Gray, Rosaire; (2002) Intracellular sodium and contractile dysfunction in left ventricular hypertrophy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Left ventricular hypertrophy (LVH) is associated with the development of heart failure and arrhythmias. The mechanisms underlying this decompensation are unclear. The hypothesis that LVH is associated with a raised intracellular sodium, [Na+]i which by upsetting the regulation of other intracellular ions impairs the positive staircase was tested. LVH was induced in guinea-pigs by ascending aortic constriction and the extent of hypertrophy quantified by measuring heart-to-body weight ratio. The control group consisted of sham-operated and unoperated animals. The tension generated in response to increasing stimulation frequency and [Na+]i were measured. The force-frequency response was depressed and [Na+]i increased from 7.4 ± 1.4 to 12.1 ± 1.4 mM with LVH. There was a close relationship between the decline of the force-frequency response and the increase of [Na+]i which was also observed when the [Na+]i was increased with strophanthidin in normal myocardium. Possible mechanisms to account for the raised [Na+]i are explored. The recovery of a raised [Na+]i after an acute acidosis was slowed in hypertrophied myocardium and stabilised at a higher level, suggesting that the membrane mechanisms that regulate [Na+]i are reset. Intracellular pH, pHi, and [Ca2+], [Ca2+]i, were measured in isolated myocytes using epifluoresence microscopy. pHi decreased progressively with increasing severity of hypertrophy and the sarcoplasmic buffering capacity increased with increasing acidosis. The recovery of pHi from an intracellular acidosis was slowed in myocytes from aortic constricted (AC) hearts but the total H+ efflux rate was not different indicating no effect on Na+-H+-exchange activity. Resting [Ca2+]i was not significantly different in myocytes from AC hearts but the caffeine induced release of [Ca2+] from the sarcoplasmic reticulum (SR) was reduced. The time course of the decay phase of the caffeine was prolonged in myocytes from AC hearts indicating reduced activity of the Na+-Ca2+-exchanger. Quantitative immunoblotting of the Na+-K+-ATPase pump isoforms was performed in a small number of samples. No significant differences were observed between the two groups.

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