Inhibition of sympathetic vasoconstriction in pigs in vivo by the neuropeptide Y‐Y₁ receptor antagonist BIBP 3226

Abstract

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 vasoconstriction. 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. pressure (by about 5 and 15 mmHg at 1 mg kg-' and 3 mg kg-', respectively), accompanied by splenic and mesenteric vasodilatation, suggesting that this effect was unrelated to Y, receptor blockade. 6 The peptide YY (PYY)-and NPY-evoked vasoconstriction 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-'). BIBP 3226 (1 mg kg-') 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 vasoconstriction 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, receptor antagonist in the pig. Endogenous NPY via Y, 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, 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 Y2-receptors in contrast to neuronally released NPY which mainly activates Y1 receptors.

Neuropeptide Y and sympathetic control of vascular tone in hypertension

“…The NS, as well as NE and ATP, induced vasoconstriction was potentiated by a NPY-Y 1 agonist and attenuated by BIBP3226 [76]. Similar results have been seen in vivo, where BIBP3226 inhibited the vasoconstrictor response to high frequency stimulation of sympathetic nerves in nasal mucosa, hindlimb and skin [74]. These results clearly suggest that endogenous NPY, acting on a Y 1 receptor, plays a role in producing long-lasting vasoconstriction in these organs or tissues.…”

“…For instance, the long-lasting vasoconstriction induced by high frequency stimulation of sympathetic nerves of the guinea pig vena cava in vitro was significantly attenuated in the presence of SR 120107 [73] or BIBP3226 (both selective NPY-Y 1 antagonists) [74,75]. It was also observed that sympathetic nerve stimulation (NS) produced concomitant vasoconstriction and NPY-ir release in the isolated perfused mesenteric arterial bed.…”

Stimulation of NPY Y2 receptors by PYY3-36 reveals divergent cardiovascular effects of endogenous NPY in rats on different dietary regimens

“…In food-restricted rats (with high endogenous NPY tone), the central effects of NPY Y 2 receptor stimulation dominated, which resulted in an increase of MAP and HR. Conversely, the peripheral effects of NPY Y 2 receptor stimulation dominated in HFD-fed rats (with low central NPY tone), which tended to decrease HR probably due to presynaptic inhibition of sympathetic neurotransmitters such as norepinephrine (16,18,23). The fact that blood pressure did not decrease after PYY in HFD-fed rats, which probably had an increased sympathetic tone, could be due to regionally selective vascular effects of Y 2 receptor stimulation.…”

Neural Control of Vascular Function in Skeletal Muscle

“…For example, using electrical field stimulation in excised vascular segments, the vasoconstrictor response includes an immediate peak response followed by a long-lasting vasoconstriction. This second component is not eliminated by reserpine indicating that it includes a nonadrenergic stimulus (173) which is reversed by BIBP 3226 ((2R)-5-…”