Pharmacology Journal

Thiazide diuretics have long since been used for the treatment of severe hypertension. They are effective in inhibiting sodium transport at the distal tubule in the mammalian nephron and hence decrease water retention. One of the most widely used thiazide diuretics is hydrochlorothiazide (HCTZ; 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadazine-7-sulfonamide 1,1-dioxide). With a 65–75% oral absorption and an elimination half-time of about 2.5 h, HCTZ is still one of the most effective diuretics used in clinics to lower blood pressure and is even used as a monotherapy. It is known, however, that in the long term, thiazide diuretics appear to reduce blood pressure by reducing peripheral resistance rather than by their diuretic effects, suggesting a direct vascular dilating action. This action was also demonstrated in rabbits and dogs.

Concentration-dependent relaxant effects of HCTZ have been demonstrated in animal and human vascular smooth muscles. Mironneau et al. reported that HCTZ, as well as indapamide (a thiazide-like diuretic) and chlorthalidone, depressed isometric contractions, calcium contractures and membrane potentials in isolated longitudinal strips from rat portal veins and suggested that this action was related to a decrease in the transmembrane Ca²⁺ influx. It has also been shown that HCTZ had direct relaxing actions in human subcutaneous resistance arteries and that this action could be mediated by the Ca²⁺-activated K⁺channel K_(Ca2+). This vasodilator activity was also related to a decrease in intracellular Ca²⁺ . In vivo, HCTZ at supra therapeutic doses (3.5 ± 0.3 μg/mL) exerted no vasodilator action in the human forearm. However, at higher doses (11.0 ± 1.6 μg/mL) HCTZ demonstrated a small vasodilator effect in the human forearm that was inhibited by tetraethylammonium, suggesting the involvement of vascular K_(Ca2+) channels in these effects. It is interesting to note that Abrahams et al. showed that in rat aortic and pulmonary artery rings and rat mesenteric portal vein, HCTZ (as well as indapamide, chlorthalidone and furosemide) had no vasorelaxant activity when preparations were perfused with Krebs solution. However, when plasma was added to the Krebs solution HCTZ exhibited a weak vasorelaxant activity (EC15=3.10⁻⁵ M). It was later shown by these authors that albumin was the main cofactor required by the diuretics for direct relaxant action in vitro. At present, however, there is no concluding evidence to explain the decrease in blood pressure during the long-term treatment with HCTZ.

A few studies have been done to test whether vasoactivity of HCTZ and other thiazide diuretics is related to direct actions on voltage-gated ionic channels. Using a double sucrose gap voltage-clamp technique, Mironneau and Gargouil  showed that indapamide, inhibited the Ca²⁺ current (I_Ca) in vascular smooth muscle. This was also shown in rat myometrium and portal vein preparations. On the other hand, it is known that chlorothiazide causes a sustained raise in intracellular Ca²⁺ in distal convoluted and connecting tubules that is due to a dihydropiridine-sensitive calcium influx through a Ca²⁺ channel composed of α_1C and β₃ subunits.

Also, little is known about the cardiac cellular actions of thiazide diuretics. In guinea pig ventricular myocytes, the diuretic indapamide was found to block the slow delayed rectifier K⁺ current I_Ks. This action was concentration- and voltage-dependent. In contrast, chlortalidone had no effect. In this study, the rapid delayed rectifier current I_Kr, was not affected by these diuretic agents. Lu et al. analysed the effects of indapamide on several ionic currents in canine atrial myocytes and reported no effects on the L-type Ca²⁺ current (I_CaL). However, it decreased in a concentration- and voltage-dependent manner the Na⁺ current (I_Na), the transient outward current (I_to) and I_Ks. In addition, indapamide also blocked I_Kr in a voltage-independent manner.

Some of these effects tend to prolong repolarizationand this action could be of clinical relevance during long-term diuretic therapy, particularly when hypokalemia, coronary disease and ventricular hypertrophy are associated. We were thus interested in further characterising the cardiac cellular electrophysiological actions of HCTZ and in investigating, with the patch-clamp technique, the interactions of this thiazide with voltage-gated channels of isolated rat ventricular cardiomyocytes.

Filed under: Cardiavascular