Effects of the neuropeptide Y Y1 receptor antagonist SR 120107A on sympathetic vascular control in pigs in vivo

Abstract

The possible involvement of neuropeptide Y in sympathetic vasoconstriction in various vascular beds in anesthetized pigs in vivo was studied using the neuropeptide Y Y1 receptor antagonist SR 120107A. Single impulse sympathetic nerve stimulation evoked rapid vasoconstrictor responses in hind limb and nasal mucosa which were not affected by SR 120107A (1.5 mg kg-1). Vascular responses to high frequency stimulation was measured in kidney, spleen (three 1 s bursts at 20 Hz or 300 impulses at 10 Hz), hind limb and nasal mucosa (three 1 s bursts at 20 Hz). High frequency stimulation evoked rapid vasoconstriction in all vascular beds studied. This was followed by a long-lasting phase of reduced blood flow in hind limb and nasal mucosa. SR 120107A (1.5 mg kg-1) attenuated the vasoconstriction evoked by the 20 Hz stimulation in the kidney, whereas a higher dose (a total of 6.0 mg kg-1) was required to reduce the vascular response in kidney to the 10 Hz simulation. SR 120107A (1.5 mg kg-1) did not inhibit the vascular responses in spleen, hind limb or nasal mucosa to the 20 Hz stimulation or the vasoconstriction in the spleen to the 10 Hz stimulation (a total of 6 mg kg-1). Subsequent addition of the adrenoceptor antagonists phenoxybenzamine (5 mg kg-1) plus timolol (2 mg kg-1) strongly reduced the vascular responses to single impulse stimulation and high frequency stimulation (20 Hz series) in all vascular beds. We conclude that endogenous neuropeptide Y acting on the neuropeptide Y Y1 receptor, as revealed by SR 120107A, is likely to account for part of the sympathetic vasoconstriction upon high frequency stimulation in the kidney.

Enhanced Y1-receptor-mediated vasoconstrictive action of neuropeptide Y (NPY) in superior mesenteric arteries in portal hypertension

“…NPY is known to mediate its pressor effects postsynaptically via Y1-receptors located on arterial vascular smooth muscle cells as has been evidenced in various species and vascular beds [34][35][36][37][38][39][40]. In accordance, in rat mesenteric arteries facilitation of adrenergic vasoconstriction induced by NPY has been demonstrated to be abolished by selective NPY Y1-receptor antagonists [41].…”

Renal effects of neuropeptide Y

“…Since these alterations occur at doses which antagonize exogenous NPY, and occur without concomitant alterations of blood pressure, these data indicate that endogenous NPY causes tonic renal vasoconstriction in anaesthetized rats. It has also been observed in pigs in vivo that the NPY receptor antagonist SR 120107A inhibits the nerve stimulation-induced vasoconstriction in the kidney but not in several other tissues [66]. Taken together these data indicate that endogenous NPY may be more important in the regulation of vasoconstriction in the kidney than in other vascular beds.…”

Effects of the neuropeptide Y Y2 receptor antagonist BIIE0246 on sympathetic transmitter release in the pig in vivo

“…[In parallel, the role of endogenous NPY in sympathetic nerve-evoked postjunctional vascular effects is not clearcut during control conditions (Lundberg and Modin 1995;Malmström and Lundberg 1996), or even after adrenoceptor blockade (unpublished observations).] Alternatively, any effect of NPY may have been still marginal in comparison with α 2 -mediated autoinhibition, taking into account the possibility of an incomplete α 2 -adrenoceptor blockade in combination with an enhanced release of noradrenaline.…”

“…-60±4*** -34±2*** +25±3*** -18± 6* BIIE0246 +1±1 -2±2 0±1 +5± 2 + PYY -33±4*** ,✝ -35±6*** +18±2*** -31± 8** Yohimbine -6±5 -6±3 +3±5 +40±13** + BIIE0246 +21±5** ,✝✝ +2±1 -1±1 +5± 2 *P<0.05, **P<0.01, ***P<0.001 significant differences from basal values ✝ P<0.001 significant difference between PYY-evoked response seen in the absence and presence of BIIE0246 ✝✝ P<0.05 significant difference between effect of BIIE0246 in the absence and presence of yohimbine thetic transmitter release in the pig kidney (Lundberg and Modin 1995;Malmström and Lundberg 1996).…”