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Hypoxic Cardiovascular Dynamics and Control
HYPOXIC CARDIOVASCULAR DYNAMICS AND CONTROL
Howard H. Erickson, Environmental Sciences Division, USAF School of Aerospace Medicine Brooks AFB, Texas 78235 H. Lowell Stone, The Marine Biomedical Institute, University of Texas Medical Branch Galveston, Texas 77550
Myocardial hypoxia may be encountered at high altitude, during pathophysiological conditions, or during exposure to carbon monoxide (CO). Stresses such as these may alter the input to the cardiovascular system and may elicit local and autonomic changes in circulatory dynamics. Our objective was to use two different types of hypoxia, hypoxic hypoxia and carbon monoxide to define the mechanisms responsible for the changes in cardiovascular dynamics during hypoxia in the conscious unanesthetized dog. The concepts presented by Starling in his famous Linacre lecture (21) at Cambridge in 1915 were perhaps some of the earliest, most significant contributions made in regard to cardiovascular regulation. Engineering control theory has recently been used to study biologic or physiologic homeostatic systems in order to relate a system's closed-loop behavior to the responses of its individual components (11, 17, 18, 19). The mammalian cardiovascular system has been described by Grodins (10) as a very complex hydrodynamic system whose many parameters are continuously operated upon by neural and humoral controlling signals. Korner (17) has decircul a tory control system in the scribed the neural circulatory intact animal. Guy ton et al. (12) in a recent description of o f the overall regulation regul a tion of the circulati tion, on, discussed the local response to decreased oxygen and modification of this response by complex o f the cardiovascular integration of neural control of system. Gregg (9) has recently discussed the relationship between coronary blood flow and metabolic changes and the coronary flow responses to natural stresses. He reports that any theory of coronary vasodilation should explain the complex and massive dilation of the coronary circulation which occurs during the stresses of everyday life. Kontos et al. (13) have compared the circulatory responses to systemic hypoxic hypoxia in man and in the unanesthetized dog. The physiologic responses to CO have also been previously described (5, 13, 18, 20), including some of the effects on the heart and cardiovascular system (2, 3). HETHODS Forty-three dogs were surgically instrumented under anesthesia with different transducers to evaluate the effects of hypoxic hypoxia and CO on coronary blood flow, cardiac dynamics, myocardial metabolism, and regional blood flow. Cardiac output,
left circumflex coronary artery, left renal artery, superior mesenteric artery, and terminal aortic blood flow were measured with Doppler or electromagnetic flow transducers. Left ventricular pressure was determined with a solid-state pressure transducer. Piezoelectric crystals were implanted on the endocardial surface of the left ventricle to measure the transverse internal diameter. Arterial pressure was measured in an exteriorized carotid artery. Catheters were placed in the left atrium and coronary sinus of the heart in order to measure left atrial pressure and to determine.blood gases, pH, and the oxygen saturation of arterial and coronary venous blood. Arterial oxygen saturation was also continuously monitored by reflection oximetry to evaluate the dynamic response to hypoxic hypoxia. RESULTS AND DISCUSSION The coronary and cardiac responses to hypoxic hypoxia were investigated in 24 conscious dogs exposed to low-oxygen atmospheres, 10% or 5% oxygen, through a permanent tracheostomy or in an environmental chamber. A summary of the results is given in Table 1. Exposure to hypoxic hypoxia resulted in a significant decrease in both arterial and coronary venous oxygen tensions and saturations (7). l.Jith With 5% 5% oxygen, there were significant increases in heart rate, cardiac output, coronary blood flow, myocardial oxygen consumption, and left ventricular dP/dt. Left atrial pressure did not change with hypoxia, but there was a decrease in left ventricular end systolic internal diameter, with little change in end diastolic diameter (4). These responses suggest an increase in autonomic activity to the heart, represented by both a positive inotropic and positive chronotropic effect (Figure 1). Tachycardia, hypertension, and increased cardiac output associated with this type of hypoxia is considered due to chemoreceptor stimulation (15, 16). Betaadrenergic blockade with propranolol attenuated the response in these variables, suggesting that the myocardial response to hypoxia was associated with chemoreceptor stimulation and increased betaa drenergic sympathetic activity. The increase in adrenergic heart rate and left ventricular dP/dt during hypoxia after beta-adrenergic blockade was attributed to a decrease in parasympathetic activity (Figure 1). An increase in ventilation rate and hypocapnia also support a change in vagal activity. The response in coronary blood flow may be primarily associated with myocardial oxygen requirements. Neural influences may modify the direct effects of
315
TABLE 1.
