Modulation of Renal Cortical Blood Flow During Static Exercise in Humans
During static exercise, several reflex systems that increase sympathetic nerve activity, heart rate, arterial pressure, and cardiac output are activated. At rest, the renal circulation receives the most blood flow per tissue weight of any organ in the body. However, the renal circulatory response to static exercise has not been studied in humans because of technical limitations in methods for measuring rapid changes in renal blood flow. The aim of this study was to determine the renal blood flow response to static exercise in healthy humans and, specifically, to clarify the reflex mechanisms underlying this response. Renal cortical blood flow was measured using dynamic positron emission tomography and the blood flow agent oxygen-15 water. Graded handgrip exercise, posthandgrip circulatory arrest, and administration of intra-arterial adenosine were performed to clarify the mechanisms controlling renal blood flow during static exercise. The major new findings in this study are that in healthy humans (1) renal cortical blood flow decreases (basal versus handgrip, 4.4±0.1 versus 3.5±0.1 mL·min−1·g−1; P=.008) and renal cortical vascular resistance increases (basal versus handgrip, 17±1 versus 26±2 U; P=.01) in response to static handgrip exercise; (2) central command and/or the mechanoreflex contributes importantly to the early decrease in renal blood flow (basal versus handgrip, 4.2±0.2 versus 3.5±0.3 mL·min−1·g−1; P=.04) and to the increase in renal cortical vascular resistance (basal versus handgrip, 20±1 versus 25±2 U; P=.04); (3) the muscle metaboreflex contributes to further decreases in renal blood flow (basal versus posthandgrip circulatory arrest, 4.3±0.1 versus 3.5±0.2 mL·min−1·g−1; P=.002) and increases in renal cortical vascular resistance (basal versus handgrip, 18±1 versus 25±3 U; P=.002); and (4) exogenous adenosine activates the muscle metaboreflex producing reflex renal vasoconstriction and decreased renal blood flow, which may implicate endogenous adenosine generated during ischemic exercise as a potential activator of the muscle metaboreflex during ischemic handgrip exercise.
During static exercise, several reflex systems are activated, leading to increased sympathetic nerve activity, heart rate, arterial pressure, and cardiac output.1 2 3 4 5 First, even before the onset of exercise, central neural activity called “central command” is activated. Central command withdraws cardiac parasympathetic nerve activity, resulting in increased heart rate and cardiac output, and also mediates an immediate increase in sympathetic vasoconstrictor activity directed to skin, decreasing cutaneous blood flow early during exercise.6
The muscle metaboreflex is the principal reflex system that activates sympathetic nerve activity directed to muscle during static exercise.7 Muscle sympathetic activity does not increase until the second minute of moderate static exercise, when ischemic metabolites, such as lactic acid, diprotonated phosphates, and adenosine, have accumulated in the exercising muscle bed.8 9 10 These ischemic metabolites activate chemosensitive afferent nerve fibers called “muscle metaboreceptors,” which increase sympathetic nerve activity directed to both nonexercising and exercising limbs.11 In nonexercising muscles, sympathetic vasoconstrictor activity tends to increase vascular resistance, but in exercising muscle, this vasoconstrictor influence is opposed by the local vasodilatory effects of these ischemic metabolites.
“Mechanoreceptors,” stimulated by muscle contraction, apparently contribute little to the reflex increases in muscle or skin sympathetic nerve activity or to the change in heart rate during static exercise in healthy humans.6 7 However, these mechanoreceptors may be important in pathological states, such as heart failure.12 In summary, this complex series of reflexes activated during static exercise works in concert to increase cardiac output and blood pressure.
At rest, the kidneys receive the most blood flow per tissue weight of any organ in the human body—4-fold that of the splanchnic circulation and 200-fold that of muscle. The kidneys receive over 20% of the cardiac output.13 In animal studies during static exercise, reflexes that increase efferent renal sympathetic nerve activity and decrease renal blood flow are activated.14 15 Thus, it is possible that exercise in humans may similarly activate systemic reflexes that increase renal vasoconstriction and decrease renal blood flow. Alternatively, since blood pressure increases markedly during static exercise,1 2 3 4 5 blood flow in the renal circulatory bed may be expected to be increased.4 The renal circulatory response to static exercise has not been studied in humans because of the technical limitations in measuring rapid changes in renal blood flow. Dynamic positron emission tomography (PET) using the blood flow agent oxygen-15 water (O-15 water) is a noninvasive, rapid, quantitative means to measure, both safely and reproducibly, renal cortical blood flow in humans.16 17 The aim of the present study was to determine the renal blood flow response to static exercise in healthy humans and, specifically, to clarify the reflex mechanisms underlying this response.
