Bradykinin B2‐receptor‐mediated modulation of membrane currents in guinea‐pig cardiomyocytes

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Abstract
In order to define the electrophysiological mechanism(s) responsible for bradykinin (BK)‐induced positive inotropic and chronotropic responses in isolated guinea‐pig atria, effects of BK on the membrane currents were examined in isolated atrial cells using patch clamp techniques. BK (0.1–1000 nM) increased the L‐type Ca2+ current (ICa), which was recorded from enzymatically‐dissociated atrial myocytes by the nystatin‐perforated patch method, in a concentration‐dependent fashion, and the calculated EC50 value for increasing ICa was 5.2 nM. In conventional ruptured patch experiments, BK inhibited the muscarinic acetylcholine receptor‐operated K+ current (IK.ACh) that was activated by the muscarinic agonist carbachol (1 μM) with an EC50 value of 0.57 nM. Both the increase in ICa and the decrease in IK.ACh were blocked by HOE140, a selective bradykinin B2 receptor antagonist. The BK‐induced inhibition of IK.ACh was significantly attenuated by staurosporine and calphostin C, protein kinase C inhibitors. In addition, the IK.ACh inhibition by BK was also attenuated by the tyrosine kinase inhibitor genistein or tyrphostin but not by daidzein, an inactive analogue of genistein. However, neither protein kinase C inhibitor nor tyrosine kinase inhibitor affected the BK‐induced increase in ICa. In the presence and absence of muscarinic stimulation, BK prolonged the action potential recorded from the atrial cells in the current clamp mode. We conclude that BK increases ICa and decreases IK.ACh in atrial cells, resulting in positive inotropic and chronotropic responses in atrial preparations. Protein kinase C activation, and possibly tyrosine kinase activation, may be involved in the B2‐receptor‐mediated IK.ACh inhibition. British Journal of Pharmacology (1998) 125, 283–292; doi:10.1038/sj.bjp.0702060