Europ. J. appl. Physiol. 33, 139--150 (1974) �9 by Springer-Verlag 1974

Regional Blood Flow Responses to Hypoxia and Exercise in Altitude.Adapted Rats*

Alan Tucker** and Steven M. Horva th

Institute of Environmental Stress, University of California, Santa Barbara, California 93106

Received June 6, 1974

Abstract. Regional blood flow, determined as the fractional distribution of i37Cs, was measured at rest and during swimming exercise in control rats raised at sea level and in rats altitude-adapted by exposure to a barometric pressure of 440 mmHg for approximately 6 weeks. During both normoxie and hypoxie (1t % 02) resting conditions, the altitude-adapted rats exhibited regional distributions of blood flow that differed significantly from those in the control animals. During normoxie and hypoxie swimming, significant redistributions of blood flow were noted in the control animals compared to the resting conditions. Ventricular, diaphragmatic, and working muscle blood flows were increased at the expense of the renal and splanchnic circulations, with a more marked redistribution during the hypoxic swims. Similar redistributions of blood flow were exhibited by the exercising altitude-adapted rats, except that renal and hepatic perfusion was maintained at a significantly higher level during both the normoxic and hypoxic swims. Blood lactate concentrations in control rats during hypoxic exercise were strikingly increased, suggesting that the lactate metabolizing ability of the liver and kidneys was impaired. In the altitude-adapted rats, however, blood lactate levels after exercise were significantly lower than those observed in the control animals. I t is suggested that the degree of polycythemia may have determined the magnitude of the blood flow redistribution and the extent of lactate metabolism impairment.

Key words: Fractional Distribution of Cardiac Output -- Bolycy~hemia -- Blood Lactate -- Lactate Metabolism -- Splanehnic Blood Flow -- Forced Swim- ming Exercise -- Simulated Altitude Adaptation.

Introduction

The inabil i W of rats to swim successfully in water at body temper- ature dur ing hypoxic exposures has been previously reported [29, 32]. Dur ing cold water swims, however, hypoxic exposures resulted in only a slight decrement in swimming performance [29]. I t was suggested t ha t in the warm water swims circulatory changes due to heat stress promoted

* Research sponsored in part by the Air Force Office of Scientific Research, Air Force Systems Command, under Grant AFOSR 73-2455.

** 1)resent address: Cardiovascular Pulmonary Research Laboratory, Depart- ment of Medicine, University of Colorado Medical Center, Denver, Colorado 80220.

140 A. Tucker and S. )/[. tIorvath

the failures, while in the cold wa te r swims cooling of the t issues reduced the t issue energy requ i rements and thus p ro tec t ed these animals f rom the de t r imen ta l effects of hypoxia . A number of c i rcu la tory changes have been r epor t ed to occur dur ing bo th hea t and hypox ie exposures. Glaser et al. [ t0] d e m o n s t r a t e d t h a t warming the skin resul ted in a shif t in b lood flow from the abdomina l beds, pa r t i cu l a r ly the l iver, to the superficial vessels of the per iphery . Similar ly, on exposure to 8 % 0 3, Vogel et al. [3t] r epo r t ed a ma jo r r e a d j u s t m e n t of the pa r t i t ion ing of cardiac o u t p u t in the res t ing r abb i t ; blood flow to the hear t , lungs, skele ta l muscles, and b ra in being increased a t the expense of b lood flow th rough the splanehnie and renal beds. These resul ts suggested t h a t t he combina t ion of high ambien t t e m p e r a t u r e and modera t e hypox i a dur ing exereise could be expec ted to resul t in a significant red i s t r ibu t ion of blood flow, leading to a concomi tan t reduc t ion in per formance and subsequent failure.

