Effects of doxazosin on vascular collagen synthesis, arterial pressure and serum lipids in the spontaneously hypertensive rat

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Hypertension in various experimental models, including spontaneously hypertensive rats (SHR), is associated with elevated rates of vascular collagen synthesis. The sympathetic nervous system is an important factor in the etiology of hypertension in SHR. The primary purpose of this study was to determine the effects of the α1adrener-gic receptor antagonist doxazosin on aortic collagen synthesis and on systolic arterial pressure in SHR. Doxazosin was administered either short-term (20 or 200 mg/kg/day by gavage over 5 days) or long-term (0.02 or 0.20 g/L in the drinking water over 8 weeks). Rates of collagen synthesis were determined by incubating aortic segments with 14C-proline in vitro and then measuring either the formation of 14C-hydroxyproline by means of high-performance liquid chromatography, or the amount of radioactivity liberated by collagenase digestion. Systolic arterial pressure was monitored with the standard tail-cuff technique. Both doses of doxazosin depressed aortic collagen synthesis at 8 weeks of treatment, but neither dose had any effect at 4 weeks. In the short-term study only the higher acute dose of doxazosin significantly reduced aortic collagen synthesis; the lower dose had no effect. In the short-term study doxazosin reduced systolic arterial pressure, with a maximum effect at 1-2 days. Tolerance to the depressor effect developed over the remaining 3-4 days, especially with the higher dose. In the 8-week study, the lower doxazosin dose had no effect on systolic arterial pressure, and the higher dose exerted a biphasic effect, moderately but significantly reducing systolic arterial pressure at 1 and 8 weeks of treatment. Assays of serum doxazosin levels suggested that the tolerance to the depressor effect was partially, but not completely, pharmacokinetic. The higher dose of doxazosin significantly reduced serum triglycerides, but none of the other treatment regimens affected serum lipid profiles (very-low-density, low-density or high-density lipoproteins or total cholesterol). The results suggest that the inhibition of vascular collagen synthesis by doxazosin in SHR may be to some extent independent of reductions in arterial pressure. © 1987 Raven Press. New York.

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Journal of Cardiovascular Pharmacology