Reduced venous responsiveness to endothelin-1 but not noradrenaline in hypertensive chronic renal failure.

BACKGROUND: Endothelin-1 (ET-1), acting mainly through the ET(A) receptor, is a potent endothelium-derived vasoconstrictor peptide. Circulating concentrations of ET-1 are increased in chronic renal failure (CRF) and may influence vascular tone. METHODS: We investigated dorsal hand vein responsiveness to local infusion of ET-1 and noradrenaline in 12 hypertensive and 12 normotensive CRF patients and in 12 age and sex matched control subjects. We also investigated dorsal hand vein responses to the ET(A) receptor antagonist, BQ-123, and the endothelium-independent vasodilator glyceryl trinitrate (GTN), in six patients with CRF. RESULTS: The dose of noradrenaline causing a 50% of maximal vasoconstriction was similar in the hypertensive (32+/-11 pmol/min) and normotensive (26+/-7 pmol/min) CRF patients and control subjects (21+/-6 pmol/min). Vasoconstriction to ET-1 (5 pmol/min) was similar in CRF patients as a whole (AUC 35+/-5%) and controls (32+/-4%; P=0.70). However, venoconstriction was significantly less in hypertensive (23+/-6%) than in normotensive CRF patients (48+/-8%; P=0.01). Overall, venoconstriction to ET-1 correlated inversely with mean arterial blood pressure in the CRF patients (R=-0.43, P=0.04). In addition, basal vein size was smaller, and plasma endothelin concentrations greater, in the hypertensive CRF group. However, infusion of BQ-123 or GTN did not cause venodilatation in these subjects. CONCLUSIONS: These studies are consistent with the hypothesis that elevated plasma ET-1 contributes to vascular tone, and elevated blood pressure, in hypertensive CRF patients, and is associated with vascular receptor downregulation consequent on the increased exposure to ET-1. The reduced vein size in CRF patients appears to be structural rather than functional in nature. Further long-term studies with endothelin antagonists are required to determine the pathophysiological role of ET-1 in the altered structure and function of blood vessels in patients with CRF.

Reduced endogenous endothelin-1-mediated vascular tone in chronic renal failure.

BACKGROUND: Endothelin-1 generated by the vascular endothelium contributes to basal vascular tone and blood pressure in healthy humans. Plasma concentrations of endothelin-1, which are elevated in chronic renal failure (CRF), may contribute to increased vascular tone. METHODS: We investigated the contribution of endogenous and exogenous endothelin-1 to the maintenance of vascular tone in patients with CRF (creatinine > or = 200 mumol/liter) and in age- and sex-matched healthy subjects. In a series of experiments, we measured forearm vascular responses to intra-arterial norepinephrine (30 to 240 pmol/min), endothelin-1 (5 pmol/min), the selective endothelin A (ETA) receptor antagonist BQ-123 (3 mg/hr), the mixed endothelin-converting enzyme and neutral endopeptidase inhibitor phosphoramidon (30 nmol/min), and the selective neutral endopeptidase inhibitor thiorphan (30 nmol/min). RESULTS: The maximum reduction in forearm blood flow (FBF) to norepinephrine in CRF (33 +/- 7%) was similar to that in controls (43 +/- 7%, P = 0.53). Endothelin-1 also produced a similar reduction in FBF in CRF (35 +/- 6%) and controls (36 +/- 5%, P = 0.81). BQ-123 increased FBF in CRF (11 +/- 4%) but significantly less than in controls (44 +/- 10%, P = 0.02). Phosphoramidon increased FBF in CRF (68 +/- 20%), again significantly less than in controls (181 +/- 41%, P = 0.001). Thiorphan reduced FBF similarly in CRF (22 +/- 6%) and controls (14 +/- 6%, P = 0.39). Responses to phosphoramidon were substantially greater than to BQ-123. CONCLUSIONS: These studies show that endogenous generation of endothelin-1 contributes to the maintenance of resting vascular tone in patients with CRF, as well as in healthy subjects. Although the contribution of endogenous endothelin-1 to resting vascular tone appears to be reduced in CRF, ETA receptor antagonism, and particularly endothelin-converting enzyme inhibition, should be explored as means by which to reduce vascular tone and blood pressure in patients with CRF.

Impairment of forearm vasodilatation to acetylcholine in hypercholesterolemia is reversed by aspirin.

