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 microM (60% decrease at 100 microM). Action potential duration at -60 mV and maximal rate of depolarization were, however, only slightly decreased by 12% and 22%, respectively, at 100 microM. At the single cell level, HCTZ (100 microM) depressed the fast Na+ current (INa) and the L-type Ca2+ current (ICaL) by 30% and 20%, respectively. The effects on ICaL were not voltage-or frequency-dependent. In cells intracellularly perfused with 50 microM cyclic adenosine, monophosphate HCTZ reduced ICaL by 33%. The transient (Ito), the delayed rectifier and the inward rectifier potassium currents were decreased by 20% at 100 microM HCTZ. The effects on Ito 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 INa and ICaL. The actions of HCTZ on multiple cardiac ionic currents could explain its weak effect on action potential duration.

The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus

“…Second, decreases in daily insulin doses have been correlated with improved arterial compliance in T2D, and a similar interaction may have occurred in our T1D cohort since total daily insulin doses decreased significantly by the end of treatment [22,50]. Third, other diuretic agents such as thiazides lower arterial stiffness and these effects are likely in part due to direct effects on vascular smooth muscle relaxation after induction of a negative sodium balance [51,52]. Similar diuretic effects with SGLT2 inhibition may have contributed to the decline in arterial stiffness in our cohort.…”

Chlorthalidone inhibits the KvLQT1 potassium current in guinea‐pig ventricular myocytes and oocytes from Xenopus laevis

“…The measured effect of chlorthalidone after a series of pulses up to +70 mV shows that the current did not change significantly as the voltage was increased (Figure 6b). This effect is not shared by other thiazide diuretics like indapamide ( Pickkers et al , 1998 ; Pickkers et al , 1998 ) or hydrochlorothiazide ( Galán et al , 2001 ). These results imply that chlorthalidone may bind with several proteins of the channels, and it may explain the same average blocking effect on both components of the current.…”

Assessment of the Optimal Generation Period and Size of Human iPSC-Derived Cardiac Organoids for Cardiotoxicity Drug Testing

“…We tested the cardiotoxicity drug response of 35-day cardiac-differentiated 1 mm hiPSC-COs, with reference to the results of previous physiological tests. The drugs examined included ve antineoplastic agents (Dasatinib [31], Doxorubicin [32], Sunitinib [33,34], Sorafenib [35][36][37], Imatinib [35,38]) and three other therapeutic agents (Hydrochlorothiazide (HCTZ) [39], Dofetilide [40,41], Nifedipine [40]) with a capability of inducing heart failure as a side effect. The drug concentrations used were approximately double those reported by previous researchers studying cardiotoxicity under 2D culture conditions.…”