Actions of non-peptide ergot alkaloids at 5-HT1-like and 5-HT2 receptors mediating vascular smooth muscle contraction.
This report describes the actions of the non-peptide ergot alkaloids methysergide, methylergometrine and ergometrine at two types of 5-HT receptor mediating vascular contraction; the well established 5-HT2 receptor in rabbit aorta and a non-5-HT2 receptor in rabbit saphenous vein which resembles the 5-HT1-like receptor in dog saphenous vein. In the rabbit aorta ergometrine (1 mumol/l) and methylergometrine (0.3 mumol/l), but not methysergide, produced small contractions (14% and 7% respectively of the maximal response to 5-HT). This contraction was not related to activation of 5-HT2 receptors since it was resistant to blockade by ketanserin (0.3 mumol/l). When examined as antagonists of 5-HT-induced contractions of rabbit aorta, each ergot displayed nanomolar affinity at the 5-HT2 receptor but only methysergide behaved as a simple competitive antagonist (pKB = 8.25). Methylergometrine and ergometrine produced surmountable blockade which was accompanied by a non-parallel displacement of the 5-HT concentration-effect curves. The selective 5-HT1-like receptor agonist GR43175 (less than or equal to 30 mumol/l) was devoid of affinity at the 5-HT2 receptor in rabbit aorta. In the rabbit saphenous vein each of the ergots produced concentration-dependent contractions which resulted in overtly biphasic concentration-effect curves. Only the first phase of contraction mimicked the effects of 5-HT and GR43175 since contractions were not blocked by MDL 72222 (1 mumol/l), but were surmountably antagonised by methiothepin (10 nmol/l), ketanserin (0.3 mumol/l) and spiperone (0.3 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)
MacLennan
S J
SJ
Analytical Pharmacology Group, Wellcome Research Laboratories, Beckenham, Kent, UK.
Martin
G R
GR
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D004876:Ergot Alkaloids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011817:Rabbits; D011985:Receptors, Serotonin / Q000187:drug effects*
D004876:Ergot Alkaloids; D011985:Receptors, Serotonin