I n order to de te rmine the cause of the impa i red exercise per formance of an imals exposed to hypoxia , this s t u d y was designed to measure the f rac t ional d i s t r ibu t ion of cardiac o u t p u t a t res t and dur ing exercise. The per formance of ra t s l iving a t sea level was compared to t h a t of ra t s a d a p t e d to s imula ted high a l t i t ude in order to eva lua te the effects of polycy~hemia and regional vascu la r a d a p t a t i o n s on the regional circu- l a t o ry responses to hypoxic exercise. I n addi t ion , the res t ing f rac t ional d i s t r ibu t ion of cardiac o u t p u t was de te rmined in control and a l t i tude- a d a p t e d ra t s and compared so t h a t the specific regional c i rcu la tory adap- t a t ions to chronic a l t i t ude exposure could be del ineated.

Methods Young male Sprague-Dawley albino rats (approximately 200 g) were placed in

a hypobarie chamber (Bethelehem 1836 HP) for a minimum of 30 days. During the first 24 h the chamber was decompressed to 560 mmItg, but thereafter the pressure was maintained at 440 mmltg (simulated altitude of 4400 m). Temperature was maintained between 22 and 25 ~ and the air flow rate was regulated at 15 1/min. Every other day the chamber was opened for t5 to 45 min in order to replace the litter, food, and water and weigh the animals. Control rats were housed in group cages in a temperature controlled room (23 ~ All animals were provided food and water ad libitum and were maintained on a 12-h light-dark cycle.

When the animals attained a weight of 370 g they were chronically carmulated with polyethylene (PE 50) catheters [20]. Under Nembutal anesthesia (40 mg/kg) an arterial catheter was placed in the left carotid artery and a venous catheter was passed into the superior vena eava via the right jugular vein. :Both catheters were secured with sutures and externalized at the back of the neck. Following this surgical procedure the rats were allowed 4 days for recovery prior to further experimentation. The altitude-adapted rats remained at sea level for the first 24 h, but were then returned to individual hypobarie chambers maintained at 440 mmI-Ig.

Four experimental conditions were used: resting--breathing ambient air (20.9 % Oe) ; resting in a Flexiglas chamber--breathing t l % 02 in N2; swimming in 37 ~ water--breathing ambient Mr (20.9 % 02) ; and swimming in 37 ~ water--

Regional Blood Flow in Altitude-Adapted Rats t41

breathing 1t % 02 in N 2. The swimming tank was similar to that described by Dawson et al. [8] with minor modifications for exteriorizing the catheters. In a previous study under similar conditions [29] many animals failed to swim for 6 min during the hypoxic swims. In order to avoid potential asphyxiation prior to the determination of the regional distribution of cardiac output, both the normoxic and hypoxie swims were terminated at 4: min. During the hypoxic exposures the chamber or swimming tank was flushed with the 11% 02-N 2 gas mixture for 7 rain prior to the start of the experiment.

The fractional distribution of cardiac output was determined using the tech- nique described by Sapirstein [23] as modified by Horvath et al. [13] with cesium (13~Cs) employed as the radioactive indicator. During the resting conditions a single injection of lSTCs in saline (2 ~C/ml), at a dosage of I ml/kg, was administered �9 via the venous catheter. This was followed 90 sec later by the injection of I ml of saturated KC1, inducing cardiac arrest. During the swimming experiments the 137Cs injection was given at 2.5 min of the swim and was followed at 4 rain with the KC1 injection. Immediately after the KC1 injection the animal was removed from the chamber or swimming tank and various organs and tissues were excised, cleaned of blood, fluid, and adherent tissues, weighed and placed in a Nuclear Chicago deep well auto gamma counter for determination of radioactivity. The radioactivity per unit weight was then compared to the total counts injected to yield the fracti- onal distribution of the isotope.

Arterial blood samples (0.5 to 0.6 ml) were obtained prior to each experiment for the determination of hematoerit, hemoglobin concentration, and resting blood lactic acid concentration. During the swimming experiments a second arterial sample for blood lactic acid determination was drawn just before the KC1 injection, between 3.5 and 4 rain of the swim.

