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The effects of cocaine on intracellular Ca 2+ handling and myofilament Ca 2+ responsiveness of ferret ventricular myocardium
Author(s) -
Perreault Cynthia L.,
Hague Nancy L.,
Ransil Bernard J.,
Morgan James P.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb14140.x
Subject(s) - medicine , endocrinology , chemistry , aequorin , lusitropy , calcium , inotrope , catecholamine , propranolol , diastole , blood pressure
1 When ferret right ventricular papillary muscles were stimulated with threshold punctate pulses (0.33 Hz; 30°C), cocaine, 10 −5 m , increased peak tension development from 815 ± 120 to 1125 ± 180 mg ( P > 0.05) and increased the rate of relaxation from peak tension (time to 80% decline from peak tension decreased from 155 ± 11 to 144 ± 11 ms; P > 0.05). These changes in the twitch were associated with comparable changes in the amplitude and time course of the calcium transient measured with aequorin (amplitude increased from 62 ± 4 to 90 ± 7% ( P > 0.05) of maximal values; time to 80% decline from peak amplitude decreased from 84 ± 8 to 64 ± 3 ms; P > 0.05). These effects were markedly attenuated in the presence of the β‐adrenoceptor‐blocking agent, propranolol, 6 × 10 −7 m , or by maximization of catecholamine release from the adrenergic nerve endings with field pulses of supratheshold strength, indicating that catecholamine release from the adrenergic nerve endings is responsible for the positive inotropic and lusitropic responses to low and moderate doses of cocaine (i.e., ≤ 10 −5 m ). 2 High doses of cocaine (i.e., > 10 −5 m ) produced negative inotropic and lusitropic effects that were associated with a decreased amplitude and prolonged duration of the calcium transient. 3 In aequorin‐loaded intact fibres, cocaine 10 −5 m did not affect the force‐calcium relationship unless catecholamines were present. Cocaine, 10 −5 m , significantly shifted the force‐calcium relationship of saponin‐skinned muscles (pCa 50 = 6.14 ± 0.05 versus 5.92 ± 0.07; P > 0.05), indicating reduced responsiveness of the myofilaments to calcium. F max (maximal Ca 2+ ‐activated force) was reduced to 58% of control in the presence of 10 −5 m cocaine, while the slope of the calcium‐force curve remained unchanged. These data indicate that cocaine may also decrease myofilament calcium sensitivity and maximal calcium‐activated force, via mechanisms independent of catecholamines, when cellular diffusion barriers are eliminated.