Characterization of adenosine-A1 receptor-mediated antilipolysis in rats by tissue microdialysis, 1H-spectroscopy, and glucose clamp studies.

Increased supply of fatty acids to muscle and liver is causally involved in the insulin resistance syndrome. Using a tissue microdialysis technique in Wistar and Zucker fatty (ZF) rats, we determined tissue glycerol levels as a marker of lipolysis in gastrocnemius muscle (gMT), subcutaneous adipose (SAT), and visceral adipose tissue (VAT) as well as the reduction of plasma free fatty acids, glycerol, and triglycerides caused by the antilipolysis-specific adenosine-A1 receptor agonist (ARA). In Wistar and ZF rats, ARA significantly lowered dialysate glycerol levels in SAT, VAT, and gMT. Whereas in SAT and VAT the decrease in dialysate glycerol indicated adipocytic antilipolysis, this decrease in gMT was not caused by a direct effect of ARA on intramyocellular lipolysis, as demonstrated by the lack of inhibition of the protein kinase A activity ratio in gMT. In addition, no differences of the fed-starved-refed dynamics of intramyocellular triglyceride levels compared with untreated controls were measured by in vivo (1)H-spectroscopy, excluding any adenylate cyclase-independent antilipolysis in muscle. Treatment with ARA resulted in pronounced reductions of plasma free fatty acids, glycerol, and triglycerides. Furthermore, in ZF rats, ARA treatment caused an immediate improvement of peripheral insulin sensitivity measured by the euglycemic-hyperinsulinemic glucose clamp technique.

In vivo neuroprotective effects of ACEA 1021 confirmed by magnetic resonance imaging in ischemic stroke.

The neuroprotective activity of ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione; licostinel), a selective antagonist at the strychnine-insensitive glycine site associated with the NMDA receptor complex, has been investigated in various models of focal cerebral ischemia. In isoflurane-anaesthesised Wistar rats with permanent ipsilateral carotid artery ligation and transient middle cerebral artery occlusion (duration of occlusion, 2 h) followed by reperfusion (24 h), intravenous administration of ACEA 1021 (bolus: 10 mg/kg, 15 min after the onset of middle cerebral artery occlusion; infusion: 7 mg/kg/h for 6 h beginning 30 min after occlusion of the artery) produced a 32% reduction in infarct volume. Similarly, in Sprague-Dawley rats with transient middle cerebral artery occlusion (2 h) followed by 24 h of reperfusion, identical treatment with ACEA 1021 decreased infarct size by 39%. Magnetic resonance imaging (MRI) confirmed these effects in the transient model, in that infarct volume observed using apparent diffusion coefficient (ADC) maps was significantly smaller after 24 h in the ACEA 1021-treated rats compared with Tris-treated controls. Furthermore, the increase in perfusion signal intensity after reperfusion was more pronounced in the ACEA 1021-treated rats than in controls. In Fisher 344 rats with permanent occlusion of the middle cerebral artery, ACEA 1021 induced a dose-related decrease in infarct volume, which was associated with an improvement in neurological outcome as measured by the rope suspension procedure. Administration of the same dose regimen, as above, in Fisher rats with permanent middle cerebral artery occlusion reduced infarct volume by 68%. This dose was as effective when administration was delayed for 2 h. In mice with permanent middle cerebral artery occlusion, ACEA 1021 (5 mg/kg, i.v., 5 min after occlusion; 30 mg/kg, s.c., 1 and 4 h post-middle cerebral artery occlusion) decreased infarct size by 42%. The consistent anti-ischemic effects of ACEA 1021 make it a valuable compound for exploratory stroke research.

Determinants of intramyocellular lipid concentrations in rat hindleg muscle.

The investigation of intramyocellular lipids (IMCLs) with proton MR spectroscopy ((1)H-MRS) in humans has recently received increasing attention. IMCL levels correlate with insulin resistance and are affected by diet and exercise, making IMCL an interesting marker for metabolic investigations. In the present in vivo study, the feasibility of using (1)H MRS for the detection of IMCL in rats is demonstrated, and the influence of various factors, such as age, gender, muscle type, and rat strain, on IMCL levels is systematically analyzed. In healthy Wistar and Sprague Dawley (SD) rats, the highest ratios of IMCL/tCr were found in young rats, and IMCL/tCr decreased with increasing age. In addition, IMCL concentration was clearly influenced by gender and muscle type. Insulin-resistant, male, obese, Zucker diabetic fatty (ZDF) rats showed significantly higher IMCL levels than Wistar or SD rats. In conclusion, although IMCL levels are clearly influenced by insulin resistance, several other factors influence IMCL levels, such as age, gender, muscle type, and rat strain. Therefore, when using IMCL as a surrogate marker for insulin resistance, it is necessary to carefully compare results with age- and gender-matched controls, and to use identical conditions.