Spironolactone Improves Angiotensin-Induced Vascular Changes and Oxidative Stress

Abstract

Abstract-Angiotensin II plays an important role in vascular remodeling. We investigated the role of aldosterone, which is stimulated by angiotensin II, as a mediator of angiotensin II-induced vascular structural and functional alterations. Sprague-Dawley rats (nϭ8 to 12/group) received angiotensin II (120 ng/kg per minute, subcutaneously) for 14 days Ϯ spironolactone or hydralazine (25 mg/kg per day). An additional group received aldosterone (750 ng/h, subcutaneously) Ϯ spironolactone. Systolic blood pressure was increased by angiotensin II (PϽ0.001) and reduced by spironolactone and hydralazine (PϽ0.001). Aldosterone-induced increase of blood pressure was reduced by spironolactone (PϽ0.05).In mesenteric small arteries studied on a pressurized myograph, media/lumen ratio was increased (PϽ0.001) and acetylcholine-mediated relaxation was impaired in angiotensin II-infused rats (PϽ0.001); both were partially improved by spironolactone (PϽ0.05) but not by hydralazine. Aldosterone-induced increase of media/lumen ratio (PϽ0.001) and impaired response to acetylcholine (PϽ0.001) were normalized by spironolactone. Response to sodium nitroprusside was similar in all groups. Aortic NADPH oxidase activity was increased (PϽ0.01) by angiotensin II and reduced by spironolactone and hydralazine. Aldosterone also increased (PϽ0.05) activation of NADPH oxidase, an effect abolished by spironolactone. Plasma thiobarbituric acid-reactive substances (a marker of oxidative stress), higher in angiotensin II and aldosterone rats (PϽ0.001), were normalized by spironolactone. In conclusion, spironolactone, which inhibited aldosterone actions, partially corrected structural and functional angiotensin II-induced abnormalities. These effects were associated with reduced vascular NADPH oxidase activity and decreased plasma markers of oxidative stress. Our findings suggest that aldosterone may mediate some of angiotensin II-induced vascular effects in hypertension, in part via increased oxidative stress.

Aldosterone: good guy or bad guy in cerebrovascular disease?

“…Benetos et al [35] found that chronic spironolactone treatment of spontaneously hypertensive rats (SHR) prevented aortic fibrosis by preventing collagen accumulation. In angiotensin II hypertensive rats, MR blockade inhibits the anticipated increase in mesenteric artery media to lumen ratio [36], again supporting the theory that some effects of angiotensin II on the vasculature are mediated by aldosterone. In SHRSP, eplerenone reduces the salt-dependent changes in vascular structure.…”

Effects of Aldosterone on the Vasculature

“…MR blockade with spironolactone improved the impaired acetylcholine-induced relaxation in Ang II-infused rats, suggesting that aldosterone induces actions attributed to direct effects of Ang II. 10 Aldosterone infusion into rats impaired endothelium-dependent relaxation in association with increased oxidative stress in the vascular wall. 11 This effect was reversed by the MR blocker spironolactone, as well as by endothelin receptor antagonism.…”

“…Impaired vascular function may be the first manifestation of aldosterone-induced cardiovascular damage. Aldosterone also increased NAD(P)H oxidase activity and reactive oxygen species (ROS) generation, and MR blockade improved endothelial function in Ang II-infused rats 10 and in a high-lipid diet rabbit model. 25 Recent data suggest that aldosterone may elicit both vasoconstrictor and vasodilatory effects in humans.…”

Angiotensin II and aldosterone-induced neuronal damage in neurons through an astrocyte-dependent mechanism

“…12,13 Along with others, we have demonstrated that Ang II often cross-talks with Aldo to mediate cardiovascular remodeling through an interaction between the AT 1 receptor and MR activation. 14,15 The AT 1 receptor and MR have been clearly identified in numerous specific regions in the brain and spinal cord. 16,17 Moreover, it has been suggested the AT 1 receptor and MR are expressed in cultured astrocytes and neurons 18,19 and mediate Ang II-induced astrocyte proliferation.…”