CALCIUM-SENSITIVITY OF SMOOTH MUSCLE CONTRACTION IN THE ISOLATED PERFUSED RAT TAIL ARTERY

Desensitization and the effects of Bay K 8644 and nifedipine on the calcium-sensitivity of smooth muscle contraction were studied in the isolated perfused rat tail artery, employing the activators noradrenaline (NA) (3μM) sand potassium chloride (KC1) (100mM). Experiments were conduced in Ca²⁺ - buffered saline. Activities were added when {Ca²⁺} free was low (1μM) and then {Ca²⁺ }free was increased stepwise to give a Ca²⁺ concentration\response curve (CRC) There was a progressive rightward shift of the CRCs with time when a series of curves was constructed. The higher the calcium concentration to which the tissue was exposed during activation, the greater was desensitization. The progressive loss in sensitivity could be attenuated by restricting the range of free calcium used for CRCs to between 1μM and 300μM Ca²⁺. Results were similar whether activation was by NA or high KC1. When the tissues were pre-exposed to NA (3μM) ("Priming") before constructing CRCs, desensitization was produced more quickly and thus sensitivity became more "stable". However, the {Ca²⁺} during priming and the maximum (Ca²⁺ ) in a CRC determined the stable level, high {Ca²⁺} reducing sensitivity. Priming and maximum at 300μM ca²⁺ was optimal for avoiding progressive desensitization. Bay K 8644 (0.1μM) decreased the sensitivity to Ca²⁺ but did not alter the rate of desensitization (activated by either NA or KC1). Desensitization complicated demonstration of potentiation by Bay K 8644 in the same tissue. Nifedipine (0.1μM) decreased the sensitivity of Ca²⁺ at the first CRC but thereafter CRC's were not significantly different from their controls. Only a small degree of inhibition could be seen between consecutive curves when nifedipine was given after drug-free control responses. Thus the rat tail artery exhibits higher sensitivity to Ca²⁺ on initial contact with activators. The results suggests that desensitization at some stage in excitation-contraction coupling, possibly by Ca²⁺ overload, occurs when high extracellular {Ca²⁺} (2.5 or 5mM) is present during activation by NA. This can be prevented by avoiding high. {Ca²⁺}, thus allowing prolonged reproducibility of high sensitivity to Ca²⁺ which, is lost.

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Keywords
Ca2+ sensitivity, desensitization, vascular smooth muscle, noradrenaline, nifedipine, Bay K 8644, rat tail artery