Co-release and functional interactions of neuropeptide Y and noradrenaline in peripheral sympathetic vascular control.
1. The immunohistochemical results suggest that NPY-LI co-exists with NA in sympathetic periarterial nerves of skeletal muscle. The corresponding veins are associated with few or no sympathetic nerves. 2. SNS evoked a detectable overflow of NPY-LI from the dog gracilis muscle in vivo during high-frequency but not low-frequency stimulation. After the administration of alpha-adrenoceptor antagonists, the overflow of NPY-LI was enhanced, indicating prejunctional inhibition of release via a mechanism similar to that for NA. Reserpine pretreatment depleted both NA and NPY-LI from skeletal muscle. The reserpine-induced depletion of NPY-LI, but not of NA, was highly dependent on intact nerve activity, since it was prevented by decentralization. 3. Slowly developing and long-lasting vasoconstriction was evoked by exogenous NPY and by high-frequency SNS in the gracilis muscle in the presence of adrenoceptor antagonists that completely blocked the vasoconstrictor response to exogenous NA. After reserpine treatment, considerably larger vasoconstrictor responses to SNS were observed in the decentralized muscle than in the intact one, in parallel with the overflow of NPY-LI. These results suggest that the released NPY may be the mediator of the adrenoceptor antagonist- and reserpine-resistant functional responses to SNS in the gracilis muscle. ATP mechanisms seem to be of less importance for the sympathetic control of gracilis muscle vasculature. 4. The plasma levels of NPY-LI and NA in man increased during physical exercise, suggesting a co-release from sympathetic nerves. This release appears to be attenuated by activation of alpha-adrenoceptors since phentolamine and clonidine, respectively, enhanced and suppressed the exercise-induced increase in the plasma levels of both NPY-LI and NA. The plasma levels of NPY-LI were increased during control conditions, and altered by clonidine and phentolamine, mainly at high work loads, which may indicate preferential release of the peptide at high levels of sympathetic activity. 5. Local i.a. infusion of NPY in man reduced forearm blood flow with a threshold effect at a plasma concentration in the low nmolar range. The reduction in forearm blood flow induced by NPY was considerably more long-lasting than that evoked by NA, which may partly be related to the long metabolic half-life of NPY. 6. NPY induced contractile effects in vitro that varied between different arteries and veins. The most pronounced effects were evoked in small human skeletal muscle arteries, where NPY caused a maximal contraction similar to that of NA.(ABSTRACT TRUNCATED AT 400 WORDS)
Pernow
J
J
Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
D000818:Animals; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009132:Muscles / Q000378:metabolism; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D009638:Norepinephrine / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D011817:Rabbits; D012110:Reserpine / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
D009478:Neuropeptide Y; D012110:Reserpine; D009638:Norepinephrine