Materials and Methods
After written informed consent was obtained, 29 normal volunteers (9 females and 20 males; mean age, 36±13 years; range, 18 to 63 years) participated in these studies. The study protocols were approved by the UCLA Human Subject Protection Committee. Normal volunteers were healthy, as confirmed by normal medical history and physical examinations, complete blood count, blood urea nitrogen, and serum creatinine, and were not taking medications. Volunteers abstained from caffeine for 18 hours before the study but otherwise were on an uncontrolled diet. The studies were performed with volunteers in the postabsorptive state.
Quantification of Renal Cortical Blood Flow Based on Dynamic PET and the O-15 Water Technique
PET affords the noninvasive measurement of renal cortical blood flow in humans, as shown previously.17 Baseline renal cortical blood flow and mean renal cortical blood flow during various interventions were measured on dynamic PET. In the present study, all renal PET images were acquired on a Siemens/CTI model 931/08-12 tomograph. This device records 15 image planes simultaneously. The axial field of view is 10.8 cm. A 30-minute blank scan was recorded as part of the daily routine procedures. Ultrasound guidance was used for adequate positioning of the kidneys in the tomograph's field of view. All subjects were imaged in the supine position. After a 20-minute transmission image for photon attenuation correction was obtained, study participants were injected with 30 mCi O-15 water over 30 seconds into a peripheral vein while acquisition of the serial transaxial tomographic images was started. Twelve 10-second, four 30-second, and one 60-second frame were acquired. Cross-sectional images were reconstructed using a Shepp-Logan filter with a cutoff frequency of 30% of the Nyquist frequency of the system, yielding an in-plane spatial resolution of ≈10.8 mm (full width and half maximum). To minimize invasiveness, the arterial tracer input function was determined from dynamic PET measurements of the abdominal aortic activity. This technique was validated recently by comparing PET measurements of abdominal aortic activity with well counter measurements of arterial blood samples.18 Correlational analysis of the areas subtended by the two input functions yielded an essentially unitary slope (1.03±0.09) with high correlation (R2>.95, P<.001). The time-activity curve of the input function was corrected for dead time and partial volume effects.18
Renal cortical blood flow was quantified on the basis of dynamic PET imaging using the blood flow agent O-15 water. Estimates of renal cortical blood flow by the O-15 water dynamic PET approach have been found to correlate linearly with those obtained invasively in dogs by the microsphere and arterial reference technique.19 The theory for the measurement of renal blood flow using O-15 water and dynamic PET has been described in detail by Nitzsche et al.17 The general principles of blood tissue exchange and its application to the measurement of blood flow have been proposed by Kety.20 O-15 water was chosen because of the short physical half-life of the O-15 isotope, which affords repetitive measurements of renal cortical blood flow within a 15-minute period. Furthermore, the metabolically inert O-15 water freely diffuses across the capillary and cellular membranes and thus rapidly equilibrates between the vascular and extravascular spaces. Achievement of such equilibration is referred to (by definition) as the first-pass extraction fraction, which in the case of O-15 water approaches unity and is independent of blood flow. Thus, the net extraction as the product of first-pass extraction fraction and renal blood flow correlates linearly with renal blood flow. For calculation of renal cortical blood flow, the data acquired within 2 minutes after tracer injection were used. The time-activity curves of the renal cortex were generated by region of interest analysis and corrected for dead time of the scanner and partial volume effects.17 Renal cortical blood flow was then estimated by fitting the PET measured time-activity curves to a validated one-compartment model for O-15 water. The renal cortical blood flow value (mL·min−1·g−1) for one kidney was calculated as the average value for all analyzed regions of interest per kidney. All analyses were performed by a single investigator (E.U.N.) blinded to the experimental conditions. Renal cortical vascular resistance (U) was estimated by dividing mean arterial pressure (one third of pulse pressure plus diastolic pressure) by renal cortical blood flow.
Adenosine (3 mg/mL, Fujisawa-SmithKline) boluses, 2 and 4 mg, were rapidly administered over 1 to 2 seconds through an arterial catheter that had been inserted into the brachial artery on the morning of the study. In a subset of subjects in protocol 5 (see “Experimental Protocols”), 100% oxygen was administered continuously through a mask placed securely over the nose and mouth and attached to a reservoir bag.
