The major cerebral arteries proximal to the Circle of Willis contribute to cerebrovascular resistance in humans

Warnert, Esther; Hart, Emma C J; Hall, Judith Elizabeth; Murphy, Kevin; Wise, Richard G.

doi:10.1177/0271678x15617952

Cited by 29 publications

(25 citation statements)

References 40 publications

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“…Our previous work has proposed that the brainstem of both the spontaneously hypertensive rat (Cates, Steed, Abdala, Langton, & Paton, 2011;Marina et al, 2015;Paton, Dickinson, & Mitchell, 2009) and humans with hypertension (Warnert, Hart, Hall, Murphy, & Wise, 2016) are chronically hypoperfused and may become hypoxic if arterial pressure falls, as it can do during sleep. This is relevant because hypoxia is a major stimulus for releasing adrenomedullin (Ji, Xue, Wang, Su, & He, 2005;Serrano et al, 2002aSerrano et al, , 2002b and is one of the few genes that can be neuroprotective to the brain (Bernaudin, Tang, Reilly, Petit, & Sharp, 2002).…”

Section: Discussionmentioning

confidence: 99%

Centrally acting adrenomedullin in the long‐term potentiation of sympathetic vasoconstrictor activity induced by intermittent hypoxia in rats

Zoccal

Colombari

Flor

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?Adrenomedullin in the rostral ventrolateral medulla (RVLM) increases sympathetic activity; given that adrenomedullin is released during hypoxia, what are the effects of its agonism and antagonism in the RVLM after chronic intermitent hypoxia (CIH) exposure? What is the main finding and its importance?CIH exposure sensitizes adrenomedullin‐dependent mechanisms in the RVLM, supporting its role as a sympathoexcitatory neuromodulator. A novel mechanism was identified for the generation of sympathetic overdrive and hypertension associated with hypoxia, providing potential guidance on new therapeutic approaches for controlling sympathetic hyperactivity in diseases such as sleep apnoea and neurogenic hypertension. Abstract Adrenomedullin in the rostral ventrolateral medulla (RVLM) has been shown to increase sympathetic activity whereas the antagonism of its receptors inhibited this autonomic activity lowering blood pressure in conditions of hypertension. Given that hypoxia is a stimulant for releasing adrenomedullin, we hypothesized that the presence of this peptide in the RVLM associated with chronic intermittent hypoxia (CIH) would cause sympathetic overdrive. Juvenile male rats (50–55 g) submitted to CIH (6% oxygen every 9 min, 8 h day−1 for 10 days) were studied in an arterially perfused in situ preparation where sympathetic activity was recorded. In control rats (n = 6), exogenously applied adrenomedullin in the RVLM raised baseline sympathetic activity when combined with episodic activation of peripheral chemoreceptors (KCN 0.05%, 5 times every 5 min). This sympathoexcitatory response was markedly amplified in rats previously exposed to CIH (n = 6). The antagonism of adrenomedullin receptors in the RVLM caused a significant reduction in sympathetic activity in the CIH group (n = 7), but not in controls (n = 8). The transient reflex‐evoked sympathoexcitatory response to peripheral chemoreceptor stimulation was not affected by either adrenomedullin or adrenomedullin receptor antagonism in the RVLM of control and CIH rats. Our findings indicate that CIH sensitizes the sympathoexcitatory networks within the RVLM to adrenomedullin, supporting its role as an excitatory neuromodulator when intermittent hypoxia is present. These data reveal novel state‐dependent mechanistic insights into the generation of sympathetic overdrive and provide potential guidance on possible unique approaches for controlling sympathetic discharge in diseases such as sleep apnoea and neurogenic hypertension.

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Section: Discussionmentioning

confidence: 99%

Centrally acting adrenomedullin in the long‐term potentiation of sympathetic vasoconstrictor activity induced by intermittent hypoxia in rats

Zoccal

Colombari

Flor

et al. 2019

Experimental Physiology

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“…In the cerebral circulation, larger arteries predominantly regulate cerebral vascular resistance to blood flow, rather than the smaller arterioles. 44,45 Alterations in the structure of the large feeder arteries and collateral vessels are, therefore, likely contributors to increased cerebral vascular resistance predisposing individuals to hypertension. For the first time, we present interesting evidence that the prevalence of congenital cerebrovascular variants confined to the posterior circulation (VAH and an incomplete posterior CoW) is greater in hypertensive patients compared with controls.…”

Section: Discussionmentioning

confidence: 99%

Is High Blood Pressure Self-Protection for the Brain?

