Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low disease activity.

OBJECTIVE: Cardiovascular mortality is excessive in patients with rheumatoid arthritis (RA). It has been proposed that the chronic inflammatory state of RA contributes to accelerated atherosclerosis. The aim of this study was to determine whether endothelial dysfunction, an early sign of arteriosclerosis, is present in young, long-term RA patients receiving standard methotrexate (MTX) therapy. Furthermore, we tested whether etanercept (ENC), a TNF-alpha receptor blocker, resulted in improved endothelial function compared to MTX in the same patients. METHODS: We studied eight RA patients twice: (1) on MTX and (2) after MTX washout and receiving ENC. Eight healthy volunteers matching for age, gender, height, weight and conventional cardiovascular risk factors served as control (C). All participants received intrabrachial infusions of increasing doses of acetylcholine (ACh, endothelium-dependent vasodilator) and glyceryl-trinitrate (GTN, endothelium-independent vasodilator). Forearm blood flow (FBF) was measured by bilateral venous occlusion plethysmography. RESULTS: Disease activity of RA was comparably low during both MTX and ENC (DAS 28 3.9+/-0.3 and 3.5+/-0.3). FBF in response to ACh was reduced in RA compared to C (P<0.01). Switching from MTX to ENC failed to improve vascular responsiveness to ACh. GTN comparably increased FBF in all groups. CONCLUSIONS: Our study for the first time demonstrates that long-term RA is associated with manifested endothelial dysfunction. Switching from MTX to ENC in stable RA patients has no beneficial effect on endothelial function.

Kidney transplantation improves endothelium-dependent vasodilation in patients with endstage renal disease.

Kidney transplantation (Tx) improves the cardiovascular outcome of patients receiving hemodialysis (HD). Therefore, we asked whether Tx improves the endothelial dysfunction of HD patients. Eight patients were studied twice: (1) during HD and (2) after Tx. We also studied eight matched control subjects. We measured forearm blood flow by venous occlusion plethysmography. We administered intrabrachial infusions of three doses of norepinephrine, glycerol trinitrate, acetylcholine (ACH), and N-monomethyl-L-arginine. The response to ACH was reduced in HD patients compared with controls (P<0.001). The response to ACH in HD patients improved after Tx, and this change was significant for low-dose ACH (P<0.05 for dose one and two compared with HD). The response to glycerol trinitrate, which was reduced in HD patients compared with controls (P<0.01), remained unchanged after Tx. N-monomethyl-L-arginine and norepinephrine comparably reduced forearm blood flow in all groups. This is the first evidence showing an improvement of endothelial dysfunction in HD patients after Tx.

Reduced agonist-induced endothelium-dependent vasodilation in uremia is attributable to an impairment of vascular nitric oxide.

Current concepts for the explanation of endothelial dysfunction and accelerated atherosclerosis in uremia propose a reduced vascular bioavailability of nitric oxide (NO). The aim of the present study was to test the contributions of NO and NO/prostacyclin (PGI(2))-independent mechanisms to both baseline vascular tone and agonist-induced endothelium-dependent vasodilation in patients on hemodialysis (HD). In 10 HD patients and eight matched healthy control subjects, forearm blood flow (FBF) was measured at rest and during intrabrachial infusions of norepinephrine (NE; endothelium-independent vasoconstrictor, 60, 120, and 240 pmol/min) and N-monomethyl-L-arginine (blocker of NO synthases, 16 micromol/min). After inhibition of cyclo-oxygenase by ibuprofen (1200 mg orally), endothelium-dependent and -independent vasodilation was assessed by infusion of acetylcholine (ACh; 1, 5, 10, 50, 100, and 300 nmol/min) and sodium-nitroprusside (2.5, 5, and 10 microg/min). NO/PGI(2)-independent vasodilation was tested by equal infusions of ACh during NO clamp. N-monomethyl-L-arginine reduced resting FBF to a comparable degree in both groups. Vascular responses to ACh were reduced in HD (P = 0.003 versus control by ANOVA), whereas those to sodium nitroprusside were mainly at control level. Infusion of ACh during NO clamp caused a similar increment of FBF in both groups. NO-mediated vasodilation as calculated by the difference between ACh-induced responses without and with NO clamp was substantially impaired in HD (P < 0.001) compared with control. In HD patients, baseline NO-mediated arteriolar tone is at control level. This study provides first evidence that endothelial dysfunction of uremic patients as shown by reduced agonist-induced endothelium-dependent vasodilation is attributable to reduced stimulation of NO, whereas the NO/PGI(2)-resistant portion of ACh-mediated vasodilation is unaffected.

Nitric oxide- and EDHF-mediated arteriolar tone in uremia is unaffected by selective inhibition of vascular cytochrome P450 2C9.

