Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and ( C hronic renal failure (CRF) interferes with the elimination of many drugs because of the reduction in GFR and tubular secretion (1). However, renal failure also diminishes the metabolic clearance of selected drugs secondary to decrease of hepatic and intestinal metabolism of these drugs (2-6). The major determinant for these metabolic changes is a reduction in enzymatic activity.Cytochrome P450 (P450) is the major catalyst of drug biotransformation. Several animal studies have shown that liver and intestinal P450 are reduced in CRF (7-10). These studies demonstrated that CRF is associated with a decrease in the activity as well as in the expression of liver and intestinal P450 isoforms secondary to reduced mRNA levels (9,10). The main hypothesis to explain P450 activity and expression downregulation is the presence in the blood of uremic animals of endogenous inhibitors that modulate the P450. Indeed, we have shown that in normal hepatocytes that were incubated for 24 h with serum from rats with CRF, total P450 level and protein expression of several P450 isoforms decreased by 45% compared with serum from control animals (11). This decrease in protein expression of P450 isoforms was secondary to reduced gene expression (11). Similar results have been shown with serum of patients with severe CRF (12). The next step was to find which factor in the uremic blood downregulates P450 in CRF.CRF is associated with multiple metabolic disturbances. As a consequence, numerous molecules are increased in CRF. However, taking into account the changes that are induced by CRF (metabolic, hormonal, and retention of toxins) and the factors that are known to affect the P450, two main mediators are most likely to be associated with downregulation of P450 in CRF: parathyroid hormone (PTH) and proinflammatory cytokines (6). Although the potency of cytokines to downregulate P450 have been established in inflammatory disease (13), we hypothesized that PTH could be implicated in the downregulation of P450 in CRF for the following reasons: (1) secondary hyperparathyroidism is frequent in CRF (14); (2) PTH is known to downregulate the mRNA of many proteins, particularly in the liver but also in other tiss...

1 The aim of this study was to assess whether the protective e ect of ischaemic preconditioning on endothelial function in coronary arteries of the rat involves kinins. 2 Isolated hearts of the rat were exposed to a 30-min low-¯ow ischaemia (¯ow rate of 1 ml min 71 ) followed by 20-min reperfusion, after which coronaries were precontracted with 0.1 mM U-46619, and the response to the endothelium-dependent vasodilator, 5-hydroxytryptamine (5-HT, 10 mM), compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 mM). 3 In untreated hearts, ischaemia-reperfusion diminished selectively 5-HT-induced vasodilatation, compared with time-matched sham hearts. The vasodilatation to SNP was una ected after ischaemiareperfusion. Preconditioning (5 min of zero-¯ow ischaemia followed by 10 min reperfusion) in untreated hearts preserved the vasodilatation produced by 5-HT. 4 Blockade of B 1 and B 2 receptors with either 3 nM [Lys 0 , Leu 8 , des-Arg 9 ]-bradykinin (LLDBK) or 10 nM Hoe 140 (icatibant), respectively, (started 15 min before ischaemic preconditioning or a corresponding sham period and stopped just before the 20-min reperfusion period) had no e ect on the vasodilatation produced by either 5-HT or SNP in sham hearts. Pretreatment with Hoe 140 did not block the protective e ect of ischaemic preconditioning on the 5-HT vasodilatation. In contrast, LLDBK halved the protective e ect of ischaemic preconditioning on endothelium-dependent vasodilatation. 5 Perfusion with either bradykinin or des-Arg 9 -bradykinin (1 nM) 30 min before and lasting throughout the ischaemia protected the endothelium. 6 In conclusion, ischaemic preconditioning a ords protection to the endothelial function in coronary resistance arteries of the rat partly by activation of B 1 receptors. Although exogenous BK perfusion can protect the endothelium, B 2 receptors do not play an important role in this protection in the rat isolated heart.

These results suggest that IPC affords protection to endothelial function in coronary arteries of the rat partially via the release of PGE2. Under our experimental conditions, the protective effect of PGE2 is mediated by PKC.