EFFECTS OF HYPOXIC HYPOXIA AND CARBON MJNOXIDE ON CARDIOVASCULAR FUNCTION
Art. POZ (mm (rmn Hg) Art. Oz Sa t. ((%) %) Cor. Ven. Ve n . Poz (mm (rmn Hg) Cor. Ven. 02 Oz Sat. A-V Diff. in 02 Oz Sa to t. (%) Heart Rate (b/m) Cor. B. F. (ml/min) LV dP/dt (mm Hg/Sec) LV O Oz2 Cons. (ml/min) Cardiac Output (ml/kg/min)
CONTROL 97 95 20 19 76 88 38 3259 4.6 149
20% COHb -24 +10 -34 +18 +23 +142 -1. 3 +15
10% 10% OXYGEN -53 -25 -7 -6 -19 +14 +22 +478 +1.4 +22
10% OXYGEN 10% B-BLOCKADE -SO -19 -6 -8 -11 +4 +17 +526 +1.4 +20
5% OXYGEN -73 -51 -12 -12 -39 +22 +62 +1202 +2.1 +42
5% OXYGEN 5% B-BLOCKADE
-71
-so -12 -14 -36 +10 +43 +620 +0.4 +34
sumption. The myocardial response to CO may be primarily under local control; but neural components appear to play a role since the heart rate response is attenuated following the administration of propranolol (1).
vasodilating substances like oxygen and act as simultaneous defense mechanisms to provide a reflex change in blood flow or flow distribution. Neurogenic modification of of local control in the peripheral circulation has been implied in the recent reviews by Guy ton et al. (12) and Korner (17), but it may also apply to the coronary circulation.
Gregg (9) has reported that the metabolic activity of the left myocardium, as reflected by its oxygen consumption, correlates closely with left coronary blood flow in various stress states. This appears to be true with hypoxic hypoxia when cardiovascular regulation results from the integration of chemoreceptor and baroreceptor control. During exposure to carbon monoxide, however, this correlation between coronary blood flow and myocardial oxygen consumption is different. different . As coronary blood flow increases, there is a decrease in myocardial oxygen consumption. Chemoreceptor and baroreceptor control during this type of hypoxia are minimal. Cardiovascular regulation is primarily under local control, but seems to be modified by the integration of neural neura l control.
Analysis of the dynamic response to hypoxia showed an increase in coronary flow a few seconds after the initial desaturation of o f oxygen or when the arterial oxygen saturation was approximately 70%. This was primarily a local vasodilation of the cor~ cor~ nary vasculature since there was no increase in heart rate or myocardial contractility. contracti1ity. This response was followed by an increase in heart rate and dP/dt which began about 10-15 sec later. In nine dogs regional vascular changes were investigated in the superior mesenteric, renal, and terminal aortic circulations (14). Severe hypoxia (5% oxygen) resulted in increases in heart rate (60 beats/min), arterial blood pressure (17 mm rmn Hg), renal blood flow (18 ml/min), and terminal aortic blood flow (99 ml/min). Exposure to hypoxia after alpha-adrenergic blockade with phenoxybenzamine still resulted in an increase in heart rate (48 beats/min), beats /min), renal (17 ml/min), m1/min), and terminal aortic (57 ml/min) blood flow; however, there was essentially no change in arterial pressure (-3 mm rmn Hg). This suggests that peripheral periphera l hypertension associmedi a ted through alphaated with hypoxia is mediated adrenergic sympathetic activity.
