RO-316930

The objective was to investigate whether myocardial adenosine triphosphate-sensitive K+ (KATP) channels open during the first 10 min of regional ischaemia in Langendorff-perfused rat hearts. Changes in monophasic action potentials and arrhythmias were studied during myocardial ischaemia in both the presence and absence of pharmacological KATP modulation. Ligation of the left main coronary artery for 10 min did not shorten the action potential duration (APD). The APD50 and APD80 (15.5 +/- 1.0 and 38.1 +/- 2.3 ms, respectively [mean +/- S.E., n = 15 hearts], immediately prior to ligation) increased transiently during the first 4 min of ligation (by 160 and 79% respectively, P < 0.05), before returning to pre-ligation values, but without a significant below-baseline-shortening. The cardiac electrogram showed no accompanying ventricular tachyarrhythmia (VT). These results raised the possibility that the myocardial KATP channels had not opened during the ligation. The KATP opener Ro 31-6930 (0.5 and 5 microM) shortened the APD50 and APD80 during coronary ligation, to significantly below both their control and pre-occlusion values (P < 0.05), and caused a concentration-dependent increase in both the incidence and duration of VT during the ligation. Ro 31-6930 at 5 microM also shortened APD50 and APD80 even before ligation (by 50 and 62% respectively, P < 0.05), and abolished the normal APD-lengthening seen during ischaemia. The KATP blocker glibenclamide (1 microM) abolished both the APD-shortening and pro-arrhythmic effects of the KATP opener, both before and during coronary ligation, yet when delivered on its own, at the same concentration which abolished the effects of KATP activation, it had no significant effect on the APD changes seen during the coronary ligation alone. These results suggest that, in Langendorff-perfused rat hearts in the absence of drugs, KATP channels do not open during early myocardial ischaemia.

We have used the whole cell recording technique to investigate voltage-activated outward currents in cultured ovine trachea submucosal gland cells. The cultured gland cells secreted lysozyme in response to secretagogues, methacholine (20 microM), phenylephrine (100 microM) and substance P (10 microM). Most cells in culture for 7-21 days expressed a voltage-activated outward current at potentials positive to -30 mV. This outward current inactivated slowly, by 44 +/- 6% during a 3 sec depolarization to +30 mV. The voltage-activated outward current was sensitive to the potassium channel inhibitors tetraethylammonium bromide (5 mM), 4-aminopyridine (500 microM) and glibenclamide (1 microM). These data suggest that the outward voltage-activated currents observed are due to K+ channel activity. In cells with little or no outward current present the potassium channel opener Ro 31-6930 produced an additional voltage-activated net outward current. This effect of Ro 31-6930 was sensitive to glibenclamide (1 microM). Our results suggest that some cultured submucosal gland cells express voltage-activated K+ currents with a mixed pharmacology to antagonists and that a portion of this current is sensitive to modulation by Ro 31-6930.