Pro Atrial Natriuretic Peptide (1-30) and 6-keto PGF1α Activity Affects Na(+) Homeostasis in Non-modulating Hypertension.

Non-modulating hypertension (NMHT) is a high renin subtype of salt sensitive hypertension, which fails to achieve renal vasodilatation and a correct Na(+) handling during sodium load. We investigate, in MHT and NMHT, the role of ANP, the renin-angiotensin system and PgI2, in the renal sodium handling mechanisms. After 10 days of low (20mmol.L) or after 72hs of high (250mmol.L) sodium intake, 13 NMHT (34±5y; 9 male) and 13 MHT (32±4y; 10male) were studied. Pro-ANP (1-30) PgI2, PRA and total exchangeable Na(+)24 (ENa(+)) were measured. Under low sodium intake, PRA (4.2±0.5ng.ml.h; p<0.05) and Pro-ANP (78.6±2pg/ml, p<0.05) were higher than in NMHT under (3.1±0.4ng.ml.h and 69.8±3 pg/ml). After 72h of high Na(+) intake, Pro-ANP (1-30) increased significantly only in MHT (82.1±3pg/ml, p<0.05). PgI2, under low sodium intake (1.83±0.2pg/24h), increased in MHT after 72h under high sodium (2.58±0.5pg/ 24h, p<0.02). Under low sodium diet, PgI2 (2.16±0.11pg/24h) was as higher in NMHT, as in MHT. After 72h under high Na+ intake, it failed to show any change (2.61±0.36 pg/24h; p=ns). A significant correlation between variations in ENa(+) and mean blood pressure (r=0.50, p<0.01), variations in Pro-ANP (1-30) values and ENa(+) in MHT (r=0.95; p<0.001) while a negative correlation between ENa(+) variations and ENa(+) (r=0.81, p<0.05) was observed in NMHT. ENa(+) variations were only significantly related to variations in FF in MHT. Thus, in NMHT, there is an unbalanced relationship between vasonstrictor and vasodilator mediators. From these, as an extrarenal homeostatic mediator, ANP seems to play an important role to compensate the altered renal sodium handling.

Telmisartan improves insulin resistance in high renin nonmodulating salt-sensitive hypertensives.

BACKGROUND: Nonmodulating (NMHT) is a high-renin subtype of salt sensitive hypertension, which additionally develops insulin resistance and oxidative stress. Conversely, modulating hypertensives (MHT) normally regulates renal hemodynamics after high sodium intake without metabolic impairment. We postulate that telmisartan, an angiotensin receptor blocker with partial peroxisome proliferators-activated receptorgamma partial agonist, may improve insulin resistance compared with ramipril, an angiotensin-converting enzyme inhibitor (ACEI) in NMHT. METHODS: We studied 18 NMTH (32 +/- 5y nine men, BMI 29 +/- 3 kg/m2) and 16 MHT (34 +/- 4, 10 men, BMI 28 +/- 5 kg/m2) before and after the crossover administration of ramipril 10 mg (3 months) or telmisartan 80 mg (3 months). In each patient studied we measured, before and after each treatment period, office blood pressure, glycemia and insulinemia before and 60 and 120 min after a glucose overload (75 g), total cholesterol, high-density lipoprotein and low-density lipoprotein fractions, triglycerides and highly sensitive C-protein-reactive protein. After that, HOMA-IR Index was calculated. RESULTS: Plasma renin activity was higher in NMHT 4.4 +/- 0.5 than MHT 2.6 +/- 0.9 ng.ml.h; P < 0.01. Blood pressure was similarly reduced either in MHT or NMHT by ramipril (MHT: from 159 +/- 10/102 +/- 4 to 142 +/- 6/93 +/- 3 mmHg, P < 0.05; NMHT: from 162 +/- 12/97 +/- 4 to 139 +/- 7/89 +/- 2 mmHg, P < 0.05) or telmisartan (MHT: from 154 +/- 8/96 +/- 5 to 137 +/- 6/88 +/- 4 mmHg, P < 0.05; NMHT: from 161 +/- 9/96 +/- 5 to 137 +/- 5/86 +/- 3 mmHg, P < 0.05). In NMHT, fasting glycemia (99 +/- 10 mg%) and insulinemia (16 +/- 4 microU%) and 120 min glycemia (110 +/- 2 mg%) and insulinemia (57 +/- 9 microU%) were higher than in MHT (fasting: 92 +/- 8 mg% and 9.2 +/- 2 mU%; 120 min: 95 +/- 5 and 21 +/- 5 microU%, P < 0.05). In MHT, after 3 months treatment with either ramipril or telmisartan no changes were found in fasting and 120 min glycemia and insulinemia. In NMHT, telmisartan, after 3 months treatment, significantly reduced fasting and 120 min insulinemia (fasting: 8.4 +/- 2, 120 min: 25 +/- 10 microU%; P < 0.01) compared either to basal values or ramipril treatment. Similarly, only in NMHT, compared with basal values and ramipril treatment, telmisartan improved the HOMA-IR index in both MHT (2.76 +/- 0.16 to 2.24 +/- 0.18, P < 0.05) and NMHT (from: 4.4 +/- 1 to 2.3 +/- 0.7) and triglyceride plasma levels (MHT: from 139 +/- 1.85 to 122 +/- 2.4 mg%, P < 0.05; NMHT: from: 223 +/- 12 to 146 +/- 10 mg%, P < 0.01). Finally, highly sensitive C-protein-reactive protein values were higher in NMHT (0.33 +/- 0.07 mg.dl) than in MHT (0.14 +/- 0.06 mg.dl; P < 0.01). Both treatments reduced highly sensitive C-protein-reactive protein in NMHT. (ramipril from 0.32 +/- 0.05 mg.dl to 0.26 +/- 0.06 m.dl (P < 0.05) and telmisartan from 0.34 +/- 0.05+/- to 0.20 +/- 0.05 mg.dl (P < 0.01). CONCLUSION: Our data suggest that the improvement of the insulin sensitivity by telmisartan, instead of a similar effect on blood pressure shown by both drugs, could be ascribed to the PPAR agonistic action of telmisartan. This opens an interesting therapeutic approach for patients with hypertension and altered glycemic metabolism.