BACKGROUND: Uremia is a state of endothelial dysfunction as demonstrated by a reduced agonist-induced endothelium-dependent vasodilatation. Recent studies suggest that an endothelial cytochrome P450 (CYP) epoxygenase (CYP 2C9) can modulate endothelium-dependent vasodilatation in two different ways: (1) by the production of epoxyeicosatrienoic acids (EETs), which elicit hyperpolarization and relaxation; and (2) by the release of oxygen-derived free radicals, which compromise the bioavailability of nitric oxide. We therefore determined whether one of these pathways is involved in endothelial dysfunction of uremia. METHODS: Using venous occlusion plethysmography, we measured forearm blood flow (FBF) in response to the intrabrachial infusion of acetylcholine (ACh; endothelium-dependent vasodilator; 1, 5, 10, 50, 100, and 300 nmol/min) and sodium nitroprusside (SNP; endothelium-independent vasodilator; 2.5, 5 and 10 microg/min) in 10 stable patients on hemodialysis (HD) and 9 healthy control subjects. In HD patients, ACh infusions were repeated together with sulfaphenazole (SPZ, 6 mg/min), a highly selective inhibitor of CYP 2C9 with and without concomitant blockade of the nitric oxide synthase (NOS) by N(omega)monomethyl L-arginine (L-NMMA, 16 microumol/min). RESULTS: Endothelium-dependent vasodilatation to ACh was reduced in HD compared to control subjects (P= 0.002), indicating endothelial dysfunction in the patients examined. Endothelium-independent vascular responses to SNP were attenuated in HD, but not significantly different to control. SPZ failed to modulate both baseline FBF and Ach-induced vasodilatation in HD. Furthermore, SPZ had no effect on baseline FBF and ACh-mediated vasodilatation in the presence of L-NMMA in HD. CONCLUSION: Our results do not support a major role for CYP 2C9-derived products in the regulation of arteriolar tone in early endothelial dysfunction of uremic subjects.

Reduced endothelin-1- and nitric oxide-mediated arteriolar tone in hypertensive renal transplant recipients.

BACKGROUND: The prevalence of hypertension is high in renal transplant recipients. It has been suggested that calcineurin inhibitors (CI) contribute to the development of post-transplant hypertension by stimulating endothelin (ET-1)-mediated and/or reducing nitric oxide (NO)-mediated vascular tone. METHODS: We tested this hypothesis using 2 groups of renal transplant recipients [normotensive patients without a need for antihypertensive medication (Normo-Tx), and hypertensive patients requiring antihypertensives (Hyper-Tx)] in the presence of CI-based immunosuppression. In addition, we studied matched control subjects (C). BQ 123 (ET-A receptor antagonist), BQ123 + BQ788 (ET-A/B-receptor antagonist), ET-1, L-NMMA (NO-synthase inhibitor), acetylcholine (ACH; endothelium-dependent vasodilator), glyceroltrinitrate (GTN, NO donor), and norepinephrine (NE, endothelium-independent vasoconstrictor) were infused into the brachial artery. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. RESULTS: Endothelium-independent vasomotion in response to GTN and NE was similar in all groups. Vascular responses to selective and combined blockade of ET receptors in both Normo-Tx and Hyper-Tx did not exceed those of C. In fact, we observed a significantly lower increase in FBF after BQ 123 (P= 0.03), as well as after BQ 123/788 (P= 0.03) in Hyper-Tx compared with Normo-Tx. This was associated with an increased vascular sensitivity to exogenous ET-1 in Hyper-Tx compared with Normo-Tx (P= 0.04). Vasoconstriction after L-NMMA was reduced in Hyper-Tx compared with Normo-Tx (P= 0.015), while the response to ACH was reduced in both groups of Tx patients to a similar degree (P= 0.005 vs. C). CONCLUSION: Our results do not support a major role for the vascular endothelin system in the hypertension of renal transplant recipients, whereas deficient baseline NO production may be a contributing factor.

Baseline blood flow and bradykinin-induced vasodilator responses in the human forearm are insensitive to the cytochrome P450 2C9 (CYP2C9) inhibitor sulphaphenazole.

A substantial portion of the vasodilator response elicited by bradykinin in the human forearm is unaffected by the combined inhibition of nitric oxide (NO) synthases and cyclo-oxygenases. The cytochrome P450 (CYP) 2C9 inhibitor sulphaphenazole was recently identified as a potent inhibitor of NO- and prostacyclin (PGI2)-independent relaxation in porcine coronary arteries. The aim of the present study was to determine the effect of sulphaphenazole on basal and bradykinin-induced NO/PGI2-independent changes in the forearm blood flow (FBF) of healthy subjects. Eleven healthy male volunteers participated in this placebo-controlled study. Test agents were infused into the brachial artery and FBF was measured by bilateral venous occlusion plethysmography. Sulphaphenazole (0.02-2 mg/min) alone did not affect basal blood flow. Inhibition of the NO synthases by NG-monomethyl-L-arginine (L-NMMA; 4 micromol/min) and cyclo-oxygenases by ibuprofen (1200 mg, orally) reduced FBF to 48 +/- 7% in the absence and 50 +/- 8% in the presence of sulphaphenazole (2 mg/min; P=not significant). After pretreatment with L-NMMA (16 micromol/min) and ibuprofen (1200 mg, orally), sulphaphenazole (6 mg/min) did not substantially inhibit bradykinin-induced vasodilation. We conclude that CYP2C9-derived metabolites (i) are not involved in the regulation of baseline blood flow, and (ii) do not mediate bradykinin-induced NO/PGI2-independent vasorelaxation in the human forearm. However, determining the contribution of this enzyme to regulation of blood flow in pathological conditions associated with endothelial dysfunction requires further studies.