Blood pressure was monitored noninvasively using an automated sphygmomanometer (Dinamap, Critikon Corp). Heart rate was monitored continuously through lead II of the electrocardiograph. Respiratory rate and thoracic excursion were measured with a pneumograph placed around the chest.
At the beginning of each experimental session, maximum voluntary contraction (MVC) was determined in the nondominant arm using a handgrip dynamometer. Subjects were instructed to breathe normally during exercise and to avoid inadvertent performance of a Valsalva maneuver.
Protocol 1: Renal Cortical Blood Flow Responses to Static Handgrip at 30% MVC (10 Subjects)
The purpose of this study was to determine the magnitude and direction of change in renal cortical blood flow during static handgrip exercise in healthy humans. Subjects were studied in the supine position in the PET scanner. The subject rested during the 20-minute transmission scan. Baseline measurements of blood pressure and heart rate were made. Then renal cortical blood flow was determined with PET O-15 water, as described above. Sustained handgrip at 30% MVC was performed for 3.5 minutes. At 1.5 minutes of exercise time, O-15 water was administered for measurement of renal cortical blood flow. Blood pressure and heart rate were measured continuously throughout exercise.
Protocol 2: Immediate Renal Cortical Blood Flow Responses to Mild Nonischemic Handgrip at 10% MVC (6 Subjects)
The goal of this study was to determine the effect of central command and/or the mechanoreflex on the renal circulation during handgrip exercise. Renal blood flow was measured at the onset of mild handgrip exercise (10% MVC), a time before the onset of muscle ischemia, which would be negligible at this level of handgrip intensity. The subject rested during the 20-minute transmission scan. Baseline measurements of blood pressure and heart rate were made. Then renal cortical blood flow was determined with PET O-15 water, as described above. Sustained handgrip at 10% MVC was performed for 2.5 minutes. Concurrent with the onset of handgrip exercise, O-15 water was administered for measurement of renal cortical blood flow. Blood pressure and heart rate were measured continuously throughout exercise.
Protocol 3: Renal Cortical Blood Flow Responses to Posthandgrip Circulatory Arrest (14 Subjects)
The purpose of this study was to determine the effect of the muscle metaboreflex on the renal circulation during handgrip exercise. During posthandgrip circulatory arrest, central command and the muscle mechanoreflex are eliminated, but the muscle metaboreflex remains activated. Eight subjects were studied in the supine position in the PET scanner. Each subject rested during the 20-minute transmission scan. Baseline measurements of blood pressure and heart rate were made. Renal cortical blood flow was determined with PET O-15 water, as described above. Sustained handgrip at 30% MVC was performed for 3.5 minutes. Just before release of the handgrip, a pneumatic cuff on the upper arm was inflated to 240 mm Hg for a total of 4 minutes. At 2 minutes of posthandgrip ischemia, O-15 water was administered for measurement of renal cortical blood flow. Blood pressure and heart rate were measured continuously throughout exercise and during posthandgrip circulatory arrest.
We considered the possibility that even in the absence of posthandgrip circulatory arrest, renal vascular resistance may not have recovered to baseline levels at 2 minutes after the handgrip. To clarify the recovery time of the renal circulation after sustained handgrip exercise, 6 subjects underwent a protocol identical to the one above, but circulatory arrest was not performed. O-15 water was injected at 2 minutes of recovery to determine if renal vascular resistance had returned to baseline.
Protocol 4: Renal Cortical Blood Flow Response to an Alerting Stimulus (4 Subjects)
The purpose of this study was to assess the possibility that a change in renal cortical blood flow during handgrip exercise may be attributable to the alerting response. Subjects were placed in the PET scanner and rested during the 20-minute transmission scan. Baseline measurements of blood pressure and heart rate were made. Renal cortical blood flow was determined with PET O-15 water, as described above. The handgrip dynamometer was then placed in the subject's hand, and the subject was urged as follows: “Be alert! We are going to have you start the contraction soon. Be alert!” Variations on this command were repeated at 10- to 15-second intervals for 3 minutes, while renal cortical blood flow, heart rate, and blood pressure were measured.