Vascular oxidative stress is associated with insulin resistance in hyper-reninemic nonmodulating essential hypertension.

BACKGROUND: Nonmodulating hypertension (NMHT) is a high-renin subtype of salt-sensitive hypertension due to renal hemodynamic alterations. AIMS: To evaluate, in NMHT, whether the increased oxidative stress, which interferes with endothelial function, could be the consequence of an elevated renin-angiotensin activity and insulin resistance. METHODS: Fourteen patients with NMHT and 12 with modulating hypertension (MHT) were included. Plasma renin activity (PRA) and glucose/insulin tolerance test were performed and homeostasis model assessment (HOMA) index and areas under the curves (AUC) calculated. Urinary nitrites and nitrates (NOx), urinary cyclic guanosine monophosphate (cGMP) activity, urinary isoprostanes and plasma nitrotyrosine levels were also measured. RESULTS: PRA was higher in NMHT than MHT. In addition, L-arginine infusion increased effective renal plasma flow in MHT but not in NMHT. Insulin levels were higher in NMHT both at fasting and at 120 min, as were HOMA and AUC values. In MHT, NOx and cGMP significantly increased when moving from low to high Na+ intake, while nitrotyrosine mass and isoprostanes failed to show any change. On the contrary, in NMHT under low Na+ intake, urinary NOx levels were significantly higher than MHT under high Na+ intake, and failed to show any change under high Na intake; cGMP also failed to show any change when patients moved from low to high Na+ intake. Nitrotyrosine mass and isoprostanes, like to NOx, were significantly higher in NMHT under both low and high Na+ intake. CONCLUSIONS: It is suggested that, in NMHT, a possible association between higher renin-angiotensin system activity, insulin resistance and endothelial dysfunction, showed for the first time in the same subjects, might result in systemic vascular and renal endothelial dysfunction, salt-sensitive hypertension and high cardiovascular risk.

Overexpression of inducible nitric oxide synthase and cyclooxygenase-2 in rat zinc-deficient lung: Involvement of a NF-kappaB dependent pathway.

