Stimulation of lumbar sympathetic nerves may produce hindlimb vasodilation via the release of pre-formed stores of nitrosyl factors.

Abstract

The physiological activation of lumbar sympathetic nerves by air-jet stress produces a hindlimb vasodilation in conscious rats. Although the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester markedly reduces the duration of this air-jet stress-induced vasodilation, it does not prevent the initial fall in resistance. These data suggest that the vasodilation is initiated by the release of an as yet unidentified factor, whereas the vasodilation is sustained by the release of nitric oxide or newly synthesized nitrosyl factors such as S-nitrosothiols. At present, the possibility that neurogenic vasodilation may be initiated by the release of pre-formed pools of nitrosyl factors from storage sites within the hindlimb vasculature has not been addressed. We reasoned that if nitrosyl factors do exist in storage pools, then we should be able to demonstrate a "use-dependent" loss of vasodilation after nitric oxide synthesis inhibition which would be the result of a gradual depletion of the releasable pools of these nitrosyl factors. In the present study, we examined the effects of repeated episodes of direct electrical stimulation of the lumbar sympathetic chain on ipsilateral hindlimb vascular resistance in pentobarbital-anesthetized rats prior to and following administration of the nitric oxide synthesis inhibitors N(G)-nitro-L-arginine methyl ester (10, 25 or 100 mumol/kg i.v.) or N(G)-nitro-L-arginine (50 mumol/kg i.v.). Three episodes of electrical stimulation of 3.2 +/- 0.4 V (20 Hz, 5 ms duration, 5 ms delay for 10 s given 5 min apart) produced pronounced and reproducible reductions in hindlimb vascular resistance in the ipsilateral hindlimb (-56 +/- 5%, -55 +/- 5% and -53 +/- 6%, respectively), but no changes in mean arterial pressure. Three episodes of electrical stimulation at 4.8 +/- 0.4 V also caused reproducible decreases in hindlimb resistance (-59 +/- 7%, -61 +/- 9% and -64 +/- 12%) and minor but reproducible decreases in blood pressure. The vasodilation produced by the first electrical stimulation at 3.2 +/- 0.4 V was completely abolished by a 25 mumol/kg dose of N(G)-nitro-L-arginine methyl ester (-11 +/- 9%). The initial episode of electrical stimulation at 4.8 +/- 0.4 V produced a pronounced fall in ipsilateral hindlimb resistance in the N(G)-nitro-L-arginine methyl ester-treated animals whereas the second and third stimulations produced progressively smaller vasodilations (-55 +/- 4%, -34 +/- 3% and -19 +/- 2%, respectively). The 10 mumol/kg dose of N(G)-nitro-L-arginine methyl ester was not effective whereas the 100 mumol/kg dose produced similar effects as the 25 mumol/kg dose. The 50 mumol/kg dose of N(G)-nitro-L-arginine produced similar effects as the higher doses of N(G)-nitro-L-arginine methyl ester. Those results suggest that lower intensity electrical stimulation of the lumbar sympathetic nerves produces vasodilation via the release of nitric oxide or newly synthesized nitrosyl factors such as S-nitrosothiols. In contrast, the vasodilation produced by higher intensity electrical stimulation may involve the mobilization and release of pre-formed pools of nitrosyl factors which undergo a "use-dependent" depletion in the absence of nitric oxide synthesis. These pre-formed pools of nitrosyl factors may exist within the sympathetic nerves themselves. In addition, they may be stored within the vascular endothelium and released by neurogenically-derived neurotransmitters/neuromodulators.