engleski

Restoration of Microvascular Reactivity to Vasoactive Stimuli in Consomic and Congenic Rat Strains Showing Normal Modulation of the Renin-Angiotensin System

Responses to vasodilator stimuli are impaired in arterioles and resistance arteries of rats on high salt (HS) diet, suggesting that the renin-angiotensin system (RAS) plays a crucial role in maintaining normal vascular relaxation mechanisms. This dissertation explores the role of the RAS in regulating vascular relaxation mechanisms in four inbred genetic rat strains showing differences in the regulation of their RAS. These are: 1) Dahl salt-sensitive (SS) rats, 2) normotensive Brown Norway (BN) rats ; 3) consomic SS.13BN rats with chromosome 13 of the BN rat introgressed into the SS background and 4) renin-congenic (RGRR) rats, which have a small portion of chromosome 13, containing a normally functioning renin-gene from the Dahl salt-resistant rat in the SS genetic background. SS rats exhibit impaired RAS regulation and are chronically exposed to low levels of renin and angiotensin II (ANG II) ; while BN, SS.13BN and RGRR exhibit normal RAS regulation. The general hypothesis of this dissertation is that normal function of the RAS is essential to maintain microvascular responses to vasodilator stimuli. Isolated middle cerebral arteries (MCA) of SS rats on low salt (LS) diet constricted in response to ACh and reduced PO2. Restoration of RAS control by introgression of a normally functioning renin gene restored vascular relaxation in response to ACh and hypoxia in SS.13BN and RGRR rats, and those responses were similar to the normal dilation of MCA from BN rats. Restoration of normal RAS regulation also restored normal relaxation of in situ cremasteric arterioles in response to acetylcholine in SS.13BN and RGRR rats. RAS suppression in response to short term (3-5 days) HS diet led to paradoxical constriction of MCA in response to ACh and hypoxia in SS.13BN and BN rats. Continuous i.v. infusion of low dose of angiotensin II (3 ng/kg/min for 3 days) restored vasodilator response to ACh and hypoxia in MCA of SS.13BN rats on HS diet, and SS rats on LS diet. AT-1 receptor blockade with losartan also resulted in a significant attenuation of dilation in response to ACh and hypoxia in SS.13BN rats on LS diet, providing additional evidence that the RAS is important in maintaining normal vascular relaxation. Studies with specific inhibitors of cyclooxygenase (COX), NO synthase (NOS), and cytochrome-P450 epoxygenase indicated that COX derived metabolites lead to paradoxical constriction of MCA in response to acetylcholine and hypoxia in SS rats, and that restoration of normal RAS regulation restores COX dependent relaxation to hypoxia and NO dependent relaxation to ACh in SS.13BN and RGRR rats. The superoxide dismutase mimetic TEMPOL (10-4 M) restored relaxation of MCA in response to ACh and hypoxia in SS rats, while responses of MCA to hypoxia and acetylcholine were unaffected by TEMPOL in MCA of SS.13BN rats. These observations suggest that oxidative stress is present in SS rats on LS diet, and could modify vascular reactivity. These results indicate that introgression of a normally functioning renin gene restores vascular relaxation in response to ACh in skeletal muscle arterioles and vasodilator responses to ACh and hypoxia in isolated MCA of consomic SS.13BN and congenic RGRR rats. Recovery of vascular relaxation appears to depend upon restoration of normal ANG II levels, because vascular relaxation in response to ACh and hypoxia is lost in SS.13BN and BN rats on HS diet, while infusion of low dose of ANG II in SS rats on LS diet and SS.13BN rats on HS diet restores normal relaxation in response to ACh and hypoxia. These studies also suggest that oxidative stress is present in SS rats, even on LS diet, and contributes to impaired vascular relaxation.

Renin-angiotensin system; salt-sensitive hypertension; physiological genomics; microcirculation; blood flow regulation

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