already been published [O'Connor, 1958 b]. emphasized that the most prominent action of adrenaline on the kidney is to

Transcription

1 THE EFFECT ON THE VOLUME AND COMPOSITION OF THE URINE OF THE INFUSION OF ADRENALINE AND NORADRENALINE. By W. J. O'CoNNoR. From the Department of Physiology, School of Medicine, University of Leeds. (Received for publication 17th April 1958) The most prominent renal effect of the infusion of adrenaline in conscious dogs was a decrease in the rate of excretion of sodium. This required the infusion of adrenaline at pig./kg./min. and was always accompanied by an increase in heart rate. A similar effect could be produced by the infusion of noradrenaline, but in larger doses ( ,g./kg./min.), and the effect was always accompanied by slowing of the heart and increased blood pressure. The nature of the urinary changes depended on the rate of excretion of sodium at the time of the infusion. If the rate was less than 0 03 m.equiv/min., decreased excretion of sodium due to adrenaline was the result largely of a decrease in the sodium concentration in the urine, with only a small fall in the volume of the urine; at higher rates, the decrease in sodium excretion was produced by decreased volume of the urine without decrease in urinary sodium concentration. Adrenaline produced a small fall in the rate of excretion of potassium, but very little change in the excretion of urea. Urinary volume was decreased when adrenaline was infused during water diuresis. Comparison was made between adrenaline and the ingestion of 0 9 per cent sodium chloride as agents altering the rate of excretion of sodium; the effect of adrenaline ( cg./kg./min.) would be counteracted by a fall of 0.15 g./100 g. in the plasma solids produced by the ingestion of saline. It is pointed out in discussion that the renal effects of adrenaline may be satisfactorily accounted for as due to a fall of about 3 per cent in glomerular filtration rate. INTRODUCTION THE literature on the renal effects of adrenaline has been reviewed by Pickford [1952]. In most instances the effects have been produced only by large doses of the drug and so are unlikely to be of importance in the normal control of renal function. Several authors [for references see Blake, 1955] have emphasized that the most prominent action of adrenaline on the kidney is to reduce the rate of excretion of sodium. This effect is produced consistently and by small rates of infusion of adrenaline, and so has been further investigated as possibly indicating one factor involved in the normal control of sodium excretion. In this paper the effects of adrenaline have been compared with the effects of ingestion of 09 per cent sodium chloride and of occlusion of the carotid arteries; these also are particularly effective in causing changes in the rate of excretion of sodium [O'Connor, 1955, 1958 a]. In addition a comparison has been made between the dose of adrenaline needed to reduce sodium excretion and that which produced tachycardia [Holgate and O'Connor, 1958]. Some effects of noradrenaline are also described. A preliminary account has already been published [O'Connor, 1958 b]. 384

2 Renal Effects of Adrenaline 385 METHODS The effects of adrenaline and noradrenaline on urine flow and composition were investigated during experiments in which blood pressure and heart rate were also recorded, with the results described by Holgate and O'Connor [1958]. The experiments were performed on three trained bitches ("Floss", "Skewbald" and "Black Sue"), which were also used for the experiments described by O'Connor [1958 a]. Operative preparations of the animals, details of the procedures and the analytical methods have already been described [Holgate and O'Connor, 1958 and O'Connor, 1958 a]. On the occasion of each individual experiment on the effect of adrenaline or noradrenaline, the animal was catheterized, and the chosen dose of urea, water or 09 per cent sodium chloride was given by stomach tube. The animal was then placed on its side on a warm table and lay quietly for the remainder of the experiment. Infusions of drugs were given through polythene tubing inserted into the malleolar vein and threaded forward so that the tip lay in the femoral or iliac vein. Infusion of 0-85 per cent saline at 026 ml./min. was established for at least half an hour before changing to a similar infusion containing adrenaline or noradrenaline. Urine was collected from the self-retaining catheter inserted at the beginning of the experiment. Where the urine flow was small (less than 0 5 ml./min.) the bladder was washed out at the end of each collection period by the procedure described by O'Connor [1958 a], but at higher flows the collecting tubing was merely drained by means of a T-piece close to the vulva. RESULTS The Effective Dose of Adrenaline and Noradrenaline.-As will be illustrated later in this paper, the effect of adrenaline was most clearly seen when the rate of excretion of sodium had been raised by the previous administration to the animal of 0 9 per cent sodium chloride. In the experiments of fig. 1 infusion of adrenaline was begun about 50 min. after the administration of 350 ml. of 0 9 per cent sodium chloride by stomach tube. The animal had also been given by stomach tube 200 ml. of saline 4 hr. previously and a dose of 300 ml. on the days preceding the experiment. The response to the administration of 09 per cent sodium chloride under these conditions has been described in previous papers [O'Connor, 1950, 1955]; in the examples of fig. 1, 50 min. after the test dose the rate of excretion of sodium had risen to 0-25 m.equiv/min. and in the absence of the infusion would have remained at this level or risen a little further in the next 20 min. However in fig. la and b the infusion of adrenaline at and 0-17,ug./kg. body weight/min. caused the rate of excretion of sodium to fall to 0-18 and 0-08 m.equiv/min., about 75 and 30 per cent of the expected rate in the absence of any infusion. The numerals at the top of fig. 1 give the heart rate and the mean arterial blood pressure; in both experiments adrenaline caused a large increase in heart rate, as has been described by Holgate and O'Connor [1958]. Fig. 2 shows on the same animal and under the same conditions the effect of the infusion of noradrenaline at 0-12 and 0 4,ug./kg./min. and again the rate of excretion of sodium was reduced by the infusions. The changes in heart rate and mean arterial blood pressure shown at the top of the fig. 2 are typical of the effects of noradrenaline on the circulation [Holgate and

