Characterization of the 5‐hydroxytryptamine receptor mediating the positive inotropic response in guinea‐pig isolated left atria

Abstract

1 5-Hydroxytryptamine (5-HT), in the presence of propranolol (1 ylM), atropine (3 tM) and ketanserin (1 ALM), induced a positive inotropic response of guinea-pig isolated electrically paced left atria (pEC5o = 7.52). The positive inotropic response was mimicked by a-methyl-5-HT (pECM = 7.26) and 5-carboxamidotryptamine (5-CT; pECm = 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 tM) or yohimbine (1O pM).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.Keywords: Guinea-pig atria, inotropic response; 5-HT; 5-carboxamidotryptamine (5-CT); a-methyl-5-HT; sumatriptran; l-(m- (Kaumann, 1986) and 5-HT-induced tachycardia in the spinal cat (Saxena et al., 1985). In the rabbit heart, the tachycardia and inotropic responses induced by 5-HT are mediated by noradrenaline release from the postganglionic cardiac sympathetic nerves via 5-HT3 receptor stimulation (Fozard, 1984). In guinea-pig atria, 5-HT can act directly via 5-HT receptors to produce both positive chronotropic and positive inotropic responses (Trendelenburg, 1960;Walter et al., 1984

The Potential Anti-Migraine Compound SB-220453 does not Contract Human Isolated Blood Vessels or Myocardium; A Comparison with Sumatriptan

“…However, the present results are consistent with the observed lack of haemodynamic effects of sumatriptan in patients, where no negative or positive inotropic effects were demonstrated (32). These studies are also in accordance with in vitro studies performed on guinea pig (33,34) cardiac tissue. In fact, the role of 5-HT 1B and 5-HT 1D receptors on the human heart is still poorly understood (36), although the 5-HT 1D receptor has been reported to mediate inhibition of noradrenaline release in human atrium (37).…”

Diverse inotropic effects of 5-hydroxytryptamine in heart muscles of various mammalian species

“…The value for -logECs0 of 5-HT we obtained in guinea pig atrial muscles (5.53) was considerably lower than that reported by Lattimer et al (7.52) [7]. Eglen and Whiting [28] found positive chronotropic effects of 5-HT in the same tissue, with the -logEC»0 value being 5.43, a value identical to ours and to that reported by Tramontana et al [29].…”

“…The inotropic effect of 5-HT has been reported to be direct in cat atria [5,6], guinea pig atria [5,7], rat hearts [8], porcine atriä [9], and human atria [10][11][12][13]; whereas indirect effects were reported for rabbit hearts [5,14,15]. In contrast, the inotropic effect was not observed in porcine [9] and human ventricles [13].…”

“…However, in contrast to their and, perhaps, our findings, Walter et al [30] showed that 5-HT exerted a positive chronotropic effect on guinea pig right atria and that 0.6 ,uM of (-)-pindolol did not antagonize this effect. Lattimer et al [7] also noted a positive inotropic effect of 5-HT in guinea pig isolated left atria, in the presence of 1uM propranolol (a dose equivalent to approximately 0.2btM pindolol, since propranolol is about five times less potent than pindolol in [3-adrenoceptor blocking activity [31]. A1-though there is no clear answer to such discrepancies in the blocking effects of pindolol against 5-HT-mediated chronotropic and inotropic effects, the concentration of pindolol used may be a factor: it was rather high in the study of Eglen and Whiting [28] and in our study (1-8~tM), compared to that in other studies (0.2-0.6 ~tM) [7,30].…”

Immunohistochemical localisation of the serotonin 5‐HT2B receptor in mouse gut, cardiovascular system, and brain

“…The presence of 5-HT2B receptors may explain partially this species dependence since the pharmacology of this receptor subtype shows a very strong species specificity [34]. In the myocardium, the 5-HT2B receptor may be similar to the one mediating the positive inotropic response to 5-HT in the atria [35]. In blood vessels, this expression may correspond to the 5-HT endothelial receptor (Fig.…”