Cardiac cellular actions of hydrochlorothiazide.
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.
Galán
L
L
Laboratorio de Electrofisiología, Instituto de Cardiología y Cirugía Cardiovascular, La Habana, Cuba Laboratorio de Fisiología Cardiovascular, Instituto de Fisiología, Universidad Autónoma de Puebla, Puebla, Mexico.
Ferrer
T
T
Artiles
A
A
Talavera
K
K
Salinas
E
E
Orta
G
G
García-Barreto
D
D
Alvarez
J L
JL
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004232:Diuretics; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D012964:Sodium / Q000378:metabolism; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*; D013268:Stimulation, Chemical
D004232:Diuretics; D015221:Potassium Channels; D049993:Sodium Chloride Symporter Inhibitors; D006852:Hydrochlorothiazide; D012964:Sodium; D002118:Calcium