RESUMEN
The objective is to elucidate the effect of nitric oxide (NO)-renin-angiotensin system (RAS) interactions on renal hemodynamic function in uncomplicated, type 1 diabetes mellitus (DM). In 14 salt-replete, male healthy volunteers (C) and 9 male DM patients on euglycemia, glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), and sodium excretion (UNaV) were measured at baseline and during a 90-min infusion of 3.0 µg·kg⻹·min⻹ NG-nitro-L-arginine-methyl-ester (L-NAME) after 3 days of pretreatment with either placebo (PL) or 50 mg losartan (LOS). Baseline GFR, RBF, and FF were higher in DM (P < 0.005). In the C group, PL + L-NAME caused declines in GFR (101 ± 3 to 90 ± 3 ml·min⻹·1.73 m⻲), RBF (931 ± 22 to 754 ± 31 ml·min⻹·1.73 m⻲), and UNaV (158 ± 12 to 82 ± 18 µmol/min) and an increase in FF (0.19 ± 0.02 to 0.21 ± 02; P < 0.001), which were not influenced by LOS pretreatment (P > 0.05 for LOS + L-NAME-C vs. PL + l-NAME-C). In DM, PL + L-NAME resulted in exaggerated renal effects, with changes in GFR (128 ± 3 to 104 ± 3 ml·min⻹·1.73 m⻲), RBF (1,019 ± 27 to 699 ± 34 ml·min⻹·1.73 m⻲), UNaV (150 ± 13 to 39 ± 14 µmol/min), and FF (0.22 ± 0.03 to 0.26 ± 0.02) that were significantly greater vs. PL + L-NAME-C (P < 0.005). LOS pretreatment blunted GFR, RBF, FF, and UNaV responses to L-NAME in DM (P < 0.005 vs. PL + L-NAME-DM), resulting in a response profile that was similar to PL + L-NAME and LOS + L-NAME in C (P > 0.05). Renal responses to L-NAME in uncomplicated, type 1 DM are exaggerated vs. C, consistent with an upregulation of NO bioactivity. LOS, without effects in C, prevents the accentuated actions of L-NAME in DM, thus indicating an augmented role for NO-RAS interactions in renal hemodynamic function in DM.
Asunto(s)
Angiotensina II/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Hemodinámica , Riñón/metabolismo , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Biomarcadores/sangre , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/fisiopatología , Inhibidores Enzimáticos/administración & dosificación , Tasa de Filtración Glomerular , Hemodinámica/efectos de los fármacos , Humanos , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/fisiopatología , Losartán/administración & dosificación , Masculino , NG-Nitroarginina Metil Éster/administración & dosificación , Natriuresis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Circulación Renal , Sistema Renina-Angiotensina/efectos de los fármacos , Transducción de Señal , Regulación hacia Arriba , Adulto JovenRESUMEN
According to the "tubulocentric" hypothesis of the glomerular hyperfiltration of diabetes mellitus (DM), tubuloglomerular feedback (TGF) is the critical determinant of the related renal hemodynamic dysfunction. To examine the role of TGF in human type 1 DM, 12 salt-replete healthy (C) and 11 uncomplicated DM individuals underwent measurements of glomerular filtration rate (GFR), renal blood flow (RBF), and lithium-derived absolute "distal" sodium delivery (DDNa). Measurements were made during two 3-h infusions of 0.012 mmol·kg(-1)·min(-1) l-arginine (ARG) buffered with either equimolar HCl (ARG.HCl) or citric acid (ARG.CITR). Our hypothesis was that changes in TGF signaling would be directionally opposite ARG.HCl vs. ARG.CITR according to the effects of the ARG-buffering anion on DDNa. Similar changes in C and DM followed ARG.CITR, with declines in DDNa (-0.26 ± 0.07 mmol/min C vs. -0.31 ± 0.07 mmol/min DM) and increases in RBF (+299 ± 25 vs. +319 ± 29 ml·min(-1)·1.73 m(-2)) and GFR (+6.6 ± 0.8 vs. +11.6 ± 1.2 ml·min(-1)·1.73 m(-2)). In contrast, with ARG.HCl, DDNa rose in both groups (P = 0.001), but the response was 73% greater in DM (+1.50 ± 0.15 mmol/min C vs. +2.59 ± 0.22 mmol/min DM, P = 0.001). RBF also increased (P = 0.001, +219 ± 20 ml·min(-1)·1.73 m(-2) C, +105 ± 14 DM), but ΔRBF after ARG.HCl was lower vs. ARG.CITR in both groups (P = 0.001). After ARG.HCl, ΔRBF also was 50% lower in DM vs. C (P = 0.001) and GFR, unchanged in C, declined in DM (-7.4 ± 0.9 ml·min(-1)·1.73 m(-2), P = 0.02 vs. C). After ARG.HCl, unlike ARG.CITR, DDNa increased in C and DM, associated with less ΔRBF and ΔGFR vs. ARG.CITR. This suggests that the renal hemodynamic response to ARG is influenced substantially by the opposite actions of HCl vs. CITR on DDNa and TGF. In DM, the association of ARG.HCl-induced exaggerated ΔDDNa, blunted ΔRBF, and the decline in GFR vs. C shows an enhanced TGF dependence of renal vasodilatation to ARG, in agreement with a critical role of TGF in DM-related renal hemodynamic dysfunction.
