A role for endothelin‐A receptors in altered blood flow and pressor responses during exercise in hypertensive adults

The recently updated blood pressure (BP) guidelines promulgated by the American College of Cardiology (ACC) and the American Heart Association (AHA) have increased the prevalence of patients now diagnosed with hypertension. There is a need to better understand the pathophysiological mechanisms associated with the new hypertensive categories. For example, exaggerated BP and attenuated peripheral blood flow responses are observed during exercise in hypertensive adults, but the mechanistic underpinnings of these altered responses have not been well characterized. Previous work (Barrett-O'Keefe et al. 2015) demonstrated that endothelin-A (ETA) receptor antagonism, via infusion of the drug BQ-123, increased leg blood flow and attenuated the exercise-induced rise in BP during single-leg knee extension exercise in older adults. Those data provide evidence for a role of endothelin-1 (ET-1), acting through ETA receptors, in modulating dysregulated blood flow and pressure responses during exercise. In resting hypertensive individuals, infusion of ET-1 or BQ-123 resulted in exaggerated vasoconstrictor and vasodilator responses, respectively, compared to healthy controls, suggesting increased ETA receptor expression and/or sensitivity to ET-1 in those with hypertension (Cardillo et al. 1999). Taken together, those studies suggest that the abnormal exercise pressor and blood flow responses in hypertensive adults may be mediated by ET-1 acting on ETA receptors. In a recent issue of The Journal of Physiology, Craig et al. 2019 sought to determine whether altered BP and blood flow responses to exercise in hypertensive adults were mediated by ET-1 acting through ETA receptors. They hypothesized that ETA receptor antagonism with intra-arterial infusion of BQ-123 would (1) increase leg blood flow at rest and progressively throughout incremental single-leg knee extension exercise, and (2) blunt the increase in arterial BP during exercise in hypertensive adults. To test these hypotheses, eight individuals (46 ± 11 years) diagnosed with hypertension (systolic BP = 136 ± 9 mmHg; diastolic BP = 86 ± 15 mmHg) completed single-leg knee extension exercise at absolute (0, 5, 10, 15 W) and relative (40, 60, 80% peak power) intensities during infusion of either saline (control) or BQ-123 (ETA blockade) into the right common femoral artery (CFA) prior to and throughout exercise. Due to the long-lasting effects of BQ-123, the saline trial was always performed first, followed by 60 min of recovery and 45 min of BQ-123 infusion before initiating the BQ-123 trial. CFA diameter and blood velocity were assessed in the infused leg using Doppler ultrasound, and were used to calculate leg blood flow during the final minute of each stage of exercise. Arterial and venous BPs were measured continuously using pressure transducers placed in catheters inserted into the CFA and femoral vein. Leg blood flow and perfusion pressure measurements were used to calculate leg vascular conductance [leg blood flow/leg perfusion pressure] and resistance [(leg perfusion pressure/leg blood flow) × 100]. Stroke volume and cardiac output were estimated using a finometer, which was also used to calculate systemic vascular resistance. As expected, ETA receptor antagonism resulted in augmented leg blood flow and vascular conductance compared to the control condition at rest and throughout exercise. Increases in leg vascular conductance, as well as O2 delivery and consumption, occurred despite a reduction in perfusion pressure at rest and during exercise up to 60% of peak power, although perfusion pressure was not different between conditions at the highest intensity (80% of peak power). Diastolic BP was reduced by BQ-123 infusion compared to saline at rest and during all exercise intensities except for 60% and 80% of peak power. Systolic BP, however, was not different between conditions at any point. Importantly, despite reductions in diastolic BP, MAP was not different between trials at any point. Stroke volume and cardiac output, but not heart rate, were increased at rest and throughout exercise in the BQ-123 trial, probably accounting for the absence of differences in MAP between trials. This study is the first to demonstrate increases in leg blood flow, vascular conductance, oxygen delivery, and oxygen consumption with ETA blockade during exercise in patients with hypertension. Concomitant reductions in leg perfusion pressure suggest that increases in leg blood flow were a result of reduced leg vascular resistance. Contrary to the authors’ hypothesis, ETA blockade did not attenuate increases in MAP during exercise, as the increase in cardiac output was sufficient to negate the reductions in vascular resistance, and thereby maintain