Bradykinin induced a positive chronotropic effect via stimulation of T- and L-type calcium currents in heart cells.
Using Fluo-3 calcium dye confocal microscopy and spontaneously contracting embryonic chick heart cells, bradykinin (10(-10) M) was found to induce positive chronotropic effects by increasing the frequency of the transient increase of cytosolic and nuclear free Ca2+. Pretreatment of the cells with either B1 or B2 receptor antagonists (R126 and R817, respectively) completely prevented bradykinin (BK) induced positive chronotropic effects on spontaneously contracting single heart cells. Using the whole-cell voltage clamp technique and ionic substitution to separate the different ionic current species, our results showed that BK (10(-6) M) had no effect on fast Na+ inward current and delayed outward potassium current. However, both L- and T-type Ca2+ currents were found to be increased by BK in a dose-dependent manner (10(-10)-10(-7) M). The effects of BK on T- and L-type Ca2+ currents were partially blocked by the B1 receptor antagonist [Leu8]des-Arg9-BK (R592) (10(-7) M) and completely reversed by the B2 receptor antagonist D-Arg[Hyp3,D-Phe7,Leu8]BK (R-588) (10(-7) M) or pretreatment with pertussis toxin (PTX). These results demonstrate that BK induced a positive chronotropic effect via stimulation of T- and L-type Ca2+ currents in heart cells mainly via stimulation of B2 receptor coupled to PTX-sensitive G-proteins. The increase of both types of Ca2+ current by BK in heart cells may explain the positive inotropic and chronotropic effects of this hormone.
Department of Anatomy and Cell Biology, 3001 12th Avenue North, University of Sherbrooke, Sherbrooke, QC J1H 5N4 Canada.
Nesrine
N
El-Bizri
Ghassan
G
Bkaily
Shimin
S
Wang
Danielle
D
Jacques
Domenico
D
Regoli
Pedro
P
D'Orléans-Juste
Rami
R
Sukarieh
D000814:Aniline Compounds; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology / Q000502:physiology*; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D005456:Fluorescent Dyes; D066298:In Vitro Techniques; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D043783:Receptor, Bradykinin B1 / Q000502:physiology; D043782:Receptor, Bradykinin B2 / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D013997:Time Factors; D014966:Xanthenes
D000814:Aniline Compounds; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D005456:Fluorescent Dyes; D015221:Potassium Channels; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D015222:Sodium Channels; D014966:Xanthenes; C059715:Fluo-3; D009543:Nifedipine; D001920:Bradykinin; D002118:Calcium