Protocol 5: Renal Cortical Blood Flow Responses to Intra-arterial Adenosine (8 Subjects)
The purpose of this study was to determine the effect of the muscle metaboreflex, activated by exogenous adenosine, on the renal circulation. A 3F polyethylene catheter was placed into the brachial artery of the nondominant arm. Subjects were placed in the PET scanner and rested during the 20-minute transmission scan. Baseline measurements of blood pressure and heart rate were made. Renal cortical blood flow was determined with PET O-15 water, as described above. In a single-blinded fashion, intra-arterial injections were rapidly administered in the following order: adenosine (2 mg), vehicle (1.5 mL saline), and adenosine (4 mg). Just before adenosine or vehicle infusion, a pneumatic cuff placed on the upper arm was inflated to 60 mm Hg to prevent systemic spillover of adenosine. The half-life of adenosine in the circulation is 1 second,21 and in prior studies,22 23 the reflex increase in muscle sympathetic nerve activity begins almost immediately and peaks within 60 seconds of adenosine bolus. Therefore, O-15 water was administered concurrently with adenosine in order to capture peak changes in renal vascular tone. Blood pressure and heart rate were measured continuously.
We considered the possibility that adenosine reached the systemic circulation and affected the renal circulation through activation of the carotid chemoreceptors. Activation of the carotid chemoreceptors leads to reflex increases in respiration. Therefore, if adenosine did spill over into the systemic circulation, it would be detectable through an effect on respiration. Respiratory rate and thoracic excursion were measured, as evidence of chemoreceptor stimulation. Additionally, in 2 subjects, renal blood flow response during adenosine was measured during 100% oxygen, which was administered to suppress potential chemoreceptor activation.24 25 26
Statistical analysis was performed by paired t tests. Values of P<.05 were considered statistically significant. Values are presented as mean±SEM.
Protocol 1: Renal Cortical Blood Flow Responses to Static Handgrip at 30% MVC
In response to static handgrip at 30% MVC, renal cortical blood flow decreased and renal cortical vascular resistance increased significantly (Table 1⇓). The mean percent decrease in renal cortical blood flow was 20±5%, and the increase in renal cortical vascular resistance was 59±17%. During static handgrip exercise, blood pressure and heart rate increased (Table 2⇓).
Protocol 2: Immediate Renal Cortical Blood Flow Responses to Mild (10% MVC) Nonischemic Handgrip (Central Command and/or Mechanoreflex)
During the early phase of mild nonischemic static handgrip exercise at 10% MVC, renal cortical blood flow decreased (Table 1⇑), and renal cortical vascular resistance increased significantly. The mean percent decrease in renal cortical blood flow was 15±7%, and the increase in renal cortical vascular resistance was 29±10%. During handgrip, blood pressure and heart rate did not increase significantly (Table 2⇑).
Protocol 3: Renal Cortical Blood Flow Responses to Posthandgrip (30% MVC) Circulatory Arrest (Muscle Metaboreflex)
During posthandgrip (30% MVC) circulatory arrest, renal cortical blood flow was decreased and renal cortical vascular resistance was increased significantly (Table 1⇑). The mean percent decrease in renal cortical blood flow was 18±3%, and the increase in renal cortical vascular resistance was 41±8%. During posthandgrip circulatory arrest, blood pressure remained elevated, but heart rate returned to baseline (Table 2⇑).
We considered the possibility that at 2 minutes of recovery following the release of handgrip exercise, even in the absence of circulatory arrest, renal vascular resistance would not yet have returned to baseline. Renal cortical blood flow and resistance were measured 2 minutes into recovery after the release of handgrip. Renal cortical vascular resistance had returned to baseline levels, but renal cortical blood flow remained lower than baseline (Table 1⇑). Heart rate had returned to baseline, and blood pressure was lower than baseline (Table 2⇑).
