The effects of calcium antagonists on extracellular potassium accumulation during global ischaemia in isolated perfused rat hearts

Abstract

The effects of equipotent concentrations of diltiazem, verapamil, and nifedipine upon the accumulation of extracellular potassium [K+]out and the left ventricular pressure (LVP) were studied during global ischemia in isolated perfused rat hearts. Measurement of [K+]out and LVP were performed in two series of experiments. Diltiazem (2 x 10(-6), 3 x 10(-6), and 10(-5) M), verapamil (3 x 10(-8), 10(-7), and 3 x 10(-7) M), and nifedipine (3 x 10(-8), 10(-7), and 1.5 x 10(-7) M) were able to slow, in a concentration-dependent manner, the initial rate of rise of [K+]out without affecting the final plateau value of [K+]out reached at t = 5 to t = 10 minutes. Notably, at the lowest concentrations, which slightly influenced LVP diltiazem, verapamil, and to a lesser degree nifedipine, were still able to slow the rise in [K+]out. In addition, after preperfusion with low-calcium media [( Ca2+] from 1.8 to 1.3 or 0.9 mM), inducing similar negative inotropic effects as those of the calcium antagonists, the rise in [K+]out was not significantly influenced. Our data indicate that the ability to slow the rise in [K+]out is a specific characteristic of calcium antagonists that is independent of their negative inotropic effects.

Opposite change with ischaemia in the antifibrillatory effects of class I and class IV antiarrhythmic drugs resulting from the alteration in ion transmembrane exchanges related to depolarization

“…Indeed, the shortening of the diastolic period is detrimental to active ion transfers which remain incomplete (Lang et al 1987;BuiXuan et al 1996); passive ion fluxes are initially enhanced by the increase in the number of systoles per time unit (Cranefield 1977;Kline and Morad 1978). Therefore the concentration of potassium ions quickly rises in the clefts (Heijnis et al 1991), while calcium ions accumulate inside the myocardial fibres (Allen and Blinks 1978) possibily reaching five times the normal level and more within a few minutes (Koretsuni and Marban 1989;Kojima et al 1994). Such increases of calcium in cytosol, which do not seem to be accompanied by similar increases of sodium (Cohen et al 1982), are consistent with the replacement of the role of sodium channels by that of calcium channels in the rhythmic systolic depolarization of the fibres.…”

“…These alterations in passive ion movements are consistent with the calcium excess in the ischaemic fibres that increases with the duration of ischaemia (Friedrich et al 1981;Tani 1990;Timour et al 1992). This excess, seen concurrently with an excess of potassium in the interstitial spaces (Steenbergen et al 1987;Heijnis et al 1991), is counteracted by calcium blockers as well as the resulting ischaemic depolarization (Clusin et al 1984;Aupetit et al 1993) and its consequences on excitability (Lyons et al 1977) and conduction (Weidmann 1955) in the ventricular fibres.…”

Delay by a calcium antagonist, amlodipine, of the onset of primary ventricular fibrillation in myocardial ischemia

“…Deprivation of oxygen supply implies a defect in the energy necessary for active ion transfers across the membrane, extrusion of sodium and calcium, and inward transfer of potassium. Depolarization is the consequence of accumulation of sodium and calcium in the cell in association with potassium depletion [28][29][30]. The shortening of MAP duration is evidence of depolarization of the ventricular fibers, given the correlation between this duration and the resting membrane potential [2].…”

“…The concentration of potassium rises from 4 to 8 mmol/1 in the extracellular space within the first minutes of ischemia [30]. Calcium antagonists tend to control both calcium overload and potassium depletion [28,29] and, consequently, the ischemic depolarization, responsible for the enhancement of excitability and slowing of conduction leading to fibrillation.…”

39K NMR measurement of intracellular potassium during ischemia in the perfused guinea pig heart

“…Most studies that report sequential potassium measurements in the intact heart during ischemia actually measure extracellular potassium (Kc+) and equate an increase in K,+ with K, ' depletion (5,(7)(8)(9)11). Since '"Na NMR shift agents are widely used to monitor intracellu-the high concentrations of DyTTHA'-required to produce an adequate shift in the J"K resonance (8.5-10 mM) did produce significant linc-broadening effects and can produce signal artifacts due to bulk magnetic susceptibility effects (20,21).…”