Nitric oxide synthase does not contribute to cerebral autoregulatory phenomenon in anesthetized dogs

doi:10.1016/0165-1838(94)90091-4

Journal of the Autonomic Nervous System

Volume 49, Supplement, September 1994, Pages 73-76

Journal of the Auton...

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Abstract

Nitric oxide (NO) is a potent vasodilator produced by nitric oxide synthase (NOS). We tested the following hypotheses: (1) cerebral blood flow (CBF) is NO dependent, (2) NO contributes to CBF autoregulation, and (3) NO participates in the neurohypophysial vasodilator response to hypotension. Three groups of sodium pentobarbital anesthetized dogs were studied using microspheres. In 7 dogs, $N^{ω} - nitro- l -arginine$ methyl ester (l-NAME; 40 mg/kg, i.v.) increased mean arterial pressure (MAP) by 12%. Cerebrovascular resistance (CVR) increased more than MAP, resulting in a 20 ± 4% reduction (range 12–-;67%) in baseline CBF. In unblocked conditions, actively autoregulated regions (e.g. cortex, white matter, median eminence) demonstrated a correlation between CVR and MAP whereas passive regions (neural lobe) did not. NOS block did not effect the relationship between MAP and CVR in most brain regions. However, a significant relationship between CVR and MAP developed in neural lobe after NOS block. Abrupt hypotension increased neural lobe blood flow to 239 ± 37% control at 3 min, despite NOS block. These results show that baseline cerebral vessel tone depends upon NOS activity. Enhanced NO release cannot explain either cerebral autoregulation or the transient hyperperfusion seen in neural lobe immediately following rapid hemorrhage.

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Cited by (21)

