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Vaccination against high blood pressure: a new strategy
A number of studies in diabetic renal disease have found an increased risk for renal function loss in patients homozygous for the D allele of the ACE/ID polymorphism compared to II patients, even during ACE inhibition. ARB treatment in hypertensive type 1 diabetic patients with DN homozygous for I or D allele of the ACE/ID polymorphism conferred similar beneficial effect on changes in urinary albumin excretion and rate of decline in GFR in patients with different genotypes. A large-scale trial comparing the effects of ARB treatment and ACE inhibition should be performed to further investigate the pharmacogenetic possibilities of ACE/ID polymorphism in treatment of diabetic renal disease.
Preliminary studies have suggested that dual blockade of the RAAS by combined treatment with ACE inhibition and ARBs is well tolerated and reduces albuminuria and blood pressure in patients with type 2 diabetes and DN responding insufficiently to antihypertensive combination therapy, including the recommended dose of ACE inhibitor. However, long-term studies of dual blockade in incipient and overt DN should be initiated. Increasing evidence suggest an implication of aldosterone in the pathogenesis of progressive renal disease, which may suggest a beneficial effect of aldosterone blockade. Therefore, selective and non-selective aldosterone blockers are being investigated as future treatment options in DN. The increased expression of renal TGF-β and other cytokines in diabetic glomerulopathy may be lowered by RAAS blockade, but probably not completely abolished even by high-dose treatment. Therefore, agents that modulate other pathogenic pathways are being evaluated as potential treatment modalities in diabetic renal disease. These studies include agents that interfere in formation of advanced glycation end products, compounds targeting the activity of protein kinase C and antibodies/receptor blockers to cytokines such as TGF-β.
After establishing the concept of renin uptake as the underlying cause of tissue angiotensin generation, focus is now on the mechanism that mediates this uptake process. Several renin receptors have already been described. These receptors also bind prorenin, and such binding results in prorenin activation, either proteolytically or non-proteotytically. This is important in view of earlier observations that prorenin levels in diabetic subjects are an indication of microvascular complications. Now that renin inhibitors will soon be clinically available, it will be of great interest to investigate how these drugs affect these mechanisms in comparison with other RAAS blockers. Eventually a new class of drugs might emerge, the renin receptor blockers, which selectively block angiotensin generation at tissue sites and/or renin receptor-mediated effects.
Evolving role of aldosterone blockers alone and in comb... American Heart Journal |
Evolving role of aldosterone blockers alone and in combination with angiotensin American Heart Journal, Volume 147, Issue 4, April 2004, Pages 564-572 Henry R Black Abstract The renin-angiotensin-aldosterone system (RAAS) plays an integral role in blood pressure regulation and has long been a target of pharmacologic approaches to controlling blood pressure. Traditionally, clinical interventions involving the RAAS have focused mainly on inhibiting the action of angiotensin II with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and limited attention has been devoted to direct inhibition of the action of aldosterone. Recent advances in understanding the role of aldosterone in cardiovascular injury have elevated the importance of direct inhibition of the action of this hormone in the long-term control of blood pressure and have led to the development of the selective aldosterone blocker eplerenone. This article reviews the role of the RAAS in the development of hypertension and discusses the rationale for the use of eplerenone with other medications affecting the RAAS to control blood pressure. PDF (187 K) |
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Vaccination against high blood pressure: a new strategy