Ranolazine has protective effects against ischaemia as exemplified by a reduction of the associated enzyme release and an attenuation of the fall of ATP and other metabolic changes. It has been suggested that ranolazine may affect GTP-binding proteins involved in the beta-adrenergic protein kinase A (PKA) cascade by interacting with Gs. Calcium channel currents are stimulated by this cascade but the effect of ranolazine upon them is not known. The whole cell patch clamp technique was used to examine the action of ranolazine on basal calcium channel currents and those stimulated by activation at various steps in the PKA cascade. 2. Ranolazine had only a small effect on the basal calcium current (100 microM caused 11.3% inhibition), but markedly attenuated the beta-adrenoceptor stimulated current (20 nM isoprenaline increased current by 2.3 fold, 10 microM ranolazine inhibited this increase by 47.6%). When the PKA cascade was activated downstream to the receptor by either G-protein activation with Gpp[NH]p or adenylate cyclase activation with forskolin, the calcium current showed a sensitivity to ranolazine similar to the basal current. Activation of the PKA cascade via H2 receptors gave rise to currents which showed an intermediate sensitivity to ranolazine. Ranolazine inhibition of ICa persisted during muscarinic attenuation of beta-adrenoceptor activation. 3. The results indicate that ranolazine, at concentrations which have significantly beneficial effects during ischaemic episodes, only greatly affects whole cell calcium current when facilitated by beta-adrenoceptor or histamine receptor activation. Ranolazine would appear to act at the receptor level, rather than at the GTP-binding or Gs/adenylate cyclase level. An additional smaller effect is also present, which may be mediated by a direct effect on the channel, or components closely associated with it.
