Elsevier

Brain Research

Volume 1309, 14 January 2010, Pages 19-28
Brain Research

Research Report
Interaction between nitric oxide synthase inhibitor induced oscillations and the activation flow coupling response

https://doi.org/10.1016/j.brainres.2009.09.119Get rights and content

Abstract

The role of nitric oxide (NO) in the activation-flow coupling (AFC) response to periodic electrical forepaw stimulation was investigated using signal averaged laser Doppler (LD) flowmetry. LD measures of calculated cerebral blood flow (CBF) were obtained both prior and after intra-peritoneal administration of the non-selective nitric oxide synthase (NOS) inhibitor, NG-nitro-l-arginine (l-NNA) (40 mg/kg). Characteristic baseline low frequency vasomotion oscillations (0.17 Hz) were observed after l-NNA administration. These LDCBF oscillations were synchronous within but not between hemispheres. l-NNA reduced the magnitude of the AFC response (p < 0.05) for longer stimuli (1 min) with longer inter-stimulus intervals (2 min). In contrast, the magnitude of the AFC response for short duration stimuli (4 s) with short inter-stimulus intervals (20 s) was augmented (p < 0.05) after l-NNA. An interaction occurred between l-NNA induced vasomotion oscillations and the AFC response with the greatest increase occurring at the stimulus harmonic closest to the oscillatory frequency. Nitric oxide may therefore modulate the effects of other vasodilators involved in vasomotion oscillations and the AFC response.

Introduction

The free radical nitric oxide (NO) is an important modulator of the activation-flow coupling (AFC) response, the coupling of neuronal activity and cerebral blood flow (CBF) for a functional task (Faraci and Breese, 1993, Iadecola et al., 1994, Villringer and Dirnagl, 1995). NO is a potent vasodilator that is readily abundant; can easily diffuse; and has a relatively short half-life (Magistretti and Pellerin, 1999). It has shown to be involved in hypercapnia associated CBF increases (Iadecola and Zhang, 1996).

NO is synthesized by a family of isoenzymes termed NO synthases (NOS). Three main isoforms of NOS exist including neuronal (nNOS), inflammatory (iNOS), and endothelial (eNOS). Both nNOS and eNOS are constitutively expressed under normal physiological conditions; whereas iNOS is produced during immunological stress (Moore and Handy, 1997, Szabo, 1996, Valko et al., 2007, Wiesinger, 2001).

The role of NO in the AFC response has been assessed in genetically engineered mice lacking either nNOS or eNOS. The AFC response for vibrissae stimulation was affected in nNOS knockout (Ma et al., 1996) but not eNOS knockout mice (Ayata et al., 1996). nNOS rather than eNOS may modulate the AFC. However, the absence of complete elimination of the AFC response in these knockout mice suggests the involvement of additional vasodilators in this coupling response (Peng et al., 2004).

The role of NO in the AFC response can also be studied using nitric oxide synthase inhibitors such as: NG-nitro-l-arginine methyl ester hydrochloride (l-NAME) (a non-selective NOS inhibitor), N′-nitro-l-arginine (l-NNA) (a non-selective NOS inhibitor), and 7-nitroindazole (7NI) (a selective nNOS inhibitor). The magnitude of the AFC response due to sciatic nerve stimulation in rats was significantly reduced after topical administration of l-NAME but restored with infusion of the NO precursor, l-arginine (Northington et al., 1992). Both topical and systemic application of l-NNA reduced the magnitude of the AFC response with systemic dispensation primarily affecting the early portion of the AFC response while topical administration dampening the entire AFC response (Dirnagl et al., 1993a, Dirnagl et al., 1993b, Dirnagl et al., 1994, Lindauer et al., 1999, Ngai et al., 1995, Peng et al., 2004). Systemic administration of 7-NI has also been shown to reduce the amplitude of the AFC response (Liu et al., 2008, Yang et al., 1999, Yang and Chang, 1998). However, these studies have typically used a protracted stimulus (1 min) separated by relatively long inter-stimulus intervals (> 1 min) (Dirnagl et al., 1993a, Dirnagl et al., 1993b, Dirnagl et al., 1994, Lindauer et al., 1999, Ngai et al., 1995, Peng et al., 2004) to assess the effects of NOS inhibitors on the AFC response. When a relatively short duration stimulus (< 10 s) with small inter-stimulus intervals (< 30 s) were applied, the magnitude of the AFC response has been shown to be either unaltered (Adachi et al., 1994) or in fact slightly increased (Matsuura and Kanno, 2002). The effects of both stimulus duration and inter-stimulus interval may affect the magnitude of the AFC response. Further characterization of the effects of NOS inhibition on the AFC response with various periodicities is therefore required.