CONCLUSION In summary, surmnary, cardiovascular dynamics and control during hypoxia have been investigated in the conscious dog, using two different types of hypoxia hypox ia as stressors or inputs to the system. sys tem. This approach has helped to define the overall regulation regul at ion of the circulatory system during exposure to hypoxia. Exposure to carbon monoxide resulted in a decrease a rterial oxygen saturation with little change in the arterial or pH. in oxygen tension, carbon dioxide tension, or Cardiovascular regulation, during exposure to carbon monoxide, appeared to be primarily under local conf actors did modify tre response. respon se. trol; however, neural factors
The physiologic responses to CO were studied in 10 dogs breathing 1500 ppm CO (1) and in 12 dogs breathing 100 ppm CO (8). The response to CO was ic hypoxia or similar to that produced by hypox hypoxic altitude hypoxia; however, there were some major differences. First, the dynamic response to CO was much slower than the response to hypoxic hypoxia. Exposure to CO resulted in no change in arterial or coronary venous oxygen tensions (Table 1). There a rterial oxygen satwas a significant decrease in arterial uration; however, coronary venous oxygen saturation increased by 10% 10% at 20% COHb. This resulted in a decrease in the A-V difference in oxygen saturation which was comparable to breathing 5% 5% oxygen. The increases in heart rate and coronary blood flow at 20% 20% COHb were comparable to breathing 10% 10% oxygen. Arterial blood pressure and maximal left ventricular dP/dt, however, did not increase and there was a significant s ignificant decrease in myocardial oxygen con-
Hypoxic hypoxia, hypox ia, however, resulted in a decrease in bo th arterial a rterial oxygen saturation and tension; there both a lso a decrease in carbon c a r bon dioxide tension te ns ion and was also i nc re ase in pH. Cardiovascular regulation re gu lation during an increase heavil y hypoxic hypoxia appeared to be modified more heavily neura l control, both alphaa lpha by the integration of neural and beta-adrenergic sympathetic activity and pa pararasympathetic activity. Stresses such as hypoxic monox ide alter the input from hypoxia and carbon monoxide Ko rner several cardiorespiratory receptor groups as Korner (17) has suggested, but there tends to be prefereninput . The reflex tial engagement by a particular input. autonomic effects, thus, become a function of the entire input profile that characterizes the disturbance.
316
REFERENCES 1.
Adams, J. D., H. H. Erickson, and H. L. Stone. Myocardial metabolism during exposure to carbon monoxide in the conscious dog. J. Appl. Physiol. 34:238, 1973.
2.
Ayres, S. M., S. Giannelli, and H. Mueller. Myocardial and systemic responses to carboxyhemoglobin. Ann. N. Y. Acad. Sci. 174: 268, 1970.
3.
4.
5.
6.
Ayres, S. M., H. S. Mueller, J. J. Gregory, S. Giannelli, and J. L. Penny. Systemic and myocardial hemodynamic responses to relatively small concentrations of carboxyhemoglobin (COHb). Arch. Environ. Health 18:699, 1969. Brown, B. G., H. L. Stone, and H. H. Erickson. Left ventricular diameter during hypoxic hypoxia. The Physiologist 15:95, 1972 Douglas, C. G., J. S. Haldane, and J. B. S. Haldane. The laws of combination of hemoglobin with CO and 02. J. Physiol., London 44:275, 19l2. 1912. Erickson, H. H., E. L. Fitzpatrick, and H. L. Stone. The transient response in coronary blood flow and left ventricular function to acute hypoxia. Conf. on Engin. in Med. and BioI. Proc. 12:100, 1970.
7.
Erickson, H. H., and H. L. Stone. Cardiac beta-adrenergic receptors and coronary hemodynamics in the conscious dog during hypoxic hypoxia. Aerospace Med. 43:422, 1972.
8.
Erickson, H. H. and D. K. Buckhold. Coronary blood flow and myocardial function during exposure to 100 ppm carbon monoxide. The Physiologist 15:128, 1972.
9.
