1. 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.