Ischemia alters the electrical activity of pacemaker cells isolated from the rabbit sinoatrial node

Abstract

The purpose of this study was to investigate the mechanisms responsible for ischemia-induced changes in spontaneous electrical activity. An ischemic-like Tyrode solution (pH 6.6) reversibly depolarized the maximum diastolic potential (MDP) and reduced the action potential (AP) overshoot (OS). We used SNARF-1, which is an indicator of intracellular pH (pH(i)), and perforated-patch techniques to test the hypothesis that acidosis caused these effects. Acidic but otherwise normal Tyrode solution (pH 6.8) produced similar effects. Basic Tyrode solution (pH 8.5) hyperpolarized the MDP, shortened the AP, and slowed the firing rate. In the presence of "ischemic" Tyrode solution, hyperpolarizing current restored the MDP and OS to control values. HOE-642, an inhibitor of Na/H exchange, did not alter pH(i) or electrical activity and did not prevent the effects of ischemic Tyrode solution or recovery after washout. Time-independent net inward current but not hyperpolarization-activated inward current was enhanced by ischemic Tyrode solution or by 30 microM BaCl(2), a selective blocker of inward-rectifying K currents at this concentration. The results suggest that 1) acidosis was responsible for the ischemia-induced effects but Na/H exchange was not involved, 2) the OS was reduced because of depolarization-induced inactivation of inward currents that generate the AP upstroke, and 3) reduction of an inward-rectifying outward K current contributed to the depolarization.

Cariporide (HOE642) attenuates lactic acidosis induced pulmonary vein arrhythmogenesis

“…In this study, lactic acid induced PV burst firing which has also been shown by Gryshchenko et al (Gryshchenko et al 2002), and increased the incidence of triggered activity of PVs (Coetzee and Opie 1987). The lactic acidosis-induced PV burst firings may be caused by a Ca 2+ overload, since lactic acid stimulates the Na + /H + exchanger which causes an increase in intracellular Na + , further overloading intracellular Ca 2+ (Cairns et al 1993).…”

“…Acidosisinduced PV arrhythmogenesis at least in part explains the increasing incidence of AF during myocardial ischemia. Additionally, similar to that observed in sino-atrial nodal cells, lactic acid reduces the basal PV spontaneous rates (Gryshchenko et al 2002). This was also seen with ischemia which causes a reduction in sino-atrial rates by reducing oscillatory Ca 2+ releases due to sarcoplasmic reticulum Ca 2+ load (Maltsev and Lakatta 2007;Stern et al 1989;Weiss et al 1990).…”

“…Intracellular acidification may possibly lead to Na + influx and further cause Ca 2+ overload with arrhythmogenesis through activation of the Na + /Ca 2+ exchanger in cells. Lactic acidosis was shown to alter the resting membrane potential (RMP), increase the amplitude of the delayed after depolarizations, and decrease beating rates in sinoatrial nodal cells (Coetzee and Opie 1987;Gryshchenko et al 2002). In addition, lactic acidosis may induce cellular uncoupling thereby electrically isolating the ischemic area.…”

Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion

“…The mechanism of this late fall is less clear. Among the possible mechanisms are recruitment of other peripheral chemoreceptor input (Bartelds et al, 1993), a synergistic effect of severe hypercarbia on carotid chemoreceptors (Blanco et al, 1984), a direct effect of ischemia on cardiac pacemaker cells (Gryshchenko et al, 2002), and an activation of the cardioinhibitory Bezold-Jarisch reflex (Aviado and Guevara, 2001;Dawes and Comroe, Jr., 1954). This latter reflex originates from the stimulation of both mechanically and chemically sensitive receptors in the ventricle which can be elicited by coronary ischemia and asphyxia (Thoren, 1972).…”

Early effects of metabolic inhibition on intracellular Ca2+in toad pacemaker cells: involvement of Ca2+stores

“…CN Ϫ also binds to cytochrome P-450 and inhibits its metabolic activity (18,25 Possible relationship between reduced Ca 2ϩ transients and slowing of the firing rate. Many pacemaker currents may contribute to the slower firing rate during ischemia or metabolic inhibition, including activation of ATP-sensitive K ϩ channels (10), inhibition of L-type Ca 2ϩ current (21), and modification of inward rectifying K ϩ currents (9). Nevertheless, the temporal association of reduced Ca 2ϩ transients and slowing of the firing rate raises the possibility that the two are associated.…”