Abstract P216: Thoracic Epidural Administration of Resiniferatoxin Improves Cardiac and Autonomic Dysfunction in Post-MI Rats

Abstract

Our recent study demonstrated that chronic ablation of the cardiac sympathetic afferent reflex (CSAR) at the time of myocardial infarction (MI) by destroying TRPV1-expressing CSAR afferent nerve endings by epicardial delivery of the afferent neurotoxin, resiniferatoxin (RTX) significantly improved cardiac and autonomic dysfunction post MI. In this study, we provide an alternative route of epidural peri-ganglion administration of RTX for CSAR ablation thus destroying TRPV1-expressing CSAR afferent neuronal soma at the level of the T1-T4 DRGs in post-MI rats. This strategy completely abolished the CSAR for up to 6 months, significantly longer than epicardial application (~3-4 months). We compared the cardioprotective effects of epidural application of RTX with [Sar 9 ,Met(O 2 ) 11 ]-substance P (SSP)-saporin (SAP) to determine if SP-containing CSAR afferents ablation mimics the cardioprotective effects of RTX in post-MI rats. Echocardiographic data demonstrated that both epidural RTX and SSP-SAP treatments significantly slowed LV chamber dilation in MI rats. Epidural application of RTX significantly decreased cardiac sympathetic tone (%max: 44±5 (n=6) vs. 11±1 (n=9), vehicle vs. RTX, P<0.01) and improved baroreflex sensitivity at 12-weeks post-MI whereas SSP-SAP had less effect on autonomic dysfunction. Compared to vehicle-treated MI rats (n=16), epidural RTX (n=13) reduced left ventricular end diastolic pressure (LVEDP: 22±1 vs. 7±1 mmHg, P<0.01) whereas epidural SSP-SAP only partially reduced LVEDP (15±2 mmHg, n=10, p<0.05) in MI rats. All groups had similar infarct size. Cardiac hypertrophy and lung edema in MI rats were reduced by epidural RTX whereas they were only partially reduced by SSP-SAP. Pressure-volume analysis data showed that epidural RTX significantly improved cardiac diastolic dysfunction in MI rats to a greater extent than SSP-SAP, neither of which improved cardiac systolic dysfunction. These data suggest that 1) epidural peri-ganglion RTX ablation of the CSAR can be used to reduce cardiac remodeling and autonomic dysfunction post-MI; 2) SP-containing thoracic afferents partially but not completely mediate the cardioprotective effects of thoracic afferent ablation post MI.