(Kniffki, Mense & Schmidt, 1981). The contraction-induced stimuli that activate

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1 Journal of Phy8iology (1992), 451, pp With 4 ftgurea Printed in Great Britain ROLE OF POTASSIUM IN THE REFLEX REGULATION OF BLOOD PRESSURE DURING STATIC EXERCISE IN MAN BY N. FALLENTIN, B. R. JENSEN, S. BYSTROM* AND G. SJ0GAARD From the National Institute of Occupational Health, Copenhagen, Denmark and the *National Institute of Occupational Health, Solna, Sweden (Received 9 September 1991) SUMMARY 1. The relationship between [K+] in venous effluent blood and alterations in mean arterial blood pressure was studied during static handgrip contractions at 15 and 30% of maximal voluntary contraction (MVC). 2. To further elucidate the importance of K+ in the reflex regulation of blood pressure a situation with normal recovery was compared with a situation in which 3 min of post-exercise occlusion was applied by arresting the circulation to the forearm just prior to the cessation of the contraction. 3. There was a temporal as well as quantitative correlation between venous [K+] and the blood pressure response during and after static exercise. During 30 % MVC mean arterial blood pressure (MAP) attained mmhg and venous [K+] 5X8 mm, while the corresponding values during 15 % MVC were mmhg and 5 0 mm. 4. In the occlusion period mean arterial blood pressure remained elevated above resting level and provided a measure of the magnitude of muscle chemoreflexes. In the same period venous [K+] was maintained at 5-3 mm and 4X6 mm following 30% MVC and 15 % MVC respectively. This is indicative of interstitial concentrations of above 8-10 mm. This level is sufficiently high to stimulate type III and IV muscle afferents involved in the reflex regulation of blood pressure, and strengthens the notion that K+ may play an important role in eliciting the pressor reflex. 5. In contrast to [K+] the time course of venous blood concentrations of lactate and ammonia (NH3) exhibited a clear dissociation from the blood pressure recordings. INTRODUCTION The cardiovascular response to isometric (static) exercise is characterized by a marked increase in mean arterial blood pressure (MAP). This increase is partly due to a reflex elicited in the active muscles and mediated by type III and IV afferents (Kniffki, Mense & Schmidt, 1981). The contraction-induced stimuli that activate these fine muscle afferents are not known. Animal studies, however, have indicated that one mechanism may be an accumulation of potassium, K+, in the interstitium of the muscle (Wildenthal, Mierzwiak, Skinner & Mitchell, 1968; Rybicki, Waldrop & Kaufman, 1985). This is supported by human experiments demonstrating a parallelism between the time course of femoral venous blood [K+] and changes in MS 9716

