Effects of azelastine on contractility, action potentials and L-type Ca(2+) current in guinea pig cardiac preparations.
Azelastine is used for symptomatic relief of allergic rhinitis and asthma bronchiale. In vitro studies in smooth muscle cells from guinea pig trachea and ileum demonstrate that the drug blocks L-type Ca(2+) current (I(Ca, L)). However, for safety reasons, it is important to know whether azelastine also affects cardiac I(Ca, L) in therapeutically relevant concentrations. We have therefore studied the effects of azelastine on I(Ca, L) in guinea pig ventricular myocytes using standard whole-cell patch-clamp technique. Force of contraction and action potentials from isolated papillary muscles of the same species were also investigated at physiological temperature (36 degrees C). Azelastine (30 microM) significantly reduced force of contraction, shortened action potential duration, and depressed maximum upstroke velocity. I(Ca, L) was elicited by 200-ms-long clamp steps from -100 to 0 mV (one pulse every 3 s). Azelastine blocked I(Ca, L) reversibly and concentration-dependently with an IC(50) of 20.2+/-1.3 microM and a Hill coefficient of 1.1. At 10 microM, azelastine shifted steady-state inactivation by 5 mV (n=7) to more negative potentials. The time course of I(Ca, L) inactivation could be described by a double exponential function. Azelastine (10 microM) significantly shortened the slow inactivation time constant (tau(s)) from 54.2+/-2.8 ms under control conditions to 38.7+/-2.9 ms (n=16) in the presence of drug. Azelastine also reduced low-voltage-activated Ca(2+) currents with a similar IC(50) value (24 microM, at -35 mV). Since the therapeutic plasma concentrations are in the order of 10-100 nM, we conclude that azelastine does indeed affect also cardiac I(Ca, L), but the concentrations required are at least two orders of magnitude larger than those obtained during drug therapy.
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Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Fetscherstrasse 74, D-01307, Dresden, Germany.
Blaschke
M
M
Heubach
J F
JF
Wettwer
E
E
Ravens
U
U
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004553:Electric Conductivity; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010793:Phthalazines / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D010793:Phthalazines; D002118:Calcium; C020976:azelastine