Prom the Department of Pharmacology, McGill University, Montreal, Canada

Transcription

1 365 J. Physiol. (I95I) II3, I EFFECTS OF NORADRENALINE ON CORONARY FLOW AND HEART CONTRACTION, AS RECORDED CONCURRENTLY IN THE ISOLATED RABBIT HEART BY F. C. LU* AND K. I. MELVILLE Prom the Department of Pharmacology, McGill University, Montreal, Canada (Received 12 July 1950) In connexion with earlier studies concerning the effects of adrenaline and other agents on coronary flow and heart contractions (Melville & Lu, 1950), the effects of noradrenaline were also similarly investigated. The object of this paper is to present the findings. While the actions of noradrenaline on coronary flow have been tested by a number of different workers, in most of these studies the concomitant effects on the heart contractions were not recorded. Crismon & Tainter (1938) have reported that racemic arterenol is twice as effective as a cardiac stimulant as laevo-adrenaline in cat heart-lung preparations-both agents increasing heart rate, decreasing systolic, diastolic and stroke volumes, and increasing the cardiac output. Using perfused frogs' hearts, West (1947) observed that racemic adrenaline was 8 to 33 times as active (dose for dose) as racemic noradrenaline in inducing cardiac stimulation. Ahlquist (1948) has observed that in the isolated perfused rabbit heart both noradrenaline and adrenaline increase the rate and amplitude of contraction, but concomitantly decrease about equally (18 and 20 %) coronary flow. Some slight increases (3 and 4 %) were also recorded in these experiments. On the other hand, Marsh, Pelletier & Ross (1948), using isolated hearts of cats and rabbits perfused by a modified Langendorf procedure (details not given), concluded that both agents produce cardioacceleration, increased cardiac output and increased coronary outflow. Burn & Hutcheon (1949) observed that in the perfused cat heart both adrenaline and noradrenaline produced identical effects (initial brief decrease followed by increase) on coronary flow. The amplitude and rate of contractions were also increased by both agents, though racemic noradrenaline (0-26,tg.) had less effect on rate than laevo-adrenaline (0.1 p,g.). With half of these doses the effect on rate was the same for both agents, but the initial * Medical Research Fellow, National Research Council, Canada.

2 366 3F. C. LU AND K. I. MELVILLE constriction was absent. In the dog heart-lung preparation (with the Morawitz cannula) these workers also found that doses of 2 usg. of laevo-adrenaline and 4,tg. of racemic noradrenaline, exerted similar coronary dilator effects, but the action of noradrenaline was more prolonged. Folkow, Frost & Uvnas (1949), from observations on coronary sinus outflow in cross-circulation coronary perfusion experiments on dogs under pentobarbitone, concluded that both adrenaline and noradrenaline increase coronary blood flow, but that noradrenaline was less potent. These workers also pointed out that coronary dilatation from these agents occur only when the heart is stimulated, and suggested the possibility that this effect might be only a consequence of the increased cardiac activity. Our own recent observations (Melville & Lu, 1950) would rather agree with the latter suggestion. METHODS The isolated rabbit heart perfused with oxygenated Locke solution was used. Full details of the apparatus and procedure used in these experiments have been described by Lu & Melville (1950). In a general way, the method employed permits recording pari pasu on a fast-moving kymograph, the changes occurring concurrently in coronary inflow rate and heart action (both amplitude and rate of contractions). The tracings reproduced in the figures show from above downwards: (1) Time, at intervals of 10 sec. (2) Coronary flow changes recorded by a signal magnet-each interval corresponding to an inflow of 3 c.c. into the coronary vessels. The rates of coronary flow per minute calculated on this basis are also shown (c.r.). (3) Heart contractions (systole above, diastole below) as recorded by a lever attached to the apex of the ventricle. The number of heart beats occurring during a short segment of the records can be counted. From this the heart rate per minute (H.R.) can be calculated. Racemic noradrenaline hydrochloride (arterenol) was used, and the volume of solution injected in each case was 1 c.c. made up in Locke. The injections were given through a rubber connexion attached to the perfusion cannula near the heart, and while the records were being taken. The reader is referred to the previous publication (Lu & Melville, 1950) for further details. RESULTS Figs. 1 and 2 show examples of the effects of increasing doses of noradrenaline on coronary flow and heart contractions. The smallest dose tested (A), as shown in Fig. 1, produced no detectable response. The record however demonstrates that under these conditions, the volume injected exerts no complicating effect. Following injection of a dose of mg. (B) one sees a rapid (within 10 sec.) decrease in the rate of coronary flow per minute, associated with some cardiac acceleration-the amplitude of the contractions was also slightly increased. Subsequently, the coronary flow promptly returned to the normal rate, although a slight increase in heart rate persisted longer. When a larger dose ( mg.) was injected at C in another experiment, there was again a brief initial decrease in the rate of coronary flow, associated with more marked stimulation of the heart. Subsequently, however, while the amplitude and the rate of the contractions were diminishing, the rate of coronary flow was definitely increased.

