HEME-HEME OXYGENASE-CARBON MONOXIDE SYSTEM IN HYPERTENSION

Tulane University Of Louisiana, New Orleans LA

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Abstract

Carbon monoxide (CO) can be endogenously formed during the enzymatic degradation of heme by heme oxygenase (HO). Although CO is generally regarded as a vasodilator, by its inhibitory effect on nitric oxide synthase it is also a vasoconstrictor. On high salt diet Dahl salt-sensitive rats (DS) develop hypertension that is accompanied by decreased NO formation. This project will investigate the role of the vascular heme-HOCO system in endothelial dysfunction during salt-induced hypertension in DS rats. The following specific aims will be addressed: Aim1: Characterize the temporal changes in various indeces of the HO system, arteriolar NO function, and cardiorenal pathologies in DS and salt-resistant (DR) rats on high and low salt diets. Aim2: Determine the effects of genetic predisposition for salt-sensitivity, high salt diet, and hypertension on various indeces of the HO system, arteriolar NO function, and cardiorenal pathologies in DS and DR rats. Aim3: Establish the effects of altered HO system function on artedolar NO function, and cardiorenal pathologies in DS and DR rats on high and low salt diets. Methods: Some animals will receive antinhypertensive treatment, others pressor treatment. Some groups will be treated with heme-L-lysinate, others with zinc protoporphyrin IX to increase or decrease endogenous CO formation, respectively. HbCO will be measured with a clinical grade analyzer (OSM3). Vascular HO-1 protein content will be studied by Western-blotting and immunohistochemistry (ABC method). NO function will be examined in isolated skeletal muscle arterioles by studying responses to a NO synthase inhibitor, an endothelium-dependent vasodilator, and a NO donor. Internal diameter of pressurized arterioles will be measured with a microscope and a video caliper. Objectives: These studies will provide information on temporal changes in HO function, cardiorenal pathologies and arteriolar NO function during salt-induced hypertension. Furthermore, they will evaluate the factors (genetic salt-sensitivity, high salt diet, and/or hypertension) contributing to HO-mediated NO dysfunction during salt-induced hypertension in DS rats. They will also examine the effects of altered endogenous CO formation on arteriolar NO function and cardiorenal injury in DS rats during salt-induced hypertension. Understanding the pathological basis of endothelial dysfunction may help to develop causetargeted therapy resulting in prolonged survival of hypertensive patients.