Systemic administration of non-selective NOS inhibitors not only decreases baseline CBF but also leads to the pronounced enhancement of characteristic ∼ 0.1 Hz low frequency oscillations (Biswal and Hudetz, 1996, Dirnagl et al., 1993b, Hudetz et al., 1995, Lindauer et al., 1999, Matsuura and Kanno, 2002, Morita-Tsuzuki et al., 1993, Peng et al., 2004). The physiological basis of these vasomotion oscillations remains unknown (Golanov and Reis, 1995, Mayhew et al., 1996). There appears to be no correlation between the frequency, amplitude, and phase of these oscillations with systemic parameters such as heart rate or respiration (Guy et al., 1999). These vasomotion oscillations can be suppressed by cerebral vasodilation induced by mild hypercapnia (inhalation of 5% CO2) (Hudetz et al., 1992).

Laser Doppler (LD) flowmetry has become a common method for studying the AFC since it can be easily performed; is non-invasive; and can dynamically measure cerebral blood flow (CBF) changes (Lacza et al., 2000). However, these CBF changes are only relative and not absolute measures (Dirnagl et al., 1989, Fabricius and Lauritzen, 1996, Fabricius et al., 1996, Haberl et al., 1989, Skarphedinsson et al., 1988) as LD signal measures red cell velocity and volume from which CBF is then calculated (Dirnagl et al., 1993b) (Stern, 1975). Previous studies have demonstrated that relative changes in LDCBF correlate with blood flow measurements by radioactive microspheres (Eyre et al., 1988) or the hydrogen clearance technique (Haberl et al., 1989, Skarphedinsson et al., 1988).

In the present study we investigated the effects of systemic administration of the non-selective NOS inhibitor l-NNA on LDCBF in the somatosensory cortex of rats. We used both single and dual LD flowmetry probes over the somatosensory cortex to characterize baseline vasomotion oscillations after l-NNA. We studied NO's role in both modulating vasomotion oscillations and the AFC response by varying the periodicity of forepaw stimulation. Our results demonstrate a possible interaction between l-NNA induced vasomotion oscillations and the AFC response depending on stimulus length and inter-stimulus interval.

Section snippets

Physiological variables were not affected by l-NNA

Physiological parameters from rats (n = 15) during resting conditions (probes placed unilaterally or bilaterally over the somatosensory cortices) were obtained before and after administration of l-NNA (mean ± SD) (Table 1). These same parameters were also obtained from rats (n = 20) during the baseline portions of stimulation paradigms (Table 1). Administration of l-NNA did not significantly affect these parameters, including systemic arterial blood pressure.

Large amplitude low frequency vasomotion oscillations were observed after administration of l-NNA

Dual probe measures of resting LDCBF were

Discussion

The major findings of this paper are: (1) the administration of the non-selective NO synthase inhibitor, l-NNA, led to vasomotion oscillations that were in phase when the two LD probes were close to each other over the same hemisphere, but were asynchronous when the LD probes were placed over bilateral somatosensory cortices, (2) after administration of l-NNA the AFC response was significantly reduced for stimuli repeatedly applied at relatively longer inter-stimulus intervals. The greatest

General preparation

Thirty-five adult male Sprague–Dawley rats (320–400 g) obtained from Charles River (Wilmington, MA) were initially anesthetized with 2–4% halothane in 70% N2O, 30% O2 by face mask. Subcutaneous 2% lidocaine was used to elevate the tail dermis away from the tail artery before incision and prevent vasospasm during catheter insertion. A polyethylene catheter (PE-50) was used to cannulate the tail artery to measure the arterial blood pressure and monitor arterial blood gasses. Rats were

Disclosure/conflict of interest

The authors declare no competing financial interests.

Acknowledgments

This work was supported by a Foundation for AIDS Research Fellowship (106729-40-RFRL) (BA), Dana Brain-Immuno Imaging Grant (DF 3857-41880) (BA), and NIH grants (1K23MH081786) (BA).

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