Reactive oxygen and nitrogen species have been implicated in the pathogenesis of pulmonary diseases. The goal of this study was to measure the response of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 enzymes (COX-2) in lung with moderate zinc deficiency. Adult male Wistar rats were divided into two groups receiving (1) a zinc-deficient diet (ZD) or (2) a zinc-adequate control diet. After 2 months of treatment, the zinc-deficient group showed a significant pulmonary edema. This was associated to a reduction of protein thiols and to a significant increase of metallothionein and glutathione disulfide levels. In addition, a higher serum and lung NO production in ZD group was positively related to the higher activity and expression of iNOS and COX-2 found in lungs. Western blot analysis revealed increased IkappaBalpha degradation, an indicator of NF-kappaB activation in ZD lungs. Anatomopathologic analysis of ZD lungs showed an increase of connective tissue fibers with an influx of polymorphonuclear cells. These cells and type II cells from the alveoli showed specific immunohistochemical signals for iNOS. The conclusion is that, during the development of zinc-deficiency, iNOS activity increases in lung and contributes to lung injury. Zinc deficiency implications must be taken into account to design therapies and public health interventions involving targeted zinc supplementation for high-risk subjects or certain diseases, such as asthma.

Mild hyperhomocysteinemia promotes renal hemodynamic dysfunction without histopathologic changes in adult rats.

BACKGROUND: Hyperhomocysteinemia is able to promote glomerular damage and generate tubulointerstitial lesions. These findings were reported in rats with unilateral nephrectomy or in weanling rats with normal function, two experimental models that are exposed to other concomitant vascular risk factors. The aim of this work is to study whether mild hyperhomocisteinemia per se can induce renal histopathologic changes in adults rats with normal renal function at either 10 or 44 weeks of hyperhomocysteinemia. METHODS: Two months old male Wistar rats (N= 52) were randomly allocated to either a normal control (N= 26) or hyperhomocysteinemic (N= 26) group. Control and hyperhomocysteinemic groups had free access to either tap water or homocysteine thiolactone 50 mg/kg/day, during 10 or 44 weeks. Plasma homocysteine levels were determined by a high-performance liquid chromatography (HPLC) method. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were calculated from inulin and sodium para-aminohippurate (PAH) clearance determinations. Structural renal changes were investigated in kidneys fixed by perfusion. Histopathologic and morphometric analysis were carried out by standard methods. RESULTS: Plasma total homocysteine levels were 53% (10 weeks) and 56% (44 weeks) higher in hyperhomocysteinemic group compared to the control group. GFR and RPF were significantly lower in hyperhomocysteinemic than in control group. The histopathologic and morphometric studies did not show any differences between the control and hyperhomocysteinemic rats at 10 or 44 weeks. CONCLUSION: The present results show that mild hyperhomocysteinemia is able to induce renal functional and biochemical alterations in male adult rats that are not associated with renal histopathologic changes.

Parallel renal and extremity blood supply abnormalities in nonmodulation: responses to ACE inhibition.

The aim of this work was to ascertain, in nonmodulating essential hypertension, whether the abnormality in the renal blood supply is extended to the extremities and showed a similar response to ACE inhibition and whether these abnormalities could be identified in normotensive offspring of hypertensives, as non-modulation is a familial process with genetic underpinnings. We measured forearm vascular blood flow (FBF) and forearm vascular resistance (FVR) by plethysmography and urinary albumin excretion in 20 normotensive without family story of hypertension (NT: 25+/-9 years), 10 modulating offspring of hypertensive parents (MHO: 25+/-6 years), 10 nonmodulating offspring of hypertensive parents (NMHO: 26+/-5 years), 12 modulating essential hypertensives (MHT: 34+/-5 years), and 11 nonmodulating essential hypertensives (NMHT: 32+/-4 years). Measurements were repeated in hypertensives after 3-month treatment with ramipril (5 mg daily). Nonmodulating individuals showed lower maximum FBF (NMHT: 41.96+/-3.3 mL/100 g per minute and NMHO: 35.6+/-9.0 mL/100 g per minute) than modulating subjects (MHT: 57.5+/-10.0 mL/100 g per minute and MHO: 51.8+/-7.0 mL/100 g per minute; P<0.003). Likewise, all nonmodulating subjects showed higher minimum FVR (NMHT: 2.5+/-0.2 AU; NMO: 2.8+/-0.5 AU) than modulating individuals (MHT: 1.9+/-0.5 AU; MHO, 1.8+/-0.3AU; P<0.025). Urinary albumin excretion was higher in NMHT and NMHO than MHT, MHO, and NT (P<0.05). Ramipril increased maximum FBF to 53.8+/-8.0 mL/100 g per minute and reduced minimum FVR to 1.9+/-0.5 AU in NMHT (P<0.01). Likewise, ramipril increased effective renal plasma flow and reduced renal vascular resistance and urinary albumin excretion only in NMHT (P<0.05). These results have shown an early involvement of the peripheral circulation in association with increased urinary albumin excretion not only in essential hypertensives but also in NMHO. The effectiveness of ramipril in reducing minimum FVR and urinary albumin excretion in NMHT also suggests a common mechanism.

