The non-neurogenic catecholamine response of the fetal adrenal to hypoxia is dependent on activation of voltage sensitive Ca2+ channels

Abstract

We have investigated the cellular mechanisms underlying the catecholamine response of the fetal sheep adrenal to hypoxia before and after the development of adrenal innervation. Adrenals were collected before (80-100 days gestation: n = 7) and after (135-146 days gestation: n = 10) development of innervation and retrogradely perfused with oxygenated Krebs bicarbonate buffer in vitro via the renal vein. Adrenal hypoxia was induced by perfusion with hypoxic Krebs buffer (pO2 = 46.7 +/- 2.4 mm Hg) for 30 min periods in the presence and absence of hexamethonium (500 microM), Ca2+ (2.5 mM), nifedipine (1 microM) and KCl (10 mM). Hypoxia stimulated an increase (P < 0.001) in the output of noradrenaline at 80-100 days (3 min pre hypoxia, 0.18 +/- 0.07 nmol/3 min; 20 min hypoxia, 0.74 +/- 0.22 nmol/3 min) and at 135-146 days (3 min pre hypoxia, 0.53 +/- 0.20 nmol/3 min; 20 min hypoxia, 1.71 +/- 0.85 nmol/3 min). Adrenaline output was also higher (P < 0.001) than basal values (80-100 days, 0.11 +/- 0.06 nmol/3 min; 135-146 days, 0.53 +/- 0.15 nmol/3 min) after 20 min hypoxia (0.41 +/- 0.20 nmol/3 min and 1.35 +/- 0.56 nmol/3 min respectively). The catecholamine responses to hypoxia were abolished by removal of Ca2+ from the adrenal perfusate. There was a reduction (P < 0.05) in the catecholamine secretory response to hypoxia in the presence of nifedipine. Noradrenaline output decreased from 4.33 +/- 0.84 nmol/30 min to 0.16 +/- 0.49 nmol/30 min and adrenaline output decreased from 3.16 +/- 1.66 nmol/30 min to -0.01 +/- 0.24 nmol/30 min in the presence of nifedipine. The fetal adrenal secretes catecholamines by a direct or non-neurogenic mechanism in response to hypoxia. This secretory response is dependent on the activation of voltage sensitive Ca2+ channels in the chromaffin cell membrane.