The negative inotropic effect of nicorandil is independent of cyclic GMP changes: a comparison with pinacidil and cromakalim in canine atrial muscle

Abstract

The negative inotropic effects of nicorandil, a nitrate with K‐channel opening properties, have been compared with those of pinacidil, cromakalim and nifedipine, in canine right atrial muscle. Cromakalim, pinacidil and nicorandil all produced a negative inotropic effect. However, even at their maximally effective concentrations, the force of contraction remained at about 10% of control levels, whereas contraction was abolished by nifedipine. The pD2 values for the negative inotropic effects of cromakalim, pinacidil and nicorandil were 5.93, 5.37 and 4.35, respectively. The negative inotropic effects of cromakalim (3 × 10−5 m), pinacidil (3 × 10−5 m and 3 × 10−4 m) and nicorandil (3 × 10−5 m) were not accompanied by changes in cyclic AMP and cyclic GMP levels, whereas that of 3 × 10−4 m nicorandil was accompanied by an increase in cyclic GMP but not cyclic AMP concentrations. The negative inotropic effect produced by 3 × 10−4 m nicorandil was greatly reduced by 10−2 m tetraethylammonium, whereas the increase in cyclic GMP produced by this concentration of nicorandil was not significantly changed. Sodium nitroprusside (10−3 m) produced a large increase in cyclic GMP concentrations but had no significant negative inotropic effect. It is concluded that the negative inotropic effects of nicorandil like those of cromakalim and pinacidil do not result from an increase in cyclic GMP concentrations. Instead these effects may be due to their action as K‐channel openers.

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

“…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).…”

“…In some experiments pinacidil was dissolved in 0.1 N hydrochloric acid, as reported by Yanagisawa et al, (1988), to obtain a stock solution and further dilutions were made in modified Chenoweth-Koelle solution.…”

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

“…ATP-sensitive K+-channel openers directly induce negative chronotropic and inotropic responses in heart preparations (Yanagisawa et al, 1988;1989;Murakami et al, 1992) but little is known about the role of the large-conductance Ca 2-activated K+-channels or other ChTX-sensitive K+-channels in heart, since no activators of these channels have yet been developed. In the present study, SCA40 produced dual effects on rat isolated atria.…”

Specific but differential antagonism by glibenclamide of the vasodepressor effects of cromakalim and nicorandil in spinally‐anaesthetized dogs

“…Another important finding obtained in the present experiments was that the cardiodepressant effects of cromakalim and nicorandil, as reflected by decreases in LV dP/dt.., were also antagonized by glibenclamide. Decreases in LV dP/dtm.x produced by the two drugs were in all probability a result of their negative inotropic effect, because nicorandil Yanagisawa et al, 1988;1989) and cromakalim (Gotanda et al, 1988;1989;Yanagisawa et al, 1988;1989) have been known to produce a negative inotropic effect both in vivo and in vitro entirely by K-channel opening. Thus, the present findings can be taken to indicate that the specific antagonism by glibenclamide of cromakalim and nicorandil occurred in left ventricular muscle cells, too.…”

“…The vasodilator effects of cromakalim, a potent antihypertensive drug with vasodilator properties (Buckingham et al, 1986), have recently been shown to involve K-channel opening more specifically than nicorandil (Weir & Weston, 1986). Also, cromakalim lacks the ability to increase intracellular guanosine 3':5'-cyclic monophosphate (cyclic GMP) as seen with nicorandil (Yanagisawa et al, 1988). Recently, it has also been shown that in rats the vasodepressor effect of cromakalim on systemic arterial pressure was specifically antagonized by glibenclamide, an oral antidiabetic drug (Cavero et al, 1988).…”