Proton as a Possible Neurotransmitter for Perivascular Axo-axonal Transmission in the Rat Mesenteric Resistance Artery

The rat mesenteric resistance arteries are densely innervated by adrenergic vasoconstrictor nerves, CGRPergic vasodilator nerves and nitric oxide-containing nerves. Those nerves have axo-axonal interactions to modulate vascular nerve function and to regulate vascular tone. The present study focused on a possible transmitter, which is involved in axo-axonal transmission of adrenergic nerves and CGRP nerves. When nicotine is applied in the rat perfused mesenteric artery, nicotine stimulates nicotinic α₃β₄ nicotinic acetylcholine receptors on adrenergic nerves. This stimulation leads to the release of proton from adrenergic nerves. Released proton activates transient receptor potential vanilloid-1 receptors on neighboring CGRP nerves and CGRP is released to cause vasodilation. The present findings would explain why CGRPergic nerves, which are capsaicin-sensitive sensory nerves, have efferent function in spite of being primary afferent nerves. Namely, efferent adrenergic nerves, which momentarily and constantly regulate the vascular tone, may send their information to the neighboring CGRPergic nerves. Proton may be used as the transmitter for axo-axonal transmission to counteract excess vasoconstriction as the efferent function of afferent sensory nerves. Recent study demonstrated that periarterial nerve stimulation of perfused mesenteric arteries resulted in a decrease in the pH level of the perfusate concomitant with CGRPergic nerve-mediated vasodilation, which was abolished by the adrenergic neuron blocker, guanethidine. These findings suggest that proton acts as a transmitter for axo-axonal transmission between adrenergic and CGRPergic nerves in mesenteric resistance arteries. In conclusion, the present study presents evidence that perivascular nerves have strong axo-axonal interaction to modulate nerve function and to regulate vascular tone.