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Download the Book of Poster Abstracts 500 Combined administration of insulin and leptin significantly increased Fos production in the arcuate nucleus and renal sympathetic nerve activity Hamza Habeeballah1, Naif Alsuhaymi1, Martin Stebbing1, Trisha Jenkins1, Emilio Badoer1. School of Health and Biomedical Sciences, RMIT University, Melbourne, Vic. Introduction. Leptin has sympatho-excitatory effects on renal sympathetic nerve activity (RSNA). Insulin also induces increases in RSNA. There is considerable interest in the central actions of leptin and insulin on sympatho-excitation. The brain regions mediating insulin’s effects are unclear, compared to leptin. Aims. This study (i) investigated whether leptin and insulin together elicits greater increases in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) than when given alone, and (ii) quantified the number of activated neurons in brain regions influencing SNA, to identify potential central sites of interaction. Methods. Anesthesia of Male Sprague-Dawley rats was induced with isoflurane (2-5%) in O2 and maintained with intravenous urethane (1.4-1.6 g/kg). RSNA, MAP and HR were recorded prior to and for 3 hours following intracerebroventricular (ICV) saline (control; n=5), leptin (7 μg; n=5), insulin (500 mU; n=4) and the combination (leptin administered 15 minutes after insulin; n=4). Results Following leptin or insulin alone, RSNA was significantly increased (74% and 62% respectively), but together, the RSNA increase (124%) was significantly greater than either alone. Insulin alone increased HR significantly but this was prevented by leptin. MAP was not significantly different between groups. Only in the arcuate nucleus did leptin and insulin together increase the number of Fos-positive cell nuclei significantly more than the increases following leptin or insulin alone. In the lamina terminalis and rostroventrolateral medulla, leptin and insulin together increased Fos similar to leptin alone. Discussion. The results suggest that where leptin and insulin are elevated, there are greater effects on RSNA. This may contribute to cardiovascular complications. The arcuate nucleus may be a common site of cardiovascular integration. 502 A small-molecule inhibitor of NLRP3 inflammasome activity, MCC950, reduces blood pressure and restores renal function in hypertensive mice Dorota M Ferens1, Shalini M Krishnan1, Michelle M Kett1, Yeong H Ling1, Avril A B Robertson2, Matthew A Cooper2, Antony Vinh1, Katrina M Mirabito Colafella1, Christopher T Chan1, Ashley Mansell3, Christopher G Sobey1, Grant R Drummond1. Biomedicine Discovery Institute, Dept of Pharmacol, Monash Univ1, Clayton, VIC; Institute for Molecular Bioscience, Univ of Qld, Brisbane, QLD2; Hudson Institute3, Clayton, VIC. Introduction: Inflammasomes are interleukin-1 processing complexes and master regulators of inflammation. We recently showed that one-kidney/deoxycorticosterone acetate/salt (1K/DOCA/salt)- and angiotensin II-dependent hypertension in mice are associated with elevated expression of the NLRP3 inflammasome in the kidneys. Moreover, genetic deficiency of a key subunit critical for NLRP3 inflammasome activity, protected mice against renal inflammation and chronic pressor responses associated with these models. Aims: We investigated whether a highly-specific, small-molecule inhibitor of NLRP3 inflammasome activity, MCC950, similarly reduces the deleterious effects of 1K/DOCA/salt on blood pressure (BP) and renal function. Methods: Male C57BL/6J mice were implanted with telemetry probes for recording of BP (mean arterial (MAP), systolic, diastolic) and heart rate (HR), or placed in metabolic cages for 24 h urine collections to assess renal function. Once baseline parameters were established, mice were uninephrectomized and received a DOCA pellet (2.4 mg/kg/d, s.c.) and 0.9% saline to drink. Following establishment of hypertension (10 d), mice were implanted with an osmotic minipump containing either MCC950 (10 mg/kg/d, s.c.) or vehicle (saline) and followed for 28 d. Results: MAP increased from 102±2 to 133±3 mmHg over the 10 d following 1K/DOCA/salt surgery. In vehicle-treated mice, MAP remained at this elevated level until the end of the treatment period. By contrast, MAP of mice treated with MCC950 gradually declined such that at d 38 it was 15 mmHg lower than that of vehicle-treated mice. Systolic and diastolic BP responses were similar to MAP, whereas HR was unaffected by MCC950. Urine flow, Na+ and albumin excretion, and osmolality were markedly increased after 10 d of 1K/DOCA/salt treatment. Consistent with its effect on BP, MCC950 reduced each of these parameters by 30-40%, whereas vehicle had no effect. Discussion: We have shown that an inhibitor of NLRP3 inflammasome activation reduces BP and restores renal function in mice with established hypertension, highlighting MCC950 as a promising candidate for future therapies. 