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Effects of prostaglandins on late coronary ligation arrhythmias in the dog.

Effects of an intravenous injection of indomethacin, prostaglandins (PGs) E1, E2 and F2 alpha and prostacyclin were examined by the use of a model of two-stage coronary ligation arrhythmias in conscious dogs. Indomethacin had no effect on the arrhythmias occurring 48 hr after coronary ligation. PGs and prostacyclin were injected after the injection of indomethacin. PGs did not show any significant antiarrhythmic effects on the arrhythmias occurring 48 hr after coronary ligation, while prostacyclin showed a transient arrhythmogenic effect. From the foregoing results, both endogenous and exogenous PGs do not seem to play a significant role in the genesis of late coronary ligation arrhythmias in the dog.


EFFECTS
There have been many studies on the effects of PGs on cardiac arrhythmias, and it seems that PGs are effective against chemically induced arrhythmias (1). However, different effects of PGs on animal coronary ligation arrhythmias have been reported depending on the animals used and the arrhythmia models used (2)(3)(4)(5)(6). Harvie et al.
(2) and Au et al. (3) reported antiarrhythmic effects of PG E2, PG Fl., and prostacyclin on the early arrhythmia soon after coronary ligation in the dog, but no such effects were observed on the 24 hr arrhythmia. Dix

Materials and Methods
Twelve beagle dogs of either sex, weighing 9 to 11 kg, were used and operated on to produce the two-stage coronary ligation arrhythmia. The details of the surgical pro cedures were described in our previous papers (7,8

Results
Forty-eight hours after coronary ligation, the dogs showed ventricular tachycardia which was continuous and so a convenient arrhythmia to examine antiarrhythmic effects of drugs. The arrhythmia 24 hr after ligation was characterized by multifocal ventricular tachycardia almost without any conducted beats, but the arrhythmia 48 hr after ligation was milder with decreased total heart rate and increased number of conducted beats.
Indomethacin at 10 mg/kg, i.v., which is a sufficient dose to inhibit prostaglandin biosynthesis (9), was injected into all dogs, and the results of this are shown in Fig. 1.  Indomethacin increased the number of conducted beats at 3 and 8 min after injection, but there was no change in the arrhythmic ratio. Indomethacin slightly increased the blood pressure soon after injection. Bar represents standard deviation. *P<0.05 and **P<0 .01 from the values of 0 min. Smaller doses did not produce any significant changes. The number of conducted beats increased at 3 and 8 min after injection, but the ratio of the number of ventricular ectopic beats and the total heart rate, an arrhythmic ratio, did not change significantly. Thus we did not judge that indomethacin had an antiarrhythmic effect. The blood pressure was slightly elevated after indomethacin, but within 15 min after injection, all these effects disappeared and the arrhythmia persisted during the experiment, less than 3 hr after indomethacin injection. After observing the direct effect of indomethacin for 1 5 min, PGs and prostacyclin were injected.
Effects of PG E, (n=5), PG E2 (n=5), PG F2 (n=6) and prostacyclin (n=8) are shown in Figs. 2-5. We used 1 to 10 mcg/kg, but only the effects by 10 mcg/kg are shown because smaller doses did not show a qualitatively different effect on arrhythmia and showed only milder effects on other cardio vascular parameters. Prostacyclin increased the arrhythmic ratio, an arrhythmogenic effect, but for only a short period. Though the number of conducted beats decreased 1 and 5 min after injection, and the arrhythmic ratio increased at 1 min, we did not observe any  fatal ventricular fibrillation. Other PGs did not show effects on the arrhythmic ratio. As for the total heart rate and atrial rate, only prostacyclin decreased them transiently as shown in Fig. 5. The blood pressure was decreased transiently by prostacyclin, PG E, and PG E2, while it was increased by PG F2-.
Drugs used in the present study did not produce serious side effects related to the central nervous system such as excitement and convulsions or gastroenteral effects such as vomiting and defecation.

Discussion
Indomethacin, a cyclooxygenase inhibitor, and PGs and prostacyclin had no anti arrhythmic effects on the 48 hr arrhythmia, and prostacyclin showed a transient worsening effect on the arrhythmia. These results seem to agree with previous studies that PGs and thromboxane A2 are not effective on animal arrhythmias occurring late after myocardial ischemia (2,3,6). However, our results on prostacyclin are not consistent with the previous study (3) that prostacyclin had no effect on the canine late coronary ligation arrhythmia, but the differ ence in the two studies may not be too great because the arrhythmogenic effect of pro stacyclin we observed was only transient and was not so serious as to induce fatal arrhy thmias.
Compared with our study of the class 1 antiarrhythmic drugs of Vaughan Williams' classification (10) on the coronary ligation arrhythmias (7,8,11), all the drugs tested in the present study can be said to have no effect on the arrhythmia. Among the anti arrhythmic drugs we tested on the two-stage coronary ligation arrhythmia, Q-blockers at a-blocking doses or concentrations, Ca blockers and lidocaine were not effective on the 24 and 48 hr arrhythmias. Therefore, while it cannot be denied that PGs and prostacyclin may have antiarrhythmic effects on other arrhythmias relating to the sympa thetic nerve and Ca channel (1, 12), they may not play an important role in the ischemic arrhythmias, even though there have been reports that ischemia releases various PGs (13).