Asunto(s)
Arginina , Diabetes Mellitus Tipo 1/fisiopatología , Glomérulos Renales/fisiología , Túbulos Renales/fisiología , Adulto , Tampones (Química) , Ácido Cítrico/farmacología , Retroalimentación , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Inulina , Masculino , Persona de Mediana Edad , Natriuresis , Circulación Renal/efectos de los fármacos , Ácido p-AminohipúricoRESUMEN
OBJECTIVE: Impaired flow-mediated dilation (FMD) is associated with cardiovascular risk factors and provides prognostic information. Despite the noninvasive nature of this technique, a major limitation to its widespread use is low reproducibility. The aim of this study was to evaluate impact of methodological standardization among different investigation sites on brachial artery FMD reproducibility. METHODS: Seven Italian centers recruited 135 healthy volunteers, aged 20-60 years. FMD was assessed by high-resolution ultrasound equipped with a stereotactic probe-holding device. Certified sonographers recorded brachial artery scans at baseline (day 1a), 1 h after (day 1b), and 1 month later (day 30). Endothelium-independent vasodilation (EIVD) to sublingual glyceril-trinitrate was recorded at day 1 and day 30. FMD and EIVD were blindly evaluated at the coordinating center by an automated edge detection system. The intra-session (day 1a versus 1b) and inter-session (day 1a versus 30) coefficients of variation were calculated. RESULTS: FMD was not significantly (P = 0.91) different at day 1a, day 1b and day 30 (6.52 ± 2.9, 6.42 ± 3.1, 6.57 ± 2.8%, respectively). The FMD intra-session coefficient of variation was 9.9 ± 8.4% (from 7.6 to 11.9% across centers). The FMD inter-session coefficient of variation was 12.9 ± 11.6% (from 11.6 to 16.1% across centers). Inter-session coefficient of variation for EIDV was 19.7 ± 16.8%. CONCLUSIONS: This study shows a homogeneous coefficient of variation for FMD among different centers. The inter-session coefficient of variation was similar to the intra-session coefficient of variation, representing the intrinsic FMD variability. We demonstrate for the first time that rigorous and standardized procedure may provide reproducible FMD assessment to study endothelial function in multicenter clinical trials.
