Adrenergic and cholinergic modulation of cerebrovascular nitrergic vasodilation

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Abstract

Large cerebral arteries at the base of the brain from several species are innervated by dense sympathetic adrenergic nerves, and parasympathetic cholinergic and nitrergic nerves. Norepinephrine (NE) and acetylcholine (ACh) released from the respective nerves are not the primary postsynaptic transmitters for vasoconstriction and dilation. Evidence has been presented to indicate that nitric oxide (NO) is the predominant transmitter for cerebral vasodilation. NE and ACh act as presynaptic transmitters in modulating NO release and therefore cerebral vascular tone. This transmitter mechanism in the large cerebral arteries appears to be different from that in the smaller vessels.

Section snippets

Cholinergic innervation

The presence of cholinergic innervation in large cerebral arteries is well established [2], [4], [6], [9], [20], [25]. The cholinergic innervation decreases in smaller arteries, and is usually not present in pial vessels that still receive sympathetic innervation [25]. Based on physiological studies, acetylcholine (ACh) released from the cholinergic nerves innervating cerebral blood vessels was originally thought to be the vasodilator transmitter [2], [6], [9]. Pharmacological studies using

Nitric oxidergic (nitrergic) innervation

Cerebral arteries from all species examined have been shown to receive dense nitric oxide synthase immunoreactive (NOS-I) fibers [9] of multiple origins [5], [7], providing direct evidence for the presence of NO synthesizing enzymes in the nitrergic vasodilator nerves in cerebral circulation. Furthermore, biochemical and pharmacological studies have demonstrated that cerebral perivascular nerves can recycle l-citrulline, the by-product of NO synthesis, to l-arginine for synthesizing NO [16]

Cholinergic–nitrergic innervation in cerebral circulation

NOS and choline acetyltransferase (ChAT) have been found to coexist in the parasympathetic ganglion and perivascular nerves in cerebral blood vessels of several species [7] (Fig. 1). Since NO mediates the major component of the neurogenic vasodilator response [9], while endogenous ACh exhibits no direct effect on the smooth muscle in cerebral arteries [8], [14], the cholinergic–nitrergic vasodilator nerves in cerebral blood vessels has been proposed [7]. This finding supports the hypothesis

N-type Ca2+ channels on cholinergic–nitrergic nerves

The relaxation of porcine basilar arteries induced by TNS at different frequencies was significantly decreased by ω-conotoxin (CTX), suggesting that Ca2+ influx via N-type Ca2+ channels plays a significant role in activating NOS and therefore NO release in perivascular nerves [19]. The residual relaxation may be due to activation of NOS by other sources of Ca2+, such as Ca2+ influx from L-type channels or release of intracellular Ca2+. In the presence of CTX, the residual relaxation in porcine

Adrenergic innervation

Cerebral arteries and veins receive a dense unilateral supply of sympathetic, adrenergic nerves of superior cervical ganglionic origin [2], [6], [10]. Small arterioles are sometimes accompanied by few fibers. Most intracerebral vessels appear to lack perivascular adrenergic nerves. The endogenous catecholamines are almost exclusively norepinephrine (NE) [11]. Sympathetic stimulation releases NE from perivascular nerves [3], [22].

Results from in vitro tissue bath studies have indicated that

Adrenergic–nitrergic interaction in cerebral arteries

Ultrastructural studies have demonstrated the close apposition of adrenergic nerve terminals and the nonadrenergic nerve terminals in the neuro-effector region [12]. The close apposition of different types of nerve terminals suggests possible functional interaction between them. It is very likely that transmitters or modulators released from one nerve terminal may act on presynaptic receptors of the neighboring nerve terminals to modulate the release of the transmitter substances from these

β2-Adrenoceptors mediate NO release in the nitrergic nerves

Using in vitro tissue bath techniques, nicotine (0.1 mM) and TNS induced neurogenic vasodilation in porcine basilar arteries. Vasodilation induced by both nicotine and TNS was abolished by nitro-l-arginine (l-NNA, 30 μM), and the blockade was reversed by l-arginine (0.3 mM). Hexamethonium and mecamylamine (10 μM) abolished the relaxation induced by nicotine, but did not affect that elicited by TNS. Furthermore, relaxation induced by nicotine was diminished by guanethidine (1–10 μM), which did

α7-nAChRs mediate nicotine-induced nitrergic neurogenic vasodilation

The mecamylamine- and hexamethonium-sensitive relaxation of isolated porcine cerebral arterial rings induced by nicotine (100 μM) was blocked by preferential α7-nAChR antagonists (methyllycaconitine and α-bungarotoxin) in a concentration-dependent manner, but was not affected by dihydro-β-erythroidine (DHβE, a preferential α4-nAChR antagonist) [23], [26]. These nAChR antagonists did not affect relaxation elicited by TNS (8 Hz) or that by sodium nitroprusside and NE. Results from double-labeling

Summary and discussion

Dense adrenergic, cholinergic and nitrergic innervations are demonstrated in large cerebral arteries at the base of the brain in several species. The endogenously released ACh and NE do not exhibit significant direct effect on postsynaptic smooth muscle cells in these arteries. These two classical transmitters act as presynaptic transmitters in modulating NO release from nitrergic nerves and therefore vasodilation. Nicotine, acting on α7-nAChRs on presynaptic sympathetic nerve terminals,

Acknowledgements

This work was supported by NIH HL 27763 and HL 47574, AHA/IHA (9807871), and SIU-CRC/EAM. We thank Jean Long for preparing the manuscript.

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