The data were analyzed on an I B ~ 360 model 75 computer using a three- factorial analysis of variance with non-repeated measures. When significant inter- actions were noted, further statistical tests were conducted to determine the simple main effects.

l~esults

Growth rates of the rats exposed to s imulated a l t i tude were reduced dur ing the first few days of exposure, so t ha t at any age the al t i tude- exposed animals weighed less t h a n the control animals. The dura t ion of ~he indiv idual exposures to the reduced barometr ic pressure ranged from 31 to 68 days, with an average dura t ion of 44 days. Following the cannula- t ion procedure the a l t i tude-adapted rats regained weight at a slower rate and therefore weighed significantly less t h a n the control rats at the t ime of exper imenta t ion (340 and 373 g, respectively).

Al t i tude-adapted rats exhibi ted the polyeythemia normal ly observed following al t i tude exposure (Table t). Both the hematocr i t and hemo- globin concentrat ions were significantly higher in the a l t i tude-adapted rats in comparison to the control rats. No significant changes in the rest ing lactate concentra t ion could be a t t r ibu ted to either hypoxie exposure or a l t i tude adapta t ion. However, the lactic acid concentrat ions a t the t e rmina t ion of the normoxic and hypoxie swims were significantly different (Table !). The hypoxie swims produced a severe lactacidemia in both groups of ra ts compared to the normoxie swims, a l though the

142 A. Tucker and S. M. Horvath

Table t. Hematologic and blood lactic acid values of control and altitude-adapted rats at rest and at the termination of the normoxic and hypoxic swims

Control Altitude -adapted P

Hematoerit (%) 47.6 (61) Hemoglobin (g %) 14.2 (61)

20.9 % 02 11% 02

Blood lactate (mg %)

Rest t3.2 (26) 14.9 (30) Swimming 61.2 (19) 156.5 (20)

60.8 (33) 0.01 19.4 (33) 0.0t

P 20.9 % O~ 11% 0 2 P

NS 15.1 (17) 15.0 (15) NS 0.01 48.0 (13)~ t16.0 (10)~ 0.0t

:Number of determinations in parentheses following mean values. a Significantly lower than the comparable control exercise values at P < 0.01

level.

Table 2. Circulatory changes due to chronic simulated altitude exposure (comparison of the regional distribution of 137Cs in various tissues and organs during rest at sea

level)

Control Altitude-adapted P (n = t5) (n = 10)

Cardiopulmonary Ventricles 1.051 1.496 Lungs 1.563 2.416 Diaphragm 0.427 0.489

Renal and splanchnie Kidneys 3.395 3.318 Liver 0.316 0.391 Spleen 0.256 0.285 Intestine 0.903 0.837

Working muscle Gastrocnemius 0.156 0.165 Foreleg 0.180 0.148 Scapular 0.t9t 0.195

Non-working muscle Back 0.219 0.222 Abdominal 0.141 0.142

Adipose tissue Abdominal fat 0.101 0.133 Subcutaneous fat 0.188 0.232 Brown fat 0.322 0.434 Omentum 0.188 0.283

Skin 0.209 0.184

Adrenals 0.610 0.838

0.01 0.01 0.05

NS 0.01 0.01 NS

NS 0.05 NS

NS NS

0.01 N8 N8 0.01

NS

0.01

l~egional Blood Flow in Altitude-Adapted l~ats t43

altitude-adapted rats were able to maintain lower lactate levels than the control rats dm'ing both of the exercise conditions.

A comparison of the specific regional blood flows in control and altitude-adapted rats during the resting normoxic condition provided an insight into the basic circulatory adaptations attributable to chronic hypoxic exposure (Table 2). The altitude-adapted animals exhibited signi- ficant increases in ventricular, pulmonary, diaphragmatic, hepatic, and splenic flows. A marked increase in adrenal blood flow was also observed. Other organ and tissue blood flows demonstrated either unchanged or variable responses to altitude adaptation.