503 Synergistic effect of the combined capsaicin and dihydrocapsaicin on in vitro platelet aggregation Safa Y Almaghrabi, Murray J Adams, Kiran DK Ahuja, Dominic P Geraghty. School of Health Sciences, UTAS, Launceston, TAS. Introduction. Capsaicinoids, including capsaicin (CAP) and dihydrocapsaicin (DHC), the pungent principles of pepper fruits, individually inhibit in vitro platelet aggregation. However, their effects when present in the relative proportions that they are found in different fruits, i.e., ~60% CAP and ~40% DHC, are not known. Aims. To compare the effects of CAP and DHC alone and in combination on in vitro platelet aggregation. Methods. Platelet-rich and -poor plasma were obtained from venous blood of four healthy subjects. The effects of 12.5 μmol/L CAP and DHC, and their combination (CAP:DHC, 3.75:2.5 μmol/L and 7.5:5 μmol/L) on arachidonic acid (AA; 300 μg/mL), ADP (5 μmol/L), and collagen (4 μg/mL) induced platelet aggregation, were determined. Aggregation data (% AUC; meanSEM) were compared using ANOVA/linear regression. Results. Compared to control (64.62.1%), CAP (49.62.7%) and DHC (48.32.3%) individually inhibited AA-induced aggregation (both p<0.01). The combination of both agents produced further inhibition in AA-induced aggregation (CAP:DHC 3.75:2.5 mol/L, 416.5%, p<0.01; 7.5:5 μmol/L, 27.57.7%, p<0.001) compared to the control. Moreover, the inhibitory effect of combined CAP:DHC (7.5:5 μmol/L) was larger than individual capsaicinoids (12.5 vs 7.5:5 mol/L, 49.62.7% vs 27.57.7%, p<0.05, 12.5 vs 7.5:5 μmol/L, 48.32.3% vs 27.57.7%, p<0.05, CAP and DHC, respectively). In contrast to the AA- induced aggregation, neither CAP nor DHC, or their combination, had a significant inhibitory effect on ADP- or collagen- induced aggregation. Discussion. The combination of CAP and DHC in the proportions they are present in pepper fruits, produces a significantly greater inhibitory effect against AA-induced platelet aggregation, compared to the individual capsaicinoids. These results warrant further investigation to determine whether these capsaicinoids may be exploited for therapeutic benefit. 504 NTU-D Against Angiotensin-induced Heart Failure Shih Yi, Lee1, Department of Pulmonary and Critical Care Medicine, Mackay Memorial Hospital, Taipei, Taiwan Introduction: Myocardial injury is associated with oxidative stress. NTU-D is a novel synthesized antioxidant. Aims: The study is aimed to evaluate whether NTU-D elicits intrinsic cardioprotection in response to chronic stress, such as angiotensin (Ang) administration. Methods: Effects of NTU-D on mice heart under chronic Ang treatment were assessed. The morphology and function of heart were measured. Results: NTU-D reduced myocardial hypertrophy and fibrosis, and preserved cardiac function in chronic Ang-treated mice, P<0.05. In Ang-treated mice, the elevation of NOX4 was ameliorated by NTU-D, P<0.05, indicating NTU-D exerts cardioprotection through a reduction of oxidative stress generation. Discussion: NTU-D diminishes myocardial remodeling caused by chronic Ang treatment through a NOX4 reduction mechanism. This makes NTU-D a potential reagent for the treatment of chronic stress-induced heart failure. To clarity its clinical application, the mechanism of NTU-D on heart during chronic stress should be further evaluated. 506 The β3-adrenoceptor agonist mirabegron increases human atrial force through β1- but not β3- adrenoceptors Weilan Mo1,2,3, Martin C Michel4, Alberto J Kaumann5, Peter Molenaar1,2,3. School of Biomedical Sciences, QUT1, Brisbane; School of Medicine, Uni QLD1,3; CCRG, The Prince Charles Hospital1,3, Brisbane, QLD; Dept Pharmacology, Johannes Gutenberg Uni4, Mainz, Germany; Dept Pharmacology, Uni Murcia5, Murcia, Spain. Introduction. Mirabegron is a β3-adrenoceptor agonist approved for overactive bladder syndrome. It has been associated with incidences of hypertension, cerebrovascular and cardiac events. Aims. To determine the cardiac effects of mirabegron and 3-adrenoceptors in human heart. Methods. Right atrial trabeculae obtained from patients undergoing coronary artery bypass, aortic valve or myomectomy surgery, were set up on electrode blocks and electrically stimulated. Single concentrations of mirabegron (1 or 10 M) were added in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1 methylxanthine (IBMX 10 M), β3- adrenoceptor antagonist L-748,337 (100 nM), β1-adrenoceptor antagonist CGP 20712A (300 nM), neuronal uptake inhibitors desipramine (1 M) or phenoxybenzamine (5 M incubation followed by washed out) and contractile force measured. Results. Mirabegron (1 and 10 μM) increased
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