- Email: [email protected]
Discussion I
iscussisn Moderator: DAVID P. LAULER, MD Participants: MORRIS J. BROWN, MD, JEROME D. COHEN, MD, PETER F. COHN, MD, C. RICHARD CONTI, MD, VINCENT L. De QUATTRO, MD, WILLIAM H. FRISH???AN; MD, RICHARD GORLIN, MD, JOEL KUPERSMITH, MD, STUART L. LINAS, MD, HILTRUD S. MUELLER, MD, WILLIAM C. ROBERTS, MD, DAVID G. SHAND, MD, and HIERONYMUS H. VINCENT, MD
Dr. Gorlin (New York, New York): I was intrigued by the reports from Drs. Brown and Vincent. They focused on the concentration of serum potassium only but in any discussion of membrane potential change and shifts of cations, we have to be concerned about the pH, and what is happening to plasma calcium, magnesium and sodium. Are we simply looking at the beginning observation in regard to these adrenaline-related changes in potassium? Is this one of the reasons we avoid the question of causality, because, perhaps, changes in magnesium have something to do with this? If you do not have the ratios of sodium and potassium for example, you really do not know whether you have affected the intrinsic irritability of a cell in terms of its membrane potential. Dr. Brown (London, England): Your points are well taken. Every time I come to the United States someone asks about magnesium. With calcium and sodium, there is absolutely no change. We have not measured pH during our adrenaline infusions. During our study of squash players, we were very concerned that any changes we observed might be due to pH. We decided against doing arterial pH measurements, because the game of squash might have been offset by the distractions of an arterial cannula. We used arterialized venous samples. During discussions of muscle with physiologists, we were told that pH was unlikely to change greatly even during the sort of exercise that is undertaken in squash. Indeed, we saw very little change in the pH. I think the mean fall was 0.01 units, which was not of sufficient magnitude to explain the change in potassium. It is noticeable that after a rally of squash ends, the player tends to hyperventilate. This may account for some of the rapidity of the decrease in potassium, but only a small part. Magnesium is the main question that we have to follow up. I think that if the presumed explanation of sodium/potassium adenosine triphosphatase stimulation is correct, one would not expect to see a decrease in magnesium. However, in relation to thiazide-induced problems, it obviously could be additive, and plasma magnesium apparently does decrease during exercise. Dr. Vincent (Rotterdam, The Netherlands): I did measure pH in the patients who received isoprenaline infusions, and there was absolutely no change in pH. I have very little data on magnesium.
Dr. Gorlin: It may be that local tissue changes are important. If you are talking about myocardial infarction, what is the extracellular and intracellular pH in relation to the concentrations of potassium? This would be important in any issue of arrhythmogenesis irrespective of what plasma potassium levels are. It may be more than a question of the systemic values being measured. Dr. Lauler (New London, Connecticut): To follow up on what Dr. Gorlin said-in the original reports there was mention of earlier reports that showed that the changes in myocardial potassium may have been in a different direction from those reported in muscle potassium. This is a little broader question than Dr. Gorlin asked, but could you comment on that, and whose observations they were? Dr. Brown: The data were not ours and, in fact, have not been published yet. They were referred to in a discussion by Clausen at a symposium like this. He found that the effects he observed in the rat soleus muscle might go the opposite way in cardiac tissue. That is, the effect of adrenaline on potassium uptake in the heart might actually be the reverse of what is seen in the soleus muscle and systemic circulation. In the whole animal, this would be very difficult to follow up. We have been trying to measure individual tissue uptake of potassium-42 in the whole animal in response to adrenaline infusion. One runs into the obvious problem that in the whole animal the adrenaline dilates the vessel bed in skeletal muscle. One does indeed observe greater uptake of potassium-42 in skeletal muscle than in the heart, and if anything, adrenaline leads to apparent loss of potassium-42 from the heart. It is difficult to know, however, if this is nothing more than adrenaline shifting the blood to the skeletal muscle bed. Additionally, adrenaline could be expected to increase potassium loss from the heart, as a consequence of the increase in cardiac contractility or rate of contraction. I would be inteiested to hear what cardiologists have to say about that. Dr. Kupersmith (New York, New York): Beta receptors influence cardiac sodium/potassium adenosine triphosphatase as strongly as they do cyclic adenosine monophosphate. For example, after local catecholamine superfusion in vitro the expected ionic changes due to enhancement of the sodium-
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potassium pump occur: decreased intracellular sodium and increased intracellular potassium. However, other factors are also important. The sodiumpotassium pump is affected by the level of extracellular potassium which, in turn, may be influenced by the /3sreceptor. Thus, if this ,f&receptor is stimulated, the following may occur: there may be little or no direct effect on the cardiac sodiumpotassium pump per se, but there will be a decrease in extracellular potassium due to effects on the peripheral pumps. This change in extracellular potassium will in turn have an indirect effect in inhibiting the cardiac sodium-potassium w-w Dr. Brown: The effects of adenosine triphosphatase inhibition is, as 1 am rapidly discovering, a very difficult area in which to unravel cause from effect. One has to be careful when examining the effects of ouabain to ascertain that one is looking at primary effects: blockade of sodium or potassium flux stimulation by ouabain does not prove that the stimulation (e.g., by adrenaline) was directly from sodium/potassium adenosine triphosphatase. Our observations with digoxin at therapeutic doses made us wonder indeed whether sodium/ potassium adenosine triphosphatase is the target of adrenaline. One has to remember that in the in vitro experiments of Clausen he was looking at both very large doses of adrenaline and even larger doses of ouabain. This may, in fact, be of some interest because there has been a long running debate as to whether the effects of digoxin are entirely mediated