Effects of the serotonin antagonists, cyproheptadine, ketanserin and mianserin, on cyclic flow reductions in stenosed canine coronary arteries.
We compared the abilities of three pharmacologically and structurally dissimilar 5-hydroxytryptamine (5-HT2) antagonists, cyproheptadine, ketanserin, and mianserin, to interrupt cyclic flow reductions (CFRs) in stenosed coronary arteries of open-chest dogs. All three drugs decreased the frequency and severity of CFRs, but differed in the doses required for total abolition. Cyproheptadine and ketanserin both reduced by approximately 50% the frequency of CFRs at 10 micrograms/kg i.v. Mianserin appeared to be less potent; an approximately 50% reduction of the frequency of CFRs required 100 micrograms/kg. These in vivo results correlated well with their abilities to inhibit epinephrine plus 5-HT-induced aggregation of canine platelet-rich plasma in vitro. The IC50 values for inhibition of aggregation stimulated by this combination of agonists were 2.21, 2.84 and 7.38 microM, respectively. Ketanserin also inhibited amplification by 5-HT of ADP-induced aggregation of canine platelets much more potently than mianserin (IC50 = 0.07 vs. 3.18 microM). Mianserin and RX 781094, a selective alpha-2 adrenoceptor antagonist, inhibited epinephrine-stimulated aggregation of human platelets more potently than ketanserin (IC50 values = 6.10, 0.19 and greater than 10 microM, respectively). Thus, the abilities of three 5-HT2 antagonists with diverse chemical structures and pharmacologic profiles (5-HT2 antagonism notwithstanding) to abolish CFRs suggests that amplification by 5-HT of other mediators, e.g. epinephrine and/or ADP, influences coronary blood flow importantly in this model.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D003533:Cyproheptadine / Q000494:pharmacology*; D004285:Dogs; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007650:Ketanserin / Q000494:pharmacology*; D008297:Male; D008803:Mianserin / Q000494:pharmacology*; D010507:Periodicity; D010974:Platelet Aggregation / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology
D008803:Mianserin; D003533:Cyproheptadine; D012701:Serotonin; D000244:Adenosine Diphosphate; D007650:Ketanserin; D004837:Epinephrine