5-Hydroxytryptamine receptor activity of the dopamine receptor agonist fenoldopam in canine tracheal smooth muscle.
Fenoldopam is a new vasodilator undergoing clinical trials for the treatment of hypertensive emergencies. Its pharmacologic effects result from activation of vascular dopamine-1 receptors. In canine tracheal smooth muscle strips, fenoldopam caused a concentration- and calcium-dependent increase in tension, which was not antagonized by atropine, indomethacin or the dopamine-1 receptor antagonist, SCH 23390. The EC50 (1.89 x 10(-6) M) exceeded that of serotonin or acetylcholine (8.38 x 10(-8) and 8.25 x 10(-8) M, respectively). Maximum tension was similar for fenoldopam and serotonin (11.6 +/- 1.5 g, n = 7 and 13.8 +/- 0.8 g, n = 24; P greater than .2) and considerably greater for acetylcholine (20.5 +/- 1.3 g, n = 14; P less than .005). The serotonin antagonists ketanserin and methysergide reversed completely the effect of fenoldopam (5 x 10(-7) M) with IC50 values of 2.5 x 10(-9) and 2.7 x 10(-9) M, respectively. Phentolamine, rauwolscine and chlorpheniramine were also effective, but they were less potent (IC50 values 6.6 x 10(-8), 1.0 x 10(-7) and 1.7 x 10(-7) M, respectively). By contrast, only very high concentrations (IC50, 5.3 x 10(-5) M) of terazosin produced an inhibition of fenoldopam-induced tension increases. The effect of antagonists could be overcome by increasing the fenoldopam concentration. Experiments performed on strips precontracted with serotonin (5 x 10(-8) M) revealed a very similar order of potency for the five antagonists. The addition of serotonin did not increase the tension produced by supramaximal concentrations of fenoldopam (and vice-versa), whereas acetylcholine increased tension further.(ABSTRACT TRUNCATED AT 250 WORDS)
Committee on Clinical Pharmacology, University of Chicago, Illinois.
D D
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Gretler
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Jones
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Murphy
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D004285:Dogs; D015259:Dopamine Agents / Q000494:pharmacology*; D004347:Drug Interactions; D018818:Fenoldopam; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008784:Methysergide / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D014132:Trachea / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001552:Benzazepines; D015259:Dopamine Agents; D011985:Receptors, Serotonin; D014665:Vasodilator Agents; D012701:Serotonin; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D001285:Atropine; D007650:Ketanserin; D018818:Fenoldopam; D000109:Acetylcholine; D007213:Indomethacin; D008784:Methysergide