Abstract-Eight Na-repleted volunteers underwent 3 separate 90-minute infusions of either N G -nitro-L-arginine methyl ester (L-NAME) 3.0 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 or endothelin-A receptor (ET-A) blocker BQ-123 (BQ) 0.125 nmol ⅐ kg Ϫ1 ⅐ min Ϫ1or 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% (PϽ0.001 versus b) in period 1, to 9.9% (PϽ0.001) in period 2 with L-NAME, and by 3.3% (PϽ0.01) to 6.6% (PϽ0.001) with L-NAME plus BQ (PϭNS 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%; PϽ0.001) but not with coinfused BQ (2.1%; PϭNA versus b, Pϭ0.005 versus L-NAME alone). RBF declined by 12.2% (PϽ0.001) to 18.3% (PϽ0.001) with L-NAME and by 4.6% (PϽ0.005) to 8.2% (PϽ0.001) with L-NAME plus BQ. These changes were smaller with L-NAME plus BQ (PϽ0.05 in period 1 and PϽ0.02 in period 2). Blunted changes were also seen for RVR (PϽ0.005 in period 1 and PϽ0.001 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.

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.

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.

Abstract-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 ⅐ kg ⅐ min Ϫ1 was infused for 90 minutes after pretreatment with either placebo, telmisartan 1 mg ⅐ kg ⅐ day Ϫ1 for 3 days, or telmisartan as well, but with co-infusion of both BQ-123 and N G -nitro-L-arginine methylester 0.5 g ⅐ kg ⅐ min Ϫ1 . 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 916Ϯ56 mL ⅐ min Ϫ1 ⅐ 1.73 m 2 to 1047Ϯ51.2 (PϽ0.001), and renal vascular resistances fell from 89Ϯ7 mm Hg ⅐ min ⅐ L Ϫ1 to 74Ϯ4 (PϽ0.001). 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. Key Words: angiotensin II Ⅲ nitric oxide Ⅲ endothelin Ⅲ kidney Ⅲ hemodynamics Ⅲ L-NAME Ⅲ receptors, endothelin H emodynamic control in both systemic circulation and kidney results physiologically from a balance of opposing vasodilator systems such as nitric oxide (NO) and prostaglandins, and vasoconstrictor systems. 1 These latter include, besides sympathetic nervous system, the 2 potent peptide vasoconstrictors angiotensin II (Ang II) and endothelin-1 (ET-1), 1 this latter being the predominant isoform of endothelin family expressed in human vasculature. 2 Vasoactive properties of ET-1 are mediated by 2 receptor subtypes, ET A and ET B , both leading to vasoconstriction in vascular smooth muscle cells, whereas activation of ET B in endothelial cells may cause vasodilation through the release of prostacyclin and NO. 2,3 At the kidney level, however, studies in both dogs 4,5 and humans 6,7,8 have indicated the ET A receptor as the main mediator of the vasoconstrictor effect of ET-1.A considerable body of evidence has shown that ET-1, although it is the most potent endogenous vasoconstrictor, assumes a major hemodynamic role and contributes to the end-organ damage, mainly under experimental and clinical pathophysiological conditions. 2,3 Furthermore, a number of interactions have been recognized between Ang II and ET...

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. Key Words: receptors, endothelin Ⅲ angiotensin II Ⅲ kidney Ⅲ hemodynamics Ⅲ human A ngiotensin II (Ang II), a potent endogenous vasoconstricting and sodium-retaining peptide, plays a key role in the regulation of renal function and arterial pressure, 1,2 mostly by activating Ang II-type 1 (AT1) receptors, which leads to elevation in blood pressure, renal vasoconstriction, and sodium retention. Several of such actions are similar to those of endothelin-1 (ET-1), which is the predominant isoform of the endothelin family in human vasculature. 3,4 Vasoactive properties of ET-1 are mediated by two receptor subtypes, ET A and ET B , both leading to vasoconstriction in vascular smooth cells, whereas activation of ET B in endothelial cells causes vasodilation as the result of release of prostacyclin and nitric oxide (NO). 3,4 In humans, however, the ET A receptor is the main mediator of ET-1 renal vasoconstriction. 5-8 ET-1, although it is the most potent endogenous vasoconstrictor, assumes a major hemodynamic role and contributes to the end-organ damage, mainly under experimental pathophysiological conditions. 3,4,9 -11 In most of these, interactions between Ang II and ET-1 may contribute largely to the observed changes. For instance, salt-sensitive hypertension, renal vasoconstriction, and cardiovascular and renal fibrotic damage, produced by chronic administration of exogenous Ang II, can be prevented by inhibition of endogenous ET-1, indicating that ET-1 mediates much of the vasoconstriction caused by chronic Ang II. 9 -11 Furthermore, ET-1 participates in the acute pressor effects of exogenous Ang II 12,13 and partly mediates the vasoconstriction from exogenous Ang II in different vascular beds, including kidney. 14,15 Interestingly, studies in rats have shown that such Ang II-ET-1 interaction may be sodium-dependent, because under elevated sodium intake, ET A blockade inhibited Ang II hypertension much more than under sodium restriction. 16 Ang II also stimulates both ET-1 synthesis and release, 3,4,17 whereas ET-1 enhances the pressor action of Ang II. 18 Finally, ET-1 and Ang II share the same intracellular signaling pathways. 3,17 Thus, ET-1 is generally considered as a powerful mediator of Ang II-dependent vasoconstriction and organ damage under experimental conditions. Conversely, little is known on the role of ET-1 and of its potential interactions with Ang II on systemic and renal hemodynamics in humans. In normal humans, systemic ET A blockade markedly blunts systemic and renal vasoconstr...