The functional role of the alpha-1 adrenergic receptors in cerebral blood flow regulation

Abstract

Cerebral vasculature is richly innervated by the α-1 adrenergic receptors similar to that of the peripheral vasculature. However, the functional role of the α-1adrenergic receptors in cerebral blood flow (CBF) regulation is yet to be established. The traditional thinking being that during normotension and normocapnia sympathetic neural activity does not play a significant role in CBF regulation. Reports in the past have stated that catecholamines do not penetrate the blood brain barrier (BBB) and therefore only influence cerebral vessels from outside the BBB and hence, have a limited role in CBF regulation. However, with the advent of dynamic measurement techniques, beat-to-beat CBF assessment can be done during dynamic changes in arterial blood pressure. Several studies in the recent years have reported a functional role of the α-1adrenergic receptors in CBF regulation. This review focuses on the recent developments on the role of the sympathetic nervous system, specifically that of the α-1 adrenergic receptors in CBF regulation.

Introduction

Perivascular nerves have been identified in close proximity to smooth muscle layers in the cerebral vessel[1–3] and the density of innervations of cerebral resistance vessels have been reported to be similar to the mesenteric and/or the femoral arterial beds.[4–5] Astrocytes and vascular cells in association with the perivascular neurons of autonomic origin constitute a functional unit to maintain the cerebral microenvironment homeostasis.[6] Animal studies have identified the cerebral arteries being richly innervated with sympathetic nerve fibers.[7–9] However, the role of autonomic neural control of the cerebral blood flow (CBF) regulation remains controversial.[10–12] CBF is maintained relatively constant despite physiological fluctuations in the cerebral perfusion pressure between ranges of 60 and 150 mmHg by intrinsic myogenic properties of cerebral autoregulation.[13] The current traditional thinking is that in the presence of normocapnia and normotension changes in sympathetic tone appear to have limited effects on CBF.[14,15] Previously, studies have reported that the sympathetic nervous system has an insignificant role in CBF regulation in normal conditions; for example, sectioning of the sympathetic nerves in dogs resulted in no effect on CBF.[15] In addition, no difference in cerebral autoregulation was observed between intact and denervated cerebral hemispheres following unilateral sympathetic denervation.[16] Chronic sympathetic denervation in animal models did not influence cerebral autoregulation.[17] However, activation of the sympathetic nervous system on cerebral vessels is effective during hypertension, hypoxia, hypercapnia, and hemorrhagic states.[18] Furthermore, several investigators have identified a direct effect of sympathoexcitation on CBF in pathophysiological conditions.[19,20] In addition, in primates, the blood flow to the brain through internal carotid and vertebral arteries was reduced by direct stimulation of the cervical and stellate ganglia of the sympathetic nerve fibers of the brain.[21] In humans, a decrease in middle cerebral artery blood velocity (MCA V) was reported during unilateral trigeminal ganglion stimulation.[22] There is also strong evidence that increases in sympathetically mediated vasoconstriction protects cerebral vessels from overperfusion during hypertension. For example, in an animal model of hypertension the breakdown of the blood brain barrier (BBB) in the cerebrum was prevented by electrically induced sympathetic stimulation.[23] Together these findings suggest a functional role of the sympathetic nervous system in CBF regulation. In addition, the exponential increase in sympathetic activity that occurs during heavy weightlifting exercise to maximum in healthy humans resulting in systolic blood pressure that exceeds 300 mmHg, extends the cerebral autoregulatory range above 150 mmHg, increases cerebrovascular tone and buffers the pulsatile increases in cerebral perfusion pressure, thereby protecting the brain.[24] In addition, the partial pressure of carbon dioxide in the arterial blood strongly regulates CBF, while other physiological factors involved in CBF regulation are partial pressure of oxygen in arterial blood, cerebral neural activity, and cerebral metabolism[25] [Figure 1].

Figure 1.

