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This study was performed to examine whether cilazapril, a novel nonsulfhydril angiotensin-converting enzyme (ACE) inhibitor, may improve regional myocardial perfusion at exercise in patients with coronary heart disease (CHD). In a single-blind, nonrandomized trial, 5 mg cilazapril or placebo was administered to eight patients with documented CHD and stable exertional angina. Multistage bicycle exercise tests were performed and each patient served as his own control. At peak exercise, as well as at rest, [99mTc]hexakis-2-methoxy-2-isobutylisonitrile myocardial images were obtained. Percent myocardial activity differences (%AD) between exercise and resting images were compared (cilazapril versus placebo). Heart rate and blood pressure were not significantly different between trials. However, after cilazapril administration, %AD was higher than after placebo, with relative differences between trials of greater than 30%, along with alleviation of clinical symptoms in seven of eight patients. These data suggest that in patients with stable-effort angina, ACE inhibition with cilazapril is able to redistribute myocardial blood flow and to improve regional oxygen supply to the ischemic myocardium.

In this work the effect of different components isolated from royal jelly (RJ) was studied using an in vitro rat T-cell proliferation assay. We found that lower concentrations of MEL 174 (final water extract of RJ) and MEL 147 (3-10-dihydroxydecanoic acid) stimulated T-cell proliferation, triggered by concanavalin A (Con-A) and the process was followed by an increase in the production of interleukin-2 (IL-2). Higher concentrations of MEL 174, MEL 247 (dry powder of RJ) and MEL 138 (trans-10-hydroxydec-2-enoic acid) inhibited T-cell proliferation. The inhibition of T-cell proliferation in the presence of MEL 174 was followed by a decrease in IL-2 production, which was partly abrogated by exogenous IL-2, a decrease in nitric oxide (NO) production and increased apoptosis. In conclusion, our results showed the complexity of biological activity of RJ and suggest that its water extract possesses the most potent immunomodulatory activity in vitro. Copyright © Informa Healthcare USA, Inc.

Royal jelly (RJ), especially its protein components, has been shown to possess immunomodulatory activity. However, almost nothing is known about the influence of RJ fatty acids on the immune system. In this work we studied the effect of 10-hydroxy-2-decanoic acid (10-HDA) and 3,10-dihydroxy-decanoic acid (3,10-DDA), isolated from RJ, on the immune response using a model of rat dendritic cell (DC)-T-cell cocultures. Both fatty acids, at higher concentrations, inhibited the proliferation of allogeneic T cells. The effect of 10-HDA was stronger and was followed by a decrease in interleukin-2 (IL-2) production and down-regulation of IL-2 receptor expression. Spleen DC, cultivated with 10 μg/ml of fatty acids down-regulated the expression of CD86 and the production of IL-12, but up-regulated the production of IL-10. In contrast, DC, pretreated with 100 μg/ml of 3,10-DDA, up-regulated the expression of CD86 and augmented the proliferation of allogeneic T cells. The highest dose (200 μg/ml) of both fatty acids which was non-apoptotic for both T cells and DC, down-regulated the expression of MHC class II and CD86, decreased the production of IL-12 and made these DC less allostimulatory. The immunosuppressive activity of 3,10-DDA was also confirmed in vivo, using a model of Keyhole lymphet hemocyanine immunization of rats. In conclusion, our results showed the immunomodulatory activity of RJ fatty acids and suggest that DC are a significant target of their action. © 2007 Elsevier B.V. All rights reserved.

OBJECTIVE We investigated whether plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) reflect impaired diastolic relaxation or its improvement after ACE inhibition. METHODS 7 long-term Type 1 diabetic patients with normal systolic but impaired diastolic function and with sympathetic myocardial dysinnervation and 10 controls were included. Exercise tolerance and maximal O 2 uptake were evaluated by bicycle exercise prior to the study. ANP, BNP and norepinephrine/epinephrine (NE/E) were determined at baseline and at 80 % .VO2 max workload and after recovery, before and following 12 weeks of treatment with fosinopril (10 mg/d). RESULTS Isovolumetric relaxation time (IVRT) and A/E wave ratio were increased by 26.7 +/- 11.5 % and 54.4 +/- 26.1 % in diabetic patients as compared to controls, respectively (p < 0.02). After 12 weeks of fosinopril treatment, no differences in IVRT or A/E wave ratio were detectable between groups. ANP was enhanced in Type 1 diabetes as compared to controls (baseline: 9.2 +/- 3.0 vs. 4.5 +/- 1.1; exercise: 22.4 +/- 7.7 vs. 7.9 +/- 1.2; recovery: 20.3. +/- 4.6 vs. 9.5 +/- 2.0 fmol/ml, p < 0.02). Fosinopril treatment abolished any differences between groups. BNP plasma levels did not differ between groups and no exercise dependent changes were observed. NE- and E-increase was greater at 80 % .VO2 max work load in Type 1 diabetes than in controls (p < 0.05). Again, fosinopril abolished differences between groups. CONCLUSION In Type 1 diabetes, impaired diastolic function is associated with elevated ANP and catecholamine plasma levels that are normalized after ACE inhibition. Thus, ANP but not BNP appears to be a sensitive biochemical marker for early diastolic dysfunction in Type 1 diabetes.

