To investigate the change in myocardial phospholipids after the administration of isoproterenol and its prevention by pretreatment with phospholipase inhibitors and calcium antagonists, we determined the phospholipid species in the heart of female Wistar rats. Isoproterenol (40 mg/kg) was administered 24 h before excising the heart, and chlorpromazine, mepacrine (phospholipase inhibitors), nifedipine, verapamil (calcium antagonists) and propranolol (beta-adrenoceptor blocker) were injected intraperitoneally 30 min prior to isoproterenol administration. The phospholipid species were quantified using silica gel precoated thin-layer rods and the hydrogen flame ionization method. Isoproterenol induced significant increases in heart/body weight ratio, myocardial protein/heart weight ratio and lysophosphatidylcholine (LPC), and significant decreases in myocardial total phosphorus, creatine kinase (CK) activity, phosphatidylethanolamine and phosphatidylcholine (PC). The significant decrease in PC and increase in LPC indicated the degradation of myocardial phospholipids. Pretreatment with nifedipine (30 mg/kg), verapamil (50 mg/kg) or propranolol (20 mg/kg) completely prevented the occurrence of myocardial injury through the preservation of myocardial phospholipid composition, total phosphorus, CK activity and heart/body and protein/heart weight ratios. On the other hand, chlorpromazine (30 mg/kg) and mepacrine (50 mg/kg) partially prevented myocardial damage through the preservation of myocardial phospholipid composition, total phosphorus and CK activity. Results suggest that not only calcium influx but also phospholipase activation plays an important role in the development of myocardial injury induced by isoproterenol.

Animals↗

PubMedDate not supplied

Hemodynamic effects of dibutyryl cyclic GMP in anesthetized dogs.

Dibutyryl cyclic GMP was given intravenously to anesthetized dogs with doses of 0.0625, 0.125, 0.25, 0.5 and 1.0 mg/kg, respectively. It induced decreases in blood pressure, heart rate, max LV dp/dt and total peripheral resistance with increase of stroke volume in a dose-dependent manner. Although these effects began to appear 30 sec after the administration in each dose, the duration of the effect was observed 50 sec after the administration. Effects of 1 mg/kg dibutyryl cyclic GMP on mean blood pressure and max LV dp/dt were almost equal to those of 3 micrograms/kg acetylcholine, but dibutyryl cyclic GMP was revealed to have a slower onset and longer acting effects than acetylcholine. The administration of atropine did not block the effect of dibutyryl cyclic GMP but blocked those of acetylcholine. These results indicate that dibutyryl cyclic GMP does not exert these effects through muscarinic receptors in spite of its acetylcholine-like effects.

Acetylcholine↗

PubMedDate not supplied

Depletion of membrane phospholipid and mitochondrial dysfunction associated with coronary reperfusion.

The role of phospholipase (PLase) in the development of heart mitochondrial dysfunction following reperfusion was studied together with the effects of dilazep on the action of PLases and reperfusion injury. In vivo experiment: Seventy six adult mongrel dogs were divided into 3 groups; the control group (n = 36), the dilazep 0.5 mg group (n = 17) and the dilazep 1 mg group (n = 23). Fifteen min after premedication with physiological saline or dilazep (0.5 mg/kg or 1 mg/kg), the left anterior descending coronary artery was occluded for 15 min and then reperfused for 5 min. Each group was further divided into two subgroups depending on the presence or absence of reperfusion arrhythmia. Immediately after 5 min of reperfusion, myocardial mitochondria were prepared from the normal and the reperfused areas. Pretreatment with dilazep induced a dose-dependent decrease in the incidence of reperfusion arrhythmia from 31% of the control to 24% (0.5 mg/kg) and 9% (1 mg/kg). In the arrhythmia cases in each group, functional deterioration of mitochondria from the reperfused area was observed with the increase in free fatty acids and the decrease in phospholipids in the reperfused mitochondria. In vitro experiment: Using L-alpha-dimyristoyl phosphatidylcholine as a substrate, myristic acid released by PLase A2 or by PLase C with or without pretreatment by dilazep was quantitatively determined. Dilazep inhibited the release of myristic acid by PLase A2 or by PLase C in a concentration-dependent manner. These results suggest that decomposition of mitochondrial membrane phospholipids caused by PLase activation following reperfusion was primarily responsible for the development of mitochondrial dysfunction, and that dilazep showed beneficial effects against reperfusion injury by inhibiting the action of PLases.

Animals↗

PubMedDate not supplied

Effects of trifluoperazine and chlorpromazine on calcium-repleted injury in isolated ventricle strips.

We observed changes in the performance of isolated right ventricle strips taken from rats when calcium was repleted following various periods of calcium depletion in order to study certain phenomena, such as the calcium paradox, in this preparation. Furthermore, to assess the possible role of calmodulin in this myocardial damage, the effects of known calmodulin inhibitors such as trifluoperazine and chlorpromazine on the contractility and resting tension were studied by means of the calcium repletion after a calcium-depleted period of 12 min. The temperature was kept at 37 degrees C, and the muscle strips were stimulated electrically at a rate of 0.25 Hz. When there was a calcium-depleted period of longer than 8 min, a marked increase in resting tension was observed and reached maximum at 2 to 4 min. The recovery of peak developed tension and peak positive or negative dT/dt worsened as the duration of the calcium depletion was longer. These findings indicate the massive intracellular calcium influx by the calcium reintroduction and the myocardial damage induced by the calcium overload as observed in isolated whole hearts. Treatment with trifluoperazine (1-5 microM) and chlorpromazine (1-5 microM) did not inhibit a rise in resting tension significantly after the calcium repletion, except for 5 microM of both drugs at 6 min. Trifluoperazine significantly improved the recovery of the contractility (developed tension and dT/dt), whereas the protective effect of chlorpromazine was not obtained. These results suggest that the depression of calmodulin activity is beneficial in the prevention of myocardial damage produced by calcium repletion, although there is a difference in the effect of the calmodulin inhibitors, trifluoperazine and chlorpromazine.

Animals↗

PubMedDate not supplied

1,2-diacylglycerol content in myocardium from spontaneously hypertensive rats during the development of hypertension.

1,2-Diacylglycerol (DAG) has been considered to play an important role as an activator of protein kinase C in the signal transduction of inositol phospholipid metabolism. To examine the relation of 1,2-DAG in heart tissues to cardiac hypertrophy associated with hypertension, we measured the amount of 1,2-DAG in spontaneously hypertensive rat (SHR) hearts at 4, 10 and 20 weeks of age, and in age-matched normotensive Wistar-Kyoto (WKY) rat hearts using thin-layer chromatography with flame ionization detection (TLC-FID). Significant cardiac hypertrophy was found in 4-week-old SHR, while SHR did not yet have significant hypertension. Major phospholipids such as phosphatidylcholine and phosphatidylethanolamine increased from 4 to 20 weeks in the myocardium, but there was no difference between the two strains. The cholesterol levels of 4- and 20-week-old SHR were significantly higher than WKY rats. The 1,2-DAG contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA content was also observed in 4-week-old SHR hearts. However, analysis of the fatty acid composition of 1,2-DAG revealed no difference between the two strains. However, there was no significant difference in the 1,2-DAG content or in its fatty acid composition between SHR and WKY rat hearts at 10 and 20 weeks of age. It is suggested that an increase in the 1,2-DAG content of SHR hearts during the early stages appears related to the initiation of cardiac hypertrophy in SHR hearts before developed hypertension.

Aging↗