Protocol 4: Renal Cortical Blood Flow Responses to an Alerting Stimulus
Protocol 5: Renal Cortical Blood Flow Responses to Adenosine (Muscle Metaboreflex)
When questioned about sensations experienced during adenosine infusion, subjects reported arm “heaviness” or “pressure,” which was greater during 4 mg compared with 2 mg adenosine infusion. In response to brachial arterial administration of adenosine, renal cortical blood flow decreased and renal cortical vascular resistance increased in a dose-dependent manner (Figure⇓). The mean percent decrease in renal cortical blood flow during 2 and 4 mg adenosine was 12±2% and 18±3%, respectively, and increase in renal cortical vascular resistance during 2 and 4 mg adenosine was 21±6% and 31±6%, respectively. There was no change in renal blood flow or renal vascular resistance in response to vehicle. Blood pressure increased with 2 mg and 4 mg adenosine, but heart rate increased only with the 4 mg adenosine dose (Table 2⇑). Respiratory rate did not change (15.7±1.5 [basal] versus 15.5±1.6 [vehicle], 15.7±1.5 [2 mg adenosine], and 16.0±1.6 [4 mg adenosine] breaths per minute; P=NS). Thoracic excursion did not change (298±31 [basal] versus 271±15 [vehicle], 268±15 [2 mg adenosine], and 322±35 [4 mg adenosine] U; P=NS). The decrease in renal blood flow in response to adenosine was not blunted in the presence of 100% oxygen (Figure⇓).
The major new findings in the present study in healthy humans are as follows: (1) Renal cortical blood flow decreases and renal cortical vascular resistance increases in response to static handgrip exercise. Renal vasoconstriction during static exercise is not due to autoregulation, since renal blood flow falls below basal levels. Autoregulation would be expected to maintain renal blood flow at control levels but would not be expected to decrease renal blood flow below control levels. (2) Central command and/or the mechanoreflex contributes importantly to the immediate decrease in renal blood flow and increase in vascular resistance. (3) The muscle metaboreflex also contributes to decreases in renal blood flow and increases in renal vascular resistance. (4) Exogenous adenosine activates the muscle metaboreflex, producing reflex renal vasoconstriction and a decrease in renal blood flow, perhaps implicating endogenous adenosine generated during ischemic exercise as a potential activator of the muscle metaboreflex during ischemic handgrip exercise.
PET measurement of renal cortical blood flow has been validated in animals by use of the microsphere technique.19 In our laboratory, we have found that PET measurement of renal blood flow is highly reproducible,16 17 and intraindividual variation of repeated PET measurement of renal blood flow has been determined to be only 2%.17 Right and left renal blood flow measured simultaneously, yet separately, is virtually identical.
In the present study, in response to static exercise, renal blood flow significantly decreased, and renal vascular resistance significantly increased. Renal cortical blood flow did not decrease during an alerting stimulus, supporting the concept that these renal circulatory responses were mediated by reflexes activated during static handgrip and not by arousal produced by the experimental setting. These changes were present during the early phase of low-intensity handgrip, consistent with contribution of central command and/or the mechanoreflex. In contrast, it has been shown that central command and the mechanoreflex do not mediate an early increase in muscle sympathetic nerve activity during mild to moderate static exercise.7 It has been hypothesized that an early increase in muscle sympathetic nerve activity during handgrip would be detrimental, since early sympathetic activation would decrease blood supply to the exercising muscle before this effect could be offset by the local vasodilatory metabolites. We speculate that in contrast to the potentially detrimental effect of an early increase in muscle vasoconstriction at the onset of exercise, an early increase in renal vasoconstriction and decrease in renal blood flow may be beneficial by offsetting the early vasodilation in nonexercising muscle beds,5 thereby contributing to the increases in cardiac output and arterial pressure characteristic of static exercise.
This important role for the central command and/or mechanoreflex modulation of renal vasomotor tone in humans during static exercise is consistent with studies performed in animals.27 28 29 In decorticate anesthetized cats, electrical stimulation of the subthalamic locomotor region simulates central command and leads to a marked increase in efferent renal sympathetic nerve activity.27 Similarly, in conscious cats, renal efferent sympathetic activity increases rapidly before or at the onset of static exercise.28 In chloralose-anesthetized cats, mechanical stimulation of the triceps surae muscle produces an immediate increase in efferent renal sympathetic nerve activity.29 Similarly, direct electrical stimulation of group III muscle afferent nerve fibers increases efferent renal sympathetic activity.29
The muscle metaboreflex also contributes to renal vasoconstriction and decreased renal cortical blood flow during static handgrip exercise in humans. During posthandgrip circulatory arrest, which eliminates central command and the mechanoreflex, renal vascular resistance remains significantly elevated and renal cortical blood flow remains significantly decreased from baseline. This persistent renal vasoconstriction during posthandgrip circulatory arrest is not simply due to slow relaxation of renal vasomotor tone after the release of handgrip, since renal vascular resistance at 2 minutes after recovery is at basal levels. Moreover, when the muscle metaboreflex is activated by an exogenous ischemic metabolite, adenosine, infused into circulation of the forearm musculature, there is significant reflex renal vasoconstriction and decrease in renal cortical blood flow.