The physiological factors known to influence cerebral blood flow regulation. In addition to these factors, recent studies have emphasized the role of the sympathetic nervous system infl uencing cerebral blood flow. CBF = cerebral blood fl ow, CO₂ = carbon dioxide, O₂ = oxygen

α-1 adrenergic receptors on the cerebral vasculature

Similar to the systemic vasculature, cerebral vessels are richly innervated with sympathetic nerve fibers connected to α-1 adrenergic receptors that appear to be located on the cerebral arterioles.[14] Although the α-1 adrenergic receptors are the most abundant adrenergic receptors in the brain, their role in the central nervous system is not yet established.[26] The alpha-1 adrenergic receptors are postsynaptic and stimulatory in nature.[26] In the vascular smooth muscle cells, α-1 adrenergic receptors bind to norepinephrine (NE), or other sympathomimetic drugs, and through receptor coupling with its Gq-protein stimulate phospholipase C activity which then promotes hydrolysis of phosphatidylinositol bisphosphate producing inositol triphosphate and diacylglycerol.[27] These molecules act as second messengers mediating intracellular Ca²⁺ release from non-mitochondrial pools and activate protein kinase C, which then leads to a cascade of events leading to activation of contractile proteins and vasoconstriction.[28] The densities of α-1 adrenergic receptors are reported to undergo a diurnal rhythm in the brain regions associated with entrainment to photoperiod demonstrated in animal models.[29] Though several animal models have been used, species difference in the anatomy of the cerebral circulation may lead to contradiction in the results. Recently, age of the animals were also reported to influence the results as sympathetic innervation density and constrictor response to NE in the brain were weak in juvenile rats when compared to mature animals.[30]

The adrenergic receptors are members of the G-protein-coupled receptor superfamily of membrane proteins. Based on evidence of α-1 adrenergic receptors heterogeneity, they are subdivided into α-1A, α-1B, and α-1D, with α-1A subtype having higher binding affinities to agonist, such as methoxamine and antagonist 5-methylurapidil. Overexpression of α-1B adrenergic receptors did not result in an increase in blood pressure and studies have reported that α-1B adrenergic receptor is not a significant player in mediating vasoconstriction. Studies have demonstrated α-1D adrenergic receptors to be involved in vascular smooth muscle contraction but less dominant than the α-1A adrenergic receptors.[26] In addition to mediating intracellular Ca²⁺ release, the α-1 adrenergic receptors are also reported to activate Ca²⁺ influx through voltage-dependent and independent calcium channels.[31] Apart from calcium mobilization, α-1 adrenergic receptors stimulate MAPK signaling pathways and significantly contribute to increased DNA synthesis and cell proliferation in human vascular smooth muscle cells.[32] α-1 adrenergic receptors are also localized in glial cells and may affect brain functions through non-neuronal mechanisms.[33] There are reports of polymorphisms in the α-1 adrenergic receptors, but have not yet been linked to functional consequences unlike members of the β-adrenergic receptors.[26]

Blood brain barrier permeability and cerebral blood flow regulation

Reports in the past have stated “that vasoactive amines do not penetrate the blood brain barrier (BBB) and only influence cerebral resistance vessels from the outside.”[34] Consequently, they concluded that “the sympathetic nerves do not effectively control the inner vascular smooth muscle of the cerebral vessels.” However, Sandor[35] refuted the impermeability of the BBB and reported that the peripheral adrenergic neurons come in close contact with the smooth muscle layer of the cerebral vessels. The density of α-1 adrenergic receptors in different regions of cerebral vessels also varies among species, which led to the differences in results among several studies.[35] Although there are reports of impermeable tight junctions on the BBB in the capillary endothelium, the tight junctions of the BBB in the endothelium of brain arterioles and venules of the cerebral microvasculature are found to be leaky and subject to greater modulation[36] [Figure 2]. Furthermore, there are reductions in the tightness by rupture of the BBB with increases in arterial pressure,[23] free radical and interlukin-6 concentrations,[37] all of which are abundant during hyperadrenergic disease states.[38] In addition, circulating NE also stimulates IL-6 production.[39] Vasoactive substances, such as bradykinin and nitric oxide, also appear to increase permeability of the BBB through activation of second messenger pathways.[40] The resultant increase in permeability of the BBB is proposed to make the α-1 adrenergic receptors accessible to the circulating NE along with local release of NE from nerve endings within the brain. Mitchell et al,[41] have recently demonstrated NE spillover from the cerebral vasculature into the internal jugular vein and identified that NE spillover originates primarily from the cerebral vasculature outside the BBB, and that the lipophilic metabolite spillover originates from both sides of the BBB. In Mitchell et al.′s[41] findings, it was noted that pure autonomic failure patients had 77% lower brain NE spillover than found in the healthy subjects, indicating that the sympathetic neuron degeneration associated with pure autonomic failure limited the NE spillover.

