Abstract
Recently, there has been growing interest in the idea that chlorthalidone should be preferred over thiazides when it comes to selecting a nonloop diuretic for treatment of hypertension.1–4 Depending on how these drugs are dosed, it is believed that the nonthiazide diuretic chlorthalidone might provide greater cardiovascular protection than thiazide diuretics because of its more potent and prolonged effects on blood pressure. However, given that the chemical structure of chlorthalidone is clearly distinct from the basic chemical structure of the thiazides (Figure), it is possible that the nonthiazide chlorthalidone might also differ from thiazides with respect to effects on determinants of cardiovascular disease other than just blood pressure. Yet, few if any studies have ever directly compared the effects of the nonthiazide chlorthalidone versus thiazides on potential cellular or molecular mechanisms of cardiovascular morbidity and mortality independent of blood pressure. Figure. The nonthiazide diuretic chlorthalidone and the thiazides, including hydrochlorothiazide, have sulfonamide groups (denoted within the unshaded ovals) that interact with the Zn(II) ion in the active site cleft of CA and with amino acid residues in the enzyme as well. A sulfonamide moiety is also present in the nonthiazide diuretics metolazone and indapamide (not shown), and these agents are also known to affect CA activity. However, the nonthiazide diuretics chlorthalidone, metolazone, and indapamide do not have the benzothiadiazine dioxide scaffold that is characteristic of the thiazides (denoted within the shaded oval). The structures of the nonthiazide diuretics beyond the sulfonamide group are clearly different from those of the thiazides and contribute to different effects of the various diuretics on CA isozyme activity profiles and perhaps to different effects on cardiovascular outcomes as well. In this issue of Hypertension , Woodman et al5 report novel in vitro experiments in which chlorthalidone was found to reduce epinephrine-induced platelet aggregation …
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