3 386 O'Connor O'Connor, 1958]; there was a slowing of the heart rate and, with the higher dose, an increase in arterial blood pressure. I I (a) MINUTES FiG. 1.-"Skewbald", 15 kg. The effect on sodium excretion of the infusion of adrenaline at (a) and (b) 0-17,ug./kg./min., during the period marked by the rectangles. Abscissae; time in min. Ordinates: continuous line (UV), rate of excretion of sodium, m.equiv/min., scale on the left; broken line (U), urinary sodium concentration, molar, scale on left; dotted line (V), rate of urine flow, ml./min., scale on right. Figures at the top give the mean arterial blood pressure (mm. Hg) and the pulse rate (per min.). Doses of 0-9 per cent sodium chloride were given by stomach tube; 300 ml. on the previous day, 200 ml. 4 hr. before the experiment and 350 ml. at zero time of the graph. (b) MINUTES FIG. 2.-"Skewbald", 15 kg. The effect on sodium excretion of infusion of noradrenaline at (a) 0-12 and (b) 0 4,ug./kg./min. Plotting and experimental conditions as in fig. 1. The effect of different rates of infusion of adrenaline was investigated under the conditions of fig. 1 in twenty-four experiments on three dogs, with the results shown in fig. 3a. Infusion at 007,ug./kg./min. or more always produced a decrease in sodium excretion and infusion at about 0-15,tg./kg./min.

4 Renal Effects of Adrenaline 387 was required to reduce sodium excretion to about half of the value expected in the absence of an infusion. Holgate and O'Connor [1958, fig. 3a] plotted in the same way the increase in heart rate and the small changes in blood pressure produced by adrenaline in these same experiments; comparison of the two figures illustrates the fact that when the dose of adrenaline was large enough to decrease the rate of excretion of sodium, there was always a large increase in heart rate, as in the examples of fig. la and b. The effect of noradrenaline on the excretion of sodium was less than that of an equal infusion of adrenaline; fig. 3b shows its effect on sodium excretion 1009 A K x 80 _ SODIUM 0 EXC.ETION A A K A A (a) A AX A aa A x ~~ (a) e x INFUSION RATE (p9/gkg/min) FIG. 3.-The effect on sodium excretion of different rates of infusion of (a) adrenaline and (b) noradrenaline. Abscissle; rate of infusion (,ug./kg./min.). Ordinates, rate of excretion of sodium in experiments like those of figs. 1 and 2: excretion during the infusion is expressed as a percentage of the mean of the rates before and after the infusion. Experiments on "Skewbald" shown by circles, on "Floss" by triangles and on "Black Sue" by crosses. in fifteen experiments on the three dogs. Infusion of 0O15,ug./kg./min. was needed to produce consistently recognizable decreases in sodium excretion. Infusions of noradrenaline which produced a decrease in sodium excretion were always large enough to produce the characteristic effects of noradrenaline on the circulation, namely slowing of the heart rate and an increase in arterial blood pressure [Holgate and O'Connor, 1958, fig. 3b]. The Effect of Adrenaline on Sodium Excretion.-In the experiments of fig. 1 and other examples in figs. 4a and 6a, infusion of adrenaline decreased the excretion of sodium in the same way; in each case the concentration of sodium in the urine was not decreased by the infusion, but the decreased rate of excretion of sodium was due to a fall in the rate of flow of the urine. The examples of figs. 1, 4a and 6a are typical of the effect of adrenaline when the rate of excretion of sodium had been raised by the previous administration of 09 per cent sodium chloride. In fig. 4c, adrenaline was infused at 0-2 1tg./kg./min. without any previous VOL. XLIII, No lb (b)