The finding that exogenous adenosine administered into the forearm circulation produced an immediate increase in renal vasomotor tone and decrease in renal cortical blood flow has two implications: First, it supports the concept that activation of the metaboreflex mediates reflex renal vasoconstriction in humans. Second, it is consistent with the possibility that endogenous adenosine generated during ischemic exercise is a potential activator of the muscle metaboreflex during ischemic handgrip exercise in humans. The finding that renal cortical blood flow and vascular resistance change during intra-arterial administration of adenosine, but not during intra-arterial administration of vehicle, supports the concept that activation of the muscle metaboreflex, and not the alerting stimulus, mediates reflex renal vasoconstriction during these experiments.
Adenosine is produced during times of increased metabolic demand, such as ischemic static handgrip exercise.30 For example, in anesthetized dogs, twitch and tetanic contraction of isolated perfused gracilis muscle produced a dramatic increase in venous adenosine concentration.31 Adenosine release is further enhanced by acidosis.30 When infused into the hindlimb circulation of anesthetized cats, 2-chloroadenosine activates a subset (≈15%) of group III and IV chemosensitive nerve endings.10 Similarly, in humans, exogenous adenosine infused into the forearm circulation activates the muscle metaboreflex, producing a significant reflex increase in sympathetic nerve activity directed to muscle in the lower extremity.22 23 Aminophylline, an adenosine receptor antagonist, blocks the reflex increase in muscle sympathetic nerve activity during handgrip exercise in humans,23 supporting the concept that endogenous adenosine contributes to the activation of the muscle metaboreflex.
Adenosine activates chemosensitive nerve endings in the carotid body in cats and in humans, stimulating respiration and sympathetic activation.32 33 To exclude the possibility that changes in the renal circulation in the present study were mediated by systemic spillover of adenosine, leading to activation of carotid chemoreceptors, respiration was measured as an indicator of carotid chemoreceptor activation.33 There was no increase in respiratory rate or thoracic excursion during adenosine or placebo compared with baseline values. Additionally, 100% oxygen, administered to blunt the potential carotid chemoreceptor contribution to renal vasoconstriction,24 25 26 had no effect on renal blood flow responses to adenosine. These findings suggest that significant adenosine did not spill over into the systemic circulation during our protocol and support the concept that activation of the muscle metaboreflex, not the carotid chemoreflex, mediates reflex renal vasoconstriction. It has been reported that adenosine infused into the renal artery in animals may cause brief (60-second) and transient renal vasoconstriction—an indirect effect apparently mediated through angiotensin II.34 Since we found no evidence of systemic adenosine spillover in the present study, it is unlikely that adenosine produced the renal vasoconstriction through this mechanism.
In animals, muscle chemosensitive and mechanosensitive afferent responses are interrelated.35 36 Kaufman et al35 tested the chemosensitivity and mechanosensitivity of group III afferent nerves in cats. Ischemia, which activates chemosensitive nerve endings, increased the responsiveness of mechanosensitive nerves. Sinoway et al36 found that the reverse was also true; ie, mechanical stimulation increased the responsiveness of chemosensitive nerves. Thus, the interaction between chemosensitive and mechanosensitive nerves is complex and cannot be categorized as merely additive or synergistic. Their interaction in humans remains undefined.
From the present data, we cannot determine the relative contribution of central command and/or mechanoreflex compared with the muscle metaboreflex in modulating renal vasoconstriction during static exercise in humans. In addition to the complexities of the interaction of muscle mechanosensitive and metabosensitive afferent neurons discussed above, the intensity of exercise during the protocol to test central command/mechanoreflex was deliberately less than that used to test the muscle metaboreflex (10% versus 30% MVC). Thus, it would be misleading to directly compare the degree of renal vasoconstriction and decrease in renal blood flow during each protocol. In the present study, we did not attempt to distinguish between central command and the mechanoreflex, although this distinction may be important, especially in heart failure patients, in whom the mechanoreflex may be augmented.12
One of the strengths of the present study was the use of a noninvasive technique, PET O-15 water, to measure renal cortical blood flow in humans. Since it was not necessary to introduce renal arterial and venous catheters to measure renal blood flow with PET, we did not measure renal spillover of norepinephrine or renin/angiotensin during handgrip. Therefore, we cannot determine if renal vasoconstriction was mediated solely by sympathetic nerve activation or if the renin-angiotensin system was also activated.