OBJECTIVE: Impaired cholinergic vasodilatation in the forearm in hypertension and hypercholesterolemia has been attributed to impaired nitric oxide bioavailability. However, inhibition of cyclooxygenase reverses the impaired cholinergic dilatation in hypertensive animals and patients. The aim of this study was to examine the effect of aspirin on cholinergic vasodilatation in hypercholesterolemic patients. METHODS: We examined responses to brachial artery infusion of acetylcholine and the endothelium-independent vasodilator sodium nitroprusside in the presence or absence of aspirin in 10 hypercholesterolemic patients (7 men/3 women; aged 38-63 yr; systolic blood pressure 133 +/- 5 mmHg; diastolic blood pressure 80 +/- 3) compared with 10 matched controls (7 men/3 women; aged 38-63 yr; systolic blood pressure 126 +/- 2; diastolic blood pressure 77 +/- 2). RESULTS: In hypercholesterolemic patients, forearm vasodilatation was impaired in response to acetylcholine (112 +/- 20 vs. 346 +/- 30% increase in blood flow in controls, at the highest dose [15 micrograms min-1]; P < 0.0001) but not in response to sodium nitroprusside. With the addition of aspirin, baseline forearm blood flow was unaltered. However, forearm vasodilatation to acetylcholine was partially restored in hypercholesterolemics (from 112 +/- 20 to 193 +/- 30%; P < 0.001) though not affected in controls. Vasodilator responses to sodium nitroprusside were unaffected by aspirin in either group. CONCLUSIONS: In hypercholesterolemia, an altered balance between vasoconstrictor and dilator prostanoids, favouring constrictors, may contribute to endothelial dysfunction either directly or through an effect on nitric oxide synthesis. Restoration of this imbalance may be a component of the therapeutic benefit of aspirin in cardiovascular disease.

Studies with iontophoretic administration of drugs to human dermal vessels in vivo: cholinergic vasodilatation is mediated by dilator prostanoids rather than nitric oxide.

AIMS: Impaired function of the vascular endothelium has been well documented in hypertension and hypercholesterolaemia. However, the 'gold standard' method for assessing endothelial function, using intra-arterial drug infusion, is invasive and has only been applied in the forearm and coronary circulations in vivo. The aim of the present study was to establish the non-invasive technique of transdermal drug iontophoresis to assess endothelial function in human dermal vessels in vivo. METHODS: In healthy male volunteers, we delivered acetylcholine (ACh) and sodium nitroprusside (SNP) to dermal vessels of the forearm using iontophoresis, and measured vasodilatation using laser Doppler fluximetry. Drugs were diluted in a methylcellulose gel vehicle which did not induce vasodilatation. To assess the contribution of nitric oxide and vasoactive prostanoids to cholinergic dilatation, the procedure was repeated during brachial artery infusion of the nitric oxide synthase inhibitor, L-N(G)-monomethyl-arginine (L-NMMA) and after intravenous administration of the cyclooxygenase inhibitor, aspirin. As a control for the vasoconstrictor effect of L-NMMA, which was measured by venous occlusion plethysmography, iontophoresis was repeated during brachial artery infusion of noradrenaline. RESULTS: Flux increased in response to iontophoresis of ACh (from 45 +/- 9 to 499 +/- 80 units; P < 0.0001) and SNP (from 32 +/- 11 to 607 +/- 82 units; P < 0.0001). Brachial artery infusions of L-NMMA or noradrenaline caused reductions in forearm blood flow (by 43 +/- 2% and 44 +/- 2%, respectively) but did not inhibit vasodilatation in response to iontophoresis of ACh or SNP. In contrast, aspirin inhibited the response to iontophoresis of ACh (from 473 +/- 81 to 222 +/- 43 units; P < 0.0001) but did not affect the response to SNP (from 348 +/- 59 to 355 +/- 58). CONCLUSIONS: We conclude that in healthy subjects, in contrast to the forearm circulation, dermal vasodilatation in response to iontophoresis of ACh is mediated predominately by a dilator prostanoid rather than by nitric oxide generation. Furthermore, the non-invasive technique of iontophoresis could complement existing invasive tests of endothelial function in future clinical studies.

Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction.

In end-stage renal failure (ESRF) symptomatic hemodialysis-related hypotension may prevent effective provision of renal replacement therapy. Endogenous inhibitors of nitric oxide synthase accumulate in ESRF and are cleared by dialysis. We, therefore, hypothesised that removal of these inhibitors by hemodialysis would increase endothelial nitric oxide generation and promote venodilation. In vivo responses of norepinephrine preconstricted dorsal hand veins to locally active doses of acetylcholine (an activator of nitric oxide synthase) and glyceryl trinitrate (GTN; a nitric oxide donor) were examined in patients undergoing maintenance hemodialysis for ESRF and in healthy age- and sex-matched controls. Patient studies were undertaken before and after dialysis. Studies before dialysis were repeated with co-infusion of either L-arginine or its inactive enantiomer D-arginine. Venodilation in response to acetylcholine was impaired before, and corrected by, dialysis whereas venodilation to GTN was similar before and after dialysis. Venodilation in response to acetylcholine before dialysis was restored by co-infusion of L- but not D-arginine. Therefore, patients with ESRF undergoing hemodialysis have impaired acetylcholine-mediated venodilation consistent with the accumulation in ESRF of functionally important inhibitors of nitric oxide synthase that are cleared by dialysis.

Physiological role of nitric oxide in regulation of renal function in humans.

