On the mechanism of isoprenaline‐ and forskolin‐induced depolarization of single guinea‐pig ventricular myocytes.

Abstract

SUMMARY1. Isoprenaline (10 nM to 1 /M) and forskolin (06-100 /M) depolarized single guinea-pig myocytes studied in vitro. Under voltage clamp both agents caused an inward current to flow.2. These effects were abolished by propranolol (100 nM) and the /,1-antagonist metoprolol (100-200 nM), but not by the fl2-antagonist salbutamol (1 ,FM).3. The interaction of isoprenaline with forskolin, caffeine or isobutylmethylxanthine (IBMX) on current amplitude was as expected if all of these drugs were causing inward current by increasing intracellular levels of cyclic adenosine monophosphate (cyclic AMP). Low concentrations of forskolin (< 600 nM) or IBMX (< 20 /M) potentiated the effect of isoprenaline, whereas isoprenaline caused no further inward current in cells in which high concentrations of forskolin (600 nM-100 /SM) or IBMX (20 /SM-1 mM) were already evoking maximum inward current.4. Isoprenaline-induced inward current was reduced 30-50 % by acetylcholine (10-30 /tM). This action of acetylcholine was blocked by atropine (100 nM).5. The effect of isoprenaline on holding current was critically dependent on temperature. The onset of the current was delayed and its amplitude reduced as the myocyte was cooled from 37°C to ambient temperature (22-24°C).6. Isoprenaline-induced inward current was not affected by the potassium channel blockers barium (2 mM) or tetraethylammonium (TEA; 10-20 mM). T. M. EGAN AND OTHERS9. The inward current was absent when external sodium was replaced by the impermeant ion tetramethylammonium (TMA).10. Isoprenaline-and forskolin-induced inward currents were associated with an increase in both membrane chord conductance and noise. The increase in conductance was most readily measured at potentials where the inwardly rectifying potassium channel, iK1, was small, or when iKl was blocked by the addition of barium (2 mM).11. The I-V relationship for the total current caused by isoprenaline or forskolin also reflected the effects of these drugs on the calcium current (ica) and the delayed rectifier (iK). When the contributions of ica and iK to the I-V curve were minimized, the remaining inward current reversed at positive potentials. Extrapolation of the linear portion of the I-V curve suggested that the true reversal potential was close to that for sodium.12. These experiments suggest that agents which increase intracellular cyclic AMP open a channel in guinea-pig ventricular sarcolemma which is permeable to sodium ions.

Modulation of the isoprenaline‐induced membrane hyperpolarization of mouse skeletal muscle cells

“…The observed hyperpolarization of the membrane potential, V., by isoprenaline in skeletal muscle fibres, has been attributed to stimulation of the Na+-K+-pump by the cyclic AMPdependent cascade (Clausen, 1986;Li & Sperelakis, 1993). From the literature on cardiac tissue however, a more complex picture emerges comprising influences on V. by the stimulation of the Na+-K+-pump (D1silets & Baumgarten, 1986), K+-conductance (Gadsby, 1983;Boyden et al, 1983a), Na+-conductance (Egan et al, 1988), Ca2+-conductance (Tsien et al, 1986) or Cl--conductance (Harvey & Hume, 1989;Ehara & Ishihara, 1990;Nakaya et al, 1990). Also combinations of these effects have been proposed (Encina et al, 1988;Harvey et al, 1991).…”

Antiarrhythmic effects of BN‐063, a newly synthesized adenosine A1 agonist, on myocardial ischaemia in rats

“…It is likely that adenosine antagonism of catecholamine stimulated increases in ICa resulted from effects on intracellular cyclic AMP levels (Lerman & Belardinelli, 1990). These actions of adenosine are mediated through adenosine Al receptors coupled to the catalytic subunit of adenylyl cyclase through a pertussis toxin-sensitive guanine nucleotide binding regulatory (Ga) protein (Belardinelli & Pelleg, 1990 (Egan et al, 1988;Boachie-Ansah et al, 1993). It has been suggested that activation of catecholamine induced currents could generate an ectopic ventricular focus leading to tachycardia.…”

“…It has been suggested that activation of catecholamine induced currents could generate an ectopic ventricular focus leading to tachycardia. If more than one focus were activated asynchronously then the rhythm could become chaotic and might precipitate ventricular fibrillation (Egan et al, 1988). Accordingly, subcutaneous administration of isoprenaline was used to facilitate ventricular fibrillation in vivo.…”

Molecular cloning and characterization of a novel truncated form (ClC‐2β) of ClC‐2α (ClC‐2G) in rabbit heart

“…A variety of potentially important C1-currents have been described in the heart, and they are suggested to play pathophysiological roles by modulating the excitability of cardiac myocyte [1][2][3][4][5][6][7][8][9]. Membrane depolarization induced by a PKAactivated C1-current may result in development of severe arrhythmias associated with acute myocardial infarction [1][2][3].…”

“…Membrane depolarization induced by a PKAactivated C1-current may result in development of severe arrhythmias associated with acute myocardial infarction [1][2][3]. A swelling-induced C1-current contributes to the pacemaker potential in sino-atrial nodal cells, and activation of this current results in acceleration of cardiac heart rate [7,8].…”