systemic MAP. Together, these findings suggest an important role for ET-1, acting through ETA receptors, in the pathophysiological responses to exercise in patients with hypertension. Subjects in this study had a systolic BP of 136 ± 9 mmHg and a diastolic BP of 86 ± 15 mmHg. According to the new ACC/AHA guidelines, individuals with systolic BP between 140 and 159 mmHg and/or diastolic BP between 90 and 99 mmHg are considered stage-2 hypertensive, whereas those with systolic BP between 130 and 139 mmHg and/or diastolic BP between 80 and 89 mmHg are now considered stage-1 hypertensive. Those with systolic BP between 120 and 129 mmHg and diastolic BP < 80 mmHg are considered pre-hypertensive. Thus, under the new guidelines, hypertensive status for these subjects ranged from pre-hypertensive to stage-2 hypertension. Previous studies have reported disparate findings regarding the influence of ETA receptor antagonism on forearm blood flow that may be explained by hypertensive status. Cardillo et al. (1999) reported an approximate 33% increase in forearm blood flow (FBF) following BQ-123 infusion in patients who are stage-2 hypertensive under the new guidelines (BP ≥140/90 mmHg), with no increase in FBF in normotensive control subjects. In contrast, in a cohort that was previously pre-hypertensive (130 ± 1/80 ± 1 mmHg) but would be considered stage-1 hypertensives under the new guidelines, Weil et al. (2012) reported a 20% increase in FBF following BQ-123 infusion compared to a 5% increase in FBF in normotensive control subjects (112 ± 1/72 ± 1 mmHg). Together, the results of these studies indicate differential and incremental responsiveness to ETA receptor antagonism based on hypertensive status and point out the need for future studies on the role of endothelin-1 in modulating exercise pressor and blood flow responses in hypertension as defined by the new BP guidelines. It is well established that hypertensive individuals have increased resting muscle sympathetic nerve activity (MSNA) and an exaggerated exercise pressor response that is largely mediated by augmented MSNA responses to sympathoexcitatory stimuli. Although not measured in this study, the authors speculate that central haemodynamics at rest and during exercise were likely to be accompanied by increased MSNA, which in turn may have influenced changes in local blood flow regulation. In a previous study, however, infusion of either BQ-123 or sodium nitroprusside (SNP) similarly reduced BP in resting hypertensive and normotensive subjects, but concomitant increases in MSNA were blunted with infusion of BQ-123 compared to SNP (Bruno et al. 2011). Thus, although the findings of that study are limited to resting conditions, they suggest that the increases in central haemodynamics observed by Craig et al. may be independent of changes in MSNA. Importantly, normotensive subjects required a larger dose of BQ-123 compared to hypertensive subjects (0.2 mg kg h−1 vs. 0.1 mg kg h−1) to elicit similar BP and MSNA responses, providing further support for the hypothesis that those with hypertension have increased ETA receptor density and/or sensitivity to ET-1. Future research may seek to elucidate the effects of ETA blockade on MSNA during exercise, and how those effects may relate to central and peripheral haemodynamics in hypertensive subjects. Additionally, a third trial to match increases in blood flow to those observed with ETA blockade, using a direct and potent vasodilator such as SNP, would probably shed further light on the specific central and peripheral effects of ET-1 acting on ETA receptors. The findings of Craig et al. (2019) provide novel and mechanistic insights into the role of ET-1, acting through ETA receptors, in the dysregulated pressor and blood flow responses to exercise that are observed in hypertensive adults. The authors suggest that ETA receptor blockade may be a viable therapeutic approach to improve blood flow during exercise in hypertensive patients. Further research is needed to better understand how ETA blockade impacts blood flow, central haemodynamic and MSNA responses during exercise in participants with varying degrees of hypertension (i.e. pre-, stage-1, or stage-2 hypertension). Future research may also seek to evaluate the long-term effects of ETA blockade during exercise in ameliorating the pathological pressor and blood flow responses in hypertensive patients. The authors have no conflicts of interests to disclose. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. All authors have read and approved the final version of this manuscript. Preparation of this manuscript was supported by NIH T-32 Grant No. 5T-32-AG-04 9676 (S.T.W.). The authors would like to thank Dr W. Larry Kenney and Dr Lacy M. Alexander for their input, critical evaluation, and feedback during the preparation of this manuscript.