Properties of normal and non-inactivating single cardiac Na+channels

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Abstract
Elementary currents through single cardiac Na+channels were studied at 19°C in inside-out patches from cultured neonatal rat heart cardiocytes, with the use of the patch clamp technique. The bimodal amplitude histogram suggests two populations of Na+channels characterized by a normal and a reduced unitary current size. The latter events were extremely rare and could be detected in some patches only. The conductance of the dominating population with the larger current size was close to 13 pS. As analysed between –60 and –30 mV, the open-time distribution followed a single exponential regardless of whether or not apparent substate current events were included in the histogram. The open state is left with a voltage-independent time constant close to 1.4 ms. Channel openings occurring late during the 115 ms duration step depolarization of the membrane have the same lifetime as most openings happening in the first 2 ms. Repetitive channel activity occurred in 0.083% of the records, i. e. a train of sequential, burst-like openings of a single Na+channel occurred during the whole membrane depolarization, which exhibited a significantly prolonged and potential-dependent mean open time. Chemical modification induced by external application of glutaraldehyde (10–3mol l–1) or racemic DPI 201-106 (3 x 10–6mol l–1) caused essentially the same repetitive Na+channel activity. As studied syste­matically with DPI, a piperazinyl-indole derivative, the prolonged and highly voltage-sensitive open state increases exponentially on shifting the membrane potential to more positive values. Three voltage-sensitive closed states were detected: one very short-lived, one long and one very long. The cycling frequency between the conductive and the non-conductive state is also a function of membrane potential. DPI-modified cardiac Na+channels can attain a substate that might result from a loss of Na+selectivity. It is concluded that spontaneously occurring and chemically induced modified Na+channel activity relies on the same mechanism, namely failure or elimination of inactivation. Spontaneous failure of inactivation and a loss of Na+selectivity may characterize properties of channel subpopulations.