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Effects of noradrenaline on intracellular pH in acutely dissociated adult rat hippocampal CA1 neurones

Garth A. M. Smith, Christopher L. Brett and John Church

1. We examined the effects of noradrenaline on steady-state intracellular pH (pH_i) and the recovery of pH_i from internal acid loads imposed by the NH₄⁺ prepulse technique in hippocampal CA1 neurones acutely dissociated from adult rats.

2. Under nominally HCO₃^--free conditions, acid extrusion was accomplished by a Na⁺-dependent mechanism, probably the amiloride-insensitive variant of the Na⁺-H⁺ exchanger previously characterized in both fetal and adult rat hippocampal neurones. In the presence of external HCO₃^-, acid extrusion appeared to be supplemented by a Na⁺-dependent HCO₃^--Cl^- exchanger, the activity of which was dependent upon the absolute level of pH_i.

3. Noradrenaline evoked a concentration-dependent and sustained rise in steady-state pH_i and increased rates of pH_i recovery from imposed intracellular acid loads. The effects of noradrenaline were not dependent upon the presence of external HCO₃^- but were blocked by substituting external Na⁺ with N-methyl-D-glucamine, suggesting that noradrenaline acts to increase steady-state pH_i by increasing the activity of the Na⁺-H⁺ exchanger.

4. The effects of noradrenaline on steady-state pH_i and on rates of pH_i recovery from imposed acid loads were mimicked by ₁- and ₂-, but not -, adrenoceptor agonists. The -adrenoceptor antagonist propranolol blocked the ability of noradrenaline to increase both steady-state pH_i and rates of pH_i recovery from acid loads.

5. The effects of noradrenaline on steady-state pH_i and on pH_i recovery rates following acid loads were not dependent on changes in [Ca²⁺]_i. However, the effects of noradrenaline were blocked by pre-treatment with the adenylate cyclase inhibitor 2',5'-dideoxyadenosine and the cAMP-dependent protein kinase inhibitors R_p-adenosine-3',5'-cyclic monophosphorothioate (sodium salt; Rp-cAMPS) and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide (H-89).

6. Forskolin, an activator of endogenous adenylate cyclase, and 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, mimicked the ability of noradrenaline to increase both steady-state pH_i and rates of pH_i recovery from imposed acid loads, as did Sp-cAMPS, a selective activator of cAMP-dependent protein kinase. The effect of forskolin on steady-state pH_i was blocked by pre-treatment with Rp-cAMPS whereas the effect of Sp-cAMPS was enhanced by pre-treatment with the protein phosphatase inhibitor, okadaic acid.

7. Noradrenaline also increased steady-state pH_i and rates of pH_i recovery from imposed acid loads in cultured postnatal rat hippocampal neurones. In this preparation, the effects of noradrenaline were occluded by 18-24 h pre-treatment with cholera toxin.

8. We conclude that noradrenaline increases the activity of the Na⁺-H⁺ exchanger in rat hippocampal neurones, probably by inducing an alkaline shift in the pH_i dependence of the antiport, thereby raising steady-state pH_i. The effects of noradrenaline are mediated by -adrenoceptors via a pathway which involves the -subunit of the stimulatory G-protein G_s (G_s), adenylate cyclase, cAMP and the subsequent activation of cAMP-dependent protein kinase which, in turn, may phosphorylate the exchange mechanism.

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