Effects of K+‐channel blockers on A₁‐adenosine receptor‐mediated negative inotropy and chronotropy of guinea‐pig isolated left and right atria

Abstract

Adenosine has previously been shown to stimulate K(+)-efflux and to block L-type calcium channels in atrial myocytes. The aim of the present study was to evaluate the contribution of K(+)-channels in the development of the negative inotropic and chronotropic responses to adenosine agonists in guinea-pig left and right atria, respectively. Tetraethylammonium (TEA) potentiated the negative inotropic and chronotropic responses to R-(-)-N6-(2-phenyl-isopropyl)-adenosine (R-PIA), seen as leftward shifts of the concentration-response curves. Glibenclamide had no effect on the negative inotropic response to R-PIA but increased the rate of onset of the negative chronotropic response in right atria. 4-Aminopyridine (4-AP, 10 mM), potentiated the left atrial inotropic responses to R-PIA, seen as a leftward shift of the concentration-response curve, but slowed the speed of onset of the response to a single concentration (10(-6) M) of R-PIA. This reduction in speed of onset of the response can explain the differences in effects of 4-AP on concentration-response curves reported here and previously. In the right atria, 4-AP (10 mM) inhibited the negative chronotropic responses to R-PIA, seen as a rightward shift of the concentration-response curve and reduction of the maximum response. 4-AP also slowed the onset of the right atrial rate response to R-PIA. These results support the theory that K(+)-efflux plays only a minor role in the negative inotropic responses of guinea-pig left atria to R-PIA. This apparently controls the speed of onset of the response. The negative chronotropic response of guinea-pig right atria to R-PIA appears to be much more dependent upon K(+)-efflux than for the negative inotropic response of the left atria.

Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria

“…These findings rule out the involvement of voltage-dependent K v cannels on the inhibitory effects of A 1 and M 2 agonists and confirm data from interaction studies between 4-AP (0.3–3 mM) and R-PIA in the guinea-pig using spontaneously beating and electrically-driven atria (De Biasi et al, 1989 ). Concerning the lack of effect of glibenclamide in antagonizing the responses to M 2 and A 1 receptor agonists in rat atria, our results agree with previous reports in the guinea-pig indicating that cardiodepression by these agents are not operated by ATP-sensitive K ATP /K IR 6 channels (Urquhart et al, 1993 ; Ford and Broadley, 1999 ).…”

“…These findings seem to be reliable because blockade of K Ca 2/SK channels cause a delay in the late phase of the cardiac repolarization (Xu et al, 2003 ; Tuteja et al, 2005 ; but see Nagy et al, 2009 ; Hancock et al, 2015 ). According to the most accepted hypothesis to explain negative inotropic effects upon GIRK/K IR 3.1/3.4 channels (Wang and Belardinelli, 1994 ; Ford and Broadley, 1999 ), inhibition of cardiac repolarizing K + currents, such as the apamin-sensitive small conductance Ca 2+ -activated K Ca 2/SK current, may increase the time available for Ca 2+ influx via Ca v 1 (L-type) channels due to action potential prolongation and this might counteract the negative inotropic effects promoted by K + efflux through GIRK/K IR 3.1/3.4 channels. In addition to the enrolment of K Ca 2/SK channels on atrial inotropic mechanisms, these channels have been identified as key players in the course of supraventricular arrhythmias (Li et al, 2009 ; Yu et al, 2012 ), which is particularly interesting in a context of anti- and pro-arrhythmic properties of adenosine and its derivates (Kabell et al, 1994 ; Bertolet et al, 1997 ; Lim et al, 2009 ).…”