Cardiac cellular actions of hydrochlorothiazide

ABSTRACT

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. Here 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 μM (60% decrease at 100 μM). Action potential duration at −60 mV and maximal rate of depolarization were, however, only slightly decreased by 12% and 22%, respectively, at 100 μM. At the single cell level, HCTZ (100 μM) depressed the fast Na⁺ current (I_Na) 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 μM cyclic adenosine, monophosphate HCTZ reduced I_CaL by 33%. The transient (I_to), the delayed rectifier and the inward rectifier potassium currents were decreased by 20% at 100 μM HCTZ. The effects on I_to 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 HCTZ on multiple cardiac ionic currents could explain its weak effect on action potential duration.