5 388 O'Connor administration of sodium salts and so the rate of excretion of sodium was low (0 003 m.equiv/min.). It was difficult to recognize any effect of adrenaline on sodium excretion or urinary volume under these conditions. In six experiments on two animals adrenaline was infused at jug./kg./min. when the rate of excretion of sodium was o006 m.equiv/min.; in each case, as in fig. 4c, any fall in sodium excretion was small, being of the order of only m.equiv/min. In the experiment of fig. 4b, 300 ml. of 0 9 per cent sodium chloride was given by stomach tube on the day before the experiment and so the rate of EXCRETION 0006K 0-12 K 012 Ur (>Os. ~~~~~~~~~~~0-08 m.eq //Oin0, eq.,nin `004 K K No 0N N0o 0 v 0005 Na 0 C URINE v is-1 v 0-IS S.2 10/sin VOLUME mi/min (al) 5 )0-0S S0 100 ISO 50 0 ISO0 MINUTES FIG. 4.-"Black Sue", 21 kg. The effect on the excretion of sodium, potassium and urea of the infusion of adrenaline. Abscissse; time in min. Ordinates: from below upwards the urinary volume (ml./min.) and the rates of excretion of sodium, potassium and urea (m.equiv/min.). The figures on the curve for sodium give its urinary concentration (Molar). Infusion in (a) at 0-13,cg./kg./min. following priming doses and 350 ml. of 0-9 per cent sodium chloride at zero time, (b) at 0-2,pg./kg./min. following 300 ml. of saline on previous day and (c) at 0-2,ig./kg./min. with no doses of saline. excretion of sodium was 0-01 m.equiv/min. when the infusion of adrenaline was given. During the infusion sodium excretion fell to m.equiv/min.; the fall in the rate of excretion of sodium was due to a fall in the urinary sodium concentration from 0.11 to Molar with only a small decrease in the rate of urine flow. There were six experiments on two dogs when adrenaline was infused at ,tg./kg./min. with the rate of excretion of sodium excretion was decreased by about sodium m.equiv/min.; m.equiv/min. and in each case there was a fall in urinary sodium concentration with a somewhat smaller decrease in the rate of flow of urine. The decreased excretion of sodium produced by adrenaline thus had several features in common with the increase in sodium excretion produced by the ingestion of saline or occlusion of both carotid arteries [O'Connor, 1958 a]. In each case the effect on sodium excretion was much larger when the rate of excretion of sodium had been increased by the prior administration of 0-9 per cent sodium chloride; at high rates of excretion of sodium, the changes produced by the ingestion of saline, carotid occlusion or adrenaline were due to changes in the volume of the urine without change in the urinary

