BACKGROUND AND PURPOSEThe hypothesis that endocannabinoids protect hearts against ventricular fibrillation (VF) induced by myocardial ischaemia and reperfusion was examined, and the concept that cannabinoids may represent a new class of anti-VF drug was tested. EXPERIMENTAL APPROACHIn rat isolated hearts (Langendorff perfusion), VF evoked by reperfusion after 60 min regional ischaemia is known to be exacerbated by inhibitors of endogenous protectants such as nitric oxide. This preparation was used to assay the effects of cannabinoid agonists and antagonists, and the protocols were varied to examine mechanisms. KEY RESULTSReperfusion-induced VF was not facilitated by relatively selective CB1 (1 μM AM251) or CB2 (1 μM AM630) antagonists. VF evoked during early (30 min) acute ischaemia was also unaffected. However, AM251 significantly increased the incidence of VF and the duration of VF episodes occurring during the later stage of acute ischaemia (30-60 min). AM630 had no such effects. In a separate study, cannabinoid perfusion (anandamide or 2-arachidonoylglycerol, both 0.01-1 μM) failed to reduce VF incidence concentration-dependently during 30 min ischaemia. In all these studies, changes in ancillary variables (QT, PR, heart rate) were unrelated to changes in VF. CONCLUSIONS AND IMPLICATIONSEndocannabinoids are not endogenous anti-VF mediators during reperfusion, but may have a weak protective effect during the late stages of ischaemia, mediated via CB1 agonism. This does not suggest endocannabinoids are important endogenous protectants in these settings, or that CB1 (or CB2) receptors are useful novel targets for developing drugs for VF. Abbreviations2-AG, 2-arachidonoylglycerol; CF, coronary flow; HR, heart rate; IZ, involved zone; SCD, sudden cardiac death; VF, ventricular fibrillation BJP British Journal of Pharmacology
Background and purpose: The mechanisms responsible for phase 2 (infarct-related) ventricular arrhythmias remain unclear. We have investigated the role of a1 and b1 adrenoceptor activation and the interaction of this with infarct neutrophil accumulation, in anaesthetized rats. Experimental approach: Neutrophil-replete Sprague-Dawley rats (n = 8-9 per group) were anaesthetized and randomized to receive vehicle, prazosin (0.5 mg·kg -1 i.v.), atenolol (4 mg·kg -1 i.v.) or their combination prior to left main coronary artery occlusion. A further group was depleted of neutrophils and received both atenolol and prazosin. Coronary ligation in all groups was maintained for 240 min. Key results: Atenolol and prazosin treatment lowered heart rates and blood pressures respectively, but neither agent given alone affected the incidence of phase 2 ventricular tachycardia or fibrillation. However, co-administration of atenolol with prazosin reduced phase 2 ventricular premature beats (log10-transformed totals were 1.25 Ϯ 0.26 vs. 2.43 Ϯ 0.18 in controls; P < 0.05). Neutrophil depletion attenuated this antiarrhythmic effect (log10-transformed total ventricular premature beats were 1.66 Ϯ 0.35; P > 0.05 vs. controls). Conclusions and implications:Phase 2 arrhythmias appear to depend in part on a complex interaction between catecholamines and neutrophils. A model of this interaction is proposed.
Chronic administration of the insulin-sensitising drugs, thiazolidinediones (TZDs), results in low bone mineral density and 'fatty bones'. This is thought to be due, at least in part, to aberrant differentiation of progenitor mesenchymal stem cells (MSCs) away from osteogenesis towards adipogenesis. This study directly compared the effects of rosiglitazone, pioglitazone, and netoglitazone treatment on osteogenesis and adipogenesis in MSCs derived from subcutaneous (SC) or visceral (PV) white adipose tissue. MSCs were isolated from adipose tissue depots of male Wistar rats and characterised using flow cytometry. The effects of TZD treatment on osteogenic and adipogenic differentiation were assessed histologically (day 14) and by quantitative PCR analysis (Pparg2 (Pparg2), Ap2 (Fabp4), Adipsin (Adps), Msx2, Collagen I (Col1a1), and Alp) on days 0, 7, and 10. Uniquely, lipid droplet formation and mineralisation were found to occur concurrently in response to TZD treatment during osteogenesis. Compared with SC MSCs, PV MSCs were more prone to lipid accumulation under controlled osteogenic and adipogenic differentiation conditions. This study demonstrated that the extent of lipid accumulation is dependent on the nature of the Ppar ligand and that SC and PV MSCs respond differently to in vitro TZD treatment, suggesting that metabolic status can contribute to the adverse effects associated with TZD treatment.
Antiretroviral (ARV) treatment may induce metabolic complications in HIV patients on long-term therapy that can affect bone health. In this study, the effects of the ARVs Stavudine (d4T), Tenofovir (TDF) and Lopinavir/ritonavir (LPV/r) on bone metabolism and lipodystrophy were directly compared in rats to negate the consequences of HIV-associated confounding factors. Healthy 12-14-week-old male Wistar rats (n = 40) were divided into four treatment groups and received an oral animal equivalent dose of either Stavudine (6.2 mg/kg/day), TDF (26.6 mg/kg/day), LPV/r (70.8 mg/kg/day) or water (Control 1.5 mL water/day) for a period of 9 weeks. Whole-body DXA measurements, a biomechanical three-point breaking test and histomorphometric analysis were performed on the femurs and tibias at the end of the treatment period. Stavudine monotherapy was found to be associated with decreased femoral bone mineral density that translated into reduced bone strength, whereas histomorphometric analysis demonstrated that Stavudine induces an imbalance in bone metabolism at tissue level, evident in higher resorption (eroded surfaces, osteoclast surfaces and osteoclast number) and lower formation parameters (osteoblast surfaces and osteoid surfaces). This was less clear in the rats treated with either TDF or LPV/r. Furthermore, both Stavudine and TDF treatment resulted in significant bone marrow adiposity, although no significant redistribution of body fat was noted in the treated rats compared to controls. The data from this study suggest that in the absence of HIV-associated factors, LPV/r is less detrimental to bone metabolism compared to Stavudine and TDF.
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