Salah Kivlighn

Is There a Pathogenetic Role for Uric Acid in Hypertension and Cardiovascular and Renal Disease

Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy.

Serum Uric Acid and Cardiovascular Events in Successfully Treated Hypertensive Patients

To determine whether pretreatment and/or in-treatment serum uric acid (SUA) is independently and specifically associated with cardiovascular events in hypertensive patients, we examined the 20-year experience of 7978 mild-to-moderate hypertensive participants in a systematic worksite treatment program. Clinical evaluation and treatment were protocol-directed. SUA was measured at entry and annually thereafter. Subjects were stratified according to gender-specific quartile of baseline SUA. Blood pressures at entry and in-treatment were, respectively, 152.5/95.6 and 138.9/85.4 mm Hg. SUA was normally distributed with a mean of 0.399+/-0.0893 and 0. 321+/-0.0833 mmol/L for men and women, respectively. Subjects with highest SUA were heavier, had greater evidence of cardiovascular disease (CVD), higher systolic blood pressure, higher creatinine, more frequent diuretic use, and lower prevalence of diabetes. During an average follow-up of 6.6 years (52 751 patient-years), 548 CVD events (183 mortal) and 116 non-CVD events occurred. In bivariate analysis, the association of SUA to CVD was more robust in nonwhites than whites and in patients at low versus high CVD risk. In multivariate analysis, CVD incidence was significantly associated with SUA with a hazard ratio of 1.22 (95% confidence interval 1.11 to 1.35), controlling for other known cardiovascular risk factors, including serum creatinine, body mass index, and diuretic use. Despite blood pressure control, SUA levels increased during treatment and were significantly and directly associated with CVD events, independently of diuretic use and other cardiovascular risk factors.

Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease

An elevated uric acid level is associated with cardiovascular disease. Hyperuricemia is predictive for the development of both hypertension and coronary artery disease; it is increased in patients with hypertension, and, when present in hypertension, an elevated uric acid level is associated with increased cardiovascular morbidity and mortality. Serum uric acid level should be measured in patients at risk for coronary artery disease because it carries prognostic information. Hyperuricemia is caused by decreased renal excretion. In this article, we suggest that this may be mediated by intrarenal ischemia with lactate generation and the inhibition of the secretion of urate by the anion-exchange transport system. The possibility that hyperuricemia directly contributes to cardiovascular or renal disease needs to be reconsidered. Although hyperuricemia is associated with a number of cardiovascular or renal risk factors, several studies have found uric acid level to be independently associated with increased mortality by multivariate analysis. If hyperuricemia is directly toxic, the most likely site is the kidney. Chronic hyperuricemia is strongly associated with chronic tubulointerstitial disease, and many of these patients have decreased renal function. Although it is possible that the hyperuricemia could simply be the consequence of the renal disease, further studies are necessary to rule out a pathogenic role for uric acid in the development of renal disease and salt-dependent hypertension.

Hyperuricemia exacerbates chronic cyclosporine nephropathy

BACKGROUND Hyperuricemia frequently complicates cyclosporine (CSA) therapy. The observation that longstanding hyperuricemia is associated with chronic tubulointerstitial disease and intrarenal vasoconstriction raised the hypothesis that hyperuricemia might contribute to chronic CSA nephropathy. METHODS CSA nephropathy was induced by the administration of CSA (15 mg/kg/day) for 5 and 7 weeks to rats on a low salt diet (CSA group). The effect of hyperuricemia on CSA nephropathy was determined by blocking the hepatic enzyme uricase with oxonic acid (CSA-OA). Control groups included rats treated with vehicle (VEH) and oxonic acid alone (OA). Histological and functional studies were determined at sacrifice. RESULTS CSA treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular injury and striped interstitial fibrosis. CSA-OA treated rats had higher uric acid levels in association with more severe arteriolar hyalinosis and tubulointerstitial damage. Intrarenal urate crystal deposition was absent in all groups. Both CSA and CSA-OA treated rats had increased renin and decreased NOS1 and NOS3 in their kidneys, and these changes are more evident in CSA-OA treated rats. CONCLUSION An increase in uric acid exacerbates CSA nephropathy in the rat. The mechanism does not involve intrarenal uric acid crystal deposition and appears to involve activation of the renin angiotensin system and inhibition of intrarenal nitric oxide production.

L-162,389: a potent orally active angiotensin II receptor antagonist with balanced affinity to both AT1 and AT2 receptor subtypes

Abstract Simple modifications made to our potent angiotensin II AT 1 selective clinical candidate MK-996 provided a compound with balanced binding affinity to both the AT 1 and the AT 2 receptor subtype. This compound, L-162,389, is orally active in rats and dogs.

Pharmacology of losartan, an angiotensin II receptor antagonist, in animal models of hypertension

Background: Clinical experience with angiotensin converting enzyme (ACE) inhibitors has shown that inhibition of the renin–angiotensin system is effective therapy for hypertension and heart failure. Losartan (DuP753, MK954, cozaar) is the first non-peptidic drug that inhibits the renin-angiotensin system by selectively blocking the interaction of angiotensin II with its receptor Differences between losartan and ACE inhibitors: Pharmacological differences between ACE inhibitors and losartan could affect comparative efficacy and/or safety. In addition to angiotensin I, ACE has other substrates (e.g. kinins). Blocking the metabolism of kinins with ACE inhibitors could be beneficial (e.g. vasodilation) and/or elicit side effects (e.g. cough) which will not be produced by losartan. Non-ACE pathways of angiotensin II formation have been described (e.g. angiotensin I convertase) which may limit the ability of ACE inhibitors to prevent formation of angiotensin II in all tissues. Losartan blocks angiotensin II responses irrespective of the route or site of angiotensin II formation. Two binding sites for angiotensin II are widely accepted, AT1 and AT2. Losartan blocks only AT1 sites while ACE inhibitors functionally block angiotensin II interaction with both sites. Since the physiological role for AT2 sites is unknown, the relevance of this difference between ACE inhibitors and losartan is questionable Hypertension: In animal models of hypertension, the efficacy of losartan is equivalent to the efficacy of ACE inhibitors. In animal models that reflect complications of hypertension, such as kidney dysfunction, cardiac and vascular hypertrophy and stroke, losartan and ACE inhibitors are also equally effective. From these results, kinin potentiation and lack of inhibition of angiotensin I convertase do not lead to differences in pharmacological efficacy between ACE inhibitors and losartan. Therefore, with respect to therapeutic efficacy, results in animal models indicate that losartan will display the beneficial pharmacology of ACE inhibitors without the detrimental side effects attributed to kinin potentiation