Chlorthalidone Decreases Platelet Aggregation and Vascular Permeability and Promotes Angiogenesis

Abstract

Abstract-Variations in diuretic-mediated inhibition of carbonic anhydrase-dependent chloride transport in platelets and vascular smooth muscle could account for the contrasting efficacy of the thiazide and thiazide-like diuretics in reducing cardiovascular morbidity in patients with hypertension. We assessed platelet carbonic anhydrase activity and catecholamine-induced platelet aggregation in the presence of a thiazide and a "thiazide-like" inhibitor of the sodium-chloride cotransporter. Individual variation in platelet carbonic anhydrase activity correlated with contrasting sensitivity to epinephrine-mediated platelet aggregation. Both chlorthalidone, which potently inhibits platelet carbonic anhydrase, and bendroflumethiazide, which has much less effect on this enzyme, increased the amount of epinephrine needed to induce platelet aggregation when compared with the absence of a diuretic. However, chlorthalidone was significantly more effective than bendroflumethiazide in reducing epinephrine-mediated platelet aggregation. Chlorthalidone also induced marked changes in the number of gene transcripts for two proteins that mediate angiogenesis and vascular permeability, vascular endothelial growth factor C and transforming growth factor-␤3; chlorthalidone and bendroflumethiazide had contrasting effects on the expression of vascular endothelial growth factor C. Chlorthalidone and bendroflumethiazide reduced vascular permeability to albumin, but only chlorthalidone increased angiogenesis. Thiazides and thiazide-like diuretics can comparably reduce blood pressure, but the drugs in this class are not all alike. It can be suggested from our findings that thiazide and thiazide-like diuretics vary in their pleiotropic effects on platelets and in the vasculature, and these differences could explain the contrasting ability of these drugs to reduce cardiovascular morbidity despite comparable reduction in blood pressure. (Hypertension. 2010;56:463-470.)

Effects of Thiazide-Type and Thiazide-Like Diuretics on Cardiovascular Events and Mortality

“…In addition, pleiotropic effects of TL diuretics may contribute to the greater risk reductions of CVE and heart failure. 8,9 Because of the longer half-life of TL diuretics, an increase in adverse events may be anticipated, especially with regard to the occurrence of adverse events related to disturbances in sodium and potassium homeostasis. In this meta-analysis, we observed a similar incidence of adverse events for TT and TL diuretics with comparable reductions in office BP.…”

“…7 In addition, experimental evidence suggests that TL diuretics exert additional effects on the vascular system by reducing platelet aggregation and vascular permeability. 8,9 On the basis of the above, it is conceivable that TL diuretics may differentially affect cardiovascular disease compared with TT diuretics. Because prospective trials comparing TT and TL diuretics are lacking, the interchangeability of these 2 classes about cardiovascular risk reduction is subject of debate.…”

Chlorthalidone Compared With Hydrochlorothiazide in Reducing Cardiovascular Events

“…CTDN decreases vascular permeability and reduces epinephrine-mediated platelet aggregation by inhibiting carbonic anhydrase. 44,45 Another possibility pertains to HCTZ's short duration of action, 3,9,[46][47][48][49] which is 16 to 24 hours after long-term dosing, Յ48 hours for amlodipine, 50 and 48 to 72 hours for CTDN. 9 Nighttime BP more closely predicts cardiovascular risk than 24-hour ambulatory BP, which is more predictive of risk than office BP.…”

Potency of Office Blood Pressure From Hydrochlorothiazide and Chlorthalidone Fails to Explain Cardiovascular Events

“…2 This suggests that the inferiority of HCTZ cannot be explained "to a large extent" by its lesser potency on office systolic blood pressure reduction. Other possible explanations for the inferiority of HCTZ include the pleomorphic effects of alternative medications, 3,4 differences in the metabolic profiles of the 2 drugs, 5 or the short duration of action of HCTZ.…”