Hyperhomocysteinemia induces renal hemodynamic dysfunction: is nitric oxide involved?

Hyperhomocysteinemia is associated with endothelial dysfunction, although the underlying mechanism is unknown. Previous studies have shown that nitric oxide (NO) plays an important role in the regulation of systemic and renal hemodynamics. This study investigated whether hyperhomocysteinemia induces renal oxidative stress and promotes renal dysfunction involving disturbances of the NO-pathway in Wistar rats. During 8 wk, control (C) and hyperhomocysteinemic (HYC) groups had free access to tap water and homocysteine-thiolactone (HTL, 50 mg/kg per d), respectively. At 8 wk, plasma homocysteine concentration, renal superoxide anion (O(2)), nitrotyrosine, and nitrite+nitrate levels, and renal function were measured. To assess NO involvement, the responses to L-Arginine (L-Arg, 300 mg/kg) and N(G)-nitro-L-arginine-methyl-ester (L-NAME, 20 microg/kg per min for 60 min) were analyzed. The HYC group showed higher homocysteine concentration (7.6 +/- 1.7 versus 4.9 +/- 1.0 micromol/L; P < 0.001), (O(2) production (157.92 +/- 74.46 versus 91.17 +/- 29.03 cpm. 10(3)/mg protein), and nitrite+nitrate levels (33.4 +/- 5.1 versus 11.7 +/- 4.3 micro mol/mg protein; P < 0.001) than the control group. Western blot analyses showed a nitrotyrosine mass 46% higher in the HYC group than in the controls. Furthermore, the HYC group showed lower GFR, renal plasma flow (RPF), and higher renal vascular resistance (RVR) than the controls. After L-Arg administration, the responses of GFR, RPF, and RVR were attenuated by 36%, 40%, and 50%, respectively; after L-NAME, the responses of RPF and RVR were exaggerated by 79% and 112%, respectively. This suggests a reduced NO bioavailability to produce vasodilation and an enhanced sensitivity to NO inhibition. In conclusion, hyperhomocysteinemia induces oxidative stress, NO inactivation, and renal dysfunction involving disturbances on the NO-pathway.

Reproducibilidad de la cuantificacion de la sensibilidad a la accion insulinica con el modelo minimo y comparacion con un test de tolerancia a bajas dosis de insulina / Repeatibility of insulin sensitivity estimation using the Minimal Model and comparison with a modified short low-dose insulin tolerance test

La hiperinsulinemia y la insulino-resistencia son disturbios metabólicos associados a obesidad central, hipertensión arterial, hipertrigliceridemia, sindrome polimetabólico, intolerancia a la glucosa y enfermedad aterosclerótica. La evaluación de los cambios en la sensibilidad a la acción insulínica in vivo (SAI in vivo) inducidos por intervenciones higiénico-dietéticas o farmacológicas requieren una técnica de adecuada reproducibilidad. En el presente estudio fue evaluada la reproducibilidad intra-individual de la SAI in vivo expresada como SI (par metro determinado utilizando el Modelo Mínimo de Bergman modificado con insulina [MMins]), em 11 sujetos con un amplio rango de SAI in vivo. SI (primer estudio) varió entre 0,82 y 8,48 x 10(-4) min(-1)/muU.mL (4,43 + 2,85 x 10(-4) min(-1)/muU.ml; média + DS) y presentó una correlación altamente significativa con SI (segundo estudio) (r = 0,89; p = 0,0002). El coeficiente de variación medio fue del 20,9 + 13,9 por ciento). La SAI in vivo fue também determinada analizando la tasa de caída de los niveles de glucemia luego del suministro IV de 0,025 U/kg de insulina cristalina humana (método de Bonora modificado o BBD), en 11 sujetos. La SAI in vivo determinada por BBD varió entre 21 y 234 mumol/ml/min (134 + 64,8 mumol/ml/min, média + DS). No se observaron hipoglucemias durante los estudios. La correlación entre los valores de SI obtenidos del MMins y los resultados del BBD fue altamente significativa ( r= 0,89, p = 0,0002). Los resultados del presente trabajo sugieren que el MMins tiene una adecuada reproducibilidad intra-sujeto y que el BBD constituye una medida aproximada de la SAI in vivo siendo particularmente aplicable cuando es necesaria la practica de un procedimiento de r pida ejecución y menor complejidad y costo.