Origin of 5‐hydroxytryptamine‐induced hyperpolarization of the rat superior cervical ganglion and vagus nerve

Self Cite

106

The pharmacological characterization of the 5‐HT3 receptors in guinea‐pig isolated tissues is described. The tissues used were ileum (longitudinal muscle‐myenteric plexus), colon and vagus nerve. The guinea‐pig isolated colon is a novel preparation. In the guinea‐pig isolated ileum, 5‐hydroxytryptamine (5‐HT, 1 × 10−8−3 × 10−5 m) and the selective 5‐HT3 receptor agonist 2‐methyl‐5‐HT (3 × 10−7−1 × 10−4 m) caused concentration‐related contractions. The 5‐HT concentration‐response curve was biphasic whilst the 2‐methyl‐5‐HT curve was monophasic. The EC50 value for the low potency portion of the 5‐HT curve was 4.1 × 10−6 m. The EC50 for 2‐methyl‐5‐HT was 1.23 × 10−5 m. Selective 5‐HT3 receptor antagonists caused rightward shifts of the 2‐methyl‐5‐HT curve and the lower potency portion of the 5‐HT curve. Neither ketanserin (1 × 10−6 m) nor methysergide (1 × 10−5 m) antagonized the responses to 5‐HT or 2‐methyl‐5‐HT. In the guinea‐pig isolated colon, 5‐HT (3 × 10−7−3 × 10−5 m; EC50 2.4 × 10−6 m) caused contractions which were mimicked by 2‐methyl‐5‐HT (1 × 10−6−1 × 10−4 m; EC50 7.2 × 10−6 m). Selective 5‐HT3 receptor antagonists caused rightward displacements of the 5‐HT concentration‐response curves. Neither ketanserin (1 × 10−6 m) nor methysergide (1 × 10−5 m) had any effect on responses to 5‐HT or 2‐methyl‐5‐HT. In the guinea‐pig isolated vagus nerve, 5‐HT (1 × 10−6−3 × 10−4 m) and 2‐methyl‐5‐HT (1 × 10−5−1 × 10−3 m; EC50 7.6 × 10−5 m) caused depolarizations; at higher concentrations there were afterhyperpolarizations. The maximum response to 2‐methyl‐5‐HT was less than half that to 5‐HT. Selective 5‐HT3 receptor antagonists caused rightward displacements of the 5‐HT concentration‐response curves. Antagonists at other 5‐HT receptors (ketanserin, 1 × 10−5 m and methysergide, 1 × 10−6 m) had no effect. The estimated affinity values of 5‐HT3 receptor antagonists correlated well between the three models. Phenylbiguanide was inactive as an agonist or antagonist (up to 1 × 10−4 m) in each preparation. Comparisons with antagonist affinity values obtained in the rat isolated vagus nerve revealed marked differences. Antagonists were generally more potent on the rat isolated vagus nerve, although the differences varied considerably between antagonists. The results are discussed in terms of species‐related receptor differences.

Section: Discussionmentioning

confidence: 87%

“…5-HT3 receptor antagonists caused rightward shifts of the concentration-depolarization response curves to 5-HT (see Table 2, Ireland &Butler et al, 1988). For some compounds (MDL 72222, ICS 205-930, GR65630, granisetron, zacopride and GR67330) the rightward shifts were accompanied by a fall in maximum response.…”

Section: Rat Vagus Nervementioning

confidence: 96%

The pharmacological characterization of 5‐HT₃ receptors in three isolated preparations derived from guinea‐pig tissues

Butler

Elswood

Burridge

et al. 1990

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106

“…The method for mounting the preparations in the baths and the techniques for recording and drug application are described in the companion paper (Ireland, 1987). As in this previous study, the temperature of each preparation was maintained at 27 ± 1VC.…”

Section: Extracellular Recordingmentioning

confidence: 99%

“…This hyperpolarization is not a consequence of 5-HT-induced depolarization and, unlike the depolarization, does not result from the activation of 5-HT3 receptors since it is resistant to blockade by MDL 72222 and metoclopramide (Ireland, 1987;. However, a more precise characterization of the receptor mediating the hyperpolarization response has not been published.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological characterization of 5‐hydroxytryptamine‐induced hyperpolarization of the rat superior cervical ganglion

