Low concentrations of certain K(ATP) channel openers have been reported to exert a moderate inhibitory effect on arrhythmias during post-ischaemic early myocardial reperfusion, but the accompanying effects on the time course of changes in action potentials in intact hearts have not yet been studied. We report that in rat isolated hearts, reperfusion following 10 min of regional no-flow ischaemia was associated with both an acute, marked, but transient, shortening of ventricular repolarisation (by 63%) during reperfusion, and a high incidence (90%) of ventricular tachyarrhythmias. The K(ATP) channel opener Ro 31-6930 [2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine 1-oxide], delivered prior to ischaemia at a relatively low concentration (0.5 microM), significantly reduced the incidence and duration of reperfusion arrhythmias, and prevented the associated acute action potential shortening during reperfusion, each in a glibenclamide (1 microM)-sensitive manner (P<0.05, n=10-15 hearts). This was associated with a moderate and non-arrhythmogenic action potential shortening during ischaemia (a potentially "cardioprotective" effect). However, these data highlight the potential harm these drugs may cause, since a higher concentration of Ro 31-6930 caused marked shortening of action potentials and significant pro-arrhythmia during ischaemia.

01 May 2000·Basic Research in CardiologyQ1 · MEDICINE

Do K ATP channels open as a prominent and early feature during ischaemia in the Langendorff-perfused rat heart?

Q1 · MEDICINE

Article

Author: MacKenzie, Ian ; Northover, Basil J. ; Workman, Antony J.

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.

01 Jul 1995·European Journal of PharmacologyQ3 · MEDICINE

The effect of K+ channel openers on submucosal gland function and epithelial transport of the ferret trachea, in vitro

Q3 · MEDICINE

Article

Author: Griffin, A

The effects of three K+ channel openers on lysozyme output from submucosal gland serous cells and epithelial albumin transport following maintained submaximal stimulation by the secretagogues methacholine and phenylephrine were examined in the ferret trachea in vitro preparation. The K+ channel openers Ro 31-6930, 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine 1-oxide (10 nM-10 microM), levcromakalim, BRL38227 (10 nM-10 microM) and pinacidil (100 nM-10 microM) produced a concentration dependent inhibition of (20 microM) methacholine-induced lysozyme output, with pD2 values of 7.64, 7.72 and 7.28 respectively. Ro 31-6930 (10 nM-10 microM), levcromakalim (10 nM-10 microM) and pinacidil (1 nM-10 microM) also produced a concentration dependent inhibition of (100 microM) phenylephrine-induced lysozyme output, with pD2 values of 7.64, 6.55 and 9.16 respectively. Furthermore, glibenclamide (1 microM) produced a modest attenuation of the K+ channel opener effects on secretagogue-induced lysozyme output. All three K+ channel openers failed to produce any significant change in either methacholine or phenylephrine-induced albumin outputs. The K+ channel openers exerted marked effects on airway secretion processes, suggesting that these compounds may have an antisecretory effect. The relevance of the use of the K+ channel openers in airway disease remains to be determined.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	-	F. Hoffmann-La Roche Ltd.	-
Heart Failure	Phase 1	-	F. Hoffmann-La Roche Ltd.	-
Hypertension	Phase 1	-	F. Hoffmann-La Roche Ltd.	-

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