INHIBITION OF SYMPATHETIC VASOCONSTRICTION IN PIGS IN-VIVO BY THE NEUROPEPTIDE Y-Y-1 RECEPTOR ANTAGONIST BIBP-3226

Recently, a potent non-peptide antagonist of neuropeptide Y (NPY)-Y-1 has been developed. In this study, the selectivity of this compound, BIBP 3226, as a functional Y-1 receptor antagonist, and the possible role of endogenous NPY in sympathetic vasoconstriction in different vascular beds have been investigated in anaesthetized pigs. 2 BIBP 3226 specifically displaced I-123-NPY binding with an IC50 value of 7 nM in membranes of pig renal arteries, which also were responsive to a Y-1 receptor agonist, but had only minor effects in the pig spleen (IC50 55 mu M), where instead I-123-NPY binding was markedly inhibited by a Y-2 receptor agonist. IC50 values in the same nM range for BIBP 3226 were also observed in rat and bovine cortex and dog spleen. 3 In anaesthetized control pigs in vivo BIBP 3226 (1 and 3 mg kg(-1)) markedly inhibited the vasoconstrictor effects of the Y-1 receptor agonist Leu(31), Pro(34) NPY(1-36), without influencing the responses to the Y-2 receptor agonist N-acetyl Leu(28), Leu(31) NPY(24-36), or to noradrenaline, phenylephrine, alpha, beta-methylene adenosine triphosphate or angiotensin II. 4 High frequency stimulation of the sympathetic trunk in control pigs caused a biphasic vasoconstrictor response in nasal mucosa, hind limb and skin: there was an immediate, peak response, followed by a long-lasting vasocontriction. BIBP 3226 (1 and 3 mg kg(-1)) reduced the second phase by about 50% but had no effect on the peak response. In the spleen, kidney and mesenteric circulation (which lack the protracted response) BIBP 3226 was likewise without effect on the maximal vasoconstriction, and did not influence noradrenaline overflow from spleen and kidney. 5 The corresponding S-enantiomer BIBP 3435 had only marginal influence on I-125-NPY binding (mu M range) and did not inhibit the vasoconstrictor effects of any of the agonists used, including the Y-1 receptor peptide agonist. Furthermore, BIBP 3435 did not affect the response to sympathetic nerve stimulation. Both BIBP 3435 and BIBP 3226 caused a slight transient decrease in mean arterial blood pressure (by about 5 and 15 mmHG at 1 mg kg(-1) and 3 mg kg(-1), respectively), accompanied by splenic and mesenteric vasodilation, suggesting that this effect was unrelated to Y-1 receptor blockade. 6 The peptide YY (PYY)- and NPY-evoked vasocontriction in the kidney of reserpine-treated pigs was markedly reduced (by 95%) by BIBP 3226 while the vasoconstrictor effect in the spleen was attenuated by only 20%. BIBP 3226 did not influence stimulation-evoked NPY release. The vasoconstrictor response in reserpine-treated pigs to single impulse stimulation, which is observed only in nasal mucosa and hind limb, was unchanged regarding maximal amplitude and the integrated effect was only moderately reduced (by about 25%) in the presence of BIBP 3226 (1 mg kg(-1)). BIBP 3226 (1 mg kg(-1)) markedly reduced (by 55-70%) the long-lasting vascular response (total integrated blood flow reduction) evoked by sympathetic nerve stimulation at high frequency (40 impulses at 20 Hz) in spleen, kidney, nasal mucosa and hind limb. Furthermore, the maximal amplitude of the vasocontriction was reduced mainly in the kidney (by 60%) and also in the spleen (by 40%). 7 It is concluded that BIBP 3226 can act as a selective Y-1 receptor antagonist in the pig. Endogenous NPY via Y-1 receptor activation may play a role in evoking the long-lasting vasoconstriction seen in nasal mucosa, hind limb and skin after high frequency stimulation of sympathetic nerves in control pigs. Furthermore, NPY via Y-1 receptor mechanisms seems to be of major importance for the long-lasting component of the reserpine resistant sympathetic vasoconstriction in many vascular beds, and for the maximal vasoconstrictor response in the kidney. Circulating NPY and PYY induce splenic vasoconstriction via Y-2-receptors in contrast to neuronally released NPY which mainly activates Y-1 receptors.