3 CARDIAC EFFECTS OF NORADRENALINE 367 T CF HR Fig. 1. Isolated rabbit heart perfusion. Reaords of three experiments, as described in the text. A, mg.; B, mg.; C, mg. noradrenaline. Fig. 2. Isolated rabbit heart perfusion. Records of two experiments, as described in the text. A, mg.; B, 0008 mg. noradrenaline.

4 368 F. C. LU AND K. I. MELVILLE Fig. 2 shows effects of still larger doses of noradrenaline. Thus, following injection of a dose of mg. at A, there is a prompt intense myocardial stimulation-systole, diastole and heart rate being increased. Concomitantly, there was no significant change in coronary flow, although the figures show a slight decrease from 10*6 (before) to 10-5 (after the injection). The record also shows clearly that as the peak of cardiac stimulation is passed and both the heart rate and amplitude of contractions are declining, coronary flow progressively increased at first (to 13-6 and 16-1 c.c./min.,), and then decreased later. The other experiment in the same figure shows similar but much more intense effects following injection (B) of a dose of mg. of noradrenaline. With this and higher doses, the intensity of the heart contractions was so marked that in order not to obscure the coronary flow record it was necessary to restrict the upper excursions of the tip of the lever. This is evident from the flattened appearance of the upper part of the record during the immediate post -injection period. This slight mechanical interference with systole could hardly have influenced the results. It is clear then that as in the preceding experiment, the rate of coronary flow was only slightly increased during the peak of the stimulation, but increased considerably when this effect was wearing off. As can be seen with the subsequent progressive decline of the heart rate and heart contractions, the coronary flow progressively decreased almost to the control rate. Similar results to those described above were obtained in several other experiments. These observations show clearly that following injections of small doses of noradrenaline, there is an initial decrease in the rate of coronary flow associated with cardiac stimulation. With larger doses the immediate intense stimulating effects of the drug predominate and concomitantly the coronary flow shows little or no increase, but as the stimulation declines good coronary dilation ensues. In the course of these investigations noradrenaline in varying doses was injected in twenty different experiments. The data obtained from ten experiments, in which doses ranging from to mg. were used, are analysed somewhat further in Table 1. The results obtained in two experiments with rather large doses (0.2 mg.) are also included. The data presented in the table show that during the control period in the different experiments the coronary flow per minute varied from 7*3 to 19'2 (average 11.8) c.c., while the heart rate per minute varied from 93 to 135 (average 119) beats, and the coronary flow per beat varied from to (average 0.099) c.c. During the 5-10 sec. immediately following the injections, both the coronary flow per minute and per beat decreased in all experiments shown, except in Exp. no. 1, in which it was unchanged, and Exps. nos. 10 and 11 where the increases were only 1-2 and 11.4%, respectively. Again, during the subsequent observation periods in Exps. nos. 1-7, there was a similar

5 CARDIAC EFFECTS OF NORADRENALINE 369 decrease in coronary flow per beat, despite the fact that the coronary flow per minute was normal (Exp. no. 2) or slightly increased (Exp. no. 7). It is apparent, therefore, that with small doses noradrenaline induces predominantly a decrease in coronary flow. Dose of noradrenaline Exp. injected no. (mg.) Control period TABLE 1. Coronary Heart Coronary inflow rate inflow Time (c..c./min.) per min. (c.c./beat) (sec.) After noradrenaline Coronary inflow (c.c./min.) * Heart Coronary rate inflow permin. (c.c./beat) Increase (+) or decrease (-) in coronary inflow per heart beat (%) * * During the later observations in Exps. nos. 8-12, there was uniformly an increase in the coronary flow per minute, associated with increase in the heart rate, but the coronary flow per beat was either increased (Exps. nos. 8, 10 and 11) or decreased (Exps. nos. 9 and 12). In the latter experiment there was also a transient increase. In the last two experiments, despite the high coronary flows per minute recorded, the intense cardiac stimulation undoubtedly impeded the flow, and the coronary flow per beat was definitely less increased. The results obtained in six other experiments, in which doses ranging from to 0-04 mg. were injected, were rather like those shown in Fig. 2, B, and need no comment. Both increases and decreases in coronary flow per minute and per beat were noted. DISCUSSION The results presented above show that noradrenaline, like adrenaline (Melville & Lu, 1950), can induce both increases and decreases in the coronary flow per minute and the coronary flow per beat is generally decreased rather than in- PH. CXIII. 24