6 Renal Effects of Adrenaline 389 sodium concentration; at low rates of excretion of sodium (below about 0-03 m.equiv/min.) changes in sodium excretion were largely due to changes in the urinary sodium concentration without great changes in the urinary volume. The effect of adrenaline was, however, small in comparison with the effect of ingestion of 0 9 per cent sodium chloride, and the effect of these two agents is compared in fig. 5. In the previous paper [O'Connor, 1958 a] the rate of excretion of sodium was plotted against the plasma solid content following ingestion of saline to give a curve which is reproduced as the solid line in fig. 5. Each experiment in which adrenaline was infused is plotted in fig I FIG. 5.-" Black Sue ", 21 kg. I Comparison of the effect of adrenaline on sodium excretion 0_10 with that of the ingestion of.5 I. 0 9 per cent sodium chloride. 0I o. Abscissie; plasma solid content E 0-08 B _ (g./100 g.). Ordinates, rate of _,o excretion of sodium (m.equiv/ min.). The continuous curve is replotted from O'Connor [1958 a] 0-06 and shows the relationship followo ing the administration of saline in e S _ the absence of adrenaline: the XU X._ circles and dotted line, plotted as described in the text, show the relationship during the infusion of R o ozk J / -l adrenaline at ug./kg./min PLASMA SOLIDS (g/1009) as follows, using the experiment of fig. 4b as an example. On this occasion adrenaline reduced the excretion of sodium from to m.equiv/min.; this was plotted as the closed circle in fig. 5 by reading from the continuous line that sodium excretion of m.equiv/min. corresponded to a plasma solid content of 7-86 and the point showing the effect of adrenaline was then plotted as 7-86, by assuming that the solid content of the plasma was not changed during the short period of the infusion. In fig. 5 the points from nine experiments on "Black Sue" all fell reasonably close to the dotted line drawn 1P5 divisions (0.15 g./100 g. plasma solids) to the right of the normal line. The effect of the adrenaline infusions was thus equal to the effect of a rise of 0-15 g./100 g. in plasma solids in experiments with "Black Sue", and was of similar magnitude in two other animals. The Effect of Adrenaline on Potassium Excretion. In eighteen experiments on two dogs the urinary content of potassium as well as of sodium was observed during the infusion of adrenaline at ,ug./kg./min. and in fifteen of them the rate of excretion of potassium was decreased during the infusion; clearly in fig. 6a, and also in figs. 6b, 4a, b and c the effect of

7 390 O'Connor adrenaline was to reduce potassium excretion. The existing rate of excretion of potassium was always low, being m.equiv/min. in six experiments where previous doses of 0 9 per cent sodium chloride had not been given (e.g. fig. 4c); *007 in five experiments in which small doses of sodium chloride were given (e.g. fig. 4b); and m.equiv/min. in seven experiments in which large doses of saline were given (e.g. fig. 4a). The average falls in potassium excretion produced by adrenaline in the three groups of experiments was 0*003, 0002 and m.equiv/min. Although the quantitative estimate can only be tentative, the decreased excretion of EXCRETIOU C002 K Ut K U (meq./mir) (m.eq~av~n) 013O<=o 0-01I ~ ~ ~~KK No No Na (a) MINVU00TE[S ~~~~~ ~H..., H0.4() (i/ 1~J(b) P MINUTES ' The effects of the infusion of adrenaline FIG. 6.-"Skewbald", 15 kg. on the excretion of sodium, potassium and urea. Plotting as in fig. 4. By stomach tube at zero time in (a) 350 ml. 0-9 per cent sodium chloride, in (b) 5 g. urea in 100 ml. water and in (c) 320 ml. water. Rates of infusion in (a) 0-13, (b) 0-17 and (c) 0.1,ug./kg./min. sodium produced by adrenaline was usually accompanied by a decreased excretion of potassium, never an increase, and the renal response to adrenaline had this feature also as a point of similarity when compared with the effects of the ingestion of saline or carotid occlusion [O'Connor, 1958 a]. The Effect of Adrenaline on the Excretion of Urea.-Whatever the existing rate of excretion of sodium, the rate of excretion of urea was usually diminished a little during an infusion of adrenaline, as in the examples of fig. 4b and c. Of fourteen experiments on two dogs, the rate of excretion of urea was decreased by adrenaline ( jug./kg./min.) in ten, unchanged in two and increased in two; the mean fall in the fourteen experiments was 10 per cent. This fall was too small to be established with certainty against the random variations which frequently occurred between urea excretion in successive periods especially when the urine flow was low or changing rapidly. Fig. 6b shows an experiment in which 5 g. of urea in 100 ml. of water was given by stomach tube; urea excretion followed the time course described by O'Connor [1950] without any large effect of the infusion of adrenaline at 0 17,ug./kg./min. Fig. 6b is typical of three experiments in which the effect of adrenaline was tested after the administration of urea.

