Effect of endothelin-1 on the blood pressure response to acute hypoxia and hyperoxia in healthy young men.

Endothelin-1 (ET-1) and its receptors are linked to increases in sensitivity of the chemoreceptors to hypoxic stress and the development of hypertension in preclinical models. We hypothesized ET receptor antagonism would lower resting blood pressure (BP) as well as the acute BP response to chemoreflex stress. Twenty-four men (31 ± 5 years, 26 ± 3 kg/m2) completed two study visits (control, bosentan). On each visit, BP was assessed under three conditions: (1) normoxia (FiO2 0.21), (2) chemoreflex excitation via hypoxia (FiO2 0.05-0.21), (3) chemoreflex inhibition via hyperoxia (FiO2 1.00). Bosentan increased plasma ET-1 (0.94 ± 0.90 to 1.27 ± 0.62 pg/mL, p = 0.004), supporting receptor blockade. Resting diastolic (73 ± 5 to 69 ± 7 mmHg, p = 0.007) and mean (93 ± 7 to 88 ± 7 mmHg, p = 0.005) BP were reduced following bosentan compared to control with no change in systolic BP (p = 0.507). The mean BP response to both acute hypoxia (-0.48 ± 0.38 to -0.25 ± 0.31 mmHg/%, p = 0.004) and hyperoxia (area under the curve -93 ± 108 to -27 ± 66 AU, p = 0.018) were attenuated following bosentan. Acute ET receptor inhibition attenuates the rise in BP during chemoreflex excitation as well as the fall in BP during chemoreflex inhibition in healthy young men. These data support a role for ET-1 in control of resting BP, possibly through a chemoreceptor-mediated mechanism.

Role of the peripheral chemoreceptors in cardiovascular and metabolic control in type 2 diabetes.

Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes (T2D) and the contribution of the peripheral chemoreceptors to resting cardiovascular and metabolic control. We hypothesized that: (1) adults with T2D exhibit exaggerated peripheral chemoreflex sensitivity; (2) the peripheral chemoreceptors contribute to cardiovascular dysfunction in T2D; and (3) attenuation of peripheral chemoreceptor activity improves glucose tolerance in T2D. Seventeen adults with diagnosed T2D [six males/11 females; aged 54 ± 11 years; glycated haemoglobin (HbA1c) 7.6 ± 1.5%] and 20 controls without T2D (9 males/11 females; aged 49 ± 13 years, HbA1c 5.2 ± 0.4%) participated in the study. The hypoxic ventilatory response (HVR) was assessed as an index of peripheral chemosensitivity. Resting heart rate, blood pressure and minute ventilation were measured when breathing normoxic followed by hyperoxic air (1.0 F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) to acutely attenuate peripheral chemoreceptor activity. A subset of participants (n = 9 per group) completed two additional visits [normoxia (0.21 F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), hyperoxia (1.0 F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ )] where glucose and insulin were measured for 2 h following an oral glucose challenge. HVR was augmented in adults with T2D (-0.84 ± 0.49 L min-1/%) vs. control (-0.48 ± 0.40 L min-1/%, P = 0.021). Attenuation of peripheral chemoreceptor activity decreased heart rate (P < 0.001), mean blood pressure (P = 0.009) and minute ventilation (P = 0.002); any effect of hyperoxia did not differ between groups. There was no effect of hyperoxia on the glucose (control, P = 0.864; T2D, P = 0.982), nor insulin (control, P = 0.763; T2D, P = 0.189) response to the oral glucose challenge. Peripheral chemoreflex sensitivity is elevated in adults with T2D; however, acute attenuation of peripheral chemoreflex activity with hyperoxia does not restore cardiometabolic function. KEY POINTS: Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes and the contribution of the peripheral chemoreceptors to resting cardiovascular control and glucose tolerance. We observed elevated peripheral chemoreflex sensitivity in adults with diabetes which was associated with glycaemic control (i.e. glycated haemoglobin). Notably, acute attenuation of peripheral chemoreflex activity with hyperoxia did not restore cardiometabolic function in the individuals studied.