Asunto(s)
Vasodilatación , Adulto , Femenino , Humanos , Italia , Masculino , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
To investigate whether bradykinin (BK) participates in the inhibition of renal effects of exogenous angiotensin II (AngII) by AngII type 1 receptor (AT1R) blockade, eight salt-repleted volunteers underwent four p-aminohippurate- and inulin-based renal studies of AngII infusion at increasing rates of 0.625, 1.25, and 2.5 ng.kg.min(-1) for 30 min. Studies 1 and 2 were preceded by 3 days of placebo, whereas studies 3 and 4 used 240 to 320 mg.day(-1) valsartan. Bradykinin B2-type receptor (BKB2R) antagonist icatibant (50 mug.kg(-1)) was coinfused in studies 2 and 4. Mean blood pressure (MBP), glomerular filtration rate (GFR), renal blood flow (RBF), and renal sodium excretion (UNaV) were measured. In study 1, MBP rose by 12.8%, UNaV decreased by 68%, and GFR and RBF also fell (p < 0.001 for all). In study 2, GFR and RBF fell as in study 1, but the rise in MBP and the fall in UNaV were accentuated [+20.0%, analysis of variance (ANOVA), p < 0.02 versus study 1 and -80.0%, p < 0.05, respectively]. In study 3, AngII had no effects, and in study 4, renal hemodynamics remained unaffected, but MBP still rose and UNaV fell (ANOVA, p < 0.02 and 0.005 versus study 3, respectively). Icatibant accentuated AngII-induced changes in MBP and UNaV. Previous AT1R blockade prevented any systemic and renal effects of AngII, but significant changes in MBP and UNaV still followed AngII plus icatibant even after AT1R blockade. BK, through BKB2Rs, participates in the inhibitory action of AT1R blockers toward actions of exogenous AngII on MBP and UNaV in healthy humans.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Angiotensina II/farmacología , Riñón/efectos de los fármacos , Receptor de Bradiquinina B2/fisiología , Tetrazoles/farmacología , Valina/análogos & derivados , Antagonistas Adrenérgicos beta/farmacología , Adulto , Presión Sanguínea/efectos de los fármacos , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B2 , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Indicadores y Reactivos , Inulina , Masculino , Circulación Renal/efectos de los fármacos , Sodio/metabolismo , Sodio/orina , Valina/farmacología , Valsartán , Ácido p-AminohipúricoRESUMEN
OBJECTIVE: To investigate whether changes in tubuloglomerular feedback (TGF) dependent upon the tubular effects of buffering anions affect the renal haemodynamic response to L-arginine in healthy (control) individuals and patients with essential hypertension. METHODS: Mean arterial pressure (MAP), glomerular filtration rate (GFR), renal blood flow (RBF) and fractional excretion of sodium (FENa), chloride (FECl) and lithium (FELi) were measured in 10 control individuals and 10 hypertensive patients during two 3-h infusions of 0.012 mmol/kg per min L-arginine buffered with either HCl or citric acid. RESULTS: FELi, FECl and FENa increased (P < 0.001) comparably in controls and hypertensive individuals with arginine-HCl and decreased with arginine-citrate (P < 0.001). MAP was unchanged in controls with arginine-HCl and decreased by 3% with arginine-citrate (P < 0.001), and decreased in hypertensive individuals with both arginine-HCl and arginine-citrate (by 3 and 7%, respectively; P < 0.001). GFR increased with arginine-citrate in controls and hypertensive individuals (by 6.1 and 5.4%, respectively; P < 0.001), but did not change with arginine-HCl in controls and declined by 4.6% in hypertensive individuals (P < 0.05). RBF increased equally after arginine-citrate in controls and hypertensive individuals (by 34 and 33%, respectively; P < 0.001); it also increased after arginine-HCl (22 and 13%, respectively; P < 0.001), but less than after arginine-citrate (P < 0.001), and 41% less in hypertensive individuals than in controls (P < 0.001). DISCUSSION: Because arginine-HCl, unlike arginine-citrate, inhibits tubular reabsorption and elicits much less renal vasodilatation than does arginine-citrate, renal haemodynamics in response to L-arginine are modulated by changes in reabsorption and TGF according to the tubular effects of the attendant anion. As renal vasodilatation in hypertensive individuals was reduced only with arginine-HCl, which activates TGF, the blunted vasodilatation of the hypertensive kidney in response to arginine-HCl reflects an exaggerated response to an activated TGF.
