Female reproductive hormones exert important non-reproductive influences on autonomic regulation of body temperature and blood pressure. Estradiol and progesterone influence thermoregulation both ...centrally and peripherally, where estradiol tends to promote heat dissipation, and progesterone tends to promote heat conservation and higher body temperatures. Changes in thermoregulation over the course of the menstrual cycle and with hot flashes at menopause are mediated by hormonal influences on neural control of skin blood flow and sweating. The influence of estradiol is to promote vasodilation, which, in the skin, results in greater heat dissipation. In the context of blood pressure regulation, both central and peripheral hormonal influences are important as well. Peripherally, the vasodilator influence of estradiol contributes to the lower blood pressures and smaller risk of hypertension seen in young women compared to young men. This is in part due to a mechanism by which estradiol augments beta-adrenergic receptor mediated vasodilation, offsetting alpha-adrenergic vasoconstriction, and resulting in a weak relationship between muscle sympathetic nerve activity and total peripheral resistance, and between muscle sympathetic nerve activity and blood pressure. After menopause, with the loss of reproductive hormones, sympathetic nerve activity, peripheral resistance and blood pressure become more strongly related, and sympathetic nerve activity (which increases with age) becomes a more important contributor to the prevailing level of blood pressure. Continuing to increase our understanding of sex hormone influences on body temperature and blood pressure regulation will provide important insight for optimization of individualized health care for future generations of women.
New Findings
What is the topic of this review?
This review article revisits an historical hypothesis that cerebral hypoperfusion, caused by elevated cerebral vascular resistances, causes the onset of ...high sympathetic nerve activity and hypertension in humans.
What advances does it highlight?
The review article highlights new evidence indicating that congenital cerebrovascular abnormalities, namely vertebral artery hypoplasia and an incomplete posterior circle of Willis, may play a role in the onset of hypertension.
Despite the harmful consequences of high blood pressure (hypertension; e.g. stroke, renal failure, dementia and even death), the underlying physiological mechanisms that cause the onset of hypertension are poorly understood. The most established finding is that hypertension occurs alongside activation of the sympathetic nervous system, yet exactly what triggers this in humans is ambiguous. This review discusses evidence for elevated sympathetic nerve activity, particularly in human hypertension, and revisits an historical theory regarding the aetiology underlying human hypertension that was proposed by Seymour Kety and John Dickinson in the 1940s–1950s. My research group hypothesizes that elevated sympathetic nerve activity and hypertension develop as a fundamental mechanism to maintain adequate cerebral blood flow, which is now termed Cushing's mechanism or the selfish brain hypothesis. Moreover, it goes against the traditional belief that high cerebrovascular resistance is a consequence of hypertension; we propose that this elevated resistance drives hypertension. This review discusses historical and new evidence in animals and humans supporting this hypothesis. In particular, unique human data indicating a higher prevalence of congenital cerebral vascular abnormalities in hypertension are considered.
Over the past several decades, studies of the sympathetic nervous system in humans, sheep, rabbits, rats, and mice have substantially increased mechanistic understanding of cardiovascular function ...and dysfunction. Recently, interest in sympathetic neural mechanisms contributing to blood pressure control has grown, in part because of the development of devices or surgical procedures that treat hypertension by manipulating sympathetic outflow. Studies in animal models have provided important insights into physiological and pathophysiological mechanisms that are not accessible in human studies. Across species and among laboratories, various approaches have been developed to record, quantify, analyze, and interpret sympathetic nerve activity (SNA). In general, SNA demonstrates "bursting" behavior, where groups of action potentials are synchronized and linked to the cardiac cycle via the arterial baroreflex. In humans, it is common to quantify SNA as bursts per minute or bursts per 100 heart beats. This type of quantification can be done in other species but is only commonly reported in sheep, which have heart rates similar to humans. In rabbits, rats, and mice, SNA is often recorded relative to a maximal level elicited in the laboratory to control for differences in electrode position among animals or on different study days. SNA in humans can also be presented as total activity, where normalization to the largest burst is a common approach. The goal of the present paper is to put together a summary of "best practices" in several of the most common experimental models and to discuss opportunities and challenges relative to the optimal measurement of SNA across species.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-measuring-sympathetic-nerve-activity/.
In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently ...needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 (P2rx3, also known as P2x3) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.
Abstract Background Augmented reflex response from peripheral chemoreceptors characterises chronic heart failure (CHF), contributes to autonomic imbalance and exercise intolerance and predicts poor ...outcome. Methods and results We present a case of a 56-year-old male patient with ischaemic CHF, who underwent surgical, unilateral carotid body resection to reduce peripheral chemosensitivity. At 2-month and 6-month follow-ups, we document a persistent decrease in peripheral chemosensitivity accompanied by an improvement in exercise capacity, sleep disordered breathing and quality of life. Autonomic balance was favourably affected as evidenced by improved heart rate variability and augmented cardiac baroreflex sensitivity. There were no procedure-related adverse events. Conclusions Denervation of a carotid body may offer a clinical strategy to restore autonomic balance and improve morbidity in heart failure ( NCT01653821 ).