Figure 2.

The factors and conditions which are reported to modulate the blood brain barrier (BBB) and make it leaky or subject to rupture allowing circulation norepinephrine (NE) to access the alpha-1 adrenergic receptors located within the brain in addition to local release of NE in the brain. IL-6 = interlukin-6; BP = blood pressure; SNA = sympathetic neural activity

Functional role of α-1 adrenergic receptors in cerebral blood flow regulation

Moreover, evidence of functional α-1 adrenoreceptors was demonstrated by an increase in cerebral vascular conductance following an experimentally induced acute hypotension with bilateral thigh cuff occlusion/release technique designed to stimulate the sympathetic nerve activity.[11] The increase in cerebral vascular conductance was attenuated by selective α-1 adrenergic blockade (prazosin) reflecting a sympathetically mediated dynamic control of the cerebral vasculature. In addition, attenuation of sympathetically mediated vascular tone induced by spinal cord stimulation resulted in increases in CBF due to withdrawal of sympathetic activation of the α-1 adrenergic receptors.[22,42] In healthy subjects, a reduction in cerebral tissue oxygenation was reported after infusion of NE.[43] These findings identify the presence of functional α-1 adrenoreceptors in the cerebral vasculature. Recently, Brassard et al.[44] demonstrated a decrease in cerebral tissue oxygenation at rest with a bolus injection of phenylephrine which was attenuated during light-intensity cycling exercise and abolished with high-intensity exercise-mediated increase in cerebral metabolism indicating the presence of “functional sympatholysis”[45] similar to that observed in the peripheral vasculature, where sympathetic activity is overridden by accumulation of local metabolites.[46] Critical closing pressure, an index of cerebral vascular tone, was also demonstrated to increase in relation to increases in sympathetic activity with increases in exercise intensity.[47] These data strongly indicate a functional role of the α-1 adrenergic receptor-mediated sympathetic nerve activity in the cerebral vasculature.