2 644 N. FALLENTIN AND OTHERS arterial blood pressure during and after static knee extension at % of maximal voluntary contraction (MVC) (Saltin, Sj0gaard, Gaffney & Rowell, 1981). However, two sets of observations have independently questioned the importance of K+ in the exercise pressor reflex. Firstly, Rybicki et al. (1985) demonstrated that group III and IV afferents responded to increasing [K+] by an initial burst of impulses which returned to control values within 26 s. These results indicate that accumulation of K+ does not appear to be solely responsible for the maintenance of the pressor response during an isometric contraction. Secondly, Hnik, Holas, Krekule, Kri'z, Mejsnar, Smiesko, Ujec & Vyskocil (1976) assessed the speed of reuptake of K+ in cat gastrocnemius muscle by preventing the loss of K+ from the working muscles by arteriovenous occlusion. They showed that when a 10 s isometric tetanus was followed by an occlusion period of approximately 50 s duration hardly any K+ was released into the venous blood from the previously occluded muscle. The indication was that K+ reuptake did take place during the occlusion and was virtually complete after approximately 1 min. This last observation is especially intriguing. A commonly used functional test of muscle chemoreflexes is the method of '3 min post-exercise occlusion' (Staunton, Taylor & Donald, 1964). The method implies that the circulation to the exercising muscles is arrested just prior to the cessation of the contraction. The occlusion is then maintained for 3 min. In this period the blood pressure remains elevated and provides a measure of muscle chemoreflexes elicited from trapped muscle metabolites. Influence from a 'central command' component, or straining manoeuvres associated with the contraction (Williams & Lind, 1987) can in this way be excluded. If, however, as Hnik's results indicate, there is a continuous and complete reuptake of K+ in the occlusion period where the blood pressure remains elevated the inevitable conclusion is a complete dissociation of K+ from the pressor reflex. It was the aim of the present study to evaluate the relationship between [K+] in venous effluent blood and alterations in MAP during and after static exercise. To elucidate further the importance of K+ in the reflex regulation of blood pressure a situation with normal recovery was compared with a situation in which 3 min of post-exercise occlusion was applied. Besides the possibility of affirming or reaffirming the relation between blood pressure and K+ the study was initiated to gain further insight into the reuptake of K+, i.e. the function of the Na+-K+ pump, in a non-flow situation. In order to extend the discussion of muscle metabolites involved in the excitation of type III/IV afferents additional blood samples were taken to determine changes in lactate and ammonia (NH3), two metabolic candidates previously suggested to be involved in the exercise pressor reflex (Lewis, 1986). METHODS Subjects. Seven healthy men (28-43 years) participated in the study after voluntary consent. The study was approved by the local Ethical Committee. Blood samples. Blood samples were drawn from the antecubital vein of the exercising arm via an indwelling catheter. The Teflon catheter (Venflon 1-0) was inserted into the vein and advanced 4-5 cm in the upstream direction. Plasma [K+] was determined by flame photometry (Radiometer) with lithium as internal standard. Whole-blood lactate was measured using a spectrophotometer (Zeiss) and plasma NH3 was determined by the fluorometric technique (Kun & Kearney, 1974). K+ and lactate values from the present study are presented in combination with blood flow data in a separate paper (Jensen, 1991).

3 POTASSIUM AND BLOOD PRESSURE REGULATION Blood pressure. Blood pressure was recorded by a finger blood pressure monitor (Finapres, Ohmeda). The monitor is based on the Penaz principle and provides non-invasive and continuous waveform and beat-to-beat values for systolic, diastolic and integrated mean arterial blood pressure (Boehmer, 1987). In order to reduce variability each blood pressure value was calculated as the mean of three successive beat-to-beat values. Protocol. MVC of the handgrip muscles was determined for each subject following a standardized test procedure (Caldwell, Chaffin, Dukes-Dobos, Kroemer, Laubach, Snook & Wasserman, 1974). After the test the catheter was inserted with the subject in a supine position. The exercise protocol consisted of 3 min of static handgrip contraction at two different relative workloads (15 and 30 % MVC) performed with and without 3 min of post-exercise occlusion. Each subject was randomly assigned to start with either of the four exercise regimens studied. If the experiment included post-exercise occlusion the circulation to the forearm was arrested just prior to the cessation of the contraction by rapidly inflating a cuff to well above systolic blood pressure (- 300 mmhg). Blood samples were drawn before, every minute during the contraction, and twice during the occlusion period. In the recovery period after contraction, or immediately after the release of the occlusion, blood samples were drawn every 5th or 10th second during the first minute and then once every minute. Total time of recovery studied was 3 min. A rest period of at least 20 min was allowed between trials. Statistics. Unless otherwise specified mean values are presented (± 1 S.D.). Significance was determined by the Friedman test and the Wilcoxon signed rank test for paired data and P < 0-05 was taken as the level for a significant difference. The Spearman rank correlation coefficient, r8, was used as a measure of correlation (Conover, 1980). 645 RESULTS The time course for MAP and venous plasma [K+] in the 15 and 30% MVC experiments are presented in Figs 1 and 2. Mean arterial pressure (MAP) MAP increased in proportion to the intensity of exercise as expected. Peak values attained at 30% MVC were (±11.5) mmhg in the post-exercise occlusion experiment and (± 10-4) mmhg in the non-occlusion experiment. In the 15 % MVC experiments peak pressures were significantly lower and corresponded to (±7-1) and (±7 9) mmhg, respectively. Differences between peak pressures during exercise at the same percentage MVC with and without occlusion were not significant. In the experiments without occlusion MAP returned towards baseline values in the immediate post-exercise period and resting values were obtained within 20 s. When the circulation to the arm was arrested by post-exercise occlusion, blood pressure only partly recovered. MAP decreased within 1 min to (± 13-9) mmhg following 30 % MVC and to (± 16-4) mmhg following 15 % MVC, but remained at this elevated level for as long as the occlusion persisted. Following the release of the occlusion MAP rapidly restored and reached resting values within 20 s. Venous plasma [K+] Venous plasma [K+] rose sharply within the first minute of exercise. In the subsequent 2 min a slower but progressive increase was seen. Peak value during 30 % MVC attained 5-8 (± 0 4) mm and was significantly higher than the 15 % MVC peak value of 5 0 (± 0'3) mm. There was no difference in peak values between experimental situations with and without post-exercise occlusion.

