The discovery that the hypothalamic-pituitary-adrenocortical (HPA) endocrine stress axis controls an alternative splicing decision in chromaffin Slo-encoded BK (big potassium) channels raised the possibility that activation of the HPA could serve as a mechanism to tune the intrinsic electrical properties of epinephrine-secreting adrenal chromaffin cells. To test this, we compared BK functional properties and cell excitability in chromaffin cells from normal and hypophysectomized (pituitaryablated) rats. Hypophysectomy was found to alter the voltage dependence and kinetics of BK gating, making channels less accessible for activation from rest. Perforated-patch recordings revealed changes in action potential waveform and repetitive firing properties. The maximum number of spikes that could be elicited with a 2 sec depolarizing current pulse was reduced by ϳ50% by hypophysectomy. The results indicate that pituitary hormones can adapt the mechanics of adrenal catecholamine release by tailoring BK channel function.Key words: hypophysectomy; BK channels; chromaffin cells; action potentials; adrenal medulla; catecholamines; stress Descending synaptic input to adrenomedullary chromaffin cells triggers the rapid release of adrenaline, or epinephrine, by eliciting Na ϩ and Ca 2ϩ channel-dependent action potentials. Thus the intrinsic excitable properties of chromaffin cells, by defining action potential responses, play perhaps as great a role in limiting or patterning epinephrine secretion as does the input. In chromaffin cells, a significant fraction of the outward current gated at physiological voltages is carried by BK (big K ϩ ) voltage-and Ca 2ϩ -activated potassium channels, leading several investigators to argue that BK channels play a central role in shaping intrinsic excitability, particularly with respect to repetitive firing Lingle et al., 1996;Lovell et al., 2000). Recent evidence that pituitary stress hormones influence alternative splicing of Slo gene-encoded BK channels has raised the hypothesis that stressrelated activation of the hypothalamic-pituitary-adrenocortical (HPA) axis may dynamically control the character of autonomic crisis responses by tuning chromaffin cell excitability (Xie and McCobb, 1998). To explore this, we have characterized changes in chromaffin cell function resulting from the surgical elimination of the HPA hormone cascade by hypophysectomy.Hypophysectomy eliminates the source of adrenocorticotropic hormone (ACTH), thereby dramatically and irreversibly reducing serum corticosterone levels to the margin of detectability by radioimmunoassay. One consequence is a precipitous decline in the adrenal transcription of the enzyme phenylethanolamine-Nmethyltransferase (PNMT), which catalyzes the conversion of norepinephrine to epinephrine (Stachowiak et al., 1988;Viskupic et al., 1994). That this reflects a dynamic and bidirectional influence of the HPA on epinephrine synthesis is supported by behavioral experiments (Stachowiak et al., 1988;Wong et al., 1992;Baruchin et al., 1993;Lemaire et ...