Cardiometabolic efficacy and toxicological evaluation of a pharmacological galanin receptor agonist

The goal of this study was to examine effects of a novel galanin receptor agonist GalR1-3 [bAla14, His15]-galanine 2-15 (G), obtained by automatic solid-phase synthesis, on the metabolic state of the area at risk and the size of acute myocardial infarction (MI) in rats in vivo and evaluate its toxicity in BALB /c mice. In anesthetized rats, regional ischemia was simulated by coronary artery occlusion and then coronary blood flow was restored. The peptide G was administered intravenously (i.v.) with a bolus after a period of regional ischemia in the dose range of 0.25-3.0 mg/kg. The sizes of MI and the activities of creatine kinase-MB (СK-MB) and lactate dehydrogenase (LDH) in blood plasma were estimated. The effect of administration of the optimal dose of G (1.0 mg/kg) on myocardial content of adenine nucleotides (AN), phosphocreatine (PCr), creatine (Cr) and lactate was studied. I.v. administration of G to rats at a dose of 1.0 mg/kg slightly affected hemodynamic parameters, but reduced MI size by 40% and decreased plasma LDH and CK-MB activity by the end of reperfusion compared to control. These effects were accompanied by a significant improvement in energy state of area at risk (AAR) – an increase in myocardial content of ATP, åAN, PCr and åCr, and combined with a decrease in myocardial lactate level compared with the control. Toxicity of peptide G was studied with a single intraperitoneal injection of 0.5-3.0% solution of the peptide substance to mice. The absence of signs of intoxication and death of animals after G injection in the maximum possible dose did not allow determining the value of the average lethal dose. The results indicate therapeutic potential of the peptide G for preventing myocardial ischemia and reperfusion injury and feasibility for further study of its pharmacological properties and mechanisms of action.

Castration induces antiapoptotic effects during myocardial regional ischemia reperfusion

Restoration of blood flow to ischemic myocardium results in the ischemia reperfusion (I/R) injury. This study was undertaken to investigate the potential role of endogenous testosterone in the regional ischemia reperfusion and apoptosis of the male rat hearts. Rats underwent surgical ligation of LAD and subjected to ischemia for 25 min and reperfusion for 40 min, and 2nd underwent surgical castration, left 3wks for recovery, then underwent surgical LAD ligation. Blood samples were collected from the heart for measurement of plasma level of cardiac troponin I (cTn-I). The hearts were harvested, and divided into 3 sections, the 1st for the measurement of cardiac apoptosis level, the 2nd homogenized for measurement of tissue (TNF-α, IL1-β, ICAM-1) and the 3rdwas fixed in 10% formalin for histological examination. Compared with the sham group, levels of tissue TNF-α & IL-1β, ICAM-1 and apoptosis; plasma cTn-I were increased (P<0.05) in the control group, all control group rats showed significant myocardial injury (P<0.05) compared with the sham group. Castration significantly counteracts the increase in myocardial levels of TNF-α, IL-1, ICAM-1, plasma cTn-I and apoptosis (P<0.05). Histological analysis revealed that castration markedly reduced (P<0.05) the severity of the heart injury in the rats underwent the regional ischemia-reperfusion procedure. This study reveals that surgical castration may ameliorate regional I/R injury and apoptosis in the ischemic heart in rats.