4 646 N. FALLENTIN AND OTHERS Following the 15 and 30% MVC experiments without occlusion venous [K+] fell significantly during the first 20 s of recovery and returned to resting values within 1 min. In the correspondent occlusion experiments, venous blood samples drawn approximately at the second minute of occlusion showed a [K+] only modestly E I E 5I0 4.0 i 30-. I Time (min) Fig. 1. Mean arterial blood pressure (MAP) and venous plasma [K+] during and after static handgrip at 30 % MVC performed with (S) and without (0) 3 min of post-exercise occlusion. Mean values+ S.E.M., n = 7 (blood pressure recordings, n = 6). reduced in comparison with peak exercise values. Mean values in the occlusion period were 5-3 (± 0 4) mm following 30 % MVC and 4-6 (± 0 3) mm following 15 % MVC. At the release of the occlusion pressure venous plasma [K+] quickly returned to resting values. The samples taken within 25 s after the occlusion period in the 30 % MVC experiment, were, however, still significantly higher than resting values. In the 15 % MVC experiment the 5 s sample was obtained for only three subjects. If, however, these values were pooled with the 10 s values for the other four subjects a significant difference from resting values could be revealed. In Fig. 3 individual peak values for exercise blood pressure are plotted against coherent K+ values. Data points are pooled from all four experimental situations and show a positive correlation (r. = 0 73) between venous blood [K+] and peak exercise MAP (individual r., values were between 0-60 and 100). Venous blood lactate concentrations followed a distinctly different pattern to [K+]. In the 30% MVC experiments peak concentrations of 3.9 and 4-4 mm were

5 POTASSIUM AND BLOOD PRESSURE REGULATION 647 I EE 0- I' E E -z T T i-i Time (min) Fig. 2. Mean arterial blood pressure (MAP) and venous plasma [K+] during and after static handgrip at 15 % MVC performed with (A) and without (A) 3 min of post-exercise occlusion. Mean values+ s. E. M. n = 7 (blood pressure recordings, n = 6). 0) I EE v 0 A A r = [K+] (mmol 1-1) Fig. 3. Peak values for mean arterial blood pressure (MAP) during 3 min of static handgrip contraction (15 or 30% MVC) versus the simultaneous venous plasma K+ concentration. Each subject is represented in the figure with four data points given identical symbols (n = 6).