through sodium/potassium adenosine triphosphatase inhibition in the heart. As far as I can tell from published studies, it appears to be true that digoxin has a much greater affinity for cardiac sodium/potassium adenosine triphosphatase than for skeletal muscle. It may be that the heart is more likely to be blocked by digoxin. But if adrenaline has a lesser effect on this pump in the heart, then it may explain why digoxin does not block hypokalemia, but is still having its protective effects on the heart. Dr. Vincent: Clausen has commented in a conference that the effects on the heart were indeed the same as in skeletal muscle without mentioning what animal he had examined. However, I think it is quite possible that even if this effect occurs in the heart as well as in skeletal muscle, the enormous amount of skeletal muscle takes up so much of the potassium that for the heart it is really the same as potassium depletion. We should consider that possibility. Dr. Conti (Gainesville, Florida): Dr. Brown, you presented data about epinephrine infusion increasing serum glucose; I thought you would say that the insulin would increase, and the potassium would then decrease. That did not happen. This was based on some experiments that were done in Missouri, I believe. Dr. Brown: What I said was that Cryer has also observed that adrenaline suppresses insulin. The data I showed you were our own. Dr. Conti: Was their experiment precisely the same as yours in terms of infusion of epinephrine? Dr. Brown: Yes. It is interesting that if you give adrenaline in the presence of an o(s blocker, you see an increase in insulin. Dr. Conti: What is the shortest time of epinephrine infusion required to decrease the serum potassium? The reason I ask this question is to determine the clinical relevance of 2 hours of epinephrine infusion. Dr. Brown: That is a very important point. The data I showed you of our dose-response curve with adrenaline were from Sminute increments of adrenaline infusion. We saw our
first decrease in potassium at a dose of 0.04 pg/kg/mm, which was preceded by 3 previous rates. It is possible that the previous rates had a cumulative effect, but even so, at 5 minutes a definite decrease was observed. Dr. Cohn (Stony Brook, New York): I have a question based on the difference in the response to isoproterenol. The normal volunteer subjects in Dr. Brown’s group differed from Dr. Vincent’s group in that their baseline heart rates were much lower. In fact, Dr. Vincent’s group had a baseline heart rate of about ‘70beats/min, which one would expect. When Dr. Brown described his squash players, I noticed that their baseline heart rate was in the 70 beatslmin range, which is also what one would expect. On the other hand, in his 6 normal volunteers the mean resting rate was 55 beats/min, indicating that these young volunteers were probably athletes or otherwise were in good condition. Could this possibly explain the difference in the isoproterenol results, or do you have other data, Dr. Brown, in volunteers with normal or near-normal physiologic control heart rates? Dr. Brown: There was one other difference that 1 noticed, which is that Dr. Vincent said his patients were mild essential hypertensives and presumably from an older age group. I don’t know the total answer to the question, but I can comment on the basal heart rate. First, there is a difference between the infusion study and the squash study: all the levels in the squash study were measured with subjects about to start the game, whereas basal levels in the infusion study were taken after 1 hour of lying down in the clinical laboratory. In fact, I would actually dispute that the normal resting heart rate for a young volunteer who is not anxious is in the 70 beatslmin range. If you have trained volunteers, who are used to having all these nasty things done to them and can lie down in the clinical laboratory without being worried, then the normal resting heart rate without their being athletes is in the 50 beats/min range. If they are athletes, then we seelevels down to 40 and even 30 beats/min. Dr. Vincent: My patients were between 20 and 40 years of age. Dr. Gorlin: Dr. Vincent, did you measure blood pressure in your differential catecholamine experiments, because that might have been very interesting-in those instances where 0s stimulation or blockade produced an increase or a decrease in norepinephrine. Did it alter the nature of the blood pressure response as opposed to the heart rate response when you gave, let’s say, an agonist like epinephrine, which gives you one kind of blood pressure response with a mixed o-P effect, compared to a situation in which norepinephrine dominates. In the latter situation you might anticipate more of an or-adrenoreceptor effect on blood pressure response. Did you make these kinds of determinations? Dr. Vincent: I am usually asked whether this increase in noradrenaline is not somehow baroreflex-mediated, because of the slight decreasethat may occur in mean arterial pressure after isoprenaline. I think there are quite sound arguments to say that that is not the case. If you ask me about the direct effects of this released noradrenaline, then, of course, this effect is compounded by the effects you get from the @agonist itself. That has always been a problem. When we studied the effects of salbutamol on blood pressure and noradrenaline levels, we observed something curious. As you might expect, because salbutamol is a &receptor agonist, there was a slight decrease in blood pressure initially. But then at high doses there was a change. Blood pressure did not decrease any further, and systolic blood pressure actually increased. At the same time, noradrenaline levels increased. This might suggest that noradrenaline itself could be the cause of the increase in
