Naloxone Potentiates Epinephrine Release during Hypoxia in Fetal Sheep: Dose Response and Cardiovascular Effects

Abstract

The effect of opiate receptor blockade on the plasma catecholamine response to hypoxemia was studied in seven chronically catheterized fetal lambs in utero. All animals underwent treatment with hypoxia alone, naloxone infusion alone (2 mg/kg) and hypoxia with naloxone at four different dosages (0.1, 0.5, 1.0, and 2.0 mg/kg). Maternal and fetal hypoxia was maintained for 20 min. There were no differences noted in the degree of hypoxemia or acidemia between the different hypoxia treatment groups. Hypoxia increased both norepinephrine and epinephrine plasma levels in all fetal sheep studied. We found a dose-dependent increase in plasma epinephrine levels in response to naloxone infusion during hypoxia. Plasma epinephrine level by 20 min of hypoxia with the 0.1 mg/kg naloxone dose (geometric mean 5366 pg/ml) was significantly more than with hypoxia alone (997 pg/ml). Naloxone at the other doses did not alter the epinephrine responses. There was no augmentation of plasma norepinephrine levels by naloxone at any dose studied. Thus, naloxone augmented the plasma epinephrine response to hypoxia in fetal sheep suggesting that the opiate peptides act as modulators of the sympathoadrenal system. The naloxone dose response differences observed in this study suggest this modulation is largely by antagonism of mu-receptors.

The Effects of Hypoxia on (Methionine) Enkephalin Peptide and Catecholamine Release in Fetal Sheep

“…The baseline values for the circulating MET-ENK plasma levels show the higher rnol wt forms of enkephalins (total MET-ENKi) predominant with mean baseline levels of 1755 versus 168 pg/mL for MET-ENKi (the low rnol wt peptides). The baseline values for norepinephrine and epinephrine levels were similar to data previously reported by our laboratory and others (16,17) and were believed to represent healthy, nonstressed animals.…”

“…Similar findings have been reported in human newborns (30). We have recently shown opiate receptor blockade with naloxone significantly augments epinephrine levels in fetal sheep exposed to hypoxia (17).…”

Plasma Catecholamine Response to Fetal Hypoxemia Is Not Potentiated by Naloxone

“…be low 10 Torr, would serve as a greater stimu lus to the opiate system. Our results are gen erally similar to those reported by Martinez et al [12], who failed to note any enhance ment of plasma E levels except following administration of low-dose (0.1 mg/kg) nal oxone. However, we did not observe any dif ference in response with the two doses (0.5 and 1.0 mg/kg) which we employed.…”

“…However, we did not observe any dif ference in response with the two doses (0.5 and 1.0 mg/kg) which we employed. Marti nez et al [12] have suggested that this doseresponse difference may reflect the approxi mately 10-fold greater affinity of naloxone for vasodepressant p-receptors over vaso pressor 8-receptors [22], Thus, naloxone at the lowest dose may more selectively block p-receptor-mediated inhibition of E release whereas this effect is masked at higher doses. However, this hypothesis conflicts with the observation of enhanced catecholamine re lease at birth in response to an even higher dose (2 mg/kg) of naloxone [16] than was employed in the current study.…”

“…Endogenous opioid peptides have been postulated to act as modulators of the sympathoadrenal response to stress since they are distributed ubiquitously throughout the brain, sympathetic ganglia and adrenal medulla [5][6][7][8][9]. We have shown previously that endogenous opioid receptor blockade with naloxone potentiates the plasma epi nephrine (E) response to asphyxia in fetal sheep [10] but does not appear to play an important role during brief periods of hyp oxemia unaccompanied by acidemia [11], Recently, Martinez et al [12] have shown that low-dose naloxone may enhance plasma E release in fetuses exposed to more pro longed periods of hypoxemia, but higher doses had no effect. Therefore, the current investigation was undertaken to evaluate the fetal plasma catecholamine response to en dogenous opiate blockade following a 1-h period of hypoxemia.…”