Changes in endothelium-derived hyperpolarizing factor in hypertension and ageing: Response to chronic treatment with renin-angiotensin system inhibitors

1. Endothelial function is impaired in hypertension and ageing and this may be associated with an increase in cardiovascular disease. Several clinical studies have shown that blocking the renin-angiotensin system (RAS) improves endothelial function not only in hypertensive patients, but also in normotensive patients with cardiovascular disease. 2. The aim of the present study was to test whether endothelium-derived hyperpolarizing factor (EDHF)-mediated smooth muscle hyperpolarization and relaxation are altered in hypertension and ageing and, if so, whether chronic treatment with RAS inhibitors (the angiotensin-converting enzyme inhibitor enalapril and the angiotensin AT ₁ receptor antagonist candesartan) would correct such changes. 3. Endothelium-derived hyperpolarizirag factor-mediated responses were examined in mesenteric arteries from 12-month-old spontaneously hypertensive rats (SHR) and 3-, 6-, 12- and 24-month-old normotensive Wistar-Kyoto (WKY) rats. Furthermore, both strains were treated for 3 months with either RAS blockers or a conventional therapy with hydralazine and hydrochlorothiazide from 9 to 12 months of age. 4. In arteries of 12-month-old SHR, EDHF-mediated responses were impaired compared with age-matched WKY rats. In SHR, all antihypertensive treatments improved the impairment of EDHF-mediated responses; however, RAS inhibitors tended to improve these responses to a greater extent compared with conventional therapy with hydralazine and hydrochlorothiazide. 5. In arteries of WKY rats, EDHF-mediated responses were impaired at the age of 12 and 24 months compared with 3- and 6-month-old rats, with the response tending to be impaired to a greater extent in 24-month-old rats. 6. Three months of treatment of WKY rats, until 12 months of age, with RAS inhibitors, but not with conventional therapy with hydralazine and hydrochlorothiazide, improved the age-related impairment of EDHF-mediated responses, despite a similar reduction in blood pressure by both treatments. 7. These findings suggest that: (i) EDHF-mediated hyperpolarization and relaxation decline with hypertension and ageing in rat mesenteric arteries; (ii) antihypertensive treatment restores the impaired EDHF-mediated responses in hypertension; (iii) RAS inhibitors may be more efficacious in improving endothelial dysfunction associated with hypertension; and (iv) chronic treatment with RAS inhibitors improves the age-related impairment of EDHF-mediated responses, presumably through the blockade of RAS but not blood pressure lowering alone.