A Study on Dilazep: II. Dilazep Attenuates Lysophosphatidylcholine-Induced Mechanical and Metabolic Derangements in the Isolated, Working Rat Heart

Abstract

ABSTRACT-The effects of dilazep, d-propranolol and lidocaine on the mechanical and metabolic changes induced by lysophosphatidylcholine (LPC) were studied in isolated, perfused working rat heart. After a stabilization period, the heart was perfused for 5 min with LPC (10 €M) alone, LPC plus dilazep (5, 10 or 20 pM), LPC plus d-propranolol (30 or 50 pM) or LPC plus lidocaine (30 or 100 pM) and then perfused with normal Krebs-Henseleit bicarbonate (KHB) buffer for a further 20 min. Perfusion with LPC for 5 min followed by KHB for 20 min irreversibly decreased cardiac mechanical function, decreased the tissue levels of adenosine triphosphate and creatine phosphate significantly, and increased the tissue levels of lactate and free fatty acids including arachidonic acid. Dilazep or d-propranolol significantly attenuated the mechanical and metabolic changes induced by LPC, but lidocaine did not. These results indicate that the exogenous LPC causes ischemia-like changes, suggesting that LPC is one of the important factors in producing ischemia-reperfusion derangements in terms of mechanical and metabolic functions, and that both dilazep and d-propranolol can prevent the LPC-induced myocardial damage.

Beneficial Effects of Dilazep on the Palmitoyl-L-carnitine-Induced Derangements in Isolated, Perfused Rat Heart: Comparison with Tetrodotoxin.

“…The cardiac ac tion of lysophosphatidylcholine is similar to or identical with that of palmitoyl-L-carnitine; it produces intracellu lar Ca 2+ accumulation through long-lasting bursts of Na+ channel openings (24). Recently, Hoque et al (25) have demonstrated that dilazep attenuates the mechanical dysfunction and metabolic derangements induced by lysophosphatidylcholine in the isolated working rat heart. Kang and Leaf (26) have shown that tetrodotoxin attenu ates the lysophosphatidylcholine-induced arrhythmias in rat myocytes.…”

Effects of β‐adrenoceptor antagonists on Ca2+‐overload induced by lysophosphatidylcholine in rat isolated cardiomyocytes

“…Moreover it has been found that the increase in [Ca2+]i induced by LPC can be inhibited by flunarizine (Ver Donck et al, 1992), which possesses high lipophilicity (Michiels et al, 1983). Our previous study (Hoque et al, 1995) revealed that non-esterified fatty acids (NEFA) accumulate in the myocardium after addition of exogenous LPC in perfused rat hearts, and (+ )-propranolol inhibited the accumulation of NEFA. This result indicates that LPC accelerates catabolism of membrane phospholipids, and (+)-propranolol inhibits it.…”

“…Because of both hydrophilic and hydrophobic properties, LPC can easily exert deleterious effects on biological membrane systems and cause electrophysiological alterations and mechanical dysfunction (Corr et al, 1984;Das et al, 1986;Datorre et al, 1991;Hoque et al, 1995). Therefore, LPC has been suspected as one of the mediators of ischaemic injury.…”

“…Our previous study (Hoque et al, 1995) revealed that (+)-propranolol, which possesses weaker fl-adrenoceptor antagonistic action (flAA) than (±)-propranolol (Cruickshank & Prichard, 1987), inhibited the cardiac dysfunction and metabolical derangements induced by exogenous LPC in perfused working rat hearts. It is, therefore, suggested that fl-adrenoceptor antagonists protect cardiomyocytes from the Ca2+-overload induced by LPC, and that /AA activity is not related to the protective mechanisms.…”

Cardioprotective Effect of K-7259, a Novel Dilazep Derivative, against Ischemia-Reperfusion Damage in Isolated, Working Rat Hearts.

“…ABSTRACT-Global ischemia (15 min) followed by reperfusion (10,20 Dilazep has been demonstrated to attenuate myocardial ischemic damage (1,2). The cardioprotective action of dilazep has been considered to be due to potentiation of the cardiovascular effects of adenosine, such as vasodilat ing and negative chronotropic effects, through inhibition of adenosine uptake into cardiac and endothelial cells (3).…”