Fundamental & clinical pharmacology vol:15 issue:1 pages:9-17
In long term treatment, thiazide diuretics such as hydrochlorothiazide (HCTZ) lower blood pressure by decreasing peripheral resistance rather than by their diuretic effect. This action has been attributed to the opening of Ca2+-activated K+ channels in vascular smooth muscle cells. However, little is known about their cardiac cellular actions, Were we investigated the possible actions of HCTZ on action potential and contraction of rat ventricular muscle strips and on the ionic currents of isolated rat ventricular cardiomyocytes. HCTZ depressed ventricular contraction with an IC30 of 1.85 muM (60% decrease at 100 muM). Action potential duration at -60 mV and maximal rate of depolarization were, however, only slightly decreased by 12% and 22%, respectively, at 100 muM. At the single cell level, HCTZ (100 muM) depressed the fast Nat current (I,,) and the L-type Ca2+ current (I-CaL) by 30% and 20%, respectively. The effects on I-CaL were not voltage-or frequency-dependent. In cells intracellularly perfused with 50 muM cyclic adenosine, monophosphate HCTZ reduced I-CaL by 33%. The transient (It,), the delayed rectifier and the inward rectifier potassium currents were decreased by 20% at 100 muM HCTZ. The effects on It, were voltage-dependent, in conclusion, HCTZ at high concentrations possesses a negative inotropic action that could be in part due to its blocking action on I-Na and I-caL The actions of WCTZ on multiple cardiac ionic currents could explain its weak effect on action potential duration.