6 648 N. FALLENTIN AND OTHERS obtained 3 min after the end of exercise or 3 min after the release of the occlusion pressure. In the 15 % MVC experiments peak concentrations were lower (approximately 2-5 mm) but again recorded after the end of the exercise or the occlusion period (Fig. 4). Ammonia levels closely paralleled lactate concentrations. The overall 5*0 z 30% MVC 3-0 _20:iz 1.0 : E 0-0, I ~5.Q. o 15%MVC 0 o2 m 4*O 3-0 I w0.0I 1.0I I ~~I 0*0,, I,, Time (min) Fig. 4. Venous blood lactate concentration during and after static handgrip at 15 or 30% MVC performed with (U) and without (OI) 3 min of post exercise occlusion (mean values+ S.E.M., n = 7). resting value was 65-3 pim. Peak values of and gm in the 30% MVC experiments and 72-8 and 9217,CM in the 15% MVC experiments were recorded several minutes after the cessation of the exercise or the release of the occlusion pressure. DISCUSSION A temporal relation between venous [K+] and cardiovascular responses has repeatedly been reported from experiments involving static handgrip (Donald, Lind, McNicol, Humphreys, Taylor & Staunton, 1967) or static knee extension (Saltin et al. 1981)). Our results substantiate these findings by further demonstrating a quantitative relationship between the magnitude of the terminal pressor response and the absolute levels of venous [K+]. In contrast, the time course of venous concentrations of blood lactate and ammonia exhibited a clear dissociation from blood pressure recordings and it is hard to envisage a major role for these metabolites in the blood pressure regulation. It should be emphasized that venous [K+] is not a direct reflection of the interstitial K+ concentration affecting fine muscle afferents involved in the exercise

7 POTASSIUM AND BLOOD PRESSURE REGULATION pressor reflex. In statically contracting muscles blood flow is restricted and large amounts of K+ may be trapped in the interstitial space of the muscle. Calculations based on coherent values of plasma flow and venous [K+] from the knee extensors (Saltin, Sj0gaard, Strange & Juel, 1987) do, however, indicate that a venous blood concentration of 5 mm may correspond to an interstitial concentration of above 8-10 mm, a level sufficiently high to stimulate type III and IV afferents (Hnik, Vyskocil, Ujec, Vejsada & Rehfeldt, 1986). Such calculated values are supported by a few direct measurements of extracellular [K+] in human muscles. Using ionselective electrodes Vyskocil, Hnli'k, Rehfeldt, Vejsada & Ujec (1983) have reported values for extracellular [K+] of up to 14-8 mm in brachioradialis during a sustained voluntary contraction. This does not necessarily mean that K+ per se is the stimulus that activates the receptors of group III and IV afferents. Other metabolites have been shown to activate fine muscle afferents, i.e. inorganic phosphate (Tibes & Groth, 1977), muscle ph (Victor, Bertocci, Pryor & Nunnally, 1988), arachidonic acid (Rotto & Kaufman, 1988) and prostaglandins (Stebbins, Muruoka & Longhurst, 1986). Furthermore Rybicki et al. (1985) questioned the importance of K+ by demonstrating an adaptation (reduction) in firing rate of type III and IV afferents despite a constant elevated interstitial [K+]. A possible explanation for these results has recently been given by Baum, Essfeld & Stegemann (1990) who showed that variations in volume of the extracellular space strongly influenced the reflex response to fixed concentrations of K+. The main finding of the present study was, however, the demonstration of an elevated venous [K+] during and after 3 min of post-exercise occlusion. The persistence of an elevated venous [K+] at a time when MAP is only partly recovered strengthens the notion that K+ may play an important role in eliciting the pressor reflex. The fact that a co-variation between venous [K+] and arterial blood pressure was seen not only during exercise but also during post-exercise occlusion has not been reported previously and raises several important questions. Firstly, it should be made clear that the interpretation of venous blood samples taken during circulatory occlusion is difficult. It is thus possible that the samples drawn during the occlusion were composed mainly of blood trapped in the veins when the occlusion was applied. However, it should be noted that an elevated venous [K+] significantly above resting values was seen after the release of the occlusion pressure. Taking into consideration the large muscle hyperaemia at this point of time (Jensen, 1991) it is highly unlikely that these samples merely contained the blood pooled in the veins during the occlusion. It is thus evident that the [K+] in the occluded muscles must have been well above resting levels in the occlusion period. The existence of an ionic imbalance throughout the occlusion period is somewhat surprising. However, it is possible that a fraction of the extracellular K+ might have been sequestered in remote parts of the interstitium not readily accessible for Na+-K+ pumps in the muscle fibre membranes. Such an inhomogeneous distribution could theoretically explain an elevated [K+] after 3 min of post-exercise occlusion, in spite of an intense activity of the Na+-K+ pump. Interestingly, the free nerve endings of type III and IV afferents are clearly associated with surrounding 649

