The bradykinin-potentiating peptides (BPPs) present in Bothrops jararaca venom are classically pyroglutamyl proline-rich oligopeptides. They were the first described naturally occurring angiotensin-converting enzyme (ACE) inhibitors. The chemical and pharmacological properties of these peptides were essential for the development of captopril as the first active site directed inhibitor of ACE, which is currently used to treat human hypertension. However, although BPPs present strong pharmacological activity in inhibiting ACE activity, recent results suggest that the physiological activity of the BPPs such as induction of hypotension can not be only explained by their effect on the ACE.
We have studied the effect of BPPs on the activity of a ligand-gated ion channel, the nicotinic acetylcholine receptor (AChR), expressed in neuronal-differentiated PC12. Whole-cell currents were recorded at a transmembrane voltage of -70mV e pH7.4, at room temperature using a ligand application technique with ms-time resolution. A cell in the whole-cell recording configuration was placed in front of a porthole of a U-tube device for rapid equilibration with ligand solutions. Carbamoylcholine (CCh), a stable analog of acetylcholine, was applied to induce ion flow through AchR channels and MK-801 was used as an allosteric antagonist of channel activity. Whole-cell experiments were initialized by a 2s application of the ligand in absence and presence of MK-801 or MK-801 and crescent concentrations of BPP. Although a direct effect of the BPPs on the functionality of the AChR could not be observed, BPPs prevent inhibition of CCh-induced whole-cell currents by allosteric antagonists, such as MK-801 and also theoretically cocaine. Therefore, BPPs are promising candidates for the treatment of cardiovascular and cerebral effects of cocaine and other allosteric inhibitors that act in a similar manner on the nAChR.