5-HT2-receptor antagonists: alpha 1- vs. 5-HT2-receptor blocking properties in blood vessels.
LY53857, spiperone, ketanserin, and setoperone were potent and competitive 5-HT2-receptor antagonists in the rat jugular vein with equivalent affinities at 5-HT2 receptors. In the rat jugular vein, ritanserin blocked 5-HT2-mediated contractile responses with a depression of the maximum response in concentrations greater than 3 X 10(-10) M. Ketanserin, spiperone, ritanserin, and setoperone were also alpha 1-adrenergic receptor antagonists, although affinity at alpha 1-adrenergic receptors was less for ritanserin and setoperone than for ketanserin or spiperone. Of the 5-HT2-receptor antagonists examined, LY53857 was the most selective with respect to alpha 1-adrenergic receptor affinity, showing 250,000-fold selectivity as an antagonist at 5-HT2 receptors. The possibility that the dual properties of 5-HT2- and alpha 1-receptor blockade confer greater antihypertensive efficacy than alpha 1-receptor blockade alone was also examined in vivo. However, acute administration of LY53857 at doses sufficient to abolish 5-HT2-receptor activation did not enhance blood pressure reduction produced by the alpha-adrenergic receptor antagonist phentolamine in normotensive or spontaneously hypertensive rats. These data argue against an important role for 5-HT2 receptors in blood pressure regulation even in combination with alpha-adrenergic receptor blockade.
Cohen
M L
ML
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Schenck
K W
KW
Kurz
K D
KD
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004873:Ergolines / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010646:Phentolamine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D016713:Ritanserin; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013134:Spiperone / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D004873:Ergolines; D010880:Piperidines; D011744:Pyrimidinones; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D016713:Ritanserin; D013134:Spiperone; D007650:Ketanserin; C045359:setoperone; C032663:LY 53857; D010646:Phentolamine