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blood pressure. But in these kinds of studies we have the direct effect of the fl agonist itself versus the indirect effect through noradrenaline. That is why it is so important to have a constant level of the p agonist and impose some stimulus, such as the cold pressor test, to see if the effects of sympathetic activity are indeed exaggerated. Dr. Brown: Why do you think the increase in noradrenaline is not a baroreflex-mediated response to a decrease in mean arterial pressure? Dr. Vincent: Because as soon as blood pressure goes up, noradrenaline levels should go back down or at least decrease to a lower range. During the highest dose of salbutamol, both blood pressure and heart rate increased, which would tend to stimulate baroreceptors and cause a lowering of sympathetic activity, yet coincidentally with these changes noradrenaline levels actually increase. Dr. Conti: One of the things that some people have been interested in is sudden death in marathon runners. Could some of the deaths have been due to exercise hyperkalemia? I doubt that any of those marathon runners were taking 0 blockers, because I personally have taken them and gotten on a treadmill; instead of being able to go to a heart rate of 212 beats/min, I got to a heart rate of 140 beats/min in about 10 minutes less exercise time. I don’t think you can complete a marathon and take /!I blockers at the same time. It is really bothersome to seea 7.4 mEq/‘liter potassium level, and I think this needs to be looked at more carefully. Maybe it has absolutely no relevance to anything. Under conditions of maximum stress with pH changes and potassium being that increased, it may mean nothing at all. Certainly it means a lot if you are just casually sitting around the room and your potassium is 7.4 mEq/liter. Dr. Cohen (St. Louis, Missouri): My question is really a generic one for either Dr. Brown or Dr. Vincent, who focused beautifully on the plasma catecholamine levels. The question relates to the receptors themselves. Has either of you looked at differential studies with respect to the quality of the receptors or changes in the sensitivity of those receptors? In the long-term use of 0 blockers, how about change in the actual quantity of the receptors? What effect might this have in terms of an effect on a given level of plasma catecholamine? Dr. Brown: I have no data other than what I can extract from reports. Acutely, it appears that administration of /3 agonists such as isoprenaline leads to an early increase in /3 receptor number, and I still think that is an alternative to the prolonged tachycardia observed after discontinuation of adrenaline infusion. In the longer term, down regulation of receptor number could be expected after even as short a period of time as 3 or 4 hours. Beta receptors when measured on lymphocytes, for instance, decrease’in number. As far as p blockade is concerned, the story-again, largely from lymphocyte /3 receptor numbers-is that after long-term /I blockade, /I adrenoceptor numbers are increased. This may be responsible, for instance, for the /3 blocker withdrawal phenomenon. Some,people have shown increased sensitivity to isoprenaline infusions after withdrawal from fl blockade. By contrast, if you use a drug such as pindolol, which is supposed to have partial agonist activity, you then reverse the down regulation of receptor numbers during long-term therapy and theoretically would see lessof a withdrawal syndrome. However, I think one has to be very careful about extrapolating data from lymphocyte receptor number studies to cardiac tissue. One should probably only take seriously studies in which isoprenaline infusions have been done in parallel with lymphocyte receptor number and simultaneous measurement
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of cardiac responses. Probably, p receptor sensitivity is increased after long-term therapy. Dr. Frishman (Bronx, New York): One of the issues regarding that point is that if@ receptor numbers and sensitivity increase with long-term P-blocker therapy, wouldn’t the tolerance effect become evident in the long-term treatment of hypertension with these drugs? The explanation, as you suggested, may be that the suspected catecholamine increment is a way to try to overcome the blockade but it is not seen because norepinephrine levels decrease. In fact, that has been an explanation for the long-term efficacy of p blockers in treatment of hypertension. Do you think it is a presynaptic or P-blocking action? Dr. Vincent: I think it is presynaptic P blockade. It could also be a central effect. That is very hard to disprove, although, of course, YOUsee the effects with more water-soluble drugs as well. Dr. Mueller (Bronx, New York): We reported a study regarding the effect of propranolol on plasma cateeholamine levels in patients with acute myocardial infarction using intravenous propranolol and also using a randomized doubleblind placebo gr0up.l Actually the reason that we measured catecholamine one-norepinephrine levels was because we were concerned that an increase could occur because of the response to the decrease in cardiac output. To our surprise, in those patients who received propranolol, the one-norepinephrine levels were sharply increased-2.4 &g/liter. Propranolol also decreased the one-norepinephrine content in the systemic circulation significantly. This study compared 35 placebo- and 35 propranolol-treated patients. We also showed that the degree of propranolol-induced decrease in plasma norepinephrine levels was related to this initial concentration. We are now in publication with the suggestion that this could be explained by presynaptic blockade of the /3 receptors by propranolol. rown: As Dr. Vincent showed, there is a probiem with rs affecting cardiac clearance of catecholamines, and it makes it very difficult to draw conclusions from the changes in plasma noradrenaline concentration as being due to changes in release rate. I think the question of whether /3 blockers increase, decrease or have no effect on noradrenaline release is unresolved. r. DeQuattro (Los Angeles, California): We measured catecholamines before and after handgrip exercise, before and after labetalol therapy. We found that there is an increase in catecholamines on standing and that labetalol enhances that increase. However, with isometric handgrip exercise, the norepinephrine increment after labetalol is less than the increment on placebo. We intepret these findings as being due to blockade of epinephrine from the presynaptic p receptor that modulates norepinephrine release. What then is happening when you give adrenaline acutely and get an early increase in potassium? Are you saying it is coming from the liver? Do /3 blockers accentuate that? Dr. Vincent: All I can say is that studies have been done that have traced this increase in potassium to somewhere in the hepatic vein, so potassium supposedly comes from the liver. I don’t know exactly by what mechanism, and I can only say that it is possible to block it by blocking cyreceptors. I have not done any studies on that myself. Dr. Brown: I think the o! effect is always there with adrenaline but one only sees it either if you look very early after acute adrenaline administration, or if you unmask it by blocking the opposite @-receptor effect. It is a small effect. 1 suspect it is mainly an unmasking.
