Adrenergic‐cholinergic interactions in left atria: a study using K + channel agonists, antagonist and pertussis toxin

Abstract

1 The role of activation of potassium conductance in the antagonism by the muscarinic agonist carbachol of positive inotropic responses to a-and #-adrenoceptor stimulation was studied in electrically driven left atrial strips of the rabbit. 2 The potassium channel antagonist, 4-aminopyridine, attenuated the direct negative inotropic response to carbachol and the reversal by carbachol of positive inotropic responses to the a-adrenoceptor agonist phenylephrine (in the presence of timolol). The inhibitory effect of carbachol on positive inotropic responses to the f-adrenoceptor agonist isoprenaline was much less affected by 4-aminopyridine. 3 Pretreatment of rabbits with pertussis toxin also attenuated the direct negative inotropic response to carbachol and the inhibitory effect of carbachol on positive inotropic responses to phenylephrine. 4 Neither carbachol nor phenylephrine, alone or in combination, had any effect on left atrial adenosine 3' :5'-cyclic monophosphate (cyclic AMP) levels. 5 The potassium channel agonist, pinacidil, exerted a dose-dependent negative inotropic response in rabbit left atria and reversed positive inotropic responses to phenylephrine and isoprenaline. In the doserange tested, pinacidil had a greater inhibitory effect on positive inotropic responses to phenylephrine than on positive inotropic responses to isoprenaline. 6 Pretreatment of left atria with pinacidil or cromakalim, another potassium channel agonist, antagonized positive inotropic responses to phenylephrine but not to isoprenaline. 7 These results suggest that activation of potassium conductance plays an important role in the inhibition by carbachol of positive inotropic responses of rabbit left atria to phenylephrine but not to isoprenaline.

Blockade by 4-Aminopyridine of the Muscarinic-receptor-mediated Responses of Guinea-pig Atria and Trachea

“…It has been shown to antagonize the negative inotropic effects of muscarinic agonists in guinea-pig (Freeman 1979; De Biasi et a1 1989) and rabbit atria (Ray & MacLeod 1990). This finding supports the suggestion that muscarinic agonists mediate their negative inotropic effects through the opening of K + channels.…”

Negative inotropic effect of pinacidil on the rat left atria

“…However, the role of ATP-sensitive potassium channels in the cardiac action potential and cardiac contractility remains to be clearly defined. Pinacidil, dissolved in HCI but not in dimethylsulphoxide, also had a negative inotropic effect on the rabbit left atria and antagonized the positive inotropic responses of this tissue to phenylephrine but not to isoprenaline (Ray & MacLeod 1990). pinacidil and cromakalim) shorten cardiac action potentials (pinacidil (Martin & Chinn I990), cromakalim (Bril & Man 1990)) and may have effects on cardiac contractility.…”

“…pinacidil and cromakalim) shorten cardiac action potentials (pinacidil (Martin & Chinn I990), cromakalim (Bril & Man 1990)) and may have effects on cardiac contractility. Recent studies have also failed to demonstrate negative inotropic effects of cromakalim on the rabbit left atria (Ray & MacLeod 1990) or the rat right ventricle (Bishop & Doggrell 1992). an ATP-sensitive potassium-channel blocker (Satoh et al 1990).…”

“…Glibenclamide had no effect but 4-aminopyridine, procaine (30 PM) and tetraethylammonium (3 mM) augmented the cardiac stimulation response. Recent studies have also failed to demonstrate negative inotropic effects of cromakalim on the rabbit left atria (Ray & MacLeod 1990) or the rat right ventricle (Bishop & Doggrell 1992). Thus, on the rat left atria.…”

“…the inward and outward rectifying channels) have a major role in the threshold, frequency and duration of cardiac action potential and of cardiac contractility. Recent studies have also failed to demonstrate negative inotropic effects of cromakalim on the rabbit left atria (Ray & MacLeod 1990) or the rat right ventricle (Bishop & Doggrell 1992). ATP-sensitive potassium-channel openers (e.g.…”