Differential effect of low dose thiazides on the Renin Angiotensin system in genetically hypertensive and normotensive rats.

Fifty years since their introduction, thiazide diuretics are established as first-line therapy in the treatment of hypertension. Because the dosing profile for thiazide agents lessened, the mechanism responsible for the blood pressure lowering effect may lie outside their diuretic properties. We evaluated the mechanism driving blood pressure reductions in spontaneously hypertensive rats (SHR) and normotensive WKY by examining the effects of low-dose hydrochlorothiazide (HCTZ) administration on renin-angiotensin system (RAS) components. The 7-day, 1.5 mg/kg/day HCTZ did not change systolic pressure in WKY, but decreased SBP by 41 +/- 2 mm Hg (p < 0.0001) in SHR. This reduction was independent of increases in water intake, urine output, or alterations in electrolyte excretion. HCTZ significantly increased the plasma concentrations of angiotensin I (Ang I) and angiotensin II (Ang II) in both WKY and SHR while reducing angiotensin converting enzyme (ACE) activity and the Ang II/Ang I ratio (17.1 +/- 2.9 before versus 10.3 +/- 2.9 after, p < 0.05) only in SHR. HCTZ increased cardiac ACE2 mRNA and activity, and neprilysin mRNA in WKY, but not SHR. Conversely in SHR, ACE2 activity was decreased and aside from a 75% increase in AT(1) mRNA in the HCTZ-treated SHR, the expression of the other variables remained unaltered. Measures of cardiac mas receptor mRNA showed no changes in response to treatment in both strains, although cardiac mas mRNA was significantly lower in untreated SHR. These data, which document for the first time the effect of low-dose thiazide on the activity of the ACE2/Ang-(1-7)/mas-receptor axis, suggest that the opposing arm of the system does not substantially contribute to the antihypertensive effect of low-dose thiazides in SHR.