Warnert

Rodrigues

Burchell

et al. 2016

Circulation Research

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H igh blood pressure (BP) affects ≈25% of the world's population and is the largest single contributor to global mortality. 1 Hypertension represents a significant economic burden to public healthcare providers, where the global cost of nonoptimal BP is estimated to be US$370 billion (10% of healthcare expenditure). 2Remarkably, despite the availability of many pharmacological treatments, BP is poorly controlled with a recent report stating that only 53% of patients prescribed antihypertensive medication have BP controlled.3 This reflects the well-known heterogeneity of the syndrome, including epigenetic and inherited factors contributing to the unknown causes in 95% of patients. Despite the devastating consequences of hypertension (eg, stroke, kidney failure, coronary heart disease, and death 1,2 ), the mechanisms that lead to the onset of hypertension in humans are poorly understood. It is well established that elevated sympathetic nerve activity (SNA) contributes to the development of hypertension in most humans, [5][6][7] but what initiates this remains unclear. Experimental data from hypertensive rats and observations in postmortem human studies suggest that blood flow to the brain might be important in setting the operating level of SNA and, thus, systemic arterial pressure. Rationale: Data from animal models of hypertension indicate that high blood pressure may develop as a vital mechanism to maintain adequate blood flow to the brain. We propose that congenital vascular variants of the posterior cerebral circulation and cerebral hypoperfusion could partially explain the pathogenesis of essential hypertension, which remains enigmatic in 95% of patients.Objective: To evaluate the role of the cerebral circulation in the pathophysiology of hypertension. Methods and Results:We completed a series of retrospective and mechanistic case-control magnetic resonance imaging and physiological studies in normotensive and hypertensive humans (n=259). Interestingly, in humans with hypertension, we report a higher prevalence of congenital cerebrovascular variants; vertebral artery hypoplasia, and an incomplete posterior circle of Willis, which were coupled with increased cerebral vascular resistance, reduced cerebral blood flow, and a higher incidence of lacunar type infarcts. Causally, cerebral vascular resistance was elevated before the onset of hypertension and elevated sympathetic nerve activity (n=126). Interestingly, untreated hypertensive patients (n=20) had a cerebral blood flow similar to age-matched controls (n=28). However, participants receiving antihypertensive therapy (with blood pressure controlled below target levels) had reduced cerebral perfusion (n=19). Finally, elevated cerebral vascular resistance was a predictor of hypertension, suggesting that it may be a novel prognostic or diagnostic marker (n=126). Conclusions:

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“…The regions of CBF control during a CPT are currently unknown, but there is strong evidence that the large extracranial arteries (e.g. ICA) are active in CBF control (Faraci & Heistad, 1990;Willie et al 2012;Lewis et al 2015;Warnert et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Cerebrovascular response to the cold pressor test – the critical role of carbon dioxide

Tymko

Kerstens

Wildfong

et al. 2017

Experimental Physiology

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What is the central question of this study? What is the role of carbon dioxide in the cerebral blood flow (CBF) response to the cold pressor test (CPT)? What is the main finding and its importance? The CBF response was elevated during the isocapnic (controlled CO ) CPT in the middle cerebral artery and the internal carotid artery compared with the poikilocapnic (uncontrolled CO ) CPT, owing to ventilation-associated reductions in end-tidal CO . Furthermore, the common carotid artery vasodilated to a greater extent during the isocapnic compared with the poikilocapnic CPT, whereas the internal carotid artery vasoconstricted during both CPTs. Our data highlight the importance of CO control when investigating the CBF response to the CPT. In addition to increasing sympathetic nervous activity, blood pressure and cerebral blood flow (CBF), the cold pressor test (CPT) stimulates pain receptors, which may increase ventilation above metabolic demand; this response is likely to reduce the partial pressure of end-tidal carbon dioxide (P ET ,CO2) and will attenuate elevations in CBF. Our hypotheses were as follows: (i) the CPT will elicit hyperventilation, effectively lowering P ET ,CO2; (ii) the CBF response will be elevated during an isocapnic (controlled P ET ,CO2) compared with a poikilocapnic CPT (uncontrolled P ET ,CO2); and (iii) in response to the CPT, the common carotid artery (CCA) will vasodilate, while the internal carotid artery (ICA) will remain unchanged to help regulate CBF. Using a new, randomized experimental design, we measured the cerebrovascular response in the middle cerebral artery (MCA), CCA and internal carotid artery (ICA), during an isocapnic and poikilocapnic CPT in 15 participants. Blood pressure and cardiac output (finger photoplethysmography), heart rate (ECG), MCA mean velocity (transcranial Doppler ultrasound) and CCA and ICA CBF (Duplex ultrasound) were recorded during both CPT trials. Our findings were as follows: (i) ventilation increased, which reduced P ET ,CO2 (-5.3 ± 6.4 mmHg) during the poikilocapnic compared with the isocapnic CPT; (ii) the CBF response was elevated during the isocapnic compared with the poikilocapnic CPT in the MCA and ICA, but not in the CCA; and (iii) the CCA dilated to a greater extent during the isocapnic compared with the poikilocapnic CPT, and the ICA vasoconstricted during both trials. Our data emphasize the importance of P ET ,CO2 control in the CBF response to the CPT and in the differential vasomotor regulation between the CCA and ICA.

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The major cerebral arteries proximal to the Circle of Willis contribute to cerebrovascular resistance in humans

Cited by 29 publications

References 40 publications

Centrally acting adrenomedullin in the long‐term potentiation of sympathetic vasoconstrictor activity induced by intermittent hypoxia in rats

Centrally acting adrenomedullin in the long‐term potentiation of sympathetic vasoconstrictor activity induced by intermittent hypoxia in rats

Is High Blood Pressure Self-Protection for the Brain?

Cerebrovascular response to the cold pressor test – the critical role of carbon dioxide

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