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Dr. Conk Dr. Brown, what is your technique of taking blood from squash players in play? Dr. Brown: Squash players have an indwelling cannula in their nonplaying arms and because the amount of blood we need for measuring potassium and catechols is small, we take it as quickly as possible. Obviously there is some inaccuracy in the time, but the Holter monitor the players wear has a button on it so that for each subject we can record exactly when the sample was taken and how long the sample drawing took. Dr. Roberts (Bethesda, Maryland): Dr. Vincent, I wonder if you have any information on measurement of potassium levels in skeletal muscle or cardiac muscle, and if so, would such measurements be accurate? I believe some investigators in the Soviet Union have explored this area by examining epinephrine/norepinephrine tissue levels. Have you done that, or would it be useful? Dr. Vincent: I think it would, but we have no tissue levels for either potassium or catecholamines. Dr. Shand (New York, New York): We have concentrated on the indirect effects of /Is receptors. Would either of you like to comment on the possibility of fis receptors in the heart? That tachycardia ‘with epinephrine is blocked by the 0s blocker is quite a spectacular effect, isn’t it? Dr. Brown: It is now clear that if you look at tissues from a wide variety of species-including man-using radioligand-binding techniques, you can detect /3sreceptors in the heart. Carlsson2 in Sweden has shown it in vivo using responses to pi& agonists and antagonists. The results are consistent with /3sreceptors in the atria. I think that in man the response to ICI 118551 is totally consistent with blocking the peripheral effects of adrenaline, which obviously raises the possibility that most of the tachycardia may initially have been due to vagal withdrawal rather than direct effect on the heart. One cannot be sure that these experiments provide any evidence for 0s receptors in the heart. If you look at the in vitro and in vivo evidence, you can no longer ignore the fact that there are probably ,& receptors mediating some of the cardiac responses to catecholamines. Dr. Conti: With the small amount of tissue you obtain with cardiac muscle biopsy, can you measure these epinephrine levels precisely? Is that what the Russians did? Dr. Roberts: They measured sodium, potassium and magnesium, too, I think. Dr. Conti: It is easy to do those experiments in the laboratory. You can pace the heart, exercise and take multiple biopsies. Dr. Brown: I think one approach is to use whole body counters for counting potassium or to use rubidium as a marker for potassium. Maybe this comes back to Dr. Gorlin’s initial question, and this is one of the reasons I showed the electrocardiographic tracings, as Dr. Vincent did also. Obviously we just do not know what is going on within the heart in man. But there are electrocardiographic changes, and I think one must assume that the heart is exposed to the same detrimental effects of hypokalemia as may occur during any other cause of hypokalemia. Dr. Linas (Denver, Colorado): We have looked at changes in potassium in skeletal muscle after insulin and catechol administration in rats. We were not able to show any change at all as far as skeletal muscle potassium is concerned. These, however, were chemical potassiums, not electrical potassium determinations.
I was interested in the recovery period. After the catechol levels have rapidly risen to normal, serum potassium continues to be low. Where does all that potassium go? Presumably it has been stored in cellsfor an hour or whatever the time period is. Why don’t we see rebound hyperkalemia? What is the protective mechanism? Dr. Vincent: It probably takes a little time for this potassium efflux to occur. Dr. Brown: I think the up and down slopes of plasma potassium are very similar. But there is something funny going on in the squash study, because plasma potassium decreased very rapidly. If you give a potassium chloride infusion such as DeFronzo3 did and look at the increase and decrease in plasma potassium, then the decrease in plasma potassium after the end of the potassium chloride infusion is much slower than that which we see in our squash players when they stop exercising. If it is simply the potassium, which had come out of the muscle during exercise,going back in again, one wonders why it is happening so rapidly. We just don’t know yet. Adrenaline is a factor, but not the major factor. Dr. Linas, in regard to your measurement of potassium in muscle, I think even with the potassium-42 experiments it can be difficult sometimes to see an increase in potassium-42, unless you choose the right time to look. Once you have reached a steady state, you may see no increase. I presume it is because you are looking for a needle in a haystack, so to speak. Dr. Frishman: I have a question regarding the exerciseinduced hyperkalemia that has been mentioned. Does this contribute to the fatigue that Dr. Conti has when he is on P-blocker therapy and exerciseson a treadmill? Although we are looking for protective effects, could that be contributing, perhaps, to the fatigue phenomenon that we all see with 0 blockers? Dr. Brown: The fatigue is very interesting. A number of people, including ourselves, have done studies trying to relate fatigue with potassium in a wide variety of metabolic parameters. In our studies, we found very little correlation to potassium and fatigue. A reverse possibility in relation to potassium and exercise is cramp. We know that cramp can be a very severe problem in squash players. I wonder whether the decrease in potassium could be playing a role in cramping. Dr. Kupersmith: I have also wondered about the needle in the haystack. In humans, if 20% of body weight is extracellular fluid and there is a 0.5 mEq/liter change in potassium, there would be a total change of 28 mEq of potassium in a TO-kgperson. One would have trouble determining where this small amount of potassium went. Could YOU really find such \ minute changes in these animals? Dr. Linas: Theoretically you could, but practically-with the methodologies available-you just cannot measure those kind of miniscule changes in the cellular potassium in huge muscle stores. Dr. Frishman: To summarize, it appears that reversal of epinephrine-induced hypokalemia by 6s adrenergic blockade may be an important clinical phenomenon. For years, we didn’t feel that the & blocking action of nonselective /? blockers was contributing very much to the therapeutic effects. It is now clear that /3sadrenergic blockade may protect patients from hypokalemia. What the significance of this hypokalemia may be in certain patients is not known. Finally, perhaps the effects of blocking presynaptic ,6 receptors and norepinephrine release may explain why /3 blockers are efficacious in treating high blood pressure.
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References 1. Mueller HS, Ayres SM, Religa A, et al. Propranolol in the treatment of acute myocardial infarction. Effect on myocardial oxygenation and hemodynamics.
