R. G. McCullough

β-Adrenergic blockade does not prevent polycythemia or decrease in plasma volume in men at 4300 m altitude

Abstract When humans ascend to high altitude (ALT) their plasma volume (PV) and total blood volume (BV) decrease during the first few days. With continued residence over several weeks, the hypoxia-induced stimulation of erythropoietin increases red cell production which tends to restore BV. Because hypoxia also activates the β-adrenergic system, which stimulates red blood cell production, we investigated the effect of adrenergic β-receptor inhibition with propranolol on fluid volumes and the polycythemic response in 11 healthy unacclimatized men (21–33 years old exposed to an ALT of 4300 m (barometric pressure 460 Torr) for 3 weeks on Pikes Peak, Colorado. PV was determined by the Evans blue dye method (PVEB), BV by the carbon monoxide method (BVCO), red cell volume (RCV) was calculated from hematocrit (Hct) and BVCO, and serum erythropoietin concentration ([EPO]) and reticulocyte count, were also determined. All determinations were made at sea level and after 9–11 (ALT-10) and 19–20 (ALT-20) days at ALT. At sea level and ALT, six men received propranolol (pro, 240 mg · day−1), and five received a placebo (pla). Effective β-blockade did not modify the mean (SE) maximal values of [EPO] [pla: 24.9 (3.5) vs pro: 24.5 (1.5) mU · ml−1] or reticulocyte count [pla: 2.7 (0.7) vs pro: 2.2 (0.5)%]; nor changes in PVEB [pla: −15.8 (3.8) vs pro: −19.9 (2.8)%], RCVCO [pla: +7.0 (6.7) vs pro: +10.1 (6.1)%], or BVCO [pla: −7.3 (2.3) vs pro: −7.1 (3.9)%]. In the absence of weight loss, a redistribution of body water with no net loss is implied. Hence, activation of the β-adrenergic system did not appear to affect the hypovolemic or polycythemic responses that occurred during 3 weeks at 4300 m ALT in these subjects.

Usual clinical dose of acetazolamide does not alter cerebral blood flow velocity

Prior reports indicate that acetazolamide, an inhibitor of carbonic anhydrase, in moderate doses reduces symptoms of acute mountain sickness, and in large doses increases cerebral blood flow. The effect on flow is not known for a moderate dose, but were flow to increase, then increased cerebral oxygen delivery would be one mechanism of benefit from acetazolamide at high altitude. We utilized Doppler ultrasound in 8 volunteers to determine whether a usual acetazolamide dose (250 mg three times daily) would increase flow velocities in internal carotid and vertebral arteries. Acetazolamide during normoxia decreased pHa, PaCO2, and PETCO2, but baseline flow velocity remained unchanged. In 2 subjects without acetazolamide, voluntary hyperventilation decreased both PETCO2 and flow velocity. Both hypoxia and hypercapnia caused increases in arterial velocities. The increases were not altered by acetazolamide administration. In one subject, 1 g acetazolamide by acute i.v. injection induced an increase in flow velocity (40%) concomitant with a 5 mm Hg decrease in PETCO2, confirming prior reports using similar intravenous dose. In doses employed for prevention of acute mountain sickness, acetazolamide induced metabolic acidosis and may have prevented the fall in velocity usually associated with hypocapnia, but it neither increased baseline cerebral blood flow velocity nor velocity responses to hypoxia and hypercapnia. Benefit of acetazolamide at high altitude may relate to mechanisms other than increased cerebral blood flow.

Combined effects of female hormones and exercise on hypoxic ventilatory response

Mild elevations in metabolic rate may influence hypoxic ventilatory response (HVR) differently in men and women. The possible involvement of the female hormones in accounting for this gender difference is supported by observations that mild exercise raised HVR in ovariectomized women treated with estrogen and progestin but not in the same women treated with placebo (Regensteiner et al., 1989). We compared the effects of mild exercise on HVR in 12 women in the follicular phase vs the luteal phase of the menstrual cycle and during MPA (medroxyprogesterone acetate, 20 mg tid) vs placebo treatment. End-tidal PCO2 fell in the luteal compared to the follicular phase and in the follicular MPA compared to the follicular placebo condition. Resting HVR was similar in subjects in the follicular versus the luteal phases of the menstrual cycle and in MPA-treated vs placebo-treated subjects at either the existing (eucapnia) or follicular placebo (normocapnia) end-tidal PCO2. Mild exercise increased expired ventilation but not HVR in placebo-treated subjects in the follicular or luteal placebo conditions. In MPA-treated subjects, exercise raised HVR in the luteal phase (P less than 0.05) and tended to increase HVR in the follicular phase (P = 0.08). The increase in HVR with exercise was greater in MPA-treated subjects than in women given placebo (delta rest to exercise = 26% vs 9%, P less than 0.05). We concluded that elevations in progestin levels achieved by administering progestin in the luteal phase of the menstrual cycle potentiated the effect of metabolic rate on HVR.

Increased metabolism contributes to increased resting ventilation at high altitude

Ventilatory acclimation to high altitude results in an increase in total or minute ventilation, and is associated with a fall in alveolar PCO2, i.e. alveolar hyperventilation. However, the extent to which the increase in total ventilation is matched by a greater metabolic rate (VO2, VCO2) vs alveolar hyperventilation is unclear. We sought to determine the contribution of changes in metabolic rate to the increase in minute ventilation observed during exposure to high altitude. In 12 healthy male subjects taken from Denver, Colorado (1600 m) to Pikes Peak, Colorado (4300 m) for 5 days, resting minute ventilation increased from low to high altitude (+ 26% for the 5 days) and arterialized PCO2 fell. Resting metabolic rate increased 16% for the 5 days and could account for more than half of the increase in minute ventilation. Among subjects the increases in ventilation on days 1, 2 and 4 were positively correlated with increased CO2 production; they were not correlated with arterial oxygen saturation on any day. During exercise at high altitude, PCO2 values were not different from those at rest and minute ventilation rose above low altitude values (+ 58% by day 5), but the increase could not be accounted for by an increased CO2 production. Thus at rest but not during exercise a substantial portion of the rise in minute ventilation could be attributed to increased metabolic rate.