In baboons, the alerting response has a rapid neurally mediated component and a delayed (>7-second) component mediated by adrenal catecholamines. Since it is not possible to measure renal efferent sympathetic nerve activity directly in humans, we cannot completely exclude the possibility that the alerting response contributed to the changes in renal blood flow observed during static handgrip.37 Nonetheless, during the alerting stimulus and during intra-arterial vehicle infusion, there was no decrease in renal blood flow, supporting the concept that reflexes activated during static handgrip, and not the alerting response, mediated the renal circulatory changes during exercise.
We chose to study static rather that dynamic exercise in the present study, although daily activities more commonly involve dynamic exercise. Nonetheless, static exercise provides a valuable and practical tool to investigate the mechanisms underlying reflex control of the cardiovascular system and, in particular, the renal circulation during exercise.4 The same reflex systems, including central command and metabosensitive and mechanosensitive types III and IV nerve endings, play a role in modulation of the cardiovascular system during static and dynamic exercise.38 39 40 In the present study, we have found that during static exercise renal vasoconstriction increases and renal cortical blood flow decreases, and we have characterized the reflex mechanisms activating these changes. Further studies in humans will be necessary to confirm that the reflex mechanisms activated during static exercise are similarly important in modulating renal cortical blood flow during dynamic exercise.
In summary, we found that in normal healthy humans in response to static exercise, there is significant renal vasoconstriction and decrease in renal blood flow, which is mediated in part by central command and/or the mechanoreflex and in part by the muscle metaboreflex. Exogenous adenosine infused into the forearm vascular bed produced significant renal vasoconstriction and decrease in renal blood flow, consistent with the possibility that endogenous adenosine is a potential activator of the muscle metaboreflex. The changes in renal cortical blood flow and renal cortical vascular resistance during exercise observed in the present study are unlikely to be detrimental in humans with normal renal blood flow and vascular resistance (and in fact are likely beneficial) but may have important hemodynamic sequelae in patients with reduced renal blood flow and/or those with elevated vascular resistance, such as patients with advanced heart failure.
This study was supported in part by US Public Health Service grant M01-RR00865-20S1A1 (Dr Middlekauff) and the Laubisch Fund (Dr Middlekauff). The authors are grateful to Michael E. Phelps, PhD, Heinrich R. Schelbert, MD, and Johannes Czernin, MD, for continued support and the PET technologists Ronald Sumida, Lawrence Pang, Francine Aguilar, Der-Jenn Liu, Priscilla Contreras, and Sumon Wongpiya for performing the PET scanning.
- Received January 16, 1996.
- Accepted October 3, 1996.
Alam M, Smirk FM. Observations in man upon a blood pressure raising reflex arising from the voluntary muscle. J Physiol (Lond). 1937;91:372-383.
Bevegard BS, Shepherd JT. Regulation of the circulation during exercise in man. Physiol Rev. 1967;47:178-213.
Rowell LB. Cardiovascular adjustments to isometric contraction. In: Rowell LB, ed. Human Cardiovascular Control. New York, NY: Oxford University Press; 1993:302-325.
Vissing SF, Scherrer U, Victor RG. Stimulation of skin sympathetic nerve discharge by central command: differential control of sympathetic outflow to skin and skeletal muscle during static exercise. Circ Res. 1991;69:228-238.
Mark AL, Victor RG, Nerhed C, Wallin BG. Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans. Circ Res. 1985;57:461-469.
Sinoway LI, Smith MB, Enders B, Leuenberger U, Gray K, Whisler S, Moore RL. Role of diprotonated phosphate in evoking muscle reflex responses in cats and humans. Am J Physiol. 1994;267:H770-H778.
Victor RG, Bertocci LA, Pryor SL, Nunnally RL. Sympathetic nerve discharge is coupled to muscle cell pH during exercise in humans. J Clin Invest. 1988;82:1301-1305.
Rotto DM, Kaufman MP. Effect of metabolic products of muscular contraction on discharge of group III and IV afferents. J Appl Physiol. 1988;64:2306-2313.
McClain J, Hardy C, Enders B, Smith M, Sinoway L. Limb congestion and sympathoexcitation during exercise: implications for congestive heart failure. J Clin Invest. 1993;92:2352-2359.