Myogenic and metabolic feedback in cerebral autoregulation: Putative involvement of arachidonic acid-dependent pathways
2016, Medical Hypotheses
Citation Excerpt :
Given that metabolic feedback involves an oxygen sensing mechanism that modulates cerebrovascular myogenic tone, a vasodilating metabolite that antagonises the 20-HETE-dependent pathways on cerebrovascular tone is likely involved. Even though nitric oxide is such a classic functional antagonist of 20-HETE signalling [54], a number of studies stress that it is a mere modulator and not a mediator of cerebral autoregulation [55–64]. In the following section, I propose epoxyeicosatrienoic acids (EETs) as more likely mediators of autoregulatory vasodilation.
The present paper presents a mechanistic model of cerebral autoregulation, in which the dual effects of the arachidonic acid metabolites 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) on vascular smooth muscle mediate the cerebrovascular adjustments to a change in cerebral perfusion pressure (CPP). 20-HETE signalling in vascular smooth muscle mediates myogenic feedback to changes in vessel wall stretch, which may be modulated by metabolic feedback through EETs released from astrocytes and endothelial cells in response to changes in brain tissue oxygen tension. The metabolic feedback pathway is much faster than 20-HETE-dependent myogenic feedback, and the former thus initiates the cerebral autoregulatory response, while myogenic feedback comprises a relatively slower mechanism that functions to set the basal cerebrovascular tone. Therefore, assessments of dynamic cerebral autoregulation, which may provide information on the response time of the cerebrovasculature, may specifically be used to yield information on metabolic feedback mechanisms, while data based on assessments of static cerebral autoregulation represent the integrated functionality of myogenic and metabolic feedback.
Nitric oxide and cerebrovascular regulation
2014, Vitamins and Hormones
Citation Excerpt :
To date, studies suggest that vascular signaling by NO is primarily mediated by smooth muscle cGMP, which is converted by NO-activated GC from guanosine triphosphate. Effects of cGMP occur through cGMP-dependent protein kinases (PKGs) or cGMP-gated cation channels (Kelly, Ritchie, & Arbuthnott, 1995; Macrae, Dawson, Norrie, & McCulloch, 1993; McPherson, Kirsch, Ghaly, & Traystman, 1995; Saito, Wilson, Hanley, & Traystman, 1994). In pressurized and isolated mice cerebral arteries, under NOS inhibition, the resting diameter is reestablished by the cGMP analogue, 8-Br-cGMP, while it is decreased in the presence of the soluble GC blocker, ODQ (iH [1,2,4]oxadiazole [4,3-a]quinoxalin-1-one) (Gao, Dhanakoti, Tolsa, & Raj, 1999; Piggott et al., 2006).
The cerebrovascular regulation involves highly complex mechanisms to assure that the brain is perfused at all times. These mechanisms depend on all components of the neurovascular units: neurons, glia, and vascular cells. All these cell types can produce nitric oxide (NO), a powerful vasodilator through different NO synthases. Many studies underlined the key role of NO in the maintenance of resting cerebral blood flow (CBF) as well as in the mechanisms that control cerebrovascular tone: autoregulation and neurovascular coupling. However, although the role of NO in the control of CBF has been largely investigated, the complexity of the NO system and the lack of specific NO synthase inhibitors led to still unresolved questions such as the origin of NO and the pathways by which it controls the vascular tone. In this chapter, the role of NO in the regulation of CBF is critically reviewed and discussed in the context of the neurovascular unit and the general principles of cerebrovascular regulation.
Age and cerebral circulation
2005, Pathophysiology
Cerebral blood flow, and its control, vary as a function of age. This review focuses on the perinatal period and compares/contrasts this age period to that of the juvenile/adult. Additionally, this review describes mechanisms important in the control of the cerebral circulation as a function of age during physiologic and pathologic conditions. Two topics of pathophysiology are considered: cerebral hypoxia ischemia, often seen in perinates due to problems with delivery or respiratory management post delivery, and traumatic brain injury, described as the shaken impact syndrome, an example of child abuse. Clinically, it is important to understand the pathophysiology of the cerebral circulation in order to optimize mechanistically appropriate therapeutic modalities.
Cerebrovascular regulation in the postural orthostatic tachycardia syndrome (POTS)
1999, American Journal of the Medical Sciences
Patients with the postural orthostatic tachycardia syndrome (POTS) have symptoms of orthostatic intolerance despite having a normal orthostatic blood pressure (BP), which suggests some impairment of cere brovascular regulation. Cerebrovascular autoregulation refers to the maintenance of normal cerebral blood flow in spite of changing BP. Mechanisms of autoregulation include myogenic, metabolic and neurogenic vaso · regulation. Beat-to-beat recording of blood-flow velocity (BFV) is possible using transcranial Doppler imaging. It is possible to evaluate autoregulation by regressing ABFV to ΔΒΡ during head-up tilt. A number of dynamic methods, relating ABFV to ΔΒΡ during sudden induced changes in BP by occluding then releasing peripheral arterial flow or by the Val salva maneuver. The ABFV to ΔΒΡ provides an index of autoregulation. In orthostatic hypotension, the autoregulated range is typically expanded. In contrast, paradoxical vasoconstriction occurs in POTS because of an in־ creased depth of respiration, resulting in hypocapnic cerebrovascular constriction, and impaired autoregulation.
Effects of nitric oxide on neuroendocrine function and behavior
1997, Frontiers in Neuroendocrinology
Nitric oxide (NO) is an unusual chemical messenger. NO mediates blood vessel relaxation when produced by endothelial cells. When produced by macrophages, NO contributes to the cytotoxic function of these immune cells. NO also functions as a neurotransmitter and neuromodulator in the central and peripheral nervous systems. The effects on blood vessel tone and neuronal function form the basis for an important role of NO on neuroendocrine function and behavior. NO mediates hypothalamic portal blood flow and, thus, affects oxytocin and vasopression secretion; furthermore, NO mediates neuroendocrine function in the hypothalamic–pituitary–gonadal and hypothalamic–pituitary–adrenal axes. NO influences several motivated behaviors including sexual, aggressive, and ingestive behaviors. Learning and memory are also influenced by NO. Taken together, NO is emerging as an important chemical mediator of neuroendocrine function and behavior.
Sevoflurane impairs cerebral blood flow autoregulation in rats: Reversal by nonselective nitric oxide synthase inhibition
2005, Anesthesia and Analgesia
In this study, we investigated the effects of 1.0 and 2.0 minimum alveolar anesthetic concentration (MAC) sevoflurane on cerebral blood flow (CBF) autoregulation before and after nonselective inhibition of nitric oxide (NO) synthase in rats. Rats were randomly assigned as follows: Group 1 (n = 8): 1.0 MAC sevoflurane; Groups 2 and 3 (n = 8 per group): 2.0 MAC sevoflurane. Assessment of autoregulation within a mean arterial blood pressure range of 140–60 mm Hg was performed by graded hemorrhage before and after administration of l-arginine methyl ester (l-NAME, 30 mg/kg IV, Groups 1 and 2) or during hypocapnia (Group 3). In 10 additional animals, brain tissue NO₂⁻ concentrations were measured at 1.0 and 2.0 MAC sevoflurane. CBF autoregulation was maintained with 1.0 MAC sevoflurane (Group 1) regardless of NO synthase status indicating that CBF autoregulation might not be related to NO availability. Sevoflurane dose-dependently increased brain tissue NO₂⁻ and impaired CBF autoregulation. Administration of l-NAME (Group 2) but not hypocapnia (Group 3) restored CBF autoregulation. This suggests that sevoflurane impairs the autoregulatory capacity secondary to an increase of the perivascular NO availability and questions the importance of basal cerebrovascular tone in terms of vasodilatory capacity during hypotensive challenges.

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Nitric oxide synthase does not contribute to cerebral autoregulatory phenomenon in anesthetized dogs

Abstract

Brain Res.

Neurosci. Lett.

Effects of endothelium-derived nitric oxide on cerebral circulation during normoxia and hypoxia in the rat

J. Cereb. Blood Flow Metab.

Extracellular potassium changes in the rat neurohypophysis during activation of the magnocellular neurosecretory system

J. Physiol. (Lond.)