Article date: October 1992
By: T.M. Cocks, P.J. Arnold, in Volume 107, Issue 2, pages 591-596
We investigated the potent 5‐hydroxytryptamine (5‐HT)‐mediated vasorelaxation of the sheep pulmonary vein. Here we present evidence that this response is due to activation of 5‐HT4 receptors.
5‐HT (1–1000 nm) caused concentration‐dependent, maintained relaxations (pEC50 = 8.4 ± 0.1) of isolated rings of sheep pulmonary vein pre‐contracted with endothelin‐1 (3 nm).
The relaxation response to 5‐HT was unaffected by either removal of the endothelium or by inhibition of NO‐synthase by NG‐nitro‐l‐arginine (100 μm).
Ketanserin, methiothepin, methysergide and MDL 72222 at concentrations that selectively block 5‐HT2, 5‐HT1‐like and 5‐HT3 receptors respectively, had no effect on the concentration‐relaxation curve to 5‐HT.
ICS 205–930 (1–10 μm) competitively antagonized the concentration‐relaxation curve to 5‐HT with a pA2 of approximately 6.7.
6 Increasing the concentration of ICS 205–930 from 10 to 30 μm did not cause a further rightward shift of the 5‐HT concentration‐relaxation curve. The pEC50 of 6.50 for 5‐HT in the presence of ICS 205–930 (30 μm) was taken as an estimate of the affinity of 5‐HT for 5‐HT1‐like receptors since methiothepin (10 nm) unmasked further competitive inhibition of 5‐HT in the presence of this concentration of ICS 205–930.
7 Other 5‐HT agonists including 5‐carboxamidotryptamine (5‐CT), α‐methyl‐5‐HT and BIMU 8 (but not 2‐methyl‐5‐HT) also relaxed the pulmonary vein. The response to 5‐CT was inhibited by methiothepin (10 nm) and methysergide (100 nm) but unaffected by ICS 205–930 (30 μm), whilst that to α‐methyl‐5‐HT and BIMU 8 was unaffected by methiothepin (10 nm) but blocked by ICS 205–930 (estimated pKB values of 6.4 and 6.9 respectively). Relaxation curves to both 5‐HT and BIMU 8 were unaffected by cocaine (6 μm).
8 In conclusion, these results indicate that the sheep pulmonary vein possesses 5‐HT4 receptors that mediate potent endothelium‐independent relaxation. 5‐HT1‐like relaxant receptors are also present in this tissue but 5‐HT has a lower affinity at these receptors. This preparation may thus provide a robust and sensitive bioassay for future development of selective 5‐HT4 receptor agonists and antagonists.
We investigated the potent 5‐hydroxytryptamine (5‐HT)‐mediated vasorelaxation of the sheep pulmonary vein. Here we present evidence that this response is due to activation of 5‐HT4 receptors.
5‐HT (1–1000 nm) caused concentration‐dependent, maintained relaxations (pEC50 = 8.4 ± 0.1) of isolated rings of sheep pulmonary vein pre‐contracted with endothelin‐1 (3 nm).
The relaxation response to 5‐HT was unaffected by either removal of the endothelium or by inhibition of NO‐synthase by NG‐nitro‐l‐arginine (100 μm).
Ketanserin, methiothepin, methysergide and MDL 72222 at concentrations that selectively block 5‐HT2, 5‐HT1‐like and 5‐HT3 receptors respectively, had no effect on the concentration‐relaxation curve to 5‐HT.
ICS 205–930 (1–10 μm) competitively antagonized the concentration‐relaxation curve to 5‐HT with a pA2 of approximately 6.7.
6 Increasing the concentration of ICS 205–930 from 10 to 30 μm did not cause a further rightward shift of the 5‐HT concentration‐relaxation curve. The pEC50 of 6.50 for 5‐HT in the presence of ICS 205–930 (30 μm) was taken as an estimate of the affinity of 5‐HT for 5‐HT1‐like receptors since methiothepin (10 nm) unmasked further competitive inhibition of 5‐HT in the presence of this concentration of ICS 205–930.
7 Other 5‐HT agonists including 5‐carboxamidotryptamine (5‐CT), α‐methyl‐5‐HT and BIMU 8 (but not 2‐methyl‐5‐HT) also relaxed the pulmonary vein. The response to 5‐CT was inhibited by methiothepin (10 nm) and methysergide (100 nm) but unaffected by ICS 205–930 (30 μm), whilst that to α‐methyl‐5‐HT and BIMU 8 was unaffected by methiothepin (10 nm) but blocked by ICS 205–930 (estimated pKB values of 6.4 and 6.9 respectively). Relaxation curves to both 5‐HT and BIMU 8 were unaffected by cocaine (6 μm).
8 In conclusion, these results indicate that the sheep pulmonary vein possesses 5‐HT4 receptors that mediate potent endothelium‐independent relaxation. 5‐HT1‐like relaxant receptors are also present in this tissue but 5‐HT has a lower affinity at these receptors. This preparation may thus provide a robust and sensitive bioassay for future development of selective 5‐HT4 receptor agonists and antagonists.
DOI: 10.1111/j.1476-5381.1992.tb12788.x
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