Sequential changes in action potential configuration, 4-amino-pyridine-sensitive transient outward current (Ito), and L-type calcium current (ICa) in association with hypertrophy were investigated in ventricular myocytes from rats with monocrotaline (MCT)-induced pulmonary hypertension. The tissue weight ratio of right ventricle (RV) to left ventricle plus septum 14 and 28 days after a subcutaneous injection of MCT increased by 29.7 and 77.2%, respectively. Action potential duration (APD) of RV cells from MCT rats increased progressively, prolonged by 73.2 and 92.2% on days 14 and 28, respectively. The current density of Ito in RV cells from MCT rats on day 14 (32.5 +/- 4.5 pA/pF, n = 13) was significantly larger than in controls (26.8 +/- 4.5 pA/pF, n = 8; P < 0.05). On day 28, however, Ito density in MCT rats (15.3 +/- 4.6 pA/pF, n = 9) was significantly less than in controls (27.3 +/- 4.2 pA/pF, n = 10; P < 0.05). There were no differences in the voltage dependence of steady-state activation and inactivation of Ito between MCT and control rats. ICa density in MCT rats on day 14 (15.7 +/- 2.6 pA/pF, n = 10) was significantly larger than in controls (10.0 +/- 2.3 pA/pF, n = 10; P < 0.05), but there was no significant difference in Ito density between MCT rats (8.3 +/- 3.7 pA/pF, n = 10) and controls (11.6 +/- 3.0 pA/pF, n = 10) on day 28. These findings suggest that hypertrophy of mammalian hearts may cause stage-dependent changes in Ito and ICa density of ventricular myocytes. The APD prolongation in the early stage of hypertrophy may be caused mainly by an increase in ICa density, whereas the APD prolongation in the late stage may be ascribed to a reduction in Ito density.

SUMMARYHeat shock and anoxia are environmental stresses that are known to trigger similar cellular responses. In this study, we used the locust to examine stress cross-tolerance by investigating the consequences of a prior anoxic stress on the effects of a subsequent high-temperature stress. Anoxic stress and heat shock induced thermotolerance by increasing the ability of intact locusts to survive normally lethal temperatures. To determine whether induced thermotolerance observed in the intact animal was correlated with electrophysiological changes, we measured whole-cell K+ currents and action potentials from locust neurons. K+ currents recorded from thoracic neuron somata were reduced after anoxic stress and decreased with increases in temperature. Prior anoxic stress and heat shock increased the upper temperature limit for generation of an action potential during a subsequent heat stress. Although anoxia induced thermotolerance in the locust flight system, a prior heat shock did not protect locusts from a subsequent anoxic stress. To determine whether changes in bioenergetic status were implicated in whole-animal cross-tolerance, phosphagen levels and rates of mitochondrial respiration were assayed. Heat shock alone had no effect on bioenergetic status. Prior heat shock allowed rapid recovery after normally lethal heat stress but afforded no protection after a subsequent anoxic stress. Heat shock also afforded no protection against disruption of bioenergetic status after a subsequent exercise stress. These metabolite studies are consistent with the electrophysiological data that demonstrate that a prior exposure to anoxia can have protective effects against high-temperature stress but that heat shock does not induce tolerance to anoxia.