Clearance of imidapril, an Angiotensin-converting enzyme inhibitor, during hemodialysis in hypertensive renal failure patients: comparison with quinapril and enalapril.

The dialyzability of imidaprilat, an active metabolite of the angiotensin-converting enzyme (ACE) inhibitor imidapril, was determined and compared with those of enalaprilat and quinaprilat in hypertensive patients on chronic hemodialysis. Imidapril (5 mg/d, n = 6), enalapril (2.5 mg/d, n = 6), or quinapril (2.5 mg/d, n = 6) was given for at least 8 weeks prior to the trial. During dialysis, enalaprilat, but not imidaprilat or quinaprilat, concentrations in both sides decreased significantly. Compared to enalaprilat, the dialyzabilities of imidaprilat and quinaprilat were significantly lower (dialyzer clearance [mL/min/m(2)]: enalaprilat, 41.8 +/- 7.4; imidaprilat, 19.0 +/- 7.8; quinaprilat, 8.9 +/- 1.3). The dialyzabilities of the 3 drugs were negatively correlated with their respective protein-binding rates. During hemodialysis, blood pressure did not change significantly in any group. These results suggest that imidapril provides good blood pressure control without a large fluctuation of drug concentration in hypertensive patients undergoing chronic hemodialysis.

Dosing-time-dependent differences in lipopolysaccharide-induced liver injury in rats.

Dosing-time-dependent differences in lipopolysaccharide (LPS)-induced liver injury were examined in rats housed under a 12 h light : dark (LD) cycle. LPS (5 mg/kg) was intravenously injected into different groups of rats at 2, 14, or 20 h after light on (HALO). Elevations in serum liver enzymes after 14 HALO were significantly greater than those after 2 HALO. These parameters were lower in rats given LPS at 20 HALO, compared to 14 HALO. The number of polymorphonuclear cells (PMN) in the liver and the amount of hepatic myeloperoxidase activity, which reflects the number of PMN in liver tissues, was significantly greater in the 14 than in the 2 HALO group. In addition, hepatic interleukin-6 (IL-6) production in the 14 HALO group was enhanced compared to that in the 2 HALO trial. These results suggest that LPS-induced liver injury is greater during the early active than during the early resting period. Dosing-time-dependent variation in the accumulation of PMN in the liver and, potentially, subsequent IL-6 production in liver tissues might be involved in this phenomenon.

Impaired ß-adrenoceptor mediated venodilation in patients with diabetes mellitus.

Aims We investigated whether venoconstriction by α-adrenoceptor stimulation, and venodilation by ß-adrenoceptor stimulation and nitroglycerin are altered in patients with diabetes mellitus (DM). Methods Eight male patients with non insulin-dependent DM and eight age-matched control subjects were included. The patients had neither hypertension nor hyperlipidaemia. Noradrenaline (1 to 512 ng min-1  ), isoprenaline (1 to 256 ng min-1  ) and nitroglycerin (0.5 to 128 ng min-1  ) were infused into a dorsal hand vein and its diameter was measured using a linear variable differential transformer. Results The venoconstricting response to noradrenaline and the venodilating response to nitroglycerin in DM patients were similar to those in control subjects, while the venodilation by isoprenaline was significantly (P<0.05) smaller in DM patients than in control subjects at the dose of 32 ng min-1 or more [32 ng min-1 : 11.5%vs 29.8% (DM vs control subjects), 64 ng min-1 : 19.0%vs 40.1%, 128 ng min-1 : 25.2%vs 49.0%, 256 ng min-1 : 34.3%vs 56.7%]. Conclusions These data suggested that venoconstriction by α-adrenoceptor stimulation and venodilation by nitroglycerin are not altered, whereas venodilation by ß-adrenoceptor stimulation might be impaired in patients with DM.