No abstract

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.

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 mol/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 g/min). U remia is a state of excessive cardiovascular mortality (1). In addition, renal insufficiency is considered to be an adverse prognostic factor for underlying cardiovascular disease (2). The mechanisms by which uremia promotes cardiovascular complications are poorly understood. Apart from conventional risk factors, it has been shown that plasma levels of asymmetric dimethyl-arginine (3), homocysteine (4), and inflammatory mediators (5-7) are positively correlated to mortality in uremia. Moreover, there is convincing evidence that end-stage renal disease (ESRD) is a state of increased oxidative stress (8,9). The various potential explanations for accelerated vascular disease in uremia share one similarity: They propose a generally reduced bioavailability of endothelium-derived nitric oxide (NO) caused either by inhibition of NO synthases (NOS) or by increased degradation of NO itself. A critical review of the literature, however, unveils serious discrepancies in this context. Systemic NO synthesis in uremia was shown to be increased (10 -14) as well as reduced (15,16) dependent on the individuals studied and on the experimental setup used. Moreover, an impairment of stimulated vascular NO was suggested to explain the compromised agonist-induced, endothelium-dependent vasodilation observed in animal models of chronic renal failure (17,18). The latter assumption, however, has never been tested in humans. A significant portion of agonist-induced endothelium-dependent vasodilation is resistant to concomitant blockade of NOS and cyclo-oxygenases and has been attributed to the release of endothelium-dependent hyperpolarizing factors (EDHF, reviewed in [19]). It is conceivable that uremia interferes with EDHF-associated signaling pathways, too. Such results have been obtained in isolated vessels of 5/6 nephrectomized rats (20). As agonist-induced, endothelium-dependent vasodilation has prognostic significance (21,22), it would be desirable to know which portion of the complex vascular response to agonists is impaired. This question is important for our understanding of uremic ...

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.