Influence of doxazosin on the activity of the endothelium-derived relaxing factor.
This work examined the effect of the selective a1-inhibitor, doxazosin (CAS 74191-85-8), on the activity of endothelium-derived relaxing factor (EDRF). In vitro, the intact thoracic aortic rings of rabbits were contracted with the a-agonist, phenylephrine, and then relaxed by sequentially increasing concentrations of the EDRF-releasing agent adenosine triphosphate (ATP). In parallel experiments, doxazosin (10(-8) mol/l) was added after the contraction but before the addition of ATP. Doxazosin enhanced the ATP-induced vasodilation by a factor of 3. Control experiments suggested that this was due to the enhanced activity of EDRF, which was related to displacement of phenylephrine from a1-adrenoceptors by doxazosin. Physiologically relevant concentrations of 6- or 7-hydroxydoxazosin (5 x 10(-10) mol/l) had no effect on EDRF activity in vitro. In vivo experiments in the rabbit were carried out using bolus, intravenous injections of acetylcholine (ACh), which stimulated EDRF release. Threshold doses of doxazosin (2 x 10(-6) g/kg) enhanced the hypotensive activity of ACh. Prefeeding the rabbits for 4 weeks with a 2% cholesterol diet significantly reduced the sensitivity of the aorta to isosorbide-5-mononitrate, a stable EDRF-analog. However, the impairment in endothelium-dependent relaxation was attenuated in the presence of doxazosin (2 x 10(-9) mol/l). The results that in addition to its known antiplatelet activity, doxazosin enhances EDRF activity.
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Pfizer Mack, Heinrich Mack Nachf. Chem.-Pharmazeutische Fabrik, Illertissen, Fed. Rep. of Germany.
D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D017292:Doxazosin / Q000494:pharmacology*; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits
D010656:Phenylephrine; D009569:Nitric Oxide; D000001:Calcimycin; D000255:Adenosine Triphosphate; D000109:Acetylcholine; D017292:Doxazosin