6 370 F. C. LU AND K. I. MELVILLE creased, except with very large doses. With small doses decreases in flow occur more frequently and are generally more marked. This coronary vasoconstriction is also apparently always associated with some cardiac acceleration and stimulation, and would therefore appear to be due to these latter effects. With moderate and large doses of noradrenaline the initial decrease in coronary flow is less evident, but the myocardial stimulation is much more intense, and usually not prolonged, since the drug is rapidly washed through the heart in this preparation. The myocardial stimulation is also always followed subsequently by an intense and prolonged increase in the rate of coronary flow. These results show clearly that noradrenaline can lead to coronary vasodilatation. The question arises, however, whether this is due to a primary effect or is. only a secondary effect resulting from the increased myocardial stimulation. A definite answer to this question cannot be given. Since the stimulating effect of adrenaline on the myocardium wears off so quickly even with large doses, it might be assumed that the injected adrenaline has either been rapidly removed from the heart by the perfusion fluid or rapidly destroyed. Why the coronary dilatation should therefore persist is not clear. It is suggested that these dilator effects may be partly due to metabolites produced during the intense myocardial stimulation induced by the drug. The results obtained with noradrenaline in these experiments were similar to those previously described in similar experiments with adrenaline (Melville & Lu, 1950), except that noradrenaline appears to exert a stronger myocardial stimulation. The effects of the two agents on heart rate and on coronary flow (both per minute and per heart beat) do not appear to be significantly different, except that decreases in coronary flow appeared to occur more often with noradrenaline than with adrenaline. This might be explained by its stronger action on the heart. The different types of results obtained with different doses of noradrenaline might also explain some of the variations in the results described by previous investigators, particularly when the coronary flow changes are not recorded in continuity. We have tried in several experiments to abolish the above-described effects of noradrenaline either by a preceding injection of ergotoxine, or ergotamine, or by perfusing with either agent. The results were rather variable. In such experiments while both the coronary and myocardial effects of small doses of noradrenaline (and adrenaline) were sometimes completely or almost completely prevented, it was always possible to obtain effects with large doses. The cardiac effects of noradrenaline then, like those of adrenaline, cannot be completely prevented by ergotoxine, or ergotamine. It is clear from the above results that noradrenaline exerts a strong myocardial stimulating action, which might conceivably play an important role in the blood-pressure responses to this agent, as suggested by one of us in the preceding paper (Melville, 1951).

7 CARDIAC EFFECTS OF NORADRENALINE SUMMARY 1. Experiments are presented to show that noradrenaline induces both coronary constriction and coronary dilatation in the isolated perfused rabbit heart, and that the coronary flow per heart beat is generally decreased except with large doses. 2. It is also shown that the drug produces marked myocardial stimulation, and it is suggested that this is largely responsible for mechanically impeding coronary flow. 3. The possibility that the coronary vasodilatation might be wholly or partly due to a secondary effect resulting from the intense myocardial stimulation is discussed. REFERENCES Ahlquist, R. P. (1948). Amer. J. Phy8iol. 152, 586. Burn, J. H. & Hutcheon, D. E. (1949). Brit. J. Pharmacol. 4, 373. Crismon, J. M. & Tainter, M. L. (1938). J. Pharmacol. 64, 190. Folkow, B., Frost, J. & Uvnas, B. (1949). Acta phy8iol. 8cand. 17, 201. Lu, F. C. & Melville, K. I. (1950). J. Pharmacol. 99, 277. Marsh, D. F., Pelletier, M. H. & Ross, C. A. (1948). J. Pharmacol. 92, 108. Melville, K. I. (1951). J. Physiol. 113, 346. Melville, K. I. & Lu, F. C. (1950). J. Pharmacol. 99, 286. West, G. B. (1947). J. Phy8iol. 106,