Changes in the regional distribution of blood flow are shown in Fig. l for both the control and altitude-adapted animals during each of the experimental conditions. Several significant changes in individual tissue blood flows were noted in the control animals during the resting hypoxic condition. Vcntrieular and diaphragmatic blood flows were increased significantly, while non-working muscle blood flow was re- duced (P < 0.0t). No significant changes in any of the other regional vascular beds were observed. The imposition of the swimming exercise resulted in marked redistribution of blood flow. Normoxie swimming increased blood flow to the actively contracting skeletal muscles, myo- cardium, and diaphragm while reducing renal, splanchnic, and adipose tissue blood flows (P < 0.01). During the hypoxic swims the control rats demonstrated the most striking changes in blood flow distribution. Ventricular, diaphragmatic, and working muscle blood flows were significantly increased with concomitant marked reductions in renal, splanehnic, and adipose tissue blood flows (P < 0.0i) that were greater than those observed during the normoxic swims. This redistribution of blood flow involved all of the examined regional circulations. Similar trends in blood flow redistribution were exhibited by the altitude- adapted animals upon exposure to the four experimental conditions (Fig. i). However, the magnitude of the variations in blood flow com- pared to the resting normoxie condition differed from those observed in the control animals. The resting hypoxic exposure produced a significant increase in ventricular blood flow and a reduction in non-working muscle blood flow (P < 0.0i). During exercise, the percent increase in working muscle, ventricular, and diaphragmatic blood flows was less than that observed in the control rats. Concurrently, renal, splanchnie, and adipose tissue blood flows were maintained at higher levels in the altitude-adapted rats. As a result, a less pronounced redistribution of blood flow was observed during exercise in the altitude-adapted animals, particularly during the hypoxie swims.

Further examination of the regional distribution data obtained from the altitude-adapted rats during the hypoxic swims revealed a distinct

10 Europ. Y. appl. Physiol., Vo]. 33

144

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A. Tucker and S. M. Horvath

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REST SWIM REST SWIM

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NORMOXIA HYPOXIA

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uo 0.5 "~

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Fig. 1. Distribution of 137Cs ( % 18~Cs injected/gm tissue) in various tissues and organs of control (D) and altitude-adapted ( I ) rats exposed to the four experi- mental conditions. E~eh control bar graph represents data from I5 animals, and each altitude-adapted bar graph represents data from 10 animals. * Significantly different from the control normoxic rest condition at P < 0.01 level; v significantly

different from the altitude-adapted normoxie rest condition at P < 0.01 level

d i c h o t o m y of the regional b lood flow response (Table 3). Ha l f of the animals exh ib i t ed a regional r ed i s t r ibu t ion s imilar to the typ ica l dis tr i - bu t ion no ted dur ing the normoxic swim (Group I) , while the remain ing animals exh ib i ted a d i s t r ibu t ion s imilar to t h a t d e m o n s t r a t e d b y the

Regional Blood Flow in Altitude-Adapted Rats 145

Table 3. Comparison of the regional distribution of 18~Cs in various tissues and organs of the two subgroups of the altitude-adapted rats exposed to the hypoxie swimming

exercise

Group I Group II P (~ = 5) ( n : 5 )

Cardiopulmonary Ventricles 2.15t 2.106 NS Lungs 1.979 t.774 NS Diaphragm 0.688 0.619 NS

Renal and splanchnie Kidneys 2.132 0.719 0.01 Liver 0.277 0.223 NS Spleen 0.140 0.03t 0.05 Intestine 0.482 0.145 0.01

Working muscle Gastrocnemius 0.264 0.378 0.05 Foreleg 0.306 0.382 NS Scapular 0.3~ 5 0.265 ~S

Non-working muscle Back 0.240 0A 02 0.0i Abdominal 0.144 0.091 0.01

Adipose tissue Abdominal fat 0.1t5 0.058 0.I0 Subcutaneous fat 0.139 0.037 0.01 Brown fat 0.244 0.066 0.01 Omentum 0.197 0.155 NS

Skin 0.114 0.040 0.01

control rats during the hypoxie swim (Group II), with a major redistri- bution of blood flow. The level of polycythemia attained appeared to be the only altered variable that could have caused such a disparity in the regional blood flow response. An average hematocrit of 63.0% was observed in the Group I animals compared to a value of 52.7 % for the Group II animals (P <0.0t).