8 Renal Effects of Adrenaline 391 The Effect of Adrenaline Infused during Water Diuresis.-Infusion of adrenaline during the rising phase of water diuresis in fig. 6c produced some slowing of the diuresis, and this experiment was typical of five experiments with two dogs where adrenaline was infused at ,tg./kg./min. during water diuresis. The rate of flow of urine in each experiment was at most halved. The time course of the inhibition in fig. 6c was typical in that the effect of the adrenaline disappeared over a period of about 20 min. after the end of the infusion. The effect of adrenaline on sodium excretion (fig. 1, 4) and on the heart rate [Holgate and O'Connor, 1958] were similarly recognizable for about 20 min. after the end of the infusion. Thus, in fig. 6c and similar experiments there was no clear evidence of a prolonged inhibition of water diuresis due to the liberation of neurohypophyseal hormone by adrenaline, as was described by Dearborn and Lasagna [1952] and Pickford and Watt [1951]. DiscuSSION The most apparent effect on renal function of small doses of adrenaline infused in conscious dogs is decreased excretion of sodium. In my experiments infusion at ,tg./kg./min. produced a decrease of about 50 per cent; similar decreases in sodium excretion were produced by Berne, Hoffman, Kagan and Levy [1952] with 1-2,tg./kg./min. and by Blake [1955] with ,tg./kg./min.; while Kaplan, Fomon and Rapoport [1952] found that ,ug./kg./min. decreased sodium excretion during the course of mannitol diuresis. The rate of infusion needed to slow sodium excretion was thus quite small, but even so it was enough to cause a large increase in the heart rate in the present work and apparently also in the experience of Blake [1955]. It seems unlikely, therefore, that changes of the rate of entry of adrenaline into the blood stream can be an important factor in determining the sodium balance of the body, since changes in the rate of excretion of sodium are not normally accompanied by changes in the heart rate. The effect on sodium excretion of noradrenaline has been studied less than the effect of adrenaline. It has been shown (fig. 3) that noradrenaline had to be infused at about twice the dose of adrenaline in order to produce the same effect on sodium excretion, and a similar difference in dose was also required to produce their characteristic effects on pulse rate and arterial blood pressure [Holgate and O'Connor, 1958]. Kaplan et al. [1952], infusing the amines in conscious dogs at ,tg./kg./min., found that adrenaline produced greater reduction in sodium excretion than did noradrenaline. Berne et al. [1952] found them equally active but at higher rates of infusion (1-2,tg./kg./min.). In anmesthetized dogs, adrenaline is more effective than noradrenaline in constricting the renal vessels [Burn and Hutcheon, 1940; Ahlquist, Taylor, Rawson and Sydow, 1954; Page and McGubbin, 1953]. The difference in the actions of the two amines on sodium excretion may not be solely due to a weaker action of noradrenaline on the kidneys. In the present experiments noradrenaline produced an increase of mm. Hg in arterial blood pressure [Holgate and O'Connor, 1958] and this would be expected to cause an increase

