ANTIARRHYTHMIC MECHANISMS OF TICAGRELOR IN MURINE MODELS OF CARDIOVASCULAR RISK FACTORS

PONCE ZUMINO AZ; BRENNAN TA; MIATELLO RM; SANCHEZ FJ; DIEZ ER; RENNA NF; PRADO NJ

Buenos Aires

Congreso; REUNION CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

SAIC-SAIB-SAI-SAA-SAB-SAB-SAFE-SAFIS-SAH-SAP

Ticagrelor (TICA) inhibits the P2Y12 receptor and interferes with cellular adenosine uptake. Increased adenosine levels during ischemia and reperfusion protect against ischemia-reperfusion injury. This work aims to prevent cardiovascular remodeling and ventricular arrhythmias with chronic administration of TICA in SHR rats fed with fructose to induce metabolic syndrome. We studied male rats from risk factor models: 1) WKY, normotensive control; 2) FFR, fructose-fed rat 10% (w/v) fructose solution during all six weeks; 3) SHR, spontaneously hypertensive rats; 4) FFHR fructose-fed hypertensive rats. These four groups were divided into TICA: (30 mg/kg intraesophageal for six weeks) or vehicle (n=8 each group). Metabolic variables and systolic blood pressure were compared at weeks six and before sacrifice at week twelve. Macroscopic and microscopic measurements evaluated cardiac remodeling. Langendorff-perfused hearts underwent 10 min of regional ischemia and assessed for reperfusion arrhythmias. Connexin-43 and PKC-epsilon expression were determined by western blot. The FFHR experimental model presented metabolic syndrome criteria and cardiac remodeling. Chronic treatment with TICA reduced ventricular fibrillation incidence in WKY, SHR and FFHR groups but failed to protect FFR. In all groups, TICA increased connexin 43. However, PKC-epsilon phosphorylated form of connexin 43 did not increase in FFR+TICA. We conclude that antiarrhythmic effects of TICA could be blunted in some risk factor models regarding connexin 43 phosphorylation by PKC. Further studies TICA effects on intercellular communication or hemichannel function of connexin 43 seem highly worthwhile.