COMPARISON OF CONTRACTILE RESPONSES TO 5-HYDROXYTRYPTAMINE AND SUMATRIPTAN IN HUMAN ISOLATED CORONARY-ARTERY - SYNERGY WITH THE THROMBOXANEA(2)-RECEPTOR AGONIST, U46619
Tm. Cocks et al., COMPARISON OF CONTRACTILE RESPONSES TO 5-HYDROXYTRYPTAMINE AND SUMATRIPTAN IN HUMAN ISOLATED CORONARY-ARTERY - SYNERGY WITH THE THROMBOXANEA(2)-RECEPTOR AGONIST, U46619, British Journal of Pharmacology, 110(1), 1993, pp. 360-368
1 The interaction between the thromboxane A2 receptor agonist, U46619
and two 5-hydroxytryptamine (5-HT) receptor agonists, the non-selectiv
e, naturally occurring agonist, 5-HT and the selective 5-HT1-like agon
ist, sumatriptan were studied in human epicardial coronary arteries in
vitro. 2 Coronary artery rings (2-4 mm in diameter) were prepared fro
m epicardial arteries from explant hearts of patients undergoing heart
transplant (cardiomyopathy, n = 13; ischaemic heart disease, n = 10)
and unused donor hearts (n = 5). Each ring of artery was set at optima
l resting conditions to record changes in isometric force. 3 The major
ity of artery rings developed phasic, rhythmic contractions either spo
ntaneously or in response to all vasoconstrictor agonists tested. Both
the spontaneous and agonist-induced phasic contractions were abolishe
d by nifedipine (0.1 muM). 4 Concentration-contraction curves to 5-HT-
receptor agonists and noradrenaline (NA), were first constructed in ar
tery rings that did not develop phasic activity. 5-HT and ergometrine
were the most potent agonists with EC50 values of 6.8 +/- 0.2 and 7.7
+/- 0.2 (-log M) respectively. Potencies (EC50's) to sumatriptan, meth
ysergide and noradrenaline could not be determined due to their poor a
bility to contract the coronary artery. Maximum contractions (E(max);
normalized as a percentage of the contraction to a maximum-depolarizin
g concentration of K+ in physiological salt solution (KPSS)) for 5-HT,
ergometrine, sumatriptan, methysergide and noradrenaline were 40 +/-
10, 9 +/- 3, < 5, < 5 and < 5% respectively. 5 In arteries without pha
sic activity, U46619 (1 nm) caused an increase in force of 3.8 +/- 1%
KPSS. With U46619 present, the E(max) values for 5-HT, ergometrine, su
matriptan and methysergide were all markedly increased. For 5-HT and s
umatriptan, E(max) values were 92 +/- 4% and 49 +/- 14% KPSS respectiv
ely. The presence of U46619 did not significantly change the sensitivi
ty (EC50) to 5-HT. 6 In a separate series of arteries, nifedipine (0.1
mum) was used to block phasic, contractile activity. The synergy obse
rved between U46619 and 5-HT or sumatriptan still occurred although th
e E(max) values for each agonist were depressed but the EC50 values we
re again unaffected. 7 In conclusion, these in vitro studies indicate
that the normally poor contractions to sumatriptan, in human coronary
arteries are significantly enhanced when active force is induced with
a thromboxane A2-receptor agonist, U46619. The enhanced response is no
t specific for either sumatriptan or 5-HT1-like receptors since contra
ctions to 5-HT, ergometrine and methysergide were also potentiated by
U46619.