The role of ET A receptors in peripheral vascular control at rest and during exercise in patients with hypertension

KEY POINTS: Exercise in patients with hypertension can be accompanied by an abnormal cardiovascular response that includes attenuated blood flow and an augmented pressor response. Endothelin-1, a very potent vasoconstrictor, is a key modulator of blood flow and pressure during in health and has been implicated as a potential cause of the dysfunction in hypertension. We assessed the role of endothelin-1, acting through endothelin A (ETA ) receptors, in modulating the central and peripheral cardiovascular responses to exercise in patients with hypertension via local antagonism of these receptors during exercise. ETA receptor antagonism markedly increased leg blood flow, vascular conductance, oxygen delivery, and oxygen consumption during exercise; interestingly, these changes occurred in the presence of reduced leg perfusion pressure, indicating that these augmentations were driven by changes in vascular resistance. These data indicate that ETA receptor antagonism could be a viable therapeutic approach to improve blood flow during exercise in hypertension. ABSTRACT: Patients with hypertension can exhibit impaired muscle blood flow and exaggerated increases in blood pressure during exercise. While endothelin (ET)-1 plays a role in regulating blood flow and pressure during exercise in health, little is known about the role of ET-1 in the cardiovascular response to exercise in hypertension. Therefore, eight volunteers diagnosed with hypertension were studied during exercise with either saline or BQ-123 (ETA receptor antagonist) infusion following a 2-week withdrawal of anti-hypertensive medications. The common femoral artery and vein were catheterized for drug infusion, blood collection and blood pressure measurements, and leg blood flow was measured by Doppler ultrasound. Patients exercised at both absolute (0, 5, 10, 15 W) and relative (40, 60, 80% peak power) intensities. BQ-123 increased blood flow at rest (79 +/- 87 ml/min; P = 0.03) and augmented the exercise-induced hyperaemia at most intensities (80% saline: Delta3818+/-1222 vs. BQ-123: Delta4812+/-1469 ml/min; P = 0.001). BQ-123 reduced leg MAP at rest (-8 +/- 4 mmHg; P < 0.001) and lower intensities (0-10 W; P < 0.05). Systemic diastolic blood pressure was reduced (0 W, 40%; P < 0.05), but systemic MAP was defended by an increased cardiac output. The exercise pressor response (DeltaMAP) did not differ between conditions (80% saline: 25 +/- 10, BQ-123: 30 +/- 7 mmHg; P = 0.17). Thus, ET-1, acting through the ETA receptors, contributes to the control of blood pressure at rest and lower intensity exercise in these patients. Furthermore, the finding that ET-1 constrains the blood flow response to exercise suggests that ETA receptor antagonism could be a therapeutic approach to improve blood flow during exercise in hypertension.