Human corticotropin-releasing hormone in man: dose-response of minute ventilation and end-tidal partial pressures of carbon dioxide and oxygen.

The respiratory stimulant properties of iv injections of 33, 67, and 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) were studied in 12 normal men in a single blind, placebo-controlled trial. All doses of hCRH induced a respiratory stimulation in every subject, and the stimulation was dose dependent. The onset of respiratory stimulation occurred within 15-30 sec after hCRH infusion was started. Initially, there was an increase in tidal volume (VT), followed by an increase in respiratory rate. The maximum minute ventilation (VE) occurred 60-120 sec after starting the injection. The 33-micrograms hCRH dose induced a 35% increase in VE from 6.3 +/- 0.6 (+/- SD) to 9.7 +/- 1.3 liters/min (P less than 0.001) due to a marked increase in VT from 531 +/- 105 to 688 +/- 142 ml (P less than 0.001) and only a slight increase in the respiratory rate from 12.4 +/- 3.0 to 14.3 +/- 3.1 breaths/min (P less than 0.001); heart rate was not altered at this dose. The 100-micrograms hCRH dose increased the VE by 81% to 11.5 +/- 1.5 liters/min, mainly due to an increase in VT. VE was elevated for 5.8, 7.2, or 8.3 min after the end of injection of the three hCRH doses. Increases in VE markedly lowered the end-tidal partial pressure of carbon dioxide (P(ET)CO2; nearly identical with the arterial PCO2 in normal subjects). hCRH (33 micrograms) lowered P(ET)CO2 from 40.3 +/- 1.2 to 37.2 +/- 1.9 mm Hg (P less than 0.001), and 100 micrograms hCRH lowered P(ET)CO2 to 33.4 +/- 1.2 mm Hg. End-tidal partial pressure of oxygen, i.e. the most sensitive parameter for the duration of action of respiratory stimulation, was elevated for 8.5, 10.2, and 14 min after injection of 33, 67, or 100 micrograms hCRH. Sixty-seven micrograms of hCRH was the lowest effective dose for an increase in the heart rate (from 66.4 to 79.0 beats/min; P less than 0.001), and 100 micrograms hCRH markedly increased the heart rate by 20% to a peak value of 83.5 beats/min. Heart rate increased within 90 sec and returned to the control value after 5-10 min. These data suggest that hCRH is a rapidly acting, dose-dependent, and potent respiratory stimulant. Since this hyperventilatory effect of hCRH occurred in every subject after all doses tested, respiratory stimulation may represent specific biological activity of CRH rather than a side-effect.