CHRONOTROPIC ACTIONS OF NA- COTRANSPORT INHIBITION IN THE ISOLATED RAT-HEART(,K+,CL)

The chronotropic actions of Na+,K+,Cl- cotransport were investigated b y studying the effects of the loop diuretics bumetanide and furosemide , specific inhibitors of the cotransporter, on an isolated rat sino-at rial node preparation. Application of bumetanide decreased the cycle l ength from 0.334 s (+/-0.087 S.D.) to 0.279 s (+/-0.083, n=16, P=6.5x1 0(-6)) in Hepes-buffered physiological salt solution (PSS). Similar de creases were recorded in bicarbonate-buffered PSS. Chloride channel bl ockers indicate that the tachycardia evoked by loop diuretics is not d ue their blocking of chloride channels. Thus, 4,4'-dinitrostilbene-2,2 '-disulphonic acid (DNDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) had a negative chronotropic action and dichloro-2,3-dihydr o-2-methyl-1-oxo-1H-inden-5-yl) oxy] acetic acid (IAA-94) produced no change in cycle length. Pharmacological manoeuvres indicate that the p ositive chronotropic action of loop diuretics is associated with catec holamine release. The positive chronotropic action of bumetanide was i nhibited by the P-adrenoceptor antagonists, propranolol and atenolol, but was unaffected by atropine.