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Circulation 1974;49:1078-1087, 2. Carkson E, Fellenius E, Lundborg P, Svenssori L. fl-adrenoceptor blockers, plasma-potassium, and exercise. Lancet 1978;2:424-425. 3. DeFronzo RA, Bia M, Guthrie B. Epinephrine and potassium homeostasis. Kidney Int 1981;20:83-91.
Dr. Gorlin (New York, New York): I was intrigued by the reports from Drs. Brown and Vincent. They focused on the concentration of serum potassium only but in any discussion of membrane potential change and shifts of cations, we have to be concerned about the pH, and what is happening to plasma calcium, magnesium and sodium. Are we simply looking at the beginning observation in regard to these adrenaline-related changes in potassium? Is this one of the reasons we avoid the question of causality, because, perhaps, changes in magnesium have something to do with this? If you do not have the ratios of sodium and potassium for example, you really do not know whether you have affected the intrinsic irritability of a cell in terms of its membrane potential. Dr. Brown (London, England): Your points are well taken. Every time I come to the United States someone asks about magnesium. With calcium and sodium, there is absolutely no change. We have not measured pH during our adrenaline infusions. During our study of squash players, we were very concerned that any changes we observed might be due to pH. We decided against doing arterial pH measurements, because the game of squash might have been offset by the distractions of an arterial cannula. We used arterialized venous samples. During discussions of muscle with physiologists, we were told that pH was unlikely to change greatly even during the sort of exercise that is undertaken in squash. Indeed, we saw very little change in the pH. I think the mean fall was 0.01 units, which was not of sufficient magnitude to explain the change in potassium. It is noticeable that after a rally of squash ends, the player tends to hyperventilate. This may account for some of the rapidity of the decrease in potassium, but only a small part. Magnesium is the main question that we have to follow up. I think that if the presumed explanation of sodium/potassium adenosine triphosphatase stimulation is correct, one would not expect to see a decrease in magnesium. However, in relation to thiazide-induced problems, it obviously could be additive, and plasma magnesium apparently does decrease during exercise. Dr. Vincent (Rotterdam, The Netherlands): I did measure pH in the patients who received isoprenaline infusions, and there was absolutely no change in pH. I have very little data on magnesium.
Dr. Gorlin: It may be that local tissue changes are important. If you are talking about myocardial infarction, what is the extracellular and intracellular pH in relation to the concentrations of potassium? This would be important in any issue of arrhythmogenesis irrespective of what plasma potassium levels are. It may be more than a question of the systemic values being measured. Dr. Lauler (New London, Connecticut): To follow up on what Dr. Gorlin said-in the original reports there was mention of earlier reports that showed that the changes in myocardial potassium may have been in a different direction from those reported in muscle potassium. This is a little broader question than Dr. Gorlin asked, but could you comment on that, and whose observations they were? Dr. Brown: The data were not ours and, in fact, have not been published yet. They were referred to in a discussion by Clausen at a symposium like this. He found that the effects he observed in the rat soleus muscle might go the opposite way in cardiac tissue. That is, the effect of adrenaline on potassium uptake in the heart might actually be the reverse of what is seen in the soleus muscle and systemic circulation. In the whole animal, this would be very difficult to follow up. We have been trying to measure individual tissue uptake of potassium-42 in the whole animal in response to adrenaline infusion. One runs into the obvious problem that in the whole animal the adrenaline dilates the vessel bed in skeletal muscle. One does indeed observe greater uptake of potassium-42 in skeletal muscle than in the heart, and if anything, adrenaline leads to apparent loss of potassium-42 from the heart. It is difficult to know, however, if this is nothing more than adrenaline shifting the blood to the skeletal muscle bed. Additionally, adrenaline could be expected to increase potassium loss from the heart, as a consequence of the increase in cardiac contractility or rate of contraction. I would be inteiested to hear what cardiologists have to say about that. Dr. Kupersmith (New York, New York): Beta receptors influence cardiac sodium/potassium adenosine triphosphatase as strongly as they do cyclic adenosine monophosphate. For example, after local catecholamine superfusion in vitro the expected ionic changes due to enhancement of the sodium-
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potassium pump occur: decreased intracellular sodium and increased intracellular potassium. However, other factors are also important. The sodiumpotassium pump is affected by the level of extracellular potassium which, in turn, may be influenced by the /3sreceptor. Thus, if this ,f&receptor is stimulated, the following may occur: there may be little or no direct effect on the cardiac sodiumpotassium pump per se, but there will be a decrease in extracellular potassium due to effects on the peripheral pumps. This change in extracellular potassium will in turn have an indirect effect in inhibiting the cardiac sodium-potassium w-w Dr. Brown: The effects of adenosine triphosphatase inhibition is, as 1 am rapidly discovering, a very difficult area in which to unravel cause from effect. One has to be careful when examining the effects of ouabain to ascertain that one is looking at primary effects: blockade of sodium or potassium flux stimulation by ouabain does not prove that the stimulation (e.g., by adrenaline) was directly from sodium/potassium adenosine triphosphatase. Our observations with digoxin at therapeutic doses made us wonder indeed whether sodium/ potassium adenosine triphosphatase is the target of adrenaline. One has to remember that in the in vitro experiments of Clausen he was looking at both very large doses of adrenaline and even larger doses of ouabain. This may, in fact, be of some interest because there has been a long running debate as to whether the effects of digoxin are entirely mediated through sodium/potassium adenosine