European journal of pharmacology
-
Hydrogen sulfide may protect multiple organ systems against ischemic-reperfusion injuries. It is unknown if treatment with sodium hydrosulfide (NaHS, a hydrogen sulfide donor) will improve myocardial function and minimize oxidative stress in hypoxic-reoxygenated newborn piglets. Mixed breed piglets (1-5 day, 1.5-2.5 kg) were anesthetized and acutely instrumented for the measurement of systemic, pulmonary and regional (carotid, superior mesenteric and renal) hemodynamics and blood gas parameters. ⋯ NaHS had no significant effect on systemic and pulmonary blood pressures, regional blood flows, plasma lactate and troponin I levels. The myocardial glutathionine ratio was reduced in piglets treated with NaHS (vs. controls, P<0.05). Post-resuscitation administration of NaHS improves cardiac function and systemic perfusion and attenuates myocardial oxidative stress in newborn piglets following hypoxia-reoxygenation.
-
We have found that a series of brief renal ischemia and reperfusion (preconditioning), before the time of ischemia significantly attenuated the ischemia/reperfusion-induced acute kidney injury through endothelial nitric oxide synthase. In this study, we examined the effects of ischemic preconditioning on renal sympathetic nervous system and kidney function in ischemia/reperfusion-induced acute kidney injury with or without nitric oxide synthase inhibitor. Ischemia/reperfusion-induced acute kidney injury was made by clamping the left renal artery and vein for 45-min followed by reperfusion, 2 weeks after the contralateral nephrectomy. ⋯ Ischemic preconditioning suppressed the enhanced renal sympathetic nerve activity during ischemia and the elevated renal venous plasma norepinephrine level after reperfusion, and attenuated renal dysfunction and histological damage. The renoprotective effect of ischemic preconditioning was diminished by N(G)-nitro-L-arginine methyl ester (0.3 mg/kg, i.v.), a nonselective nitric oxide synthase inhibitor, 5 min before the start of ischemic preconditioning. Thus, ischemic preconditioning decreased renal sympathetic nerve activity and norepinephrine release probably through activating nitric oxide production, thereby improving ischemia/reperfusion-induced acute kidney injury.
-
Enhancement of renal sympathetic nerve activity during renal ischemia and norepinephrine overflow from the kidney after reperfusion play important roles in the development of ischemic acute kidney injury. Recently, we have found that moxonidine, an α2/imidazoline Ι1-receptor agonist, has preventive effects on ischemic acute kidney injury by suppressing the excitation of renal sympathetic nervous system after reperfusion. In the present study, to clarify the renoprotective mechanisms of moxonidine (360 nmol/kg, i.v.) against ischemic acute kidney injury, we investigated the effect of intravenous (i.v.) and intracerebroventricular (i.c.v.) injection of efaroxan, an α2/Ι1 receptor antagonist, on the moxonidine-exhibited actions. ⋯ The suppressive effect of moxonidine on enhanced renal sympathetic nerve activity during renal ischemia was not observed in the rat treated with either i.v. (360 nmol/kg) or i.c.v. (36 nmol/kg) of efaroxan. Furthermore, i.v. injection of efaroxan eliminated the preventive effect of moxonidine on ischemia/reperfusion-induced kidney injury and norepinephrine overflow, and i.c.v. injection of efaroxan did not completely inhibit the moxonidine's effects. These results indicate that moxonidine prevents the ischemic kidney injury by sympathoinhibitory effect probably via α2/Ι1 receptors in central nervous system and by suppressing the norepinephrine overflow through α2/Ι1 receptors on sympathetic nerve endings.
-
The aim of the present study was to evaluate the effect of combined treatment of pioglitazone (PGZ) and prednisolone (PDL) on the progression of adjuvant-induced arthritis in rats. Adjuvant arthritis was induced by single intra-dermal injection of 0.1 ml Freund's complete adjuvant (0.05% w/v Mycobacterium butyricum in mineral oil) into foot pads of left hind paws of Wistar rats of either sex. There were six experimental groups: Group I was healthy animals as control, Group II was arthritic animals without drug treatment, Group III was arthritic animals treated with a standard non-steroidal anti-inflammatory drug aspirin (100 mg/kg), Group IV was arthritic animals received PGZ (10 mg/kg) alone, Group V was arthritic animals received PDL (10 mg/kg) alone, and Group VI was arthritic animals treated with a combined suspension of PGZ and PDL (20 mg/kg). ⋯ Treatment with aspirin or combined suspension of PGZ and PDL in the arthritic animals produced significant reductions in HPV and TJT, normalized BW, and significantly decreased plasma levels of TNF-α and IL-6. These observations suggest that the combined administration of PGZ and PDL was effective in modulating the inflammatory response and suppress arthritis progression in experimental animal model. These findings may help to improve the treatment of rheumatoid arthritis.
-
The bone is the most common site to which breast cancer metastasises. Recently, denosumab, a fully human monoclonal antibody that binds to receptor activator of nuclear factor kappa-B ligand (RANKL) has been developed as a new targeted bone therapy. In a large randomized phase III study with a head-to-head comparison of denosumab to zoledronic acid in patients with bone metastases of breast cancer, denosumab significantly delayed the time to first skeletal related event. ⋯ Preclinical data suggest an effect of denosumab on tumour growth and even on carcinogenesis. This review describes the current indications for denosumab in the various settings of breast cancer treatment, with special attention for efficacy, short and long term toxicity and other relevant issues for clinical practice. Furthermore possible and necessary future research questions are proposed.