Mineralocorticoid Blockade Reduces Vascular Injury in Stroke-Prone Hypertensive Rats

Abstract

Abstract-Chronic treatment of saline-drmkmg stroke-prone spontaneously hypertensive rats (SHRSP) with agents that interfere with the formation or actions of angotensm II (Ang II) prevents the development of stroke and renal vascular damage Ang II, m addltlon to its direct vascular effects, stimulates the synthesis and release of aldosteroneTo assess the role of aldosterone m the development of pathologc changes m these rats, we implanted time-release pellets containing 200 mg of the mmeralocortlcold receptor antagomst, spu-onolactone, mto 14 SHRSP at 7 5 weeks of age Eight SHRSP httermates received placebo pellets Over the period of study (3 to 4 weeks), systolic blood pressure (SBP) (PRA) and aldosterone as independent nsk factors for heart attack and stroke ' They found that among the patients who developed strokes and myocardlal mfarctlons, all had normal or high PRA, and aldosterone secretlon Previous studies by our group and others have provided expenmental evidence to support a role for the renm-angotensm-aldosterone system (RAAS) m the development of vascular qury, as angotensm converting enzyme (ACE) mhlbltors2-6 and Ang II receptor antagonlsts7-9 prevented the development of stroke and malignant nephrosclerosls m SHRSP Since these studies were conducted m salt-loaded SHRSP, which respond to these agents with nummal blood pressure lowermg, they provided evidence for a pathophyslolog& role for Ang II m the development of vascular lesions of malignant nephrosclerosls independent of severely elevated blood pressure Consistent with a role for Ang II was the finding that SHRSP display a paradoxical increase m PRA with rime, despite continued salt-loading 3 9,'" Although Ang II stimulates the synthesis and release of aldosterone," " m addmon to its direct vascular actions, a role for mmeralocortlcolds m the pathology of SHRSP

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

“…In addition, recent animal and clinical studies support a beneficial effect of MR blockade on the progression of renal injury. In rats, MR antagonists markedly ameliorated glomerular and/or tubulointerstitial injury in several models of nephropathy, including spontaneously hypertensive strokeprone rats (50,51), angiotensin II and NO synthase inhibitortreated rats (52), aldosterone-treated rats (25), and in a ureteral obstruction model (66). Moreover, Aldigier et al (2) reported that MR blockade not only reduced the development of glomerulosclerosis but also induced regression of existing glomerulosclerosis in rats after 5/6 nephrectomy.…”

Aldosterone as a Mediator of Progressive Renal Dysfunction: Evolving Perspectives.

“…Recent experimental data have shown the ability of aldosterone receptor antagonists to attenuate proteinuria and renal damage. As described previously, Rocha et al (32) demonstrated that aldosterone receptor blockade with spironolactone markedlyattenuated urinary protein excretion, as well as prevented the development of nephrosclerotic and cerebrovascular lesions, independent of changes in arterial blood pressure in saline-drinking SHRSRSpironolactone, although an effective aldosterone receptor antagonist, also has affinity for other steroid receptors, thereby producing unwanted adverse effects. Consequently, the same investigators recently conducted a second study using eplerenone, a selective aldosterone receptor antagonist (58).…”

“…Although many studies have demonstrated a beneficial ef-feet of ACEinhibition in retarding progressive renal disease, it must be emphasized that this intervention does not differentiate between the relative contribution of renin-angiotensin versus aldosterone. To evaluate the possible contribution of aldosterone per se, Rocha et al conducted a series of experiments in SHRSPthat succeeded in dissociating the relative contributions of aldosterone and the renin-angiotensin system (12,32). Initially, they implanted time-release pellets of spironolactone, an aldosterone receptor antagonist, or placebo pellets in saline-drinking (1% NaCl) SHRSP ingesting a Stroke-Prone Rodent diet (32).…”

“…To evaluate the possible contribution of aldosterone per se, Rocha et al conducted a series of experiments in SHRSPthat succeeded in dissociating the relative contributions of aldosterone and the renin-angiotensin system (12,32). Initially, they implanted time-release pellets of spironolactone, an aldosterone receptor antagonist, or placebo pellets in saline-drinking (1% NaCl) SHRSP ingesting a Stroke-Prone Rodent diet (32). This model is known to induce severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy as observed in malignant nephrosclerosis.…”

Eplerenone

“…10 -12 Concurrent angiotensin-converting enzyme (ACE) inhibition blocks the development of ventricular hypertrophy but not the myocardial fibrosis, suggesting that the fibrotic effects of aldosterone occur in the absence of Ang II. 39 Aldosterone receptor antagonism with either spironolactone or eplerenone prevents aortic 13 and myocardial fibrosis 14,15 in rat models of primary and secondary hypertension, even in the absence of blood pressure effects. Aldosterone also causes renal fibrosis.…”