Asunto(s)
Arginina/farmacología , Tasa de Filtración Glomerular/efectos de los fármacos , Hipertensión/fisiopatología , Glomérulos Renales/fisiopatología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/fisiopatología , Adulto , Aniones , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Ácido Cítrico , Retroalimentación Fisiológica , Femenino , Humanos , Ácido Clorhídrico , Concentración de Iones de Hidrógeno , Glomérulos Renales/efectos de los fármacos , Túbulos Renales Proximales/irrigación sanguínea , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Tasa de Depuración Metabólica/fisiología , Persona de Mediana Edad , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND: Rates of cardiovascular morbidity and mortality are greater in heavy alcoholics than in either teetotallers or light-to-moderate drinkers. OBJECTIVE: On the assumption that factors leading to atherosclerotic damage remain operative even after long-term alcohol withdrawal, we studied the possible mechanisms of raised cardiovascular risk in former heavy alcoholics. METHODS: Forty-two apparently disease-free, normotensive alcoholics detoxified for 37.1 +/- 31.9 (SD) months, median 24, participated in the study. They were compared with 39 lifetime alcohol-abstaining control subjects, carefully matched for age, sex, body mass index, smoking and dietary habits, physical activity, lipids and fasting glucose. Endothelial function (flow-mediated dilation of brachial artery, high-resolution ultrasound technique), blood pressure, and some parameters of endothelial activation, oxidative stress, vascular inflammation and insulin sensitivity were measured. RESULTS: The maximal percentage of flow-mediated dilatation was reduced in detoxified alcoholics (10.1 +/- 4.6 versus 14.9 +/- 7.4, P < 0.001) who also showed significantly higher blood pressure (systolic 127.5 +/- 12.9 versus 118.2 +/- 10.7 mmHg, P < 0.001; diastolic 79.4 +/- 7.1 versus 74.6 +/- 6.4 mmHg, P < 0.01; mean 95.4 +/- 8.2 versus 89.1 +/- 7.3 mmHg, P < 0.001), uric acid (5.0 +/- 1.1 versus 4.4 +/- 0.8 mg/dl, P < 0.05), high-sensitivity C-reactive protein (2.1 +/- 2.0 versus 1.0 +/- 0.9 mg/l, P < 0.01), endothelin-1 (0.38 +/- 0.11 versus 0.17 +/- 0.10 pg/ml, P < 0.001) and fasting insulin (10.4 +/- 4.5 versus 5.6 +/- 1.6 muU/ml, P < 0.001) with abnormal homeostasis model assessment index of insulin resistance (2.3 +/- 1.1 versus 1.2 +/- 0.4, P < 0.001). CONCLUSION: Previous heavy alcoholism, in spite of long-term withdrawal, is associated with endothelial dysfunction and a wide cluster of haemodynamic, vascular and metabolic abnormalities that indicate an unfavourable cardiovascular and metabolic risk profile even in apparently disease-free former alcoholics.
Asunto(s)
Alcoholismo/complicaciones , Enfermedades Cardiovasculares/fisiopatología , Endotelio Vascular/fisiopatología , Vasodilatación/fisiología , Adulto , Alcoholismo/rehabilitación , Biomarcadores/sangre , Presión Sanguínea/fisiología , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/fisiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Femenino , Humanos , Inflamación , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Medición de Riesgo , Templanza , Tiempo , UltrasonografíaRESUMEN
To investigate whether endothelin-A receptors mediate hemodynamic changes caused by exogenous Angiotensin II in humans, 7 healthy volunteers on a 250-mmol sodium diet underwent 3 separate p-aminohippurate and inulin-based renal hemodynamic studies. In 2 studies, Angiotensin II (increasing rates of 0.625, 1.25, and 2.5 ng/kg per minute, each for 30 minutes) was infused either alone or combined with endothelin-A blocker, BQ123, 0.4 nmol/kg per minute. A third infusion of BQ123 alone was not followed by any change. Angiotensin II infusion alone produced a progressive decrease in renal blood flow (1080+/-94 mL/minx1.73 m2 to 801+/-52, P<0.001, versus baseline) and glomerular filtration rate (115+/-7 mL/minx1.73 m2 to 97+/-7, P<0.001) with increase in filtration fraction (0.188+/-.017 to 0.220+/-.030, P<0.01). Mean arterial pressure and renal vascular resistance increased markedly (86.8+/-3.1 to 97.5+/-4.4 mm Hg, P<0.001 and 83+/-7 to 133+/-20 mm Hg/min per liter, P<0.001, respectively). With Angiotensin II+BQ 123, mean arterial pressure still rose (86.2+/-3.1 to 91.1+/-4.3, P<0.05 versus both baseline and BQ123 alone) but significantly less than with Angiotensin II alone (P<0.05). Renal blood flow (1077+/-76 to 993+/-79, P<0.001) and glomerular filtration rate (115+/-7 to 105+/-7, P<0.05) also changed to a significantly lesser extent than with Angiotensin II alone (P<0.05 for both), whereas filtration fraction remained unchanged (0.185+/-.015 to 0.186+/-.016). Renal vascular resistance rose only by 17% (82+/-5 to 95+/-9, P<0.001 versus baseline as well as versus BQ123 or Angiotensin II alone). The results show that endothelin through Endothelin-A receptors contributes substantially to the systemic and renal vasoconstriction of low-dose exogenous Angiotensin II in healthy humans.
