Reduction of the soluble cyclic GMP vasorelaxing system in the vascular wall of stroke-prone spontaneously hypertensive rats: effect of the α1-receptor blocker doxazosin

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Abstract
The aim of the present study was to analyse the nitric oxide (NO)/cyclic GMP (cGMP) relaxing system in spontaneously hypertensive rats of the stroke-prone substrain (SHRSP). The study was performed in 20-week-old SHRSP rats. A group of normotensive Wistar–Kyoto (WKY) rats was used as control. The endothelium-dependent relaxation to acetylcholine was reduced in SHRSP rats (n = 15). No modifications in the expression of the endothelial nitric oxide synthase were found in the vascular wall of WKY rats (n = 15) and SHRSP rats. SHRSP rats demonstrated an impaired relaxing response to the NO-donor sodium nitroprusside that was accompanied by a reduction in the level of the main second messenger of NO, cyclic GMP. The expression of the soluble guanylate cyclase (sGC) β1-subunit was markedly reduced in the vascular wall of SHRSP rats. In the experimental model of SHRSP, an increased concentration of catecholamines has been reported. Therefore, we evaluated the effect of an α1-receptor blocker, doxazosin, on the NO/cGMP system. Doxazosin [10 mg/kg body weight (bw) per day for 15 days, n = 15] reduced mean arterial pressure (MAP) in SHRSP rats. Treatment with doxazosin preserved the endothelium-independent relaxation response to sodium nitroprusside in aortic segments from SHRSP rats which was associated with an increased expression of the sGC β1-subunit. A dose of doxazosin (1 mg/kg bw per day, n = 15) that did not modify MAP partially prevented sGC protein expression in the vascular wall. Independently of the endothelial NO-generating system, impaired vasorelaxation could also result from vascular smooth muscle cell layer dysfunction. Doxazosin treatment improved the endothelial-independent relaxation and preserved the cGMP generating system in the vascular wall of SHRSP rats.