Hypoxic states of the cardiovascular system are undoubtedly associated with the most frequent diseases of modern times. They originate as a result of disproportion between the amount of oxygen supplied to the cardiac cell and the amount actually required by the cell. The degree of hypoxic injury depends not only on the intensity and duration of the hypoxic stimulus, but also on the level of cardiac tolerance to oxygen deprivation. This variable changes significantly during phylogenetic and ontogenetic development. The heart of an adult poikilotherm is significantly more resistant as compared with that of the homeotherms. Similarly, the immature homeothermic heart is more resistant than the adult, possibly as a consequence of its greater capability for anaerobic glycolysis. Tolerance of the adult myocardium to oxygen deprivation may be increased by pharmacological intervention, adaptation to chronic hypoxia, or preconditioning. Because the immature heart is significantly more dependent on transsarcolemmal calcium entry to support contraction, the pharmacological protection achieved with drugs that interfere with calcium handling is markedly altered. Developing hearts demonstrated a greater sensitivity to calcium channel antagonists; a dose that induces only a small negative inotropic effect in adult rats stops the neonatal heart completely. Adaptation to chronic hypoxia results in similarly enhanced cardiac resistance in animals exposed to hypoxia either immediately after birth or in adulthood. Moreover, decreasing tolerance to ischemia during early postnatal life is counteracted by the development of endogenous protection; preconditioning failed to improve ischemic tolerance just after birth, but it developed during the early postnatal period. Basic knowledge of the possible improvements of immature heart tolerance to oxygen deprivation may contribute to the design of therapeutic strategies for both pediatric cardiology and cardiac surgery.

The present study was undertaken to evaluate the effects of chronic treatment with cis-4-[4-(3- adamantan-1-yl-ureido)cyclohexyl-oxy]benzoic acid (c-AUCB), a novel inhibitor of soluble epoxide hydrolase (sEH), which is responsible for the conversion of biologically active epoxyeicosatrienoic acids (EETs) to biologically inactive dihydroxyeicosatrienoic acids (DHETEs), on blood pressure (BP) and myocardial infarct size in male heterozygous Ren-2 transgenic rats (TGR) with established hypertension. Normotensive Hannover Sprague-Dawley (HanSD) rats served as controls. Myocardial ischemia was induced by coronary artery occlusion. Systolic BP was measured in conscious animals by tail-plethysmography. c-AUCB was administrated in drinking water. Renal and myocardial concentrations of EETs and DHETEs served as markers of internal production of epoxygenase metabolites. Chronic treatment with c-AUCB, which resulted in significant increases in the availability of biologically active epoxygenase metabolites in TGR – assessed as the ratio of EETs/DHETEs – was accompanied by a significant reduction in BP and significantly reduced infarct size in TGR as compared with untreated TGR. The cardioprotective action of c-AUCB treatment was completely prevented by acute administration of a selective EETs antagonist (14,15-epoxyeicosa5(Z)-enoic acid), supporting the notion that the improved cardiac ischemic tolerance conferred by sEH inhibition is mediated by EETs actions at the cellular level. These findings indicate that chronic inhibition of sEH exhibits antihypertensive and cardioprotective actions in this transgenic model of angiotensin II-dependent hypertension.