Characterization of the 5-hydroxytryptamine receptor mediating the positive inotropic response in guinea-pig isolated...

1. 5-Hydroxytryptamine (5-HT), in the presence of propranolol (1 microM), atropine (3 microM) and ketanserin (1 microM), induced a positive inotropic response of guinea-pig isolated electrically paced left atria (pEC50 = 7.52). The positive inotropic response was mimicked by alpha-methyl-5-HT (pEC50 = 7.26) and 5-carboxamidotryptamine (5-CT; pEC50 = 6.56) but not by sumatriptan or 1-(m-chlorophenyl) piperazine (m-CPP). 2. The 5-HT induced positive inotropic response was competitively antagonized by both mesulergine (pA2 = 7.68) and methiothepin (pA2 = 6.67). Methysergide was a surmountable antagonist at 3 nM producing a rightward shift in the 5-HT concentration-response curve giving an apparent pA2 = 9.2 with no significant reduction in the maximum. At higher concentrations, methysergide behaved as an insurmountable antagonist, significantly reducing the maximum response to 5-HT as well as producing rightward shifts in the 5-HT concentration-response curves. 3. The 5-HT-induced positive inotropic response was not antagonized by either tropisetron (10 microM) or yohimbine (10 microM). 4. The guinea-pig atrial 5-HT receptor does not satisfy the criteria for any of the currently recognised 5-HT receptor subtypes and appears to have some similarities to the atypical 5-HT receptors previously described in other peripheral tissues.