Ireland

Jordan

1987

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A study has been made of the pharmacology of 5‐hydroxytryptamine (5‐HT)‐induced hyperpolarization responses recorded extracellularly from the rat isolated superior cervical ganglion (SCG). Hyperpolarization responses induced by 5‐HT (1 × 10−8‐1 × 10−4 m) in the presence of MDL 72222 (1 × 10−5 m) were not antagonized by phentolamine (1 × 10−6 m), prazosin (1 × 10−7‐3 × 10−7 m), haloperidol (1 × 10−6 m) or ketanserin (1 × 10−7‐1 × 10−6 m). However, the latter two compounds both potentiated and increased the persistence of the hyperpolarization induced by moderate to high concentrations of 5‐HT. Spiperone (1 × 10−7 m) caused similar effects. All further experiments were performed in the presence of ketanserin (1 × 10−6 m) as well as MDL 72222. 8‐Hydroxy‐2(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT; 1 × 10−7‐1 × 10−4 m) and ipsapirone (3 × 10−5‐3 × 10−4 m) behaved as weak hyperpolarizing agonists on the SCG. However, at concentrations below those required to produce hyperpolarization, both compounds acted as unsurmountable antagonists of 5‐HT‐induced hyperpolarization. 5‐Carboxamidotryptamine (5‐CT; 1 × 10−9‐1 × 10−5 m) mimicked the hyperpolarizing activity of 5‐HT on the SCG. The EC50 for 5‐CT was approximately 9 fold lower than that for 5‐HT. Spiperone (1 × 10−7‐1 × 10−5 m) behaved as a reversible competitive antagonist of hyperpolarization responses induced by 5‐HT with a pKB value of 7.40 ± 0.09. Spiperone (1 × 10−7‐1 × 10−6 m) also caused concentration‐dependent rightward displacement of the 5‐CT concentration‐hyperpolarization response curve. In this case, the pKB was 7.80 ± 0.05. (±)‐Cyanopindolol (3 × 10−7‐3 × 10−6 m) caused non‐parallel rightward displacements of the 5‐HT concentration‐response curve. Against 5‐CT, (±)‐cyanopindolol (3 × 10−7‐3 × 10−6 m) caused a concentration‐independent rightward displacement of the concentration‐response curve, accompanied by a large increase in the maximum response. 5‐CT‐induced hyperpolarization recorded in the presence of (±)‐cyanopindolol (3 × 10−7 m) was not significantly antagonized by methiothepin (1 × 10−6 m) or methysergide (1 × 10−6 m). It is concluded that 5‐HT‐induced hyperpolarization of the rat SCG is mediated via a 5‐HT1‐like receptor which resembles the 5‐HT1A binding site. However, a lack of selective drugs precludes more definitive characterization of this receptor.

“…Up to six ganglion preparations were used in each experiment. For full details of tissue preparation and recording, see Ireland (1987).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological characterization of angiotensin‐induced depolarizations of rat superior cervical ganglion in vitro

Hawcock

Barnes

Michel

1992

The.AT,-selective non-peptide antagonist losartan (DuP 753; 0.03 and 0.1 uM) produced a parallel rightward displacement of the angiotensin II concentration-response curve, with an apparent pKB of 8.3 + 0.1. A higher concentration of losartan (0.3 pM) depressed the maximum agonist response by 32 + 6.5%, possibly reflecting non-competitive behaviour of the antagonist. The potency of losartan was not influenced by bacitracin. 6 The AT2-selective non-peptide antagonist, PD123177 (3pM) failed to antagonize the angiotensin IIinduced depolarizations. 7 DTT (1 mM) produced a 22% reduction of the maximum response to angiotensin II. 8 We conclude that the angiotensin II-induced depolarizations of the rat superior cervical ganglion are mediated by angiotensin II receptors of the AT1 subclass. The ability of peptidase inhibitors to modify the potency of peptide agonists and antagonists highlights the difficulties associated with the use of peptide agents to characterize angiotensin II receptors in this preparation.