triphosphatase inhibition in the heart. As far as I can tell from published studies, it appears to be true that digoxin has a much greater affinity for cardiac sodium/potassium adenosine triphosphatase than for skeletal muscle. It may be that the heart is more likely to be blocked by digoxin. But if adrenaline has a lesser effect on this pump in the heart, then it may explain why digoxin does not block hypokalemia, but is still having its protective effects on the heart. Dr. Vincent: Clausen has commented in a conference that the effects on the heart were indeed the same as in skeletal muscle without mentioning what animal he had examined. However, I think it is quite possible that even if this effect occurs in the heart as well as in skeletal muscle, the enormous amount of skeletal muscle takes up so much of the potassium that for the heart it is really the same as potassium depletion. We should consider that possibility. Dr. Conti (Gainesville, Florida): Dr. Brown, you presented data about epinephrine infusion increasing serum glucose; I thought you would say that the insulin would increase, and the potassium would then decrease. That did not happen. This was based on some experiments that were done in Missouri, I believe. Dr. Brown: What I said was that Cryer has also observed that adrenaline suppresses insulin. The data I showed you were our own. Dr. Conti: Was their experiment precisely the same as yours in terms of infusion of epinephrine? Dr. Brown: Yes. It is interesting that if you give adrenaline in the presence of an o(s blocker, you see an increase in insulin. Dr. Conti: What is the shortest time of epinephrine infusion required to decrease the serum potassium? The reason I ask this question is to determine the clinical relevance of 2 hours of epinephrine infusion. Dr. Brown: That is a very important point. The data I showed you of our dose-response curve with adrenaline were from Sminute increments of adrenaline infusion. We saw our
first decrease in potassium at a dose of 0.04 pg/kg/mm, which was preceded by 3 previous rates. It is possible that the previous rates had a cumulative effect, but even so, at 5 minutes a definite decrease was observed. Dr. Cohn (Stony Brook, New York): I have a question based on the difference in the response to isoproterenol. The normal volunteer subjects in Dr. Brown’s group differed from Dr. Vincent’s group in that their baseline heart rates were much lower. In fact, Dr. Vincent’s group had a baseline heart rate of about ‘70beats/min, which one would expect. When Dr. Brown described his squash players, I noticed that their baseline heart rate was in the 70 beatslmin range, which is also what one would expect. On the other hand, in his 6 normal volunteers the mean resting rate was 55 beats/min, indicating that these young volunteers were probably athletes or otherwise were in good condition. Could this possibly explain the difference in the isoproterenol results, or do you have other data, Dr. Brown, in volunteers with normal or near-normal physiologic control heart rates? Dr. Brown: There was one other difference that 1 noticed, which is that Dr. Vincent said his patients were mild essential hypertensives and presumably from an older age group. I don’t know the total answer to the question, but I can comment on the basal heart rate. First, there is a difference between the infusion study and the squash study: all the levels in the squash study were measured with subjects about to start the game, whereas basal levels in the infusion study were taken after 1 hour of lying down in the clinical laboratory. In fact, I would actually dispute that the normal resting heart rate for a young volunteer who is not anxious is in the 70 beatslmin range. If you have trained volunteers, who are used to having all these nasty things done to them and can lie down in the clinical laboratory without being worried, then the normal resting heart rate without their being athletes is in the 50 beats/min range. If they are athletes, then we seelevels down to 40 and even 30 beats/min. Dr. Vincent: My patients were between 20 and 40 years of age. Dr. Gorlin: Dr. Vincent, did you measure blood pressure in your differential catecholamine experiments, because that might have been very interesting-in those instances where 0s stimulation or blockade produced an increase or a decrease in norepinephrine. Did it alter the nature of the blood pressure response as opposed to the heart rate response when you gave, let’s say, an agonist like epinephrine, which gives you one kind of blood pressure response with a mixed o-P effect, compared to a situation in which norepinephrine dominates. In the latter situation you might anticipate more of an or-adrenoreceptor effect on blood pressure response. Did you make these kinds of determinations? Dr. Vincent: I am usually asked whether this increase in noradrenaline is not somehow baroreflex-mediated, because of the slight decreasethat may occur in mean arterial pressure after isoprenaline. I think there are quite sound arguments to say that that is not the case. If you ask me about the direct effects of this released noradrenaline, then, of course, this effect is compounded by the effects you get from the @agonist itself. That has always been a problem. When we studied the effects of salbutamol on blood pressure and noradrenaline levels, we observed something curious. As you might expect, because salbutamol is a &receptor agonist, there was a slight decrease in blood pressure initially. But then at high doses there was a change. Blood pressure did not decrease any further, and systolic blood pressure actually increased. At the same time, noradrenaline levels increased. This might suggest that noradrenaline itself could be the cause of the increase in
August
