Pharmacology of noradrenaline and neuropeptide tyrosine (NPY)-mediated sympathetic cotransmission

Abstract

Pharmacological and physiological aspects for neuropeptide Y (NPY) and noradrenaline (NA) cotransmission have been studied in the peripheral sympathetic nervous control of blood vessels, heart, spleen and vas deferens. NPY coexists with NA in large dense cored vesicles and is released compared to NA mainly upon high frequency stimulation or strong reflex sympathetic activation. NPY release is inhibited via prejunctional alpha-2 adrenoceptors and adenosine receptors but facilitated by angiotensin II or beta-receptor activation. NPY exerts prejunctional inhibitory actions on both NA and NPY release, enhances the vasoconstrictor effect of NA and evokes potent, long-lasting vasoconstriction. Specific receptor mechanisms for NPY exist at both the pre- and postjunctional levels; a large amidated C-terminal portion of NPY is necessary for receptor binding, inhibition of cyclic AMP formation and vasoconstrictor effects. Denervation results in supersensitivity for both NA and NPY-evoked vasoconstriction. Reserpine pretreatment is associated with depletion of NA as well as NPY; the effect on NPY is entirely dependent on an intact nerve activity. Reserpine treatment combined with preganglionic denervation depletes NA by 99% while NPY levels are maintained intact. The characteristic appearance of the nerve stimulation evoked vasoconstrictor response with a high correlation to NPY outflow after reserpine treatment, suggests that NPY may be involved as a transmitter in a variety of vascular beds. NPY-synthesis in ganglia seems to be regulated by nicotinic receptor activity; secondary stimulation by eg reserpine stimulates and nicotine antagonists decrease NPY-synthesis. Many classical pharmacological agents including guanethidine, clonidine, yohimbine, angiotensin II, nicotine and desipramine influence NPY release. A complex interplay therefore seems to occur at both the pre- and postjunctional levels of transmission for the classical transmitter NA and the coexisting peptide NPY, creating a great diversity of chemical signalling potential.