RESUMO
BACKGROUND: Experimentally-induced hyperuricaemia [due to inhibition of uricase with oxonic acid (OA)] in rats causes hypertension and renal alterations which can be prevented by lowering uric acid (UA) with allopurinol. Febuxostat (Fx), an investigational, nonpurine and selective xanthine oxidase inhibitor, is a more effective UA-lowering agent than allopurinol. We therefore tested the hypothesis that Fx might be useful in treating hyperuricemia-induced hypertension and renal damage. METHODS: Four groups of male rats were studied: OA (750 mg/kg by daily gavage) was given for 8 weeks and Fx (5-6 mg/kg/day in drinking water; OA+Fx: n = 10) or placebo (OA+P: n = 11) were administered for 4 weeks beginning at 4 weeks after initiation of the study. Two groups of normal (N) rats were studied as controls (N+P and N+Fx: n = 10/group). Systolic blood pressure (SBP) and fasting plasma UA were measured in all animals at baseline and at 4 and 8 weeks. Glomerular haemodynamics by micropuncture techniques were determined at 8 weeks followed by histological evaluation of glomerular and afferent arteriole morphologies. RESULTS: In OA-induced hyperuricaemic rats, Fx lowered UA and ameliorated systemic and glomerular hypertension as well as mesangial matrix expansion and the development of preglomerular arteriolar disease as indicated by a reduction of the arteriolar area and media-to-lumen ratio. In normal rats, Fx tended to lower UA and had no effect on blood pressure, renal hemodynamics and afferent arteriole morphology. CONCLUSION: These results suggest that Fx merits further evaluation for the treatment of hypertension and renal alterations induced by hyperuricaemia.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Supressores da Gota/uso terapêutico , Hipertensão Renal/tratamento farmacológico , Hiperuricemia/complicações , Tiazóis/uso terapêutico , Xantina Oxidase/antagonistas & inibidores , Animais , Febuxostat , Seguimentos , Hipertensão Renal/sangue , Hipertensão Renal/etiologia , Hiperuricemia/sangue , Hiperuricemia/induzido quimicamente , Glomérulos Renais/patologia , Masculino , Ácido Oxônico/toxicidade , Ratos , Ratos Sprague-Dawley , Circulação Renal/efeitos dos fármacos , Ácido ÚricoRESUMO
BACKGROUND: The 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) catalyzes the conversion of cortisol (F) to cortisone (E), avoiding the interaction of cortisol with the mineralocorticoid receptor. If it fails, cortisol will stimulate sodium and water reabsorption, increasing the intravascular volume that suppresses renin and secondarily increase the blood pressure. OBJECTIVE: To look for the possible contribution of a decreased ability of 11betaHSD2 to convert cortisol to its inactive metabolite cortisone in the pathogenesis of low renin hypertension (LREH). PATIENTS AND METHODS: We studied 64 LREH patients (plasma renin activity, PRA < 1 ng/ml per h), eighty normo-renin essential hypertensives (NREH) (PRA: 1-2.5 ng/ml per h) and 74 normotensives. Serum aldosterone (SA), F, E and serum F/E ratio was determined in all patients. A serum F/E ratio was considered high when it was higher than X + 2SD from the normotensive value. Cytosine-adenine (CA)-repeat microsatellite region in intron 1 of HSD11B2 gene was genotyped in all patients and normotensives volunteers. In 13 LREH with high F/E ratio we performed HSD11B2 gene sequencing. RESULTS: LREH had serum F/E ratio higher than NREH and normotensive controls (3.6 (2.9-4.3) versus 2.9 (2.2-4.3) versus 3.0 (2.4-3.7) (P = 0.004), respectively). We observed an inverse relation between F/E ratio and SA and PRA. In NREH and normotensives we did not find correlation between these variables. In the LREH subset the longer 155 bp CA-allele showed the highest serum F/E ratio. No mutations in coding region or short introns were found in LREH patients. CONCLUSION: In this study we show that low-renin essential hypertensives had increased serum cortisol/cortisone ratios as compared with normotensive subjects. This suggest that some essential hypertensives, with suppressed renin activity, may have an impairment in the cortisol inactivation catalyzed by the enzyme 11betaHSD2, whose low activity in LREH patients could be associated with the length of CA-repeat microsatellite in intron 1 of the HSD11B2 gene.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Hipertensão Renal/sangue , Hipertensão Renal/genética , Polimorfismo Genético , Renina/sangue , Adulto , Idoso , Feminino , Genótipo , Humanos , Íntrons , Modelos Lineares , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Sequências Repetitivas de Ácido NucleicoRESUMO
This study examined the effect on mean blood pressure of a new orally active nonpeptide angiotensin II (Ang II) receptor antagonist, EXP 3174, in doses that completely block exogenous Ang II action. Anesthetized and conscious two-kidney, two clip chronic renovascular hypertensive rats and sham-operated animals were used. In anesthetized hypertensive rats, intracerebroventricular administration of the inhibitor had no effect on blood pressure, whereas blood pressure was normalized by intravenous injection of the antagonist (163 +/- 12 to 110 +/- 9 mm Hg, P < .05). In sham anesthetized rats, intravenous injection of EXP 3174 also lowered blood pressure (112 +/- 6 to 96 +/- 6mm Hg, P < .05). In conscious rats, intravenous EXP 3174 induced a fall in pressure that was larger in hypertensive (156 +/- 9 to 132 +/- 5 mm Hg, P < .05) than in sham (104 +/- 3 to 94 +/- 4 mm Hg, P < .05) rats. Plasma renin activity was very high in anesthetized animals (hypertensive versus sham, 87.8 +/- 8.3 versus 95.7 +/- 10.2 ng Ang I/mL per hour); differences were not significant either between anesthetized hypertensive and sham or in conscious animals (hypertensive versus sham, 9.42 +/- 1.58 versus 6.74 +/- 2.32 ng Ang I/mL per hour). Angiotensinogen concentration was higher in cerebrospinal fluid in anesthetized hypertensive rats (36.4 +/- 3.0 versus 26.0 +/- 2.4 ng Ang I/mL, P < .05) and in the artery wall of hypertensive conscious rats (103.1 +/- 10.3 versus 75.2 +/- 7.8 ng Ang I/g, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão Renal/sangue , Hipertensão Renal/fisiopatologia , Imidazóis/farmacologia , Renina/sangue , Tetrazóis/farmacologia , Angiotensinogênio/líquido cefalorraquidiano , Angiotensinogênio/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Artérias/metabolismo , Imidazóis/administração & dosagem , Injeções Intravenosas , Injeções Intraventriculares , Losartan , Masculino , Ratos , Ratos Wistar , Tetrazóis/administração & dosagemRESUMO
Foremost in the differential diagnosis of hypertension is the identification of surgically correctable lesions. Increased plasma renin activity in a hypertensive patient suggests the presence of a renovascular or renal etiology. We have recently seen two adolescent patients whose hyperreninemia was cuased by a pheochromocytoma. Secondary hyperaldosteronism was an associated finding.