EFFECTS OF PRECONTRACTION WITH ENDOTHELIN-1 ON ALPHA-2-ADRENOCEPTOR-DEPENDENT AND (ENDOTHELIUM-DEPENDENT) NEUROPEPTIDE-Y-MEDIATED CONTRACTIONS IN THE ISOLATED VASCULAR BED OF THE RAT TAIL

1. The pressor effects to bolus doses of the α2-adrenoceptor agonist UK-14,304 were studied in the isolated vascular bed of the perfused rat tail before and after increasing the perfusion pressure with infusions of endothelin-1. Those of neuropeptide Y were studied before and after pre-constriction with endothelin-1 or 5-hydroxytryptamine. The pressor effects of neuropeptide Y were studied before and after functional disruption of the endothelium with the detergent CHAPS. 2. Endothelin-1 and the α1-adrenoceptor agonist phenylephrine induced dose-dependent vasoconstriction, endothelin-1 being some 104 times more potent than phenylephrine [log dose (mol) of the ED50 for endothelin-1 and phenylephrine: -11.8 ± 0.2 (n = 7), -8.2 ± 0.2 (n = 5) respectively]. 3. Under control conditions, at basal perfusion pressures, UK-14,304 and neuropeptide Y were virtually inactive as vasoconstrictors. Following a sustained increase in perfusion pressure by infusions of endothelin-1 (2.5-10 nM at 0.8 ml min-1), however, both UK-14,304 and neuropeptide Y induced dose-dependent pressor responses and both were some 102 times more potent than phenylephrine [log dose (mol) of the ED50 for UK-14,304 and neuropeptide Y: -10 ± 0.5 (n = 6), -10.3 ± 0.4 (n = 6) respectively]. Responses to neuropeptide Y also were uncovered when vascular tone was increased with 5-hydroxytryptamine (5-20 nM) [log dose (mol) of the ED50 for neuropeptide Y: -10.2 ± 0.2 (n = 6)]. 4. Pre-constriction-induced pressor responses to UK-14,304 were inhibited by 1 μM ruawolscine whilst those to neuropeptide Y were inhibited by disruption of the endothelium. Removal of the endothelium had no significant effect on the pressor response to 4 pmol or 8 pmol endothelin-1 and had no effect on the increase in perfusion pressure induced by the endothelin-1 infusions but did decrease the time-course of pressor responses to bolus injections of endothelin-1. Endothelial disruption had no significant effect on the vasoconstriction induced by all but one of the doses of phenylephrine administered [log dose (mol) of the ED50 for phenylephrine after CHAPS: -8.6 ± 0.2 (n = 5)], indicating that the responsiveness of the vascular smooth muscle was not destroyed by CHAPS. This treatment did, however, slow the onset and prolong the time course of the phenylephrine-induced responses. 5. These results indicate that, in the isolated vascular bed of the rat tail, pressor responses to both α2-adrenoceptor- and neuropeptide Y receptor-activation are uncovered by agonist-induced preconstriction including that to endothelin-1. Neuropeptide Y-induced vasoconstriction was endothelium-dependent.