Asunto(s)
Angiotensina II/farmacología , Riñón/fisiología , Receptores de Endotelina/fisiología , Vasoconstrictores/farmacología , Adulto , Presión Sanguínea/efectos de los fármacos , Antagonistas de los Receptores de Endotelina , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Masculino , Natriuresis/efectos de los fármacos , Péptidos Cíclicos/farmacología , Receptor de Endotelina A , Vasoconstricción/efectos de los fármacosRESUMEN
To investigate whether endothelin-A receptors and nitric oxide modulate renal hemodynamics in man under angiotensin II receptor-1 blockade, 6 healthy volunteers, on a 240 mmol Na diet, underwent 4 separate renal hemodynamic measurements, in 3 of which endothelin-A blocker BQ-123 0.2 nmol.kg.min(-1) was infused for 90 minutes after pretreatment with either placebo, telmisartan 1 mg.kg center dot day(-1) for 3 days, or telmisartan as well, but with co-infusion of both BQ-123 and N(G)-nitro-L-arginine methylester 0.5 microg.kg center dot min(-1). A fourth infusion was made with N(G)-nitro-L-arginine methylester alone. No change followed infusion of either N(G)-nitro-L-arginine methylester alone or BQ-123 alone. With BQ-123 after telmisartan, renal blood flow rose from 916 +/- 56 mL center dot min(-1) center dot 1.73 m(2) to 1047 +/- 51.2 (P<0.001), and renal vascular resistances fell from 89 +/- 7 mm Hg center dot min center dot L(-1) to 74 +/-4 (P<0.001). These changes were fully abolished by the co-infused N(G)-nitro-L-arginine methylester. Infusion of BQ-123, devoid of renal hemodynamic effects at baseline, produces significant renal vasodilation when angiotensin II receptors are blocked, indicating an increasing renal hemodynamic role of endothelin-A--receptor activity. Because such a vasodilation is prevented by nonvasoconstricting microdoses of N(G)-nitro-L-arginine methylester, nitric oxide--endothelin balance controls substantially renal hemodynamics under angiotensin II blockade. These findings are consistent with a rationale of the association of endothelin-A blockers with angiotensin II blockers or angiotensin-converting enzyme inhibitors in treating nitric oxide--deficient conditions such as arterial hypertension, heart failure, and chronic renal diseases.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Endotelinas/fisiología , Riñón/fisiología , Óxido Nítrico/fisiología , Angiotensina II/fisiología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bencimidazoles/farmacología , Benzoatos/farmacología , Hemodinámica , Humanos , Riñón/efectos de los fármacos , TelmisartánRESUMEN
For investigation of whether interactions between prostaglandins and angiotensin II modulate renal response to acute nitric oxide synthesis inhibition in humans, seven young volunteers who were kept on a 240-mM Na diet underwent four experiments with 90 min of infusion of 3.0 microg/kg.min(-1) NG-nitro-L-arginine methyl ester (L-NAME), each preceded by a 3-d treatment with placebo (PL), 50 mg of losartan (LOS), 75 to 125 mg of indomethacin (IND), or both drugs. Mean arterial pressure (MAP), GFR, effective renal plasma flow (ERPF), and Na excretion rate (UNaV) were measured at baseline and from 0 to 45 min and 45 to 90 min of L-NAME infusion. After PL, L-NAME reduced GFR by 5% at 45 min (P < 0.05) and by 9% at 90 min (P < 0.001), ERPF by 11 to 17% (P < 0.001), and UNaV by 28 to 45% (P < 0.001). MAP, unchanged at 45 min, rose by 5% (P < 0.001) at 90 min. LOS prevented pressor but not renal effects of L-NAME. With L-NAME+IND, MAP rose even at 45 min (+5%; P < 0.001 versus baseline) with a 10% rise at 90 min (P < 0.001). Changes in GFR (-13 to -20%), ERPF (-19 to -26%), and UNaV (-51 to -70%) were greater than those with L-NAME+PL or L-NAME+LOS (P < 0.05 to 0.001). With L-NAME+IND+LOS, MAP did not increase, and GFR, ERPF, and UNaV fell much less than with L-NAME+IND alone (P < 0.02 to 0.001) with no differences versus PL or LOS alone. Angiotensin II blockade does not affect renal changes caused by L-NAME but prevents their potentiation by prostaglandin inhibition. Thus, endogenous prostaglandins counteract renal actions of endogenous angiotensin II in Na-repleted humans even when nitric oxide synthesis is inhibited.