8 650 N. FALLENTIN AND OTHERS connective tissue structures in the skeletal muscle (Stacey, 1969; von During, Andres & Schmidt, 1984) and an elevated [K+] located in this specific area of the interstitium could be responsible for the maintenance of the pressor reflex in the occlusion period. Alternatively, the elevated venous [K+] seen after the occlusion period could indicate a reduced functional capacity of the Na+-K+ pump. According to Sahlin (1986) the increase in ADP seen in a fatigued muscle is likely to interfere with the function of the Na+-K+-ATPase (the Na+-K+ pump) and affect the ion balance over the muscle cell membrane. It is possible that this malfunction of the Na+-K+ pump in a fatigued muscle will be extended into an occlusion period where the ischaemic muscle is solely dependent on anaerobic energy utilization. Interestingly, Zwarts, Van Werden & Haenen (1987) measured muscle fibre conduction velocity during and after fatiguing isometric contractions at 40 % MVC and found no recovery of muscle fibre conduction velocity as long as the muscle was made ischaemic by post-exercise occlusion. These results support the idea of an insufficient Na+-K+ pump, incapable of restoring membrane potential and ionic equilibrium in an occluded muscle. In summary the results of the present study indicate that K+ is a possible product of a discrepancy between blood flow and metabolism capable of eliciting a blood pressure raising reflex during exercise as well as post-exercise occlusion. The study was supported by grants from the Danish Medical Research Council, Research Academy and the Working Environment Fund, Denmark. the Danish REFERENCES BAUM, K., ESSFELD, D. & STEGEMANN, J. (1990). Reduction in extracellular muscle volume increases heart rate and blood pressure response to isometric exercise. European Journal of Applied Physiology 60, BOEHMER, R. D. (1987). Continuous, real-time, noninvasive monitor of blood pressure: Penaz methodology applied to the finger. Journal of Clinical Monitoring 3, CALDWELL, L. S., CHAFFIN, D. B., DuKES-DoBos, F. N., KROEMER, K. H. E., LAUBACH, L. L., SNOOK, S. H. & WASSERMAN, D. E. (1974). A proposed standard procedure for static muscle strength testing. American Industrial Hygiene Association Journal 35, CONOVER, W. J. (1980). Practical Nonparametric Statistics. John Wiley & Sons, New York. DONALD, K. W., LIND, A. R., McNIcoL, G. W., HUMPHREYS, P. W., TAYLOR, S. H. & STAUNTON, H. P. (1967). Cardiovascular responses to sustained (static) contractions. Circulation Research 20-21, suppl. I, HNIK, P., HOLAS, M., KREKULE, I., KRIZ, N., MEJSNAR, S., SMIESKO, V., UJEC, E. & VYSKOCIL, F. (1976). Work-induced potassium changes in skeletal muscle and effluent venous blood assessed by liquid ion exchanger micro-electrodes. Pflilgers Archiv 362, HNIK, P., VYSKOCIL, F., UJEC, E., VEJSADA, R. & REHFELDT, H. (1986). Work-induced potassium loss from skeletal muscles and its physiological implications. In Biochemistry of Exercise VI: International Series on Sport Sciences, vol. 16, ed. SALTIN, B., pp Human Kinetics Publishers, Champaign, IL, USA. JENSEN, B. R. (1991). Isometric contractions of small muscle groups. Ph.D. Thesis, National Institute of Occupational Health, Copenhagen. KNIFFKI, K. D., MENSE, S. & SCHMIDT, R. F. (1981). Muscle receptors with fine afferent fibres which may evoke circulatory reflexes. Circulation Research 48, suppl. I, KUN, E. & KEARNEY, E. B. (1974). Ammonia. In Methodsof Enzymatic Analysis, ed. BERGMEYER, H. U. pp Academic Press, New York. LEWIS, S. F. (1986). Coupling of muscle energy metabolism with cardiovascular response to exercise in man. In Biochemistry of Exercise VI: International Series on Sport Sciences, vol. 16, ed. SALTIN, B., pp Human Kinetics Publishers, Champaign, IL, USA.

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