Experimental physiology
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Experimental physiology · Nov 2019
Tacrolimus restores the high- and low-pressure baroreflex control of renal sympathetic nerve activity in cisplatin-induced renal injury rats.
What is the central question of this study? Does immunosuppression restore the baroreflex control of renal sympathetic nerve activity (RSNA) in an animal model of kidney injury? What is the main finding and its importance? Tacrolimus, a calcineurin inhibitor, restored the high- and low-pressure baroreflex control of RSNA following cisplatin-induced renal injury. ⋯ Cisplatin administration causes depression of renal haemodynamic and excretory function and is associated with renal sympatho-excitation and loss of baroreflex regulation of renal sympathetic nerve activity (RSNA). This study investigated whether administration of the immunosuppressant tacrolimus in this cisplatin-mediated renal injury model could restore, or the acute intra-renal infusion of tumour necrosis factor α (TNF-α) could blunt, the high- or low-pressure baroreflex control of RSNA. Groups of control and cisplatin-treated (5 mg kg-1 , i.p. on day 0) rats received either saline or tacrolimus (0.25 mg kg-1 day-1 , i.p.) for 7 days prior to study. Rats were anaesthetised and prepared for measurement of mean arterial pressure (MAP), heart rate (HR) and RSNA. Baroreflex gain curves were generated and the degree of renal sympatho-inhibition determined (area under the curve (AUC) reported as %RSNA min) during acute volume expansion. Intrarenal TNF-α infusion (0.3 µg kg-1 h-1 ) in control rats decreased baroreflex gain by 32% (P < 0.05) compared to intra-renal saline infusion. In the cisplatin group (MAP: 98 ± 14 mmHg; HR: 391 ± 24beats min-1 ), the baroreflex gain for RSNA was 39% (P < 0.05) lower than that for the control group (MAP: 91 ± 7 mmHg; HR: 382 ± 29 beats min-1 ). In cisplatin-treated rats given daily tacrolimus (MAP: 84 ± 12 mmHg; HR: 357 ± 30 beats min-1 ), the baroreflex gain and renal sympatho-inhibition (AUC, 2440 ± 1071 vs. 635 ± 498% min) were restored to normal values. These findings provide evidence for the view that cisplatin administration initiates an injury involving inflammation which may contribute to the deranged baroreflex regulation of RSNA. This phenomenon appears mediated in part via the renal innervation.
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Experimental physiology · Nov 2019
Effect of flunarizine on defibrillation outcomes and early refibrillation in a canine model of prolonged ventricular fibrillation.
What is the central question of this study? Can successful electrical shock in combination with a delayed after-depolarization (DAD) blocker suppress early refibrillation episodes following long duration ventricular fibrillation (LDVF)? What is the main finding and its importance? Flunarizine significantly reduced the activation of LDVF and early ventricular fibrillation (VF) recurrence following LDVF, suggesting that DADs potentially contribute to refibrillation in prolonged VF. Thus, DAD inhibition can be used as an adjunctive therapy for electrical defibrillation to treat prolonged VF and suppress refibrillation following LDVF. ⋯ This study attempts to detect changes in the defibrillation threshold (DFT) at different stages of ventricular fibrillation (VF) (short duration VF, SDVF; long duration VF, LDVF) and during early refibrillation following successful defibrillation of LDVF by giving flunarizine, a blocker of delayed after-depolarizations (DADs). Twelve beagles were divided into two groups (the control group, n = 6; and the flunarizine group, n = 6). Two 64-electrode basket catheters were deployed into the left and the right ventricles for global endocardium mapping. The DFTs of SDVF and LDVF were determined at 20 s and 7 min, respectively, after VF induction in each group. Any refibrillation episodes were recorded within 15 min after the first successful defibrillation of LDVF. In the flunarizine group, the SDVF-DFT values before and after the drug were not significantly different. The 7 min LDVF-DFTs were markedly reduced by 26% (P < 0.05, the control group) and 38% (P < 0.01, the flunarizine group) compared to the 20 s SDVF-DFTs within each group. The difference between SDVF-DFT and LDVF-DFT after flunarizine was larger than that in the control group (213 ± 65 vs. 120 ± 84 V, P < 0.05). The number of refibrillation episodes per animal (1.3 ± 1.0) following successful defibrillation of LDVF after flunarizine was 48% of that in controls (2.7 ± 2.0, P < 0.05). The effect of flunarizine on SDVF-DFT and LDVF-DFT indicates that the role of DADs in the defibrillation mechanism may differ as VF continues. Flunarizine significantly reduced early VF recurrence following LDVF, suggesting that DADs potentially contribute to refibrillation in a canine model of prolonged VF.