blood pressure. But in these kinds of studies we have the direct effect of the fl agonist itself versus the indirect effect through noradrenaline. That is why it is so important to have a constant level of the p agonist and impose some stimulus, such as the cold pressor test, to see if the effects of sympathetic activity are indeed exaggerated. Dr. Brown: Why do you think the increase in noradrenaline is not a baroreflex-mediated response to a decrease in mean arterial pressure? Dr. Vincent: Because as soon as blood pressure goes up, noradrenaline levels should go back down or at least decrease to a lower range. During the highest dose of salbutamol, both blood pressure and heart rate increased, which would tend to stimulate baroreceptors and cause a lowering of sympathetic activity, yet coincidentally with these changes noradrenaline levels actually increase. Dr. Conti: One of the things that some people have been interested in is sudden death in marathon runners. Could some of the deaths have been due to exercise hyperkalemia? I doubt that any of those marathon runners were taking 0 blockers, because I personally have taken them and gotten on a treadmill; instead of being able to go to a heart rate of 212 beats/min, I got to a heart rate of 140 beats/min in about 10 minutes less exercise time. I don’t think you can complete a marathon and take /!I blockers at the same time. It is really bothersome to seea 7.4 mEq/‘liter potassium level, and I think this needs to be looked at more carefully. Maybe it has absolutely no relevance to anything. Under conditions of maximum stress with pH changes and potassium being that increased, it may mean nothing at all. Certainly it means a lot if you are just casually sitting around the room and your potassium is 7.4 mEq/liter. Dr. Cohen (St. Louis, Missouri): My question is really a generic one for either Dr. Brown or Dr. Vincent, who focused beautifully on the plasma catecholamine levels. The question relates to the receptors themselves. Has either of you looked at differential studies with respect to the quality of the receptors or changes in the sensitivity of those receptors? In the long-term use of 0 blockers, how about change in the actual quantity of the receptors? What effect might this have in terms of an effect on a given level of plasma catecholamine? Dr. Brown: I have no data other than what I can extract from reports. Acutely, it appears that administration of /3 agonists such as isoprenaline leads to an early increase in /3 receptor number, and I still think that is an alternative to the prolonged tachycardia observed after discontinuation of adrenaline infusion. In the longer term, down regulation of receptor number could be expected after even as short a period of time as 3 or 4 hours. Beta receptors when measured on lymphocytes, for instance, decrease’in number. As far as p blockade is concerned, the story-again, largely from lymphocyte /3 receptor numbers-is that after long-term /I blockade, /I adrenoceptor numbers are increased. This may be responsible, for instance, for the /3 blocker withdrawal phenomenon. Some,people have shown increased sensitivity to isoprenaline infusions after withdrawal from fl blockade. By contrast, if you use a drug such as pindolol, which is supposed to have partial agonist activity, you then reverse the down regulation of receptor numbers during long-term therapy and theoretically would see lessof a withdrawal syndrome. However, I think one has to be very careful about extrapolating data from lymphocyte receptor number studies to cardiac tissue. One should probably only take seriously studies in which isoprenaline infusions have been done in parallel with lymphocyte receptor number and simultaneous measurement
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of cardiac responses. Probably, p receptor sensitivity is increased after long-term therapy. Dr. Frishman (Bronx, New York): One of the issues regarding that point is that if@ receptor numbers and sensitivity increase with long-term P-blocker therapy, wouldn’t the tolerance effect become evident in the long-term treatment of hypertension with these drugs? The explanation, as you suggested, may be that the suspected catecholamine increment is a way to try to overcome the blockade but it is not seen because norepinephrine levels decrease. In fact, that has been an explanation for the long-term efficacy of p blockers in treatment of hypertension. Do you think it is a presynaptic or P-blocking action? Dr. Vincent: I think it is presynaptic P blockade. It could also be a central effect. That is very hard to disprove, although, of course, YOUsee the effects with more water-soluble drugs as well. Dr. Mueller (Bronx, New York): We reported a study regarding the effect of propranolol on plasma cateeholamine levels in patients with acute myocardial infarction using intravenous propranolol and also using a randomized doubleblind placebo gr0up.l Actually the reason that we measured catecholamine one-norepinephrine levels was because we were concerned that an increase could occur because of the response to the decrease in cardiac output. To our surprise, in those patients who received propranolol, the one-norepinephrine levels were sharply increased-2.4 &g/liter. Propranolol also decreased the one-norepinephrine content in the systemic circulation significantly. This study compared 35 placebo- and 35 propranolol-treated patients. We also showed that the degree of propranolol-induced decrease in plasma norepinephrine levels was related to this initial concentration. We are now in publication with the suggestion that this could be explained by presynaptic blockade of the /3 receptors by propranolol. rown: As Dr. Vincent showed, there is a probiem with rs affecting cardiac clearance of catecholamines, and it makes it very difficult to draw conclusions from the changes in plasma noradrenaline concentration as being due to changes in release rate. I think the question of whether /3 blockers increase, decrease or have no effect on noradrenaline release is unresolved. r. DeQuattro (Los Angeles, California): We measured catecholamines before and after handgrip exercise, before and after labetalol therapy. We found that there is an increase in catecholamines on standing and that labetalol enhances that increase. However, with isometric handgrip exercise, the norepinephrine increment after labetalol is less than the increment on placebo. We intepret these findings as being due to blockade of epinephrine from the presynaptic p receptor that modulates norepinephrine release. What then is happening when you give adrenaline acutely and get an early increase in potassium? Are you saying it is coming from the liver? Do /3 blockers accentuate that? Dr. Vincent: All I can say is that studies have been done that have traced this increase in potassium to somewhere in the hepatic vein, so potassium supposedly comes from the liver. I don’t know exactly by what mechanism, and I can only say that it is possible to block it by blocking cyreceptors. I have not done any studies on that myself. Dr. Brown: I think the o! effect is always there with adrenaline but one only sees it either if you look very early after acute adrenaline administration, or if you unmask it by blocking the opposite @-receptor effect. It is a small effect. 1 suspect it is mainly an unmasking.
