Effect of SMP-300, a New Na+/H+ Exchange Inhibitor, on Myocardial Ischemia and Experimental Angina Models in Rats

Abstract

We evaluated the effects of SMP-300 (N-(aminoiminomethyl)-11-chloro-5,6,7,8-tetrahydro-8-oxo-4H-pyrrolo[3,2,1-kl][1]benzazocine-2-carboxamide monomethanesulfonate monohydrate), a newly synthesized compound, on Na+/H+ exchange activity in rat cardiomyocytes and on other ion transporters, channels and receptors. We also investigated the protective effects of SMP-300 in isolated ischemic rat hearts and rat isoproterenol- or vasopressin-induced experimental angina models. SMP-300 concentration-dependently inhibited recovery from acidosis in rat myocytes, and its IC50 for Na+/H+ exchange was 6 nM. In comparison, its IC50s for Na+/Ca2+ exchange and for the Na+ channel were >1000 nM, and those for other channels or receptors tested were >10,000 nM. In rat isolated perfused hearts, SMP-300 (10(-8)-10(-7) M), administered only at preischemia and not during reperfusion, significantly improved the postischemic recovery of cardiac function. SMP-300 (0.03-0.3 mg/kg, i.v.) or 5-(N-ethyl-N-isopropyl)-amiloride (1 mg/kg, i.v.) prevented the isoproterenol-induced ST-segment depression in the ECG of anesthetized rats, in a dose-dependent manner. SMP-300 (0.1 mg/kg, i.v.) and 5-(N-ethyl-N-isopropyl)-amiloride (1 mg/kg, i.v.) also inhibited the vasopressin-induced ST-segment depression in the ECG of anesthetized rats. This is the first report presenting the protective effect of Na+/H+ exchange inhibitors on isoproterenol- or vasopressin-induced ECG changes in rats, providing the future perspective of SMP-300, a potent Na+/H+ exchange inhibitor, as an anti-anginal drug.

Inhibition of Rho-Kinase by Hydroxyfasudil Prevents Vasopressin-Induced Myocardial Ischemia in Donryu Rats by Attenuating Coronary Vasoconstriction

“…The present study confi rmed previous reports that systemic administration of AVP in Donryu rats caused electrocardiographic S-wave depression, indicative of myocardial ischemia [10,14,20,22] . However, as expected, AVP also signifi cantly increased systemic blood pressure, which was not often investigated in other studies.…”

“…Electrocardiogram (ECG) ST segment shift is commonly used as a non-invasive index of myocardial ischemia. Systemic administration of AVP can induce S-wave depression in Donryu rats, which has been used as an experimental model of myocardial ischemia [10,20,22] . However, the mechanism for AVP-induced S-wave depression in this model is unclear since AVP can cause both coronary vasoconstriction and systemic hypertension, thus affecting both myocardial oxygen supply and demand.…”

Combined Effects of Benidipine and Diltiazem in a Rat Model of Experimental Angina

“…Changes in ST-segment were used as an index of ischemic severity. According to the previous report (2), the fall of S-wave was regarded as the fall of ST. Maximal S-wave depression was observed 4 -5 min following AVP injection, consistent with previous reports (10,11). Both benidipine (3 and 10 m g / kg) and diltiazem (300 and 1000 mg/ kg) significantly inhibited the S-wave depression in a dose-dependent manner (Fig.…”

Effects of Benidipine in a Rat Model of Experimental Angina

“…According to a previous report, 5) the fall of the Swave was regarded as the fall of ST. Maximal S-wave depression was observed about 4 min after AVP injection (data not shown), and is consistent with the results of previous reports. [7][8][9] Benidipine signiˆcant-ly inhibited the depression at 3 and 10 mg/kg in a dose-dependent manner (Fig. 2).…”

“…4) AVP-induced angina is a useful model for evaluating the e‹cacy of compounds in vasospastic angina. [5][6][7][8] Karasawa et al 5) reported that benidipine has beneˆ-cial eŠects in various experimental angina models, including the AVP-induced angina model. We have demonstrated recently that the antianginal e‹cacy of benidipine 10 mg/kg was similar to that of diltiazem 1000 mg/kg in the AVP-induced angina rat model, indicating that benidipine exerts potent antivasospastic anginal eŠects.…”