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In order to elucidate the mode of action of the Ca2+-antagonistic inhibitor nifedipine, its effect on Ca2+-mediated action potentials and transmembrane slow inward current in papillary muscles of guinea pigs and cats was studied. Nifedipine (0.5 mg/1 approximately 1.4 X 10(-6) M) depressed upstroke velocity and overshoot of the Ca2+-mediated action potential and reduced the transmembrane slow inward current by about 50%, but the kinetics of inactivation and recovery from inactivation were not affected. The decrease of upstroke velocity was accompanied by a proportional diminution of isometric contractile force. This indicates that nifedipine exerts its Ca2+-antagonistic effect on excitation-contraction coupling in mammalian ventricular myocardium by inhibition of the transmembrane Ca2+ inward current. The inhibitory action of nifedipine on contractile tension development could be neutralized by an augmentation of the extracellular Ca2+ concentration from 2 mM to 4 mM or by beta-receptor stimulation (isoproterenol) that promotes the transmembrane Ca2+ uptake during excitation. Simultaneously, in the Ca2+-rich medium or under the influence of isoproterenol the upstroke velocity of the Ca2+-mediated action potentials rose even above the initial values which were measured prior to the nifedipine administration.

The work of Cannon and Rosenblueth and their collaborators on the hypersensitivity of denervated structures has given rise to a general impression that after the denervation of a tissue there is always an increased response to a chemical stimulus. However, there are notable exceptions to this rule even among the limited class of sympathomimetic amines acting on structures innervated by postganglionic sympathetic fibres. Burn and Tainter (1931) observed that the iris of the cat's eye was insensitive to the dilator action of tyramine and much less sensitive to that of ephedrine when the superior cervical ganglion was removed one or two weeks previously. On the iris of the rabbit Drake, John, Renshaw, and Thienes (1939) found that p-hydroxyamphetamine, which caused dilatation of the normal iris, failed to do so after denervation. Burn (1932) found that the constrictor action of tyramine and of ephedrine in the vessels of the cat's foreleg was diminished or abolished by removal of the stellate ganglion 2-3 weeks previously. These results suggested that the effect of tyramine was depressed by denervation in all tissues, but Bacq (1937) stated that this conclusion did not hold good for the nictitating membrane in the cat under Dial anaesthesia. Bu1bring and Burn (1938) therefore investigated the action of tyramine in a series of cats and found that the most usual result was that the denervated membrane was more sensitive to low doses, but the normal membrane was more sensitive to high doses.At the same time they investigated hydroxytyramine and neosynephrine (Sympatol). Their general conclusion was that the more the structure of the compound departed from that of adrenaline the more often the denervated membrane was found to respond less than the normal membrane.While it was thus clear that substances such as tyramine and ephedrine did not stimulate denervated tissue in general as much as normal tissue, the change in the response of the nictitating membrane in the early period after the operation was still unknown. We have therefore studied this question in some detail with a wider range of substances, and have been able to show that sympathomimetic amines fall into three groups so far as their action on the denervated membrane is concerned. METHOD The right superior cervical ganglion was removed in an aseptic operation on each of 60 cats. After a varying interval each cat was anaesthetized with ether, and the spinal cord was divided by Dale's method (Burn, Finney, and Goodwin, 1950) without clamping the carotid arteries during the operation. The anaesthetic was discontinued and artificial respiration was given. The left cervical sympathetic chain was cut. The cat's head was then fixed rigidly and threads were passed through the nictitating membranes so that their contractions could be recorded by an isotonic lever which magnified the contractions 7.4 times. The blood pressure was recorded from one femoral artery and injections were made into the femoral vein of the opposite side. RESULTSThe sympathomimetic amines w...

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