Seiichiro Kano

Effects of Bibr-277, an angiotensin Ii type 1 receptor antagonist, on stunned myocardium in dogs

BackgroundAngiotensin converting enzyme inhibitors can protect the myocardium from ischaemic damage. We examined the effect of BIBR-277, an angiotensin II receptor type 1 antagonist, on myocardial stunning in dogs. MethodsPentobarbital-anaesthetized open-chest dogs were subjected to 20 min ligation of the left anterior descending coronary artery, followed by reperfusion for 60 mm. Saline or 0.3, 1 or 3 mg/kg body weight BIBR-277 was injected intravenously 10 min before coronary ligation. The myocardial contractile function was measured by ultrasonometry. The tissue levels of energy metabolites in the 60 min reperfused heart were determined. ResultsMyocardial contractile function assessed in terms of percentage segment-shortening in the saline-treated group decreased during ischaemia and returned towards the pre-ischaemic level during reperfusion but incompletely (myocardial stunning). A significant and dose-dependent improvement in the percentage segment-shortening during reperfusion was observed in the BIBR-277-treated groups. The levels of ATP, ADP and AMP in the reperfused heart were not modified by BIBR-277 treatment compared with those in the saline-treated group. ConclusionBIBR-277 ameliorates the myocardial contractile dysfunction during reperfusion after ischaemia, although it did not bring about any improvement in the high-energy phosphate levels in the reperfused heart.

The effect of a nucleotide-nucleoside solution on hepatic regeneration after partial hepatectomy in rats

After hepatectomy, purine and pyrimidine metabolism is a key process in the synthesis of DNA and RNA and maintaining cellular energy metabolism. The purpose of this study is to evaluate changes in blood purine and pyrimidine levels after partial hepatectomy and the effect of purine and pyrimidine nucleoside solution injection on hepatic regeneration under the hypothesis that the rat after partial hepatectomy requires substrates for salvage nucleotide synthesis and changes blood nucleoside and nucleobase levels. Blood levels of nucleotides, nucleosides, and nucleobase by high-performance liquid chromatography method and liver ATP level by enzymatic analysis, and the effect of preoperative injection of nucleoside solution (OG-VI) on hepatic regeneration ratio and hepatocytes DNA synthesis, were assessed in rats after 70% partial hepatectomy. Decreased liver adenosine triphosphate and increased plasma xanthine and hypoxanthine after partial hepatectomy indicated an increase in catabolism of purine nucleotides in regenerating liver. Plasma thymidine and cytidine levels increased, then returned to the prevalue, suggesting that the thymidine and cytidine pool was enlarged. OG-VI increased labeling indices of hepatocytes at postoperative d 1 (POD) and hepatic regeneration ratio at POD 14. Blood purine nucleobase and pyrimidine nucleoside levels change after partial hepatectomy and preoperative supply of nucleoside solution is effective for increasing hepatocytes DNA synthesis and hepatic regeneration after partial hepatectomy.

Improvement of Stunned Myocardium in Dogs with Olmesartan, an Angiotensin II Type 1 Receptor Antagonist, Is Independent of Type 2 Receptors

Olmesartan is a selective angiotensin II type 1 receptor (AT1) antagonist. In pentobarbital-anesthetized open-chest dogs, ischemia/reperfusion was induced by ligating the left anterior descending coronary artery for 20 min and releasing it for 60 min, respectively. The myocardial contraction in the ischemic area decreased and returned towards its pre-ischemic level during reperfusion but incompletely. Olmesartan improved the recovery of myocardial contraction during reperfusion associated with restoration of myocardial ATP. Angiotensin II repelled by AT1 receptors occupied by olmesartan can reach and stimulate the angiotensin II type 2 (AT2) receptors, resulting in some beneficial effects on the ischemic myocardium. In fact, AT2 receptor mRNA was found in the adult dog myocardium. In addition, the plasma level of angiotensin II was significantly increased by olmesartan. PD123319, a selective AT2 receptor antagonist, however, did not modify the effect of olmesartan on the cardiac contraction. The hypertensive response to exogenous angiotensin II was completely inhibited by olmesartan, whereas PD123319 did not abolish the effect of olmesartan. In conclusion, olmesartan protects the ischemic/reperfused heart against ischemic injury through inhibition of AT1 receptors but not indirect activation of AT2 receptors.

EFFECTS OF OG-VI, A NUCLEOSIDE/NUCLEOTIDE MIXTURE, ON STUNNED MYOCARDIUM IN DOGS : IS THE ADENOSINE A1 RECEPTOR INVOLVED ?

BackgroundOG-VI is a solution composed of 30 mmol/l inosine, 30 mmol/l sodium 5′-guanylate, 30 mmol/l cytidine, 22.5 mmol/l uridine and 7.5 mmol/l thymidine; it limits myocardial stunning in dogs. We examined whether adenosine A1 receptors were involved in the mechanism of action of OG-VI. MethodsDogs anesthetized with pentobarbital were subjected to 20 min of left anterior descending coronary artery ligation followed by 30 min of reperfusion. Saline, OG-VI in several doses, adenosine or inosine was infused at 0.1 ml/kg/min, starting 30 min before the ischemia. In some experiments, 1 or 3 mg/kg 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist, was injected intravenously 15 min before the start of the OG-VI infusion. The percentage myocardial segment shortening (%SS) was measured by sonomicrometry. The tissue concentration of ATP was measured in the 30-min-reperfused hearts. ResultsIn the saline group, %SS that had been decreased by ischemia returned toward pre-ischemic values after reperfusion, although the metabolic recovery was incomplete, with a low concentration of ATP. The %SS was almost completely restored by 12 and 1.2 µmol/kg/min OG-VI, but 0.4 µmol/kg/min was less effective. Administration of adenosine or inosine did not modify the changes in %SS during ischemia/reperfusion. Pretreatment with DPCPX worsened the recovery of %SS during reperfusion after ischemia in both the saline and the OG-VI groups. Infusion of DPCPX (3 mg/kg) with saline caused the animals to die shortly after the onset of ischemia. However, the enhancement of %SS recovery during OG-VI reperfusion was observed in the presence of DPCPX. ConclusionOG-VI improves the recovery of %SS during reperfusion after brief ischemia in a dose-dependent manner. This effect is not brought about by stimulation of adenosine A1 receptors. Coronary Artery Dis 9:29–34