Vascular 5-HT1-like receptors that mediate contraction of the dog isolated saphenous vein and carotid arterial vasoconstriction in anaesthetized dogs are not of the 5-HT1A or 5-HT1D subtype.
1. There is controversy about whether 5-HT1A receptors mediate contraction of isolated cerebral blood vessels. We have therefore compared the vascular actions of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) with those of the 5-HT1-like receptor agonist, sumatriptan, on the dog isolated saphenous vein, which contains a 5-HT1-like receptor similar to those on cerebral blood vessels, and in the carotid circulation of the anaesthetized dog. 2. 5-Hydroxytryptamine (5-HT), sumatriptan and 8-OH-DPAT each caused contraction of dog isolated saphenous vein with a rank order of agonist potency of 5-HT greater than sumatriptan greater than 8-OH-DPAT and EC50 values (95% confidence limits) of 0.06 (0.04-0.08), 0.3 (0.1-0.8) and 3.9 (2.0-7.5) microM respectively. The maximum contractile effect produced by each agonist was similar. 3. The contractile effects of 5-HT, sumatriptan and 8-OH-DPAT in the dog isolated saphenous vein were resistant to antagonism by the 5-HT1A receptor antagonists spiperone, spiroxatrine and pindolol (all 1 microM). The 5-HT1D receptor ligands, metergoline (0.1 microM) rauwolscine (1 microM) and yohimbine (1 microM) had little or no antagonist activity. In contrast, the non-selective 5-HT1-like receptor blocking drug, methiothepin (0.03-0.3 microM) potently antagonized the contractile effects of 5-HT, sumatriptan and 8-OH-DPAT to a similar degree, suggesting that all three agonists act at the same receptor. 4. In ganglion-blocked, anaesthetized dogs, intra-carotid administration of 8-OH-DPAT (0.3-3 pggkg-1) and sumatriptan (0.1l-1 pgkg -), caused dose-dependent carotid arterial vasoconstriction. The two agonists were approximately equipotent in this respect. 5. The carotid arterial vasoconstrictor actions of 8-OH-DPAT and sumatriptan were not modified by spiperone (1 mgkg- , i.v.) but were antagonized to a similar extent by the subsequent administration of methiothepin (1 mgkg- 1, i.v.). 6. These results suggest that 8-OH-DPAT contracts the dog isolated saphenous vein and constricts the carotid arterial circulation of anaesthetized dogs by activation of 5-HT1-like receptors which are not of the 5-HTlA subtype, nor, on the basis of data with metergoline in the dog isolated saphenous vein, of the 5-HTID subtype. The receptor involved in these actions appears to be the same as that mediating the vasoconstrictor effects of sumatriptan. This receptor does not appear to be like any known 5-HT1 ligand binding site; hence the current description, 5-HT1-like, remains the most appropriate.
Pharmacology Division, Glaxo Group Research Limited, Ware, Hertfordshire.
M J
MJ
Perren
W
W
Feniuk
P P
PP
Humphrey
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000758:Anesthesia; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects; D004285:Dogs; D005730:Ganglionic Blockers / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008719:Methiothepin / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011738:Pyrilamine / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012501:Saphenous Vein / Q000187:drug effects; D013134:Spiperone / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D018170:Sumatriptan; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D005730:Ganglionic Blockers; D007211:Indoles; D011985:Receptors, Serotonin; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D014662:Vasoconstrictor Agents; D013134:Spiperone; D008719:Methiothepin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D001285:Atropine; D018170:Sumatriptan; D007650:Ketanserin; D011738:Pyrilamine