Discussion

Changes in the regional distribution of blood flow due to altitude adaptation have not been systematically studied in a single series of experiments. In most studies only changes in blood flow to a single organ or tissue have been measured. Alterations in individual circulations following altitude exposure have been reported, but the results have been either incomplete or contradictory [14]. For example, following pro- longed hypoxic exposures, renal blood flow has been shown to be either

10,

146 A. Tucker and S. 1K. Horvath

increased [5] or reduced [4]. Hepatic blood flow was shown to be in- creased after a moderate period of exposure to altitude [21], while reductions in both coronary and cutaneous blood flow were observed during altitude exposures [9, i i , i7, 18]. In the present study blood flow to the ventricles, lungs, and diaphragm of Mtitude-adapted rats was increased in accordance with the cardiac hypertrophy and hyperventila- tion that have been noted during such chronic hypoxie exposures. Several investigators have reported a greater number of secondary coronary branches and interarterial coronary anastomoses in high altitude natives and animals [2, 22], suggesting that bo th myocardial vascularity and coronary blood flow were increased by altitude adapta- tion. Splenic and hepatic blood flows were also higher in the altitude- exposed animals. The increased splenic blood flow was indicative of the increased splenic hematopoietic activity that has been demonstrated during hypoxic exposures [i2, 19]. The hepatic blood flow increase may have been a compensation for the reduced oxygen content of the portal blood perfusing the liver. Such a response would have helped to maintain hepatic oxygen consumption and hepatic metabolic activity. Adrenal blood flow was markedly elevated, confirming the frequent observation of adrenal hyperactivity during hypoxic exposures [12, 28]. The small reduction in skin blood flow may have constituted an adaptive mechanism for maintaining blood flow to other tissues. The redistribution of blood flow attributable to altitude adaptation was directed toward supplying sufficient blood flow to tissues with elevated oxygen demands (heart, lungs, spleen, liver, and adrenals) while reducing blood flow to tissues that required little oxygen (sMn and skeletal muscles). Adequate per- fusion of each of the regional vascular beds was maintained. Presumably, a similar degree of tissue hypoxia existed in each of the organs and tissues, and organ dysfunction due to circulatory failure may have been avoided.

I t was suggested that the cause of impaired exercise performance in hypoxic situations was a failure in oxygen transport to the tissues, resulting in an increased lactic acid production and concentration in the blood [29, 32]. The results of this study confirmed these suggestions and implicated regional circulatory failure as another factor. During the hypoxie swims the majority of the control rats appeared exhausted after only g rain of exercise, at a time concurrent with the precipitous fall in oxygen uptake (from 35 to i5 ml/kg-min) reported in rats exposed to the same conditions [29]. With oxygen transport to the tissues im- paired, anaerobic glycolysis became the primary energy source and lactic acid production increased markedly.

The regional distribution of blood flow in the control rats at rest was similar to that reported by Stevens [26] and Horvath et al. [t3].

Regional Blood Flow in Altitude-Adapted Rats 147

Exposure to t i % 02 for l0 min in the present study resulted in a few significant regional blood flow alterations. Cardiopulmonary blood flow was increased 2i % while a compensatory 24 % reduction in non-working muscle blood flow was noted. However, in rabbits exposed to severe hypoxia (8% 03) for 30 rain, Vogel et al. [3t] demonstrated marked increases in myocardial (91%), diaphragmatic (86%), and limb muscle (175%) blood flows with a concomitant reduction in splanchnic flow (30%). The hypoxie challenge of breathing 1i% 03 was apparently insufficient to cause major changes in regional blood flow.