Rowell LB. Control of individual vascular beds: splanchnic and renal circulations. In: Human Circulation Regulation During Physical Stress. New York, NY: Oxford University Press; 1986:78-95.
Crayton SC, Aung-Din R, Fixler DE, Mitchell JH. Distribution of cardiac output during induced isometric exercise in dogs. Am J Physiol. 1979;236:H218-H224.
Matsukawa K, Wall PT, Wilson B, Mitchell JH. Reflex responses of renal nerve activity during isometric muscle contraction in cats. Am J Physiol. 1990;258:H1380-H1388.
Middlekauff HR, Nitzsche EU, Hamilton MA, Schelbert HR, Fonarow GC, Moriguchi JD, Hage A, Saleh S, Gibbs GG. Evidence for preserved cardiopulmonary baroreflex control of renal cortical blood flow in humans with advanced heart failure: a positron emission tomography study. Circulation. 1995;92:395-401.
Nitzsche EU, Choi Y, Killion D, Hoh CK, Hawkins RA, Rosenthal JT, Buxton DB, Huang SC, Phelps ME, Schelbert HR. Quantification and parametric imaging of renal cortical blood flow in-vivo based on Patlak graphical analysis: a simplified but accurate method applied to dynamic positron emission tomographic renal imaging. Kidney Int. 1993;44:985-996.
Germano G, Chen BC, Huang SC, Gambhir SS, Hoffman EJ, Phelps ME. Use of the abdominal aorta for arterial input function determination in hepatic and renal PET studies. J Nucl Med. 1992;33:613-620.
Kety S. The theory and applications of the exchange of inert gas at the lungs and tissues. Pharmacol Rev. 1951;2:1-41.
Moser GH, Schrader J, Deussen A. Turnover of adenosine in plasma of human and dog blood. Am J Physiol. 1989;256:C799-C806.
Nguyen AH, Nitzsche EU, Gibbs GG, Schelbert HR, Middlekauff HR. Evidence for a neuroexcitatory role for adenosine in humans. Circulation. 1995;92(suppl I):I-133. Abstract.
Costa F, Biaggioni I. Role of adenosine in the sympathetic activation produced by isometric exercise in humans. J Clin Invest. 1994;93:1654-1660.
Engelstein ED, Lerman BB, Somers VK, Rea RF. Role of arterial chemoreceptors in mediating the effects of endogenous adenosine on sympathetic nerve activity. Circulation. 1994;90:2919-2926.
Nunn JF. Applied Respiratory Physiology. 3rd ed. Stoneham, Mass: Butterworth Publishers; 1987:371.
Hajduczok G, Hade JS, Mark AL, Williams JL, Felder RB. Central command increases sympathetic nerve activity during spontaneous locomotion in cats. Circ Res. 1991;69:66-75.
Victor RG, Rotto DM, Pryor SL, Kaufman MP. Stimulation of renal sympathetic activity by static contraction: evidence for mechanoreceptor-induced reflexes from skeletal muscle. Circ Res. 1989;64:592-599.
Biaggioni I, Olafsson B, Robertson RM, Hollister AS, Robertson D. Cardiovascular and respiratory effects of adenosine in conscious man: evidence for chemoreceptor activation. Circulation. 1987;61:779-786.
Hall JE, Granger JP, Hester RL. Interactions between adenosine and angiotensin II in controlling glomerular filtration. Am J Physiol. 1985;248:F340-F346.
Kaufman MP, Rybicki KJ, Waldrop TG, Ordway GA. Effect of ischemia on responses of group III and IV afferents to contraction. J Appl Physiol. 1984;57:644-650.
Sinoway LI, Hill JM, Pickar JG, Kaufman MP. Effects of contraction and lactic acid on the discharge of group III muscle afferents in cats. J Neurophysiol. 1993;69:1053-1059.
Smith OA, Hohimer AR, Astley CA, Taylor DJ. Renal and hindlimb vascular control during acute emotion in the baboon. Am J Physiol. 1979;236:R198-R205.
Freund PR, Rowell LB, Murphy TM, Hobbs SF, Butler SH. Blockade of the pressor response to muscle ischemia by sensory nerve block in man. Am J Physiol. 1979;237:H433-H439.
Kalia M, Mei SS, Kao FF. Central projections from ergoreceptors (C fibers) in muscle involved in cardiopulmonary responses to static exercise. Circ Res. 1981;48(suppl I):I-48-I-62.