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(Circulation Research. 2001;88:1036.)
© 2001 American Heart Association, Inc.

Cellular Biology

Hypoxia Alters the Sensitivity of the L-Type Ca²⁺ Channel to -Adrenergic Receptor Stimulation in the Presence of ß-Adrenergic Receptor Stimulation

Livia C. Hool

From the Department of Physiology, The University of Western Australia, Crawley, Western Australia.

Correspondence to Dr Livia Hool, Department of Physiology, The University of Western Australia, Stirling Highway, Crawley, WA 6009, Australia. E-mail lhool{at}cyllene.uwa.edu.au

Abstract—The effects of -adrenergic receptor (-AR) stimulation alone and the effects in the presence of ß-adrenergic receptor (ß-AR) stimulation were examined on L-type Ca²⁺ currents (I_Ca-L) in the absence and presence of hypoxia. The -AR agonist methoxamine either had no effect or had a slight inhibitory effect on basal I_Ca-L in the absence and presence of hypoxia. Hypoxia significantly decreased the K_0.5 for activation of I_Ca-L by norepinephrine from 79.8±6.6 to 13.3±0.7 nmol/L. To determine whether hypoxia specifically altered the sensitivity of the channel to -AR stimulation, cells were exposed to increasing concentrations of methoxamine in the presence of 100 nmol/L isoproterenol (Iso). In the absence of hypoxia, methoxamine inhibited the Iso-activated I_Ca-L in a concentration-dependent manner with an EC₅₀ of 86.9±9.9 µmol/L. However, in the presence of hypoxia, the EC₅₀ for inhibition of I_Ca-L by methoxamine was significantly increased to 266.7±10.8 µmol/L. Methoxamine had little effect on I_Ca-L activated by forskolin or histamine in the absence or presence of hypoxia. In addition, inhibition of protein kinase C by bisindolylmaleimide 1 or protein kinase C ß peptide inhibitor had no effect on the methoxamine-induced antagonism of I_Ca-L in the absence or presence of hypoxia. The tyrosine kinase inhibitor genistein attenuated the methoxamine response in nonhypoxic cells only. However, during hypoxia it was attenuated with the phospholipase A₂ inhibitors mepacrine and indomethacin. These findings represent a novel regulation of the L-type Ca²⁺ channel by the phospholipase A₂ pathway and illustrate the complexity of regulation of the channel under hypoxic conditions.

Key Words: -adrenergic receptor • ß-adrenergic receptor • hypoxia • L-type Ca²⁺ channels • phospholipase A₂

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