Hein A. Koomans

Tetrahydrobiopterin restores endothelial function in hypercholesterolemia.

In hypercholesterolemia, impaired nitric oxide activity has been associated with increased nitric oxide degradation by oxygen radicals. Deficiency of tetrahydrobiopterin, an essential cofactor of nitric oxide synthase, causes both impaired nitric oxide activity and increased oxygen radical formation. In this study we tested whether tetrahydrobiopterin deficiency contributes to the decreased nitric oxide activity observed in hypercholesterolemic patients. Therefore, L-mono-methyl-arginine to inhibit basal nitric oxide activity, serotonin to stimulate nitric oxide activity, and nitroprusside as endothelium-independent vasodilator were infused in the brachial artery of 13 patients with familial hypercholesterolemia and 13 matched controls. The infusions were repeated during coinfusion of L-arginine (200 microg/kg/min), tetrahydrobiopterin (500 microg/min), or the combination of both compounds. Forearm vasomotion was assessed using forearm venous occlusion plethysmography and expressed as ratio of blood flow between measurement and control arm (M/C ratio). Tetrahydrobiopterin infusion alone did not alter M/C ratio. Both the attenuated L-mono-methyl-arginine-induced vasoconstriction as well as the impaired serotonin-induced vasodilation were restored in patients during tetrahydrobiopterin infusion. Tetrahydrobiopterin had no effect in controls. In conclusion, this study demonstrates restoration of endothelial dysfunction by tetrahydrobiopterin suppletion in hypercholesterolemic patients.

Endothelin-A Receptor Antagonist–Mediated Vasodilatation Is Attenuated by Inhibition of Nitric Oxide Synthesis and by Endothelin-B Receptor Blockade

BACKGROUND The role of endothelin (ET)-1 in maintenance of basal vascular tone has been demonstrated by local and systemic vasodilatation to endothelin receptor antagonists in humans. Although the constrictor effects mediated by the vascular smooth muscle ET(A) receptors are clear, the contribution from endothelial and vascular smooth muscle ET(B) receptors remains to be defined. The present study, in human forearm resistance vessels in vivo, was designed to further investigate the physiological function of ET(A) and ET(B) receptor subtypes in human blood vessels and determine the mechanism underlying the vasodilatation to the ET(A)-selective receptor antagonist BQ-123. METHODS AND RESULTS Two studies were performed, each in groups of eight healthy subjects. Brachial artery infusion of BQ-123 caused significant forearm vasodilatation in both studies. This vasodilatation was reduced by 95% (P=.006) with inhibition of the endogenous generation of nitric oxide and by 38% (P<.001) with coinfusion of the ET(B) receptor antagonist BQ-788. In contrast, inhibition of prostanoid generation did not affect the response to BQ-123. Infusion of BQ-788 alone produced a 20% reduction in forearm blood flow (P<.001). CONCLUSIONS Selective ET(A) receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo. This response appears to result in major part from an increase in nitric oxide generation. ET(B) receptor antagonism either alone or on a background of ET(A) antagonism causes local vasoconstriction, indicating that ET(B) receptors in blood vessels respond to ET-1 predominantly by causing vasodilatation.

Reduction of Sympathetic Hyperactivity by Enalapril in Patients with Chronic Renal Failure

BACKGROUND Inhibition of angiotensin-converting enzyme (ACE) reduces the risk of cardiovascular problems in patients with chronic renal failure. This effect may be due in part to a decrease in sympathetic nervous activity, but no direct evidence of such an action is available. METHODS We studied muscle sympathetic-nerve activity in 14 patients with hypertension, chronic renal failure, and increased plasma renin activity before, during, and after administration of the ACE inhibitor enalapril. Ten other patients with similar clinical characteristics were studied before and during treatment with the calcium-channel blocker amlodipine. Normal subjects matched for age and weight were included in both studies. RESULTS At base line, mean (+/-SD) muscle sympathetic-nerve activity was higher in the group of patients who received enalapril than in the control subjects (35+/-17 vs. 19+/-9 bursts per minute, P=0.004). The baroreflex curve, which reflects changes in muscle sympathetic-nerve activity caused by manipulations of blood pressure with sodium nitroprusside and phenylephrine, was shifted to the right in the patients, but baroreflex sensitivity was similar to that in the control subjects (-2.1+/-1.9 and -2.7+/-1.3 bursts per minute per mm Hg, respectively; P=0.36). A single dose of the sympatholytic drug clonidine caused a greater fall in blood pressure in the patients than in the control subjects. Treatment with enalapril normalized blood pressure and muscle sympathetic-nerve activity (at 23+/-10 bursts per minute) in the patients and shifted the baroreflex curve to the left, reflecting normal blood-pressure levels, without significantly changing sensitivity (-2.3+/-1.8 bursts per minute per mm Hg, P=0.96). In the patients who received amlodipine, treatment also lowered blood pressure but increased muscle sympathetic-nerve activity, from 41+/-19 to 56+/-14 bursts per minute (P=0.02). CONCLUSIONS Increased sympathetic activity contributes to hypertension in patients with chronic renal disease. ACE inhibition controls hypertension and decreases sympathetic hyperactivity.

Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication

To study whether vascular dysfunction in hypercholesterolaemia is reversible, we investigated patients without overt arterial disease who were taking maintenance treatment for hypercholesterolaemia. Medication was stopped for 2 weeks, reinstituted for 12 weeks, and again stopped for 6 weeks. During both maintenance treatment and the 12 weeks of step-up medication the lipid profile was improved but did not return to normal. Dose-response curves for serotonin-induced vasodilatation, an index of nitric oxide-dependent vasodilatation, showed a comparable and significant rightward shift after a medication-free period of 2 and 6 weeks compared with control subjects, indicating endothelial dysfunction, which was already maximum after 2 weeks. After 12 weeks of lipid-lowering medication, the difference in endothelial function between controls and patients had disappeared. Co-infusion of L-arginine, the substrate for nitric oxide synthase, returned the impaired serotonin response during hypercholesterolaemia to normal, but had no effect on this response in controls or in patients while on lipid-lowering medication. Neither endothelium-independent vasorelaxation, assessed by sodium nitroprusside infusion, nor vasoconstriction induced by the nitric oxide blocker L-NMMA, were different between controls and patients, whether the latter were on or off lipid-lowering medication. Our results show an L-arginine-sensitive, impaired nitric-oxide-mediated vascular relaxation of forearm resistance vessels in hypercholesterolaemia which is reproducible, and reversible after short-term lipid-lowering therapy. Demonstration of such changes in this readily accessible vascular bed will allow larger trials assessing vascular function during lipid-lowering therapy to be done.

Sympathetic Hyperactivity in Chronic Renal Failure: A Wake-up Call

Sympathetic hyperactivity plays an important and distinct role in hypertension associated with chronic renal failure (CRF). Renal ischemia, elevated angiotensin II, and suppressed brain nitric oxide (NO) all stimulate sympathetic activity. Evidence is accumulating for a role of sympathetic hyperactivity in renal and cardiac damage in patients with CRF. Decreased NO availability and increased oxidative stress, characteristic in CRF patients, seem to sensitize target organs for damaging actions of sympathetic hyperactivity. Fortunately, sympatholytic agents can slow down progression of renal and cardiac dysfunction. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists suppress sympathetic activity, but complete elimination of the effect of sympathetic hyperactivity can be obtained only with specific adrenergic blockers. However, this important therapeutic option is grossly neglected, painfully illustrated by the unwillingness to treat CRF patients with beta-blockers, even if they have had a myocardial infarction. After discussion of mechanisms and effects of the sympathetic hyperactivity, a case is made for increased application of specific adrenergic blockers in patients with CRF.

Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure

In patients with chronic renal failure (CRF), atherosclerosis is a major cause of cardiovascular morbidity and mortality. Generally, atherosclerosis has been associated with a reduced bioavailability of nitric oxide (NO). Experimental studies have indicated the presence of enhanced NO degradation by reactive oxygen species as well as decreased NO production as possible causes for this reduced NO bioavailability. So far, the question whether or not NO production is impaired in patients with CRF has never been investigated. Therefore, we measured whole body NO production in 7 patients with CRF, and in 7 matched healthy subjects. To assess the relative importance of a dysfunction of NO synthase (NOS), we compared the NO production of these patients to that of 2 other groups known to have endothelial dysfunction, ie, 7 patients with familial hypercholesterolemia (FH) who did not yet have signs of clinical cardiovascular disease (all nonsmokers), and 5 cigarette smokers. These groups were also compared with 7 nonsmoking, age-matched healthy subjects. Whole body NO production, determined as in vivo arginine-to-citrulline conversion, was assessed by giving an intravenous infusion of [15N2]-arginine as a substrate for NOS and measuring isotopic plasma enrichment of [15N]-citrulline by LC-MS. NO production in the CRF patients (0.13+/-0.02 micromol. kg-1. h-1) was significantly lower (P<0.05) than in the corresponding control group (0.23+/-0.09 micromol. kg-1. h-1). NO production also tended to be lower in the FH patients (0.16+/-0.04 micromol. kg-1. h-1), but the difference with the corresponding control group did not reach significance (0.22+/-0.06 micromol. kg-1. h-1). In the group of smokers, NO production was similar to that in nonsmokers (0. 22+/-0.09 micromol. kg-1. h-1). In conclusion, it is demonstrated for the first time that basal whole body NO production is reduced in patients with CRF. This finding implies that therapeutic interventions to endothelial dysfunction in these patients should be primarily directed toward improvement of NO production. The finding of only a tendency toward reduction of NO production in patients with FH and the absence of a reduction in cigarette smokers suggests that other mechanisms such as enhanced NO degradation may be involved in the decrease of NO bioavailability in these groups.

Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia : A randomized placebo-controlled trial

BACKGROUND Folates have been suggested to be of benefit in reducing cardiovascular risk. The present study was designed to examine whether oral folic acid supplementation could improve endothelial function as an intermediate end point for cardiovascular risk in patients with increased risk of atherosclerosis due to familial hypercholesterolemia (FH). METHODS AND RESULTS In a prospective, randomized, double-blind, placebo-controlled study with crossover design, we evaluated the effects of 4 weeks of treatment with oral folic acid (5 mg PO) on endothelial function in FH. In 20 FH patients, forearm vascular function was assessed at baseline, after 4 weeks of folic acid treatment, and after 4 weeks of placebo treatment by venous occlusion plethysmography, with serotonin and sodium nitroprusside used as endothelium-dependent and -independent vasodilators. In addition, we examined the vasoconstrictor response to the NO synthase inhibitor N(G)-monomethyl-L-arginine to assess basal NO activity. In FH patients, folic acid supplementation restored the impaired endothelium-dependent vasodilation, whereas it did not significantly influence endothelium-independent vasodilation or basal forearm vasomotion. There was a trend toward improvement in basal NO activity. CONCLUSIONS These data demonstrate that oral supplementation of folic acid can improve endothelial function in patients with increased risk of atherosclerotic disease due to hypercholesterolemia, without changes in plasma lipids.

Transluminal vascular stents for ostial atherosclerotic renal artery stenosis

We implanted transluminal stents in 24 hypertensive patients with a critical atherosclerotic ostial renal artery stenosis (28 arteries). Immediate revascularisation was successful in all. Follow-up angiography at 6 months, available in 18 patients, revealed restenosis twice. In another patient restenosis was suspected and confirmed by angiography at 2 months. Hence, the total restenosis rate was 3 of 19 patients (16%) and 3 of 23 arteries (13%). Two patients developed renal insufficiency due to cholesterol embolism. In the remaining 22 patients renal function improved (n = 8) or stabilised (n = 14). Although all had to resume antihypertensive treatment, blood pressure normalised in 15 patients, improved in one, remained unchanged in five and worsened in one.

Causes and consequences of increased sympathetic activity in renal disease

Abstract—Much evidence indicates increased sympathetic nervous activity (SNA) in renal disease. Renal ischemia is probably a primary event leading to increased SNA. Increased SNA often occurs in association with hypertension. However, the deleterious effect of increased SNA on the diseased kidney is not only caused by hypertension. Another characteristic of renal disease is unbalanced nitric oxide (NO) and angiotensin (Ang) activity. Increased SNA in renal disease may be sustained because a state of NO–Ang II unbalance is also present in the hypothalamus. Very few studies have directly compared the efficacy of adrenergic blockade with other renoprotective measures. Third-generation &bgr;-blockers seem to have more protective effects than traditional &bgr;-blockers, possibly via stimulation of NO release. Although it has been extensively documented that muscle SNA is increased in chronic renal failure, data on renal SNA and cardiac SNA are not available for these patients before end-stage renal disease. It is also unknown whether additional treatment with third-generation &bgr;-blockers can delay the progression of renal injury and prevent cardiac injury in chronic renal failure more efficiently than conventional treatment with angiotensin-converting enzyme inhibitors only.

Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure

The aim of this study was to compare the effects on BP and sympathetic activity of chronic treatment with an angiotensin (Ang)-converting enzyme (ACE) inhibitor and an AngII receptor blocker in hypertensive patients with chronic renal failure (CRF). In ten stable hypertensive CRF patients (creatinine clearance, 46 +/- 17 ml/min per 1.73 m(2)), muscle sympathetic nerve activity (MSNA), plasma renin activity (PRA), baroreceptor sensitivity, and 24-h ambulatory BP were measured in the absence of antihypertensive drugs (except diuretics) after 6 wk of enalapril (10 mg orally) and after 6 wk of losartan (100 mg orally). The order of the three phases was randomized. Normovolemia was controlled with diuretics and confirmed with extracellular fluid volume measurements throughout the study. Both enalapril and losartan reduced MSNA (from 33 +/- 10 to 27 +/- 13 and 27 +/- 13 bursts/min, respectively; P < 0.05) and average 24-h BP (from 141 +/- 8/93 +/- 8 to 124 +/- 9/79 +/- 8 and 127 +/- 8/81 +/- 9 mmHg; P < 0.01). PRA was not different during the treatments. The change in BP and the change in MSNA during the treatments were correlated (r = 0.70 and r = 0.63, respectively; both P < 0.05). Baroreceptor sensitivity was not affected by the treatments. This is the first study to compare the effects of ACE inhibition and AngII blockade on MSNA. In hypertensive CRF patients, enalapril and losartan equally reduced BP and MSNA. Differences in modes of action of the two drugs did not result in differences in effects on MSNA, supporting the view that AngII-mediated mechanisms contribute importantly in the pathogenesis of sympathetic hyperactivity in these patients.