Effects of maturation, artery size, and chronic hypoxia on 5-HT receptor type in ovine cranial arteries

To test the hypothesis that variations in cerebrovascular reactivity to 5-HT among arteries of different size or type, during maturation, or during acclimatization to high altitude involve differences in serotonergic receptor subtype, we determined relative agonist potency orders and antagonist affinities in common carotid (Com), main branch middle cerebral (Main), and second branch middle cerebral (2BR) arteries from term fetal lambs and nonpregnant adult sheep acclimatized at sea level or at an altitude of 3,820 m for ≃110 days. In normoxic adult Com segments, agonist potency order was 5-hydroxytryptamine (5-HT) > 5-carboxamidotryptamine (5-CT) ≤ 8-hydroxy- 2(di-n-propylamino)tetraline (8-OH-DPAT); sumatriptan (Suma) produced no contractile response; and antagonist dissociation constant (pK(b)) values were 9.4 and 9.5 for ketanserin against 5-HT and 5-CT, 7.5 for GR-127935 against 5-HT, and 7.2 for SB-206553 against 5-HT. In normoxic adult Main segments, agonist potency order was 5-HT > 5-CT ≤ Suma ≤ DPAT, and pK(b) values were 9.1 and 9.2 for ketanserin against 5-HT and 5-CT and 7.4 and 8.5 for GR-127935 against 5-HT and Suma, respectively. In the 2BR segments from normoxic adults, agonist potency order was 5-CT > 5-HT > Suma > DPAT and pK(b) values were 7.4 and 7.2 for ketanserin against 5-HT and 5-CT and 10.0 and 8.7 for GR-127935 against 5-HT and Suma, respectively. Compared with normoxic adults, none of these values were significantly different in hypoxic adults and in fetuses only the pK(b) values for ketanserin against 5-HT in the 2BR segments (8.8) were greater. From these results we propose that the ratio of 5-HT₂ to 5-HT₁ receptors is greatest in the Com and decreases progressively to its smallest values in 2BR or smaller segments. Because this gradient appears stable and relatively resistant to the effects of maturation and chronic hypoxia, changes in reactivity associated with these perturbations may involve alterations in receptor density and/or coupling efficiency for 5-HT in ovine cranial arteries.