Endothelium-derived substances and regional hemodynamics in experimental hypertension

Abstract: The spontaneously hypertensive rat (SHR), a model for experimental hypertension, is considered to have similarities with essential hypertension in humans. Differences between SHR and normotensive Wistar Kyoto rats (WKY) in the vascular response to endothelial-derived substances such as nitric oxide (NO) have been intensively studied in vitro. Acetylcholine-induced relaxation, used as an indicator of endogenous NO activation, has been suggested to be attenuated in the SHR. In this dissertation, in vivo hemodynamics were evaluated using the microsphere method in the strains with emphasis in renal, myocardial and cerebral hemodynamics.Resting hemodynamics in the SHR revealed increases in total peripheral resistance, blood pressure and heart rate, whereas cardiac output was decreased. Vascular resistance was increased in many organs in the SHR compared to WKY, but blood flow was higher in the myocardium and some cerebral areas in SHR. Acetylcholine (2 µg/kg/min) induced vasodilation in the kidney and heart in WKY, but not in SHR. No difference between the groups was found by the exogenous NO donor nitroprusside (1 µg/kg/min). NO synthase inhibition, using a L-arginine analogue, L-NMMA, abolished acetylcholine-induced vasodilation in the WKY, suggesting NO as the mediator. L-NMMA (20 mg/kg) alone revealed similar or increased basalvasodilating NO-tone in the SHR in the kidney, heart, skeletal muscle and brain compared to WKY. Acetylcholine-induced vasodilation could be demonstrated in cerebral tissues in the WKY only when endothelin-A receptors were blocked by BQ123 (1 mg/kg), whereas an attenuated acetylcholine-induced cerebral vasodilation could be demonstrated in the SHR. BQ123 alone induced no major effect on any regional blood flow, indicating a low basal endothelin receptor activation in both strains. Long-term oral carvedilol treatment did not improve acetylcholine-mediated vasoconstriction in SHR despite a reduction in blood pressure. In contrast, a vasoconstrictive response to acetylcholine was seen in the kidney. An immunohistochemical comparison between SHR and WKY showed similar expression of endothelial NO synthase in the endothelium in aorta, renal, cerebral, skeletal muscle and cardiac arteries.In conclusion, attenuation of acetylcholine-induced vasodilation was found in vivo in some vascular beds in the SHR, whereas basal NO-release seemed not to be reduced in the SHR. Expression of NO synthase in the endothelium was similar in the two strains. Furthermore, carvedilol treatment did not improve acetylcholine-mediated vasodilation in the SHR.