Ca2+ channel antagonists enhance tension in skinned skeletal and heart muscle fibres

Abstract

Striated muscle fibres, both skeletal and cardiac of different species including human, skinned by freeze-drying, were activated in solutions strongly buffered for Ca2+. The single fibres were immersed in solutions with different [Ca2+]. Sarcomere length was set and controlled by laser diffraction. Fibre type was determined by Sr2+ activation. The relation between the negative logarithm of the Ca2+ concentration and the normalized tension, the Ca2+ sensitivity curve, was investigated. The effect on the contractile machinery of three different Ca2+ channel antagonists (verapamil, diltiazem and nifedipine) in a therapeutic concentration (10(-6) M) was investigated. The possible effects on the Ca2+ sensitivity curve were quantified by: (1) the change in maximal tension developed at pCa2+ = 4.4; (2) the change in pCa2+ value at which 50% of the tension induced at pCa2+ = 4.4; (3) the steepness of the Ca2+ sensitivity curve in this point. The three drugs tested, at a therapeutic concentration of 1 microM, all enhanced maximal induced tension by respectively 25, 20 and 7%. The sarcomere length dependency of the effect proved to be dependent upon the drug, but also slightly on fibre type (skeletal or cardiac), or on species. It is concluded that the drug influences the cooperativity of the two different types of binding sites on troponin-C (low- and high-affinity sites). Tension enhancement was due to increased stiffness of the actin-myosin interaction site.