alpha receptors, and that this mechanism does not include a stimulation of the calcium transmembrane influx.

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Section: Discussionsupporting

confidence: 81%

Some characteristics of the inotropic effects of histamine H1- and H2-receptor agonists in comparison with those of alpha- and beta-adrenoceptor agonists

et al. 1982

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“…These and the present results suggest that the positive inotropic effect of phenylephrine in the presence of propranolol, at least in rabbit and cattle, is mediated by a-adrenoceptors and that it is probably related to an increase in the slow calcium inward current. However, contradictory results were reported by Ledda et al (1980) and Sanchez-Chapula (1981) who found that the effects of phenylephrine on slow action potentials in guinea-pig papillary muscles were completely abolished by P-blocking agents. These discrepancies do not necessarily contradict the conclusion drawn above; they are more likely to be due to species differencies.…”

Section: Voltage Clamp Experimentsmentioning

confidence: 87%

Effects of α‐adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart

Brückner

Scholz

1984

British J Pharmacology

125

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The mechanism of the cyclic AMP-independent positive inotropic effect of cardiac alpha-adrenoceptor stimulation was studied by analyzing the effects of phenylephrine on force of contraction, calcium-dependent slow action potentials and the slow inward current (Isi) in bovine ventricular trabeculae. The preparations were electrically driven at 0.3 Hz in the presence of propranolol 1 mumol 1(-1). Phenylephrine increased the force of contraction in a concentration-dependent manner (maximum about 200% of control at 30 mumol 1(-1). The effect was surmountably antagonized by phentolamine. The positive inotropic effect of phenylephrine was accompanied by a concentration-dependent increase in time to peak force and occurred without any detectable increase in cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels. The positive inotropic effect of phenylephrine was accompanied by an increase in action potential duration both at 20% and 90% repolarization. Calcium-dependent slow action potentials were also prolonged by phenylephrine and there was a distinct increase in the maximal rate of depolarization (dV/dtmax) of these slow potentials. These effects were also completely reversible on washing and surmountably blocked by phentolamine. However, the increase in dV/dtmax was smaller than that of isoprenaline in concentrations producing similar inotropic effects. Voltage-clamp experiments with the single sucrose-gap method showed that the phenylephrine-induced increase in force of contraction was associated not only with an increase in peak slow calcium inward current, Isi max, but also with a delay in the inactivation of Isi. Outward currents were not detectably altered by phenylephrine. It is concluded that the alpha-adrenoceptor mediated, cyclic AMP-independent positive inotropic effects of phenylephrine in bovine cardiac muscle are associated with an increase in slow inward current. Additionally, the amount of calcium influx during excitation is probably increased by a delay in the inactivation of Isi. Both effects can explain the phenylephrine-produced prolongation of the action potential, and probably contribute to the positive inotropic effect of alpha-adrenoceptor stimulation. However, as the effect on dV/dtmax is smaller than that of isoprenaline, other (still unknown) mechanisms may also be involved.

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“…Although it has been proposed that a, agonists increase , others have suggested that the predominant effect is not an increase in ICa (24,25) but, rather, a reduction in time-independent (26) or timedependent (27, 28) …”

Section: Introductionmentioning

confidence: 99%

“…Although it has been proposed that a, agonists increase ICa (20)(21)(22)(23), others have suggested that the predominant effect is not an increase in ICa (24,25) but, rather, a reduction in time-independent (26) or timedependent (27,28) Pharmacologic agents were applied by pressure ejection from 1-to 3-,um "puffer" pipettes placed within =25 ,um of the cell surface. A PMA stock solution was prepared at 1 mM in dimethyl sulfoxide, aliquoted, and stored under N2 at -70°C; the PDA stock was 0.1 mM in dimethyl sulfoxide.…”

mentioning

confidence: 99%

Alpha 1-adrenergic agonists selectively suppress voltage-dependent K+ current in rat ventricular myocytes.

Apkon

Nerbonne

1988

Proc. Natl. Acad. Sci. U.S.A.

200

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The effects of a1-adrenergic agonists on the waveforms of action potentials and voltage-gated ionic currents were examined in isolated adult rat ventricular myocytes by the whole-cell patch-clamp recording technique. After "puffer" applications of either of two a, agonists, phenylephrine and methoxamine, action-potential durations were increased. In voltage-clamped cells, phenylephrine (5-20 isM) or methoxamine (5-10 #M) reduced the amplitudes of Ca2"-independent voltage-activated outward K+ currents (Io); neither the kinetics nor the voltage-dependent properties of 'out were significantly affected. The effects of phenylephrine or methoxamine on 'out were larger and longer-lasting at higher concentrations and after prolonged or repeated exposures; in all experiments, however, lout recovered completely when puffer applications were discontinued. The suppression of IoUt is attributed to the activation of a1-adrenergic receptors, as neither P-nor r2-adrenergic agonists had measurable effects on IOt; in addition, the effect of phenylephrine was attenuated in the presence of the a antagonist phentolamine (10 ,uM), but not in the presence of the (3 antagonist propranolol (10 ,IM). Voltage-gated Ca2+ currents, in contrast, were not altered measurably by phenylephrine or methoxamine and no currents were activated directly by these agents. Suppression of Iot was also observed during puffer applications ofeither oftwo protein kinase C activators, phorbol 12-myristate 13-acetate (10 nM-1 pM) and 1-oleoyl-2-acetylglycerol (60 ,uM). We conclude that the activation of a1-adrenergic receptors in adult rat ventricular myocytes leads to action-potential prolongation as a result of the specific suppression of 'out and that this effect may be mediated by activation of protein kinase C.Although it seems certain that the major effects of sympathomimetic agents on the mammalian heart are mediated by activation of 8-adrenergic receptors, the presence of aadrenergic receptors, which appear to be predominantly of the a, subtype (1, 2), has also been demonstrated in many preparations, including human atrial (3) and ventricular (4) muscle. In addition to variations among species (2), both the absolute and relative numbers of a,-and /3-adrenergic receptors are altered under some pathological conditions (5, 6). Although stimulation of a receptors results in actionpotential (AP) prolongation and inotropic responses similar (although not identical) to those seen on p-receptor activation (1, 2, 6), the mechanisms involved in mediating these effects are not well understood (1, 6). This contrasts markedly with 13-receptor stimulation, which results in increased cAMP, activation of cAMP-dependent protein kinase, and, presumably, protein phosphorylation (7); at the membrane level, p-receptor agonists increase the amplitude (7) of voltagegated inward Ca2" currents (Ica), by increasing the number and/or the opening probability of functional Ca2" channels (8,9). The effects of a, agonists are apparently not mediated by a similar mechanism, as...

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Α‐sympathomimetic Amines and Calcium‐mediated Action Potentials in Guinea‐pig Ventricular Muscle

Cited by 34 publications

References 29 publications

Some characteristics of the inotropic effects of histamine H1- and H2-receptor agonists in comparison with those of alpha- and beta-adrenoceptor agonists

Some characteristics of the inotropic effects of histamine H1- and H2-receptor agonists in comparison with those of alpha- and beta-adrenoceptor agonists

Effects of α‐adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart

Alpha 1-adrenergic agonists selectively suppress voltage-dependent K+ current in rat ventricular myocytes.

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