Neuronal Nitric-Oxide Synthase Inhibition Facilitates Adrenergic Neurotransmission in Rat Mesenteric Resistance Arteries

Abstract

The effects of nonselective nitric-oxide synthase (NOS) inhibitors [N--nitro-L-arginine methyl ester (L-NAME) and N--nitro-L-arginine (L-NNA)] and specific neuronal NOS (nNOSon adrenergic nerve-mediated vasoconstriction were studied in rat perfused mesenteric vascular beds without endothelium. Perfusion of L-NAME, L-NNA, or L-VNIO markedly augmented vasoconstrictor responses to periarterial nerve stimulation (PNS; 2-8 Hz) without affecting vasoconstriction induced by exogenously injected norepinephrine (NE). Addition of L-arginine, a precursor for the synthesis of nitric oxide (NO), reversed the augmentation of the PNS response by L-NAME. The PNS (8 Hz)-evoked NE release in the perfusate was increased by L-NAME perfusion. In preparations treated with capsaicin [a depleter of calcitonin gene-related peptide (CGRP)-containing nerves], L-NAME did not augment vasoconstrictor responses to PNS or NE injection. Combined perfusion of CGRP(8-37) (a CGRP receptor antagonist) and L-NAME induced additive augmentation of the vasoconstrictor response to PNS but did not affect the response to NE injection. In preparations with active tone produced by methoxamine and in the presence of guanethidine, L-NAME perfusion did not affect the vasodilator response induced by PNS. Immunostaining of the mesenteric artery showed the presence of nNOS-like immunopositive nerve fibers, which were absent in arteries pretreated with capsaicin. These findings suggest that NO, which is released from perivascular capsaicin-sensitive nerves, presynaptically inhibits neurogenic NE release to modulate adrenergic neurotransmission.

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

“…In circuits of larger animal species, NO derived from nNOS has been suggested to act either as a co-transmitter with CGRP or as a single neuromodulator released from nitrergic nerve terminals, as recently revisited by Hatanaka et al (2006). Assuming that in our model, 7-NI selectively inhibits the neuronal isoform, our results would support an important role for nNOS as a pre-junctional modulator of the CGRPreleasing nerve terminals since the inhibitor potentiated the response to NANC stimulation.…”

“…It is noteworthy that Ralevic (2002) showed that the release of transmural NO represses NANC-dependent vasodilatation, albeit the specific contribution of the neuronal isoform was not identified. In addition, Hatanaka et al (2006) have recently reported that nNOS is a potent repressor of adrenergic-dependent vasoconstriction following perivascular nerve stimulation of the rat arterial mesenteric bed. Therefore, nNOS may significantly depress the overall (that is autonomic and C-fibre-dependent) perivascular nervous control of mesenteric tone in the mouse model.…”

“…In addition, Hatanaka et al (2006) have recently reported that neuronal nitric oxide synthase (nNOS) physiologically represses the vasoactive response to adrenergic neurotransmission in the rat arterial mesenteric bed. Such modulator roles of the nNOS isoform on NANC responses to PNS however remain to be investigated.…”

Altered function of nitrergic nerves inhibiting sympathetic neurotransmission in mesenteric vascular beds of renovascular hypertensive rats

“…2 Thus, perivascular NO-containing nerves (nitrergic nerves) have been shown to distribute in various blood vessels as nonadrenergic noncholinergic nerves. [5][6][7] In addition to NO's direct vasodilator effect, it has also been shown to modulate adrenergic neurotransmission. 8,9 Our previous study showed that NO, which is released from nitrergic nerves, presynaptically inhibits neurogenic noradrenaline release to modulate adrenergic neurotransmission in rat mesenteric arteries without an endothelium.…”

“…8,9 Our previous study showed that NO, which is released from nitrergic nerves, presynaptically inhibits neurogenic noradrenaline release to modulate adrenergic neurotransmission in rat mesenteric arteries without an endothelium. 6 Furthermore, several studies have shown that inhibition of NO synthesis results in augmented adrenergic nerve-mediated vasoconstriction in the rat tail artery, 10 the large coronary artery of anesthetized dogs 11 and the isolated adrenal medulla vessels of dogs. 8 These findings imply that NO has a role in the modulation of adrenergic neurotransmission.…”