The selective carotid arterial vasoconstrictor action of GR43175 in anaesthetized dogs.
1. GR43175 is a highly selective agonist at 5-HT1-like receptors in the dog saphenous vein. This study describes the haemodynamic effects of GR43175 in barbitone-anaesthetized dogs. 2. GR43175 (1-1000 micrograms kg-1, i.v.) produced dose-dependent decreases in carotid arterial blood flow with little or no change in arterial blood pressure. The decrease in blood flow was associated with an increase in carotid arterial vascular resistance. In preliminary studies, the dose of GR43175 producing 50% of the maximum carotid vasoconstrictor response was 39 +/- 8 micrograms kg-1, i.v. 3. In comparative regional haemodynamic studies, GR43175 (1-1000 micrograms kg-1, i.v.) had little effect on total peripheral resistance or resistance in the mesenteric, vertebral and coronary arterial vascular beds. Low doses of GR43175 decreased, whilst high doses (100 micrograms kg-1, i.v. and above) increased femoral arterial vascular resistance. GR43175 (1-1000 micrograms kg-1, i.v.) had no effect on respiratory inflation pressure. In doses of 100 micrograms kg-1 i.v. and above, GR43175 caused small decreases in heart rate. 4. The carotid arterial vasoconstrictor action of GR43175 was resistant to antagonism by the 5-HT2 receptor, 5-HT3 receptor and alpha-adrenoceptor blocking drugs, ketanserin, MDL72222 and phentolamine respectively, but could be antagonized by the non-selective 5-HT1-like receptor blocking drug methiothepin. Methiothepin had no effect on the carotid vasoconstrictor action of the thromboxane A2 mimetic, U46619. 5. The results demonstrate that GR43175 produces a selective vasoconstriction in the carotid arterial circulation of anaesthetized dogs via activation of 5-HT1-like receptors, which appear similar to those mediating contraction of the dog isolated saphenous vein.
Feniuk
W
W
Pharmacology Division, Glaxo Group Research, Ware, Hertfordshire.
Humphrey
P P
PP
Perren
M J
MJ
D000818:Animals; D001462:Barbital / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects*; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D018170:Sumatriptan; D014326:Tropanes / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D007211:Indoles; D012702:Serotonin Antagonists; D013449:Sulfonamides; D014326:Tropanes; D014662:Vasoconstrictor Agents; D008719:Methiothepin; D001462:Barbital; D018170:Sumatriptan; D007650:Ketanserin; C042253:bemesetron; D010646:Phentolamine