Aims
Augmented reflex responses from peripheral chemoreceptors, which are mainly localized in the carotid bodies (CBs), characterize patients with systolic heart failure and contribute to adrenergic ...hyperactivation. We investigated whether surgical resection of CBs in these patients can be performed safely to decrease sympathetic tone.
Methods and results
We studied 10 male patients with systolic heart failure (age, 59 ± 3 years; LVEF, 27 ± 7%) who underwent unilateral right‐sided CB resection (four patients) or bilateral CB resection (six patients). Primary endpoints of the study were changes in muscle sympathetic nerve activity (MSNA) and peripheral chemosensitivity measured as ventilatory response to hypoxia from baseline to 1 month post‐CB resection. Safety analysis included analysis of arterial blood gas and oxygenation at night through 2 months post‐procedure and adverse events assessed up to 12 months. At the 1‐month visit, CB resection was associated with a significant decrease both in MSNA (86.6 ± 3.1 vs. 79.7 ± 4.2 bursts/100 beats, P = 0.03) and in peripheral chemosensitivity (1.35 ± 0.19 vs. 0.41 ± 0.17 L/min/SpO2, P = 0.005). It also resulted in improved exercise tolerance. Amongst some patients with bilateral CB resection, there was a trend towards worsening of oxygen saturation at night, which in one case required therapy with non‐invasive ventilation.
Conclusion
We present first‐in‐man evidence that CB resection in patients with systolic heart failure is associated with a decrease in sympathetic activity. A bilateral procedure may carry a risk of worsening oxygenation at night. CB modulation constitutes an interesting research avenue, but careful consideration of the balance between safety and efficacy is necessary before further clinical trials.
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.
To evaluate the role of the cerebral circulation in the pathophysiology of hypertension.
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).
Our data indicate that congenital cerebrovascular variants in the posterior circulation and the associated cerebral hypoperfusion may be a factor in triggering hypertension. Therefore, lowering blood pressure may worsen cerebral perfusion in susceptible individuals.
Non‐Technical Summary In young men, sympathetic nerve activity is directly related to the level of vasoconstrictor tone in the peripheral vasculature. However, in young women this relationship does ...not exist, suggesting that certain factors (potentially related to the female sex hormones) offset the transfer of sympathetic nerve activity into vasoconstrictor tone in this population. In the present study we show that, in young women, the β‐adrenergic receptors (which cause vasodilatation in response to noradrenaline) blunt the vasoconstrictor effect of resting sympathetic nerve activity in young women. This mechanism does not occur in young men or postmenopausal women. It is possible that the β‐adrenergic receptors may partially protect young women against the sometimes harmful effects of high sympathetic nerve activity. This may explain why the risk of developing hypertension is greater in young men and postmenopausal women (who have very high sympathetic nerve activity) compared to young women.
In men, muscle sympathetic nerve activity (MSNA) is positively related to total peripheral resistance (TPR) and inversely related to cardiac output (CO). However, this relationship was not observed in young women. We aimed to investigate whether simultaneous β‐adrenergic stimulation offsets this balance in young women. Furthermore, we aimed to examine whether the ability of the β‐adrenergic receptors to offset the transduction of MSNA into vasoconstrictor tone was lost in postmenopausal women. We measured MSNA (peroneal microneurography), arterial pressure (brachial line), CO (Modelflow), TPR and changes in forearm vascular conductance (FVC) to increasing doses of noradrenaline (NA; 2, 4 and 8 ng (100 ml)−1 min−1) before and after systemic β‐blockade with propranolol in 17 young men, 17 young women and 15 postmenopausal (PM) women. The percentage and absolute change in FVC to the last two doses of NA were greater during β‐blockade in young women (P < 0.05), whereas the change in FVC was similar before and during β‐blockade in young men and PM women (P > 0.05). Before β‐blockade there was no relationship of MSNA to TPR or mean arterial pressure (MAP) in young women. Following β‐blockade, MSNA became positively related to TPR (r= 0.59, P < 0.05) and MAP (r= 0.58, P < 0.05). In the PM women and young men, MSNA was positively associated with TPR. β‐Blockade had no effect on this relationship. Our data suggest that the β‐adrenergic receptors offset α‐adrenergic vasoconstriction in young women but not young men or PM women. These findings may explain in part the tendency for blood pressure to rise after menopause in women.
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