9 392 O'Connor of about 20 per cent in the rate of excretion of sodium [O'Connor, 1955, 1958 a]. The effect of noradrenaline on sodium excretion may thus be the resultant of two opposing actions, namely the renal action of noradrenaline and its hypertensive action. Adrenaline had no effect on the blood pressure [Holgate and O'Connor, 1958]. Superficially, the fact that adrenaline reduced the excretion of sodium and potassium without greatly affecting the excretion of urea suggests that it has a specific effect on the handling of electrolytes by the renal tubules. However, as described in this paper, the renal action of adrenaline had many features similar to the effects in the same animals of ingestion of 0-9 per cent sodium chloride or occlusion of both carotid arteries. In previous papers [O'Connor, 1955, 1958 a] the effect of the ingestion of saline was attributed to increased glomerular filtration produced by dilution of the plasma protein, and the effect of carotid occlusion to the increased glomerular filtration produced by the raised arterial blood pressure. The similarities suggest that the effects of adrenaline are due to a fall in glomerular filtration produced by its vasoconstrictor action on the renal vessels. This explanation appears to be accepted by Blake [1955] as accounting for at any rate a large part of the renal effects of adrenaline. Quantitatively, the effect of adrenaline was small in comparison with the increased excretion of sodium produced by the ingestion of saline; according to fig. 5 it was equal to the effect of a fall of 0X15 g./100 g. in plasma solids. From considerations based on the results of Wesson, Anslow, Raisz, Bolomey and Ladd [1950] and discussed by O'Connor [1955], a rise of 0.15 g./100 g. in plasma solids corresponds to a fall of 1-5 ml./min. in glomerular filtration rate, and so a change of glomerular filtration rate from 50 to 48-5 ml./min. is all that need be postulated to explain the renal actions of adrenaline described in this paper. Mannitol, inulin or creatinine clearances during the infusion of adrenaline in conscious dogs have been reported by several authors. Kaplan et at. [1952] found a reduction of 10 per cent or more; Berne et at. [1952] found a reduction of 15 per cent in denervated kidneys but no change in normal kidneys; Blake [1955] found a fall of 10 per cent in the first clearance period during the infusion and a change varying from +20 to - 20 per cent in the second collection period. Thus, many of the results do in fact show a fall, the statistical significance of which cannot be assessed from the data provided. The data in fact favours and is totally inadequate to exclude, a fall of 3 per cent in glomerular filtration rate and so cannot contradict the explanation that the effect of adrenaline on the excretion of sodium is due to a small fall in glomerular filtration. Some actions of adrenaline which have been described in the literature were not observed in my experiments. In the perfused kidney and in anaesthetized animals adrenaline may increase the flow of urine [Richards and Plant, 1922; Winton, 1931; Toth, 1937]. In a recent review, Pickford [1952] expressed the impression that increased flow of urine was more likely when small doses of adrenaline were injected or infused. I have never observed this in conscious dogs with rates of infusion as low as 0*01,tg./kg./min.

10 Renal Effects of Adrenaline Dearborn and Lasagna [1952] produced a prolonged inhibition of water diuresis by large single injections of adrenaline and showed that this was due to the release of antidiuretic hormone from the neurohypophysis. Pickford and Watt [1951] found that infusion of adrenaline (0.47 jtg./kg./min.) produced an inhibition outlasting the probable duration of the action of adrenaline, but such an effect was not observed in my experiments. O'Connor and Verney [1945] found that single injections of adrenaline could inhibit the release of antidiuretic hormone from the neurohypophysis during emotional stress. There has been no indication in the present experiments that infusion of adrenaline could block the normal release of antidiuretic hormone and so produce a transient diuresis. ACKNOWLEDGMENT I wish to thank Mr. J. Brook for his very patient technical assistance. 393 REFERENCES AHLQUIST, R. P., TAYLOR, J. P., RAWSON, C. W. and SYDOW, V. L. (1954). J. Pharmacol. 110, BERNE, R. M., HOFFMAN, W. R., Jr., KAGAN, A. and LEVY, M. N. (1952). Amer. J. Physiol. 171, BLAKE, W. D. (1955). Amer. J. Physiol. 181, BuRN, J. H. and HUTCHEON, D. E. (1940). Brit. J. Pharmacol. 4, DEARBORN, E. H. and LASAGNA, L. (1952). J. Pharmacol. 106, HOLGATE, J. A. and O'CONNOR, W. J. (1958). Quart. J. exp. Physiol. 43, KAPLAN, S. A., FOMON, S. J. and RAPOPORT, S. (1952). Amer. J. Physiol. 169, O'CONNOR, W. J. (1950). Quart. J. exp. Physiol. 36, O'CONNOR, W. J. (1955). Quart. J. exp. Physiol. 40, O'CONNOR, W. J. (1958 a). Quart. J. exp. Physiol. 43, O'CONNOR, W. J. (1958 b). J. Physiol. 142, 52P. O'CONNOR, W. J. and VERNEY, E. B. (1945). Quart. J. exp. Physiol. 33, PAGE, I. H. and MCGUBBIN, J. W. (1953). Amer. J. Physiol. 173, PICKFORD, M. (1952). Pharmacol. Rev. 4, PICKFORD, M. and WATT, J. A. (1951). Quart. J. exp. Physiol. 36, RICHARDS, A. N. and PLANT, 0. H. (1922). Amer. J. Physiol. 59, TOTH, L. A. (1937). Amer. J. Physiol. 119, WESSON, L. G., Jr., ANSLOW, W. P., Jr., RAISZ, L. G., BOLOMEY, A. A. and LADD, M. (1950). Amer. J. Physiol. 162, WINTON, F. R. (1931). J. Physiol. 73,