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Dr. Conk Dr. Brown, what is your technique of taking blood from squash players in play? Dr. Brown: Squash players have an indwelling cannula in their nonplaying arms and because the amount of blood we need for measuring potassium and catechols is small, we take it as quickly as possible. Obviously there is some inaccuracy in the time, but the Holter monitor the players wear has a button on it so that for each subject we can record exactly when the sample was taken and how long the sample drawing took. Dr. Roberts (Bethesda, Maryland): Dr. Vincent, I wonder if you have any information on measurement of potassium levels in skeletal muscle or cardiac muscle, and if so, would such measurements be accurate? I believe some investigators in the Soviet Union have explored this area by examining epinephrine/norepinephrine tissue levels. Have you done that, or would it be useful? Dr. Vincent: I think it would, but we have no tissue levels for either potassium or catecholamines. Dr. Shand (New York, New York): We have concentrated on the indirect effects of /Is receptors. Would either of you like to comment on the possibility of fis receptors in the heart? That tachycardia ‘with epinephrine is blocked by the 0s blocker is quite a spectacular effect, isn’t it? Dr. Brown: It is now clear that if you look at tissues from a wide variety of species-including man-using radioligand-binding techniques, you can detect /3sreceptors in the heart. Carlsson2 in Sweden has shown it in vivo using responses to pi& agonists and antagonists. The results are consistent with /3sreceptors in the atria. I think that in man the response to ICI 118551 is totally consistent with blocking the peripheral effects of adrenaline, which obviously raises the possibility that most of the tachycardia may initially have been due to vagal withdrawal rather than direct effect on the heart. One cannot be sure that these experiments provide any evidence for 0s receptors in the heart. If you look at the in vitro and in vivo evidence, you can no longer ignore the fact that there are probably ,& receptors mediating some of the cardiac responses to catecholamines. Dr. Conti: With the small amount of tissue you obtain with cardiac muscle biopsy, can you measure these epinephrine levels precisely? Is that what the Russians did? Dr. Roberts: They measured sodium, potassium and magnesium, too, I think. Dr. Conti: It is easy to do those experiments in the laboratory. You can pace the heart, exercise and take multiple biopsies. Dr. Brown: I think one approach is to use whole body counters for counting potassium or to use rubidium as a marker for potassium. Maybe this comes back to Dr. Gorlin’s initial question, and this is one of the reasons I showed the electrocardiographic tracings, as Dr. Vincent did also. Obviously we just do not know what is going on within the heart in man. But there are electrocardiographic changes, and I think one must assume that the heart is exposed to the same detrimental effects of hypokalemia as may occur during any other cause of hypokalemia. Dr. Linas (Denver, Colorado): We have looked at changes in potassium in skeletal muscle after insulin and catechol administration in rats. We were not able to show any change at all as far as skeletal muscle potassium is concerned. These, however, were chemical potassiums, not electrical potassium determinations.
I was interested in the recovery period. After the catechol levels have rapidly risen to normal, serum potassium continues to be low. Where does all that potassium go? Presumably it has been stored in cellsfor an hour or whatever the time period is. Why don’t we see rebound hyperkalemia? What is the protective mechanism? Dr. Vincent: It probably takes a little time for this potassium efflux to occur. Dr. Brown: I think the up and down slopes of plasma potassium are very similar. But there is something funny going on in the squash study, because plasma potassium decreased very rapidly. If you give a potassium chloride infusion such as DeFronzo3 did and look at the increase and decrease in plasma potassium, then the decrease in plasma potassium after the end of the potassium chloride infusion is much slower than that which we see in our squash players when they stop exercising. If it is simply the potassium, which had come out of the muscle during exercise,going back in again, one wonders why it is happening so rapidly. We just don’t know yet. Adrenaline is a factor, but not the major factor. Dr. Linas, in regard to your measurement of potassium in muscle, I think even with the potassium-42 experiments it can be difficult sometimes to see an increase in potassium-42, unless you choose the right time to look. Once you have reached a steady state, you may see no increase. I presume it is because you are looking for a needle in a haystack, so to speak. Dr. Frishman: I have a question regarding the exerciseinduced hyperkalemia that has been mentioned. Does this contribute to the fatigue that Dr. Conti has when he is on P-blocker therapy and exerciseson a treadmill? Although we are looking for protective effects, could that be contributing, perhaps, to the fatigue phenomenon that we all see with 0 blockers? Dr. Brown: The fatigue is very interesting. A number of people, including ourselves, have done studies trying to relate fatigue with potassium in a wide variety of metabolic parameters. In our studies, we found very little correlation to potassium and fatigue. A reverse possibility in relation to potassium and exercise is cramp. We know that cramp can be a very severe problem in squash players. I wonder whether the decrease in potassium could be playing a role in cramping. Dr. Kupersmith: I have also wondered about the needle in the haystack. In humans, if 20% of body weight is extracellular fluid and there is a 0.5 mEq/liter change in potassium, there would be a total change of 28 mEq of potassium in a TO-kgperson. One would have trouble determining where this small amount of potassium went. Could YOU really find such \ minute changes in these animals? Dr. Linas: Theoretically you could, but practically-with the methodologies available-you just cannot measure those kind of miniscule changes in the cellular potassium in huge muscle stores. Dr. Frishman: To summarize, it appears that reversal of epinephrine-induced hypokalemia by 6s adrenergic blockade may be an important clinical phenomenon. For years, we didn’t feel that the & blocking action of nonselective /? blockers was contributing very much to the therapeutic effects. It is now clear that /3sadrenergic blockade may protect patients from hypokalemia. What the significance of this hypokalemia may be in certain patients is not known. Finally, perhaps the effects of blocking presynaptic ,6 receptors and norepinephrine release may explain why /3 blockers are efficacious in treating high blood pressure.
August
References 1. Mueller HS, Ayres SM, Religa A, et al. Propranolol in the treatment of acute myocardial infarction. Effect on myocardial oxygenation and hemodynamics.
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Circulation 1974;49:1078-1087, 2. Carkson E, Fellenius E, Lundborg P, Svenssori L. fl-adrenoceptor blockers, plasma-potassium, and exercise. Lancet 1978;2:424-425. 3. DeFronzo RA, Bia M, Guthrie B. Epinephrine and potassium homeostasis. Kidney Int 1981;20:83-91.