Redistributions of blood flow consequent to normoxic swimming were similar to those described for other swimming rats [13] and treadmill- exercised rats [26]. Blood flow to the working muscles was increased at the expense of renal, splanchnic, and adipose tissue blood flow, with sufficient perfusion of the other regional vascular beds. The imposition of the exercise under hypoxic conditions resulted in fl~rther redistribu- tions of blood flow. Renal and splanchnie peffusion was markedly reduced and adipose tissue blood flow was decreased by 54% in order to supply blood to the working muscle and cardiopulmonary circulations. A similar redistribution of blood flow away from the splanchnic and renal beds has been observed in chronically anemic exercising dogs [30]. The combination of exercise and hypoxia, induced by severe anemia, resulted in a compensatory reduction and diversion of visceral blood flow to the coronary and muscular beds. Failure of the control rats to per- form adequately during the hypoxic swims in the present study may have been due to the combination of severe arterial hypoxemia and disproportionate blood flow distribution. Hepatic and renal tissue hypoxia, resulting from lowered oxygen content and reduced blood flow, may have caused organ dysfunction and subsequently contributed to the circulatory collapse.

The substantial disparity in renal and splanchnic blood flow noted between the altitude-adapted and control rats may have been the determining factor relating to the ability or inability of the animals to complete the hypoxie swim. Of particular interest was the relationship between renal and hepatic blood flow and organ metabolic activity, since both the liver and kidney have been described as primary sites of lactate metabolism [t, 15, 24]. In addition, the appearance of elevated blood lactate levels has been associated with liver dysfunction in rats exposed to severe hypoxia [25]. The lactate metabolizing function of the liver may have been impaired by the combination of reduced avMlable oxygen and decreased hepatic blood flow during the hypoxic swim. Several investigators have indicated that severe hypoxemia increased blood lactate concentration by actually inducing the production of lactic acid by the liver [3, 6, t6, 27], although the reduction in hepatic

i48 A. Tucker and S. ~. tIorvath

lactate metabolism Mone would have added large amounts of lactate to the circulating blood [7]. The marked reductions in renal and hepatic blood flow observed in the failing control rats, concurrent with the severe laetacidemia, suggested that lactate metabolism was impaired. The increased perfusion of liver and kidneys noted in the altitude-adapted rats, combined with the observed low blood lactate, provided evidence that maintenance of adequate organ perfusion, perhaps due to the increased oxygen-carrying capacity of the blood, sustained the lactate metabolizing function of these organs.

The dependence of circulatory stability upon the degree of polycythe- mia was also evident in the comparison of the two altitude subgroups ex- posed to the hypoxic swimming condition. In those altitude-adapted rats with the greater polycythemia, significantly higher renal and hepatic blood flows during hypoxic exercise were found. Apparently there was a critical polycythemic level between the hematocrit values observed for the two groups (63.0 and 52.7 %). Above this critical polycythemic level the elevated oxygen-carrying capacity of the blood enabled the circu- latory system to supply oxygen to the working muscles without reducing oxygen transport to the metabolizing visceral organs and adipose tissue. However, below this critical polycythemic level the reduced oxygen- carrying capacity at normal perfusion provided an inadequate oxygen supply to the working muscles, so skeletal muscle blood flow was in- creased at the expense of other regional vascular beds. Consequent to the reduced blood flow, organ dysfunction occurred, leading to aberrant metabolism, acid-base imbalance, and a subsequent reduction in per- formance.

The ability of the altitude-adapted rats to perform more successfully during the hypoxic exercise condition was apparently the result of a number of physiological adaptation that increased the efficiency of the oxygen transport system. Adaptation to high altitude, such as poly- cythemia, increased tissue vascularity, increased blood volume, re- distribution of blood flow, and increased cellular oxidative capacity, functioned to maintain or augment oxygen transport to the cells despite a reduction in oxygen availability. With an increase in total oxygen trans- port, energy production was maintained by oxidative metabolism so that an increase in anaerobic metabolism was not required. The subsequent reduction in lactic acid production, resulting in a less severe arterial acidosis, in association with the circulatory adaptations to high altitude exposure, improved the exercise capacities of the altitude-adapted animals.

Acknowledgments. We wish to express our appreciation to IYfs. Terri Shabram for valuable assistance in this investigation.

Regional Blood Flow in Altitude-Adapted Rats 149

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150 A. Tucker and S. 1VI. Horvath

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Prof. Steven M. Horvath Director Institute of Environmental Stress University of California Santa Barbara, California 93106, USA