Measurement of static vs. dynamic changes in cerebral blood flow

Static cerebral autoregulation (sCA) refers to the relative steady-state relationship between CBF and arterial blood pressure (ABP), characterized by a positive slope of 0.8% (often referred to as a plateau) increase in CBF/mmHg between the autoregulatory range of 60 to 150 mmHg ABP.[48,49] Dynamic cerebral autoregulation (dCA) corresponds to the transient response of CBF to beat-to-beat fluctuations in ABP during acute changes in arterial pressure.[50,51] Hence, dCA is important for rapidly adjusting the CBF to its steady-state flow, when challenged by acute changes in perfusion pressure.[25] The importance of dCA on sCA and its effect on oxygen delivery to the brain is at the forefront of current research in CBF regulation.[25] Historically, the predominant measurement technique for assessing sCA was the Kety-Schmidt technique using ¹³³Xenon, which required one to establish steady-state conditions for the measure to be valid. This process resulted in elimination of dynamic assessment of CBF resulting from transient changes in ABP. Therefore, the dynamic changes in CBF were undetected, resulting in a reported constant CBF. Consequently, the cerebral metabolic rate for oxygen during exercise has been reported as unchanged.[52] Furthermore, the jugular venous sampling required for the Kety-Schmidt method was compromised, because it is now known that the internal jugular vein is collapsed in the upright position.[53,54] In the upright posture, venous drainage from the brain is dependent on the spinal veins of the vertebral plexus.[55–57] In addition, it is now known that cerebral activation is directly associated with increases in regional CBF and metabolism, as detected by positron emission tomography.[58] With the advent of dynamic noninvasive measurement techniques, such as transcranial Doppler (TCD) of MCA V changes and near infrared spectroscopic analysis of cerebral tissue oxygenation, the dynamic regulation of CBF by dCA, when ABP is rapidly changing, can be accomplished. Because of these techniques, there is a growing body of evidence identifying that increases in sympathetic neural activity result in local release of NE within the brain and circulating NE which can bind to the accessible α-1 adrenergic receptors on the smooth muscle of the cerebral arterioles and influence dCA and sCA.[43,11] The MCA V obtained from TCD does not take into account the vessel diameter which could possibly be increased due to sympathetically mediated decrease in vessel diameter. However, during exercise, the MCA V increases in parallel with the internal carotid artery blood flow.[59,60] This suggests that sympathetic modulation does not significantly alter the diameter of the MCA, and that sympathetic regulation of CBF occurs mainly in the cerebral resistance arterioles rather than in the large cerebral conductance arteries. It is reasonable to propose that if the diameter of the MCA decrease in response to sympathoexcitation, the MCA V would increase; in fact, the opposite occurs and conductance is decreased, indicating that sympathetic vasoconstriction of the cerebral vessels occurs at the small resistance arterioles.

Arterial baroreflex interaction with the cerebral vasculature

Studies in the past were unable to identify any relationship between the cerebral vasculature and its response to carotid baroreceptor stimulation,[61,62] despite cerebral arteries being richly innervated with sympathetic nerve fibers.[8,63] However, a reduction in CBF was observed when sympathetic nerves were activated through sinoaortic deafferentation, a procedure that produces marked elevation of peripheral sympathetic tone and extreme hypertension.[15] Stimulation of the carotid baroreceptors of baboons decreased their CBF, while at the same time maintaining the cerebral inflow pressure.[64] Similar results were obtained in a human study where MCA V decreased during unilateral trigeminal ganglion stimulation.[22] Zhang et al.[65] have demonstrated that dCA is altered with ganglion blockade using trimethaphan and thus speculated a tonic control of the autonomic nervous system in beat-to-beat CBF regulation. Patients with idiopathic orthostatic intolerance exhibit an excessive decline in CBF upon orthostasis despite sustained systemic blood pressure. However, this decline in CBF was abolished with phentolamine blockade of the α-adrenoreceptors during head-up tilt.[19] β-1 adrenergic blockade during dynamic cycling exercise in healthy humans diminished cardiac output as well as MCA V. In addition, because stellate ganglion blockade eliminated the β-1 blockade-induced decreases in MCA V, it was concluded that the exercise pressor reflex-induced sympathoexcitation resulting from underperfused exercising muscle was the cause of the reduction in MCA V.[66] The decrease in MCA V is indicative of an augmentation of sympathetic-mediated vasoconstriction in the cerebral vessels.[67] During recovery from acute hypotension induced by an ischemic thigh cuff occlusion/release protocol,[68] sympathoexcitation was evident from the decrease in cerebral vascular conductance identified by the rate of regulation (RoR), quantifying cerebral autoregulation. The RoR was attenuated by α-1 adrenoreceptor blockade[11] indicating arterial baroreflex control of the cerebral circulation through the sympathetic nervous system. Therefore, we conclude that the arterial baroreflex-mediated alterations of sympathetic nervous system are crucial in the beat-to-beat regulation of CBF.

Conclusion

There is evidence of the dynamic functional role of the α-1 adrenergic receptor control of sympathetic neural activity in the cerebral circulation. It appears that increases in sympathetic activity increases cerebral vascular tone and by interaction with the myogenic properties of the smooth muscle cells of the cerebral vessels results in cerebral vasoconstriction and enhanced CA. Therefore, the use of vasoconstrictor drugs to support a patients’ ABP during hemorrhage, surgery, and emergency care medicine requires further evaluation.