Effect of weight loss on whole body and cellular lipid metabolism in severely obese humans. Am. J. Physiol. 270 (Endocrinol. Metab. 33): E739-E745, 1996.-We evaluated the effect of diet-induced weight loss on whole body and cellular lipid metabolism in persons with severe upper body obesity in two study protocols. In protocol 1, palmitate and glycerol rates of appearance (R a ) in plasma were determined during basal conditions in seven subjects [initial body mass index (BMI) = 41.3 ± 2.2 kg/m 2 J before and after 20.4 ± 3.0 kg weight loss. Total glycerol and palmitate R a decreased from 231.0 ± 19.4 and 166.2 ± 16.6 μmol/min, respectively, before weight loss to 162.7 ± 9.5 and 105.0 ± 9.7 μmol/min, respectively, after weight loss (P < 0.01). However, glycerol and palmitate R a expressed per kilogram fat mass were similar both before and after weight loss. In protocol 2, subcutaneous abdominal adipose tissue was obtained before and after 14.4 ± 2,1 kg weight loss in five subjects (initial BMI = 41.6 ± 2.6 kg/m 2 ). Weight loss caused a 38 ± 8% decrease in adipocyte hormone-sensitive lipase concentration (P < 0.05) but was not associated with any consistent changes in the concentrations of GTP-dependent regulatory proteins, G i 1α, G i 2α, and G S α. We conclude that diet-induced weight loss ameliorates the increase in basal lipolytic rates in persons with severe upper body obesity. These alterations are associated with changes in cellular hormone-sensitive lipase but not GTP-dependent regulatory protein concentrations.

In order to investigate the effect of euglycemic hyperinsulinemia on skeletal muscle blood flow and renal blood flow, catheters were inserted into both femoral arteries, one femoral vein and one renal vein of 7 healthy men. Constant infusions of indocyanine-green dye (intraarterial) and of p-aminohippuric acid (intra-venous) were used to estimate leg plasma flow (ELPF) and renal blood flow (ERPF), respectively, prior to and during a euglycemic, hyperinsulinemic clamp (1.0 mU/kg.min of human insulin, serum concentrations of insulin before and during the clamp: 4.6 +/- 0.9 microU/ml and 65.5 +/- 20.6 microU/ml, respectively, t = 120 min). ERPF (basal: 1220 +/- 320 ml/min) remained unchanged throughout the period of induced hyperinsulinemia in each volunteer (mean: 1135 +/- 490 ml/min), whereas mean leg plasma flow (ELPF) rose from basal 206 +/- 99 ml/min up to 275 ml/min 90 minutes after the beginning of the euglycemic clamp study (p < 0.01). This was due to the marked rise in ELPF from 149 +/- 24 ml/min up to 243 +/- 25 ml/min (p < 0.01) seen in 5 subjects. In two men, who presented a markedly higher basal ELPF (332 and 365 ml/min, respectively), no further rise in ELPF was seen during induced hyperinsulinemia. Fractional renal extraction of insulin was unchanged during induced hyperinsulinemia (28 +/- 5%; basal: 22 +/- 18%), as was fractional extraction of insulin by the leg (10 +/- 5%; basal: 13 +/- 11%). The observed dissociation of ERPF and ELPF suggests a differential response to insulin in renal vs. leg vasculature which possibly is due to increased peripheral glucose metabolism.

In open and double-blind trials, tiapamil was given intravenously and/or orally to 22 patients with coronary heart disease and exertional angina. Multistage bicycle exercise tests were performed before and after drug treatment and patients acted as their own controls. Thallium-201 exercise myocardial imaging was also performed. Exercise tolerance increased and angina was improved under tiapamil treatment. Heart rate and blood pressure decreased slightly, consistent with reduced myocardial oxygen demand. Myocardial oxygen consumption, as indicated by the pressure-rate product, varied little, but exercise myocardial imaging indicated an increase in regional perfusion. The findings suggest that tiapamil is an effective antianginal agent.