The physiological role of endogenous nitric oxide in regulation of renal function in humans is unclear. Eight healthy men received an inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (L-NMMA, 3 mg/kg), and saline placebo intravenously on two occasions. L-NMMA significantly increased mean arterial pressure (+7%) and total peripheral resistance (+36%). However, because renal plasma flow did not decrease significantly, the increase in renal vascular resistance (+21%) was significantly less than the increase in total peripheral resistance. Glomerular filtration rate (-19%), filtration fraction (-10%), urine flow rate (-18%), sodium (-28%), and free water excretion (-25%) all decreased significantly. Fractional distal, but not proximal, sodium reabsorption increased. L-NMMA also significantly decreased plasma nitrate and urinary excretion of nitrate and dopamine. There were no significant changes in plasma renin activity, plasma endothelin, and aldosterone or in platelet number and ex vivo aggregation. L-NMMA had a plasma half-life of 75 min. Basal generation of nitric oxide appears to contribute less to vascular tone in the kidney than systemically but may alter afferent arteriolar tone. Decreased fractional sodium excretion supports an important physiological role for nitric oxide in inhibition of tubular sodium reabsorption, possibly mediated by the renal dopaminergic system.

Erythropoietin enhances vascular responsiveness to norepinephrine in renal failure.

The mechanism of hypertension induced by recombinant human erythropoietin (rHuEPO) is unclear but may include an increase in peripheral vascular resistance. We studied changes of arterial pressure and plasma endothelin in nine consecutive hemodialysis patients before, and 6 and 12 weeks after, starting rHuEPO. In six patients, changes in cardiac index (CI), stroke index (SI) and total peripheral resistance index (TPRI) were measured by bioimpedance, and forearm vascular responsiveness to intra-arterial norepinephrine (30 to 240 pmol/min) and endothelin-1 (5 pmol/min) were assessed. Six healthy age and sex matched subjects also underwent assessment of forearm vascular responsiveness to norepinephrine and endothelin-1. Treatment with rHuEPO significantly increased hemoglobin and mean arterial pressure (MAP). TPRI also increased by 35 +/- 11%. Plasma endothelin, although elevated basally, remained unchanged. Intra-arterial infusion of norepinephrine caused a maximal increase in forearm vascular resistance (FVR) of 17 +/- 9% before rHuEPO, significantly less than the 32 +/- 5% increase in healthy control subjects (P = 0.04). The response increased to 65 +/- 15% (P = 0.03) after 12 weeks rHuEPO treatment (P = 0.51 vs. controls). Endothelin-1 caused a maximal increase of FVR at 60 minutes of 45 +/- 24% before rHuEPO, which was not significantly different from controls, and tended to decrease with rHuEPO therapy. The response to endothelin-1, but not norepinephrine, correlated inversely with MAP (r = -0.52; P = 0.03) and TPRI (r = -0.51; P = 0.04). In conclusion, these studies show that anemia in chronic renal failure is associated with depressed vascular responsiveness to norepinephrine which is restored by rHuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct and sympathetically mediated venoconstriction in essential hypertension. Enhanced responses to endothelin-1.

Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide. Although circulating concentrations are not increased in essential hypertension, enhanced sensitivity to endothelin-1 has been observed in animal models of hypertension. We investigated dorsal hand vein responses to local infusion of endothelin-1 and norepinephrine in 12 patients with essential hypertension who had never received treatment and in 12 age and sex matched normotensive control subjects. The maximal venoconstriction and the geometric mean of the dose of norepinephrine that caused 50% of maximal venoconstriction were similar in hypertensive (mean +/- SE; 80 +/- 4%; 31 +/- 8 pmol/min) and normotensive subjects (87 +/- 5%, 22 +/- 9 pmol/min). In contrast, mean venoconstriction to endothelin-1 was significantly greater in hypertensive (49 +/- 5%) than in normotensive subjects (27 +/- 2%; P = 0.004). Sympathetically mediated venoconstriction elicited by deep breath was substantially potentiated by endothelin-1 in hypertensive (67 +/- 7% at 90 min) but not normotensive subjects (11 +/- 3% at 90 min; P = 0.001). Venoconstriction to endothelin-1 correlated positively with mean arterial pressure in the hypertensive subjects (r = 0.82; p = 0.001) but negatively in the normotensive subjects (r = -0.58; p = 0.047). Endothelin-1 may contribute to the reduction of venous compliance occurring in the early stages of essential hypertension and to the altered systemic hemodynamics in this condition.

Cystometrography provides a previously unrecognized opportunity for successful management of urinary leaks after renal transplantation.

We report 3 cases of urinary leakage occurring in male kidney transplant recipients within 6 weeks of renal transplantation. Voiding cystometrography showed that high voiding detrusor pressure was the contributing factor. Endoscopic bladder outlet surgery restored normal detrusor voiding pressure and led to spontaneous resolution of urinary leakage without recurrence in all cases.