The Relation Between Vascular Relaxant and Cardiac Electrophysiological Effects of Pinacidil

1 The effects of pinacidil (10, 30, 50,M) on contractility (+dP/dt,,), coronary perfusion pressure (cP), and ECG intervals (PR, QRS, QT) have been studied on constant-flow perfused guinea-pig hearts, driven at four frequencies (2.5, 3, 3.5, 4 Hz).2 Pinacidil decreased +dP/dt,,,, cP and the QT interval in a dose-dependent manner, whereas the PR interval was increased. QRS duration was not modified. All these effects were independent of driving frequency. Pinacidil decreased the interval from Q-wave to T-wave peak (QTpeak) to a greater extent than the QT interval, thus decreasing the QTpeak/QT ratio. This effect, unlike that on QT interval, was more evident at the highest frequency of stimulation. 3 In 4 out of 20 hearts treated with pinacidil sustained ventricular fibrillation (VF) occurred following a short run of premature ventricular beats (R on T phenomenon). 4 In separate experiments, an attempt to induce VF electrically was made at drug concentrations ranging from 1OpM to 1OM (8 experiments for each concentration). In control conditions and at the lowest concentration of pinacidil tested (1OpM) VF could never be induced; in the presence of 30pMm pinacidil VF was induced in 5 out of 8 experiments. Drug concentrations higher that 50 gM permitted the induction of VF in every case. 5 Although the concentrations of pinacidil producing ventricular fibrillation are 30-40 times higher than those found in patients under long term treatment with this agent, it is suggested that caution should be used in prescribing this drug, at least in patients suffering from myocardial ischaemia.

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Effects of pinacidil on guinea‐pig isolated perfused heart with particular reference to the proarrhythmic effect

Padrini

Bova

Cargnelli

et al. 1992

“…Pinacidil produced a dose-dependent negative inotropic response in rabbit left atrial strips, although it was less potent than has been found in dog atrium (Yanagisawa et al, 1988) and in cat right ventricular papillary muscle (Steinberg et al, 1988). The direct negative inotropic response to pinacidil is believed to be related to its ability to promote the efflux of potassium, which in turn may shorten the action potential duration and reduce the influx of calcium (Steinberg et al, 1988).…”

Section: Discussionmentioning

confidence: 92%

“…The direct negative inotropic response to pinacidil is believed to be related to its ability to promote the efflux of potassium, which in turn may shorten the action potential duration and reduce the influx of calcium (Steinberg et al, 1988). The explanation for the lower sensitivity of rabbit atrium to pinacidil is not known.…”

Section: Discussionmentioning

confidence: 99%

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

Ray

MacLeod

1990

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.

“…In vivo, ATP-sensitive K+-channel openers lowered blood pressure and caused reflex tachycardia (Richer et al, 1990). In vitro, ATP-sensitive K+-channel openers have been shown to suppress spontaneous and oscillatory activities in isolated cardiac Purkinje fibres (Steinberg et al, 1988) and to produce a negative chronotropic response in a dog heart preparation (Murakami et al, 1992). On the other hand, an arrhythmogenic effect of ATP-sensitive K+-channel openers has been postulated (Steinberg et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular effects of SCA40, a novel potassium channel opener, in rats

Michel

Laurent

Bompart

et al. 1993

1 Experiments have been performed to investigate the cardiovascular actions in the rat of SCA40, a novel potassium channel opener which is a potent relaxant of guinea-pig airway smooth muscle in vivo and in vitro.2 SCA40 (0.01-30 JM) caused a complete and concentration-dependent relaxation of rat isolated thoracic aorta contracted with 20 mM KCI but failed to inhibit completely the spasmogenic effects of 80 mM KCI.3 The ATP-sensitive K'-channel blocker, glibenclamide (3 JAM), failed to antagonize the relaxant action of SCA40 on 20 mM KCl-contracted rat isolated thoracic aorta. 4 SCA40 (0.001-100 JM) had dual effects on rat isolated atria. At low concentrations, SCA40 produced a concentration-dependent decrease in the rate and force of contractions. At higher concentrations (greater than I JM) SCA40 induced concentration-dependent increases of atrial rate and force.5 In vivo, in normotensive Wistar rats, SCA40 elicited a dose-dependent (1-100 fg kg-') decrease in mean arterial pressure which was accompanied by a moderate dose-dependent increase in heart rate. SCA40 (100 tg kg-') had a slightly greater hypotensive effect than cromakalim (100 ig kg-') but the duration of the hypotension was longer with cromakalim than with SCA40. 6 The hypotensive effect of SCA40 was not reduced by propranolol, atropine, NG-nitro-L-arginine methyl ester (L-NAME) or glibenclamide. 7 It is concluded that the mechanism by which SCA40 relaxes vascular smooth muscle in vitro and in vivo involves activation of K+-channels distinct from glibenclamide-sensitive ATP-sensitive K+-channels.