Nicoletta Carra

Endothelin-A Blockade Attenuates Systemic and Renal Hemodynamic Effects of L-NAME in Humans

Eight Na-repleted volunteers underwent 3 separate 90-minute infusions of either N(G)-nitro-L-arginine methyl ester (L-NAME) 3.0 mg. kg(-1). min(-1) or endothelin-A receptor (ET-A) blocker BQ-123 (BQ) 0.125 nmol. kg(-1). min(-1) or both. Mean arterial pressure (MAP), glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistances (RVR), and sodium excretion rate (UNaV) were measured at baseline (b) and from 0 to 45 minutes (period 1) and 45 to 90 minutes (period 2) of infusion. BQ alone had no effect. GFR declined by 4.9% (P<0.001 versus b) in period 1, to 9.9% (P<0. 001) in period 2 with L-NAME, and by 3.3% (P<0.01) to 6.6% (P<0.001) with L-NAME plus BQ (P=NS between L-NAME and L-NAME plus BQ). UNaV fell equally with L-NAME or L-NAME plus BQ. MAP rose significantly in period 2 with L-NAME (6.9%; P<0.001) but not with coinfused BQ (2. 1%; P=NA versus b, P=0.005 versus L-NAME alone). RBF declined by 12. 2% (P<0.001) to 18.3% (P<0.001) with L-NAME and by 4.6% (P<0.005) to 8.2% (P<0.001) with L-NAME plus BQ. These changes were smaller with L-NAME plus BQ (P<0.05 in period 1 and P<0.02 in period 2). Blunted changes were also seen for RVR (P<0.005 in period 1 and P<0.001 in period 2 between L-NAME alone and L-NAME plus BQ). These findings show that systemic and renal vasoconstriction due to L-NAME are attenuated by BQ, which suggests that an interaction between endogenous nitric oxide production and ET-A activity participates in the maintenance of baseline systemic and renal vascular tone in humans.

Endothelial dysfunction and cardiovascular risk profile in long-term withdrawing alcoholics.

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 μU/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.

Endothelin-A Receptors Mediate Renal Hemodynamic Effects of Exogenous Angiotensin II in Humans

Abstract—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/min×1.73 m2 to 801±52, P <0.001, versus baseline) and glomerular filtration rate (115±7 mL/min×1.73 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.

Impaired renal haemodynamic response to L-arginine in essential hypertension : role of buffering anion and tubuloglomerular feedback

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.