Effects of activation of ATP-sensitive K+ channels in mammalian ventricular myocytes

Abstract

A cromakalim analogue, SR 44866, is shown to open ATP-sensitive K+ channels in ventricular myocytes. The channels opened by SR 44866 were closed by internal ATP and had the same current-voltage relationship as ATP-sensitive K+ channels; channels closed by ATP could be opened by SR 44866. SR 44866 was effective when applied to either side of excised membrane patches and when included in the pipette during cell-attached membrane recordings. SR 44866 also opened channels in cell-attached membrane patches when it was applied to the cell membrane outside of the pipette. The current evoked by SR 44866 in whole cell recordings was inhibited by tolbutamide. SR 44866 reduced the duration of action potentials and the amplitude and duration of evoked muscle contractions in guinea pig papillary muscle, with dissociation constants of 6.8 microM at 24 degrees C and 1.9 microM at 34 degrees C and Hill coefficients of 1.72 and 1.71, respectively. We conclude that the opening of ATP-sensitive K+ channels has profound inhibitory effects on the electrical and mechanical activity of cardiac muscle.

Effects of the KATP channel opener bimakalim on coronary blood flow, monophasic action potential duration, and infarct size in dogs.

“…In subsequent infarct studies, dogs were subjected to 60 minutes of LAD occlusion followed by 4 hours of reperfusion. Based on preliminary studies, two doses of bimakalim that did not shorten MAPD during nonischemic conditions (0.1 and 0.3 ,ug/min) and one that markedly shortened MAPD during nonischemic conditions (3.0 Lg/min) or an equal volume of vehicle were infused into the LAD during the initial 10 minutes of coronary artery occlusion. Transmural myocardial blood flow was measured at 5 and 30 minutes of occlusion by the radioactive microsphere technique, and infarct size was determined at the end of 4 hours of reperfusion by triphenyltetrazolium staining.…”

Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs

“…SR 44866, a compound which is structurally identical to EMD 52692 has been shown to have inhibitory effects on the electrical and mechanical activity of cardiac muscle (Findlay et al, 1989) In anaesthetized animals a substantial fraction of the cardiac output is shunted through arteriovenous anastomoses (Kaihara et al, 1968;Saxena & Verdouw, 1985), which is reflected by the large entrapment of the microspheres in the lungs after induction of anaesthesia (Van Woerkens et al, 1990). Figure 4 shows that although cardiac output did not change, the nutritional fraction increased with increasing doses of EMD 52692.…”

“…The aim of the present study was to investigate the systemic haemodynamics and the distribution of cardiac output (radioactive microsphere technique) in response to intravenous infusions of EMD 52692 in the anaesthetized pig. EMD 52692 (Figure 1), a novel benzopyran derivative, structurally identical to SR 44866 (Findlay et al, 1989), has been shown to hyperpolarize smooth muscle cells, which has been attributed to activation of ATP-dependent potassium channels (Findlay et al, 1989;De Peyer et al, 1989;Gericke et al, 1989 Ltd, 1990 effects, we also studied the effects of EMD 52692 on myocardial performance after intracoronary infusion of the compound.…”

Modulation of potassium channels by antiarrhythmic and antihypertensive drugs.

“…Less than 10% of the K ATP current that could be activated by SR 44866 was sufficient to make an isolated guinea pig myocyte electrically inexcitable. 78 Thus, very small increases in the P o of K ATP channels by PCOs, even in the presence of near normal [ATP],, will result in considerable shortening of cardiac action potentials (Figure 3). The effect of PCOs on K ATP activity depends on [ATP],; less of a stimulatory effect occurs at higher internal ATP levels.…”