Gregg, D. E. Relationship between coronary metabo lic changes. Cardiology 56: flow and metabolic 29l, 291, 1971-72.
10.
cardiovascul a r F . S. Integrative cardiovascular Grodins, F. physiology. A mathematical synthesis of cardiac and blood vessel hemodynamics. BioI. 34:93, 1959. Quart. Rev. Biol.
11.
Grodins, F. S. Contrel Theory and Biological Systems. New York: Columbia Univ. Press, 1963.
12.
Guy ton, A. C., T. G. Co leman , and H. J. Granger. Circulation: Overall regulation. Physiol. Rev. 34:13, 1972.
13.
Haldane, J. B. S. The dissociation of oxyhemoglobin in human blood during partial CO poisoning. J. Physiol. London 45:22, 1912-13.
14.
Jones, E. T., A. H. Nelson, H. H. Erickson, and H. L. Stone. Regional blood flow during hypoxia. The Physiologist 15:185, 1972.
15.
Kontos, H. A., J. E. LeVasseur, D. W. Richardson, H. P. Mauck, and J. L. Patterson. Patterson . Comparative circulatory responses to systemic hypoxia in man and in unanesthetized dogs. J. Appl. Physiol. 23:381, 1967.
16.
Kontos, H. A., G. W. Vetrovec, and D. W. Richardson. Role of carotid chemoreceptors in circulatory response to hypoxia in dogs. J. Appl. Physiol. 28:561, 1970.
17.
Korner, P. I. Integrative neural cardiovascular control. Physiol. Rev. 51:312, 1971.
18.
Milhorn, H. T., Jr. Application of Control Theory to Physiological Systems. Philadelphia: W. B. Saunders Co., 1966.
19.
Milsum, J. H. Biological Control System Analysis. New York: McGraw-Hill, 1966.
20.
Root, W. W. Carbon monoxide. In: Handbook of Physiology Respiration. Washington, D. C.: Am. Physiol. Soc. 1965, sect. 3, vol. 11, chapt. 43, p. 1087.
21.
Starling, E. H. The Linacre Lecture on the Law of the Heart. London: Longmans, Green, 19l9. 1919.
The animals involved in this study were maintained in accordance with the "Guide for Laboratory Animal Facilities and Care" as published by the National Academy of Sciences--National Research Council. This work was supported in part by the National Aeronautics and Space Administration under Contract No. A94544.
r-1
AUTONOIIIC CONTROL
BARORECEPTOR SET POINT CHEIIORECEPTOR POINT SET PO'NT
CENTRAl CENTRAL NERVOUS SYSTEII
ARTERiAl Po, Peo , ANO pH
ARTERiAl CHEMORECEPTORS
SYIlPATHETlC SYIIPATHETlC ANO PARASYMPATHETlC
ARTERiAl BARORECEPTORS
CORONARY CIRCULATION IIAND ANO AND ~ OTHER 10NOTROPlC IACTIVITY ORGANS
HEAlT HEART
- ----CHRONOTROPIC
1-----
'-
I I
ARTERiAl PRESSURE
r~
Figure 1 Hechanisms of cardiovascular control during hypoxia.
317
Howard H. Erickson, Environmental Sciences Division, USAF School of Aerospace Medicine Brooks AFB, Texas 78235 H. Lowell Stone, The Marine Biomedical Institute, University of Texas Medical Branch Galveston, Texas 77550
Myocardial hypoxia may be encountered at high altitude, during pathophysiological conditions, or during exposure to carbon monoxide (CO). Stresses such as these may alter the input to the cardiovascular system and may elicit local and autonomic changes in circulatory dynamics. Our objective was to use two different types of hypoxia, hypoxic hypoxia and carbon monoxide to define the mechanisms responsible for the changes in cardiovascular dynamics during hypoxia in the conscious unanesthetized dog. The concepts presented by Starling in his famous Linacre lecture (21) at Cambridge in 1915 were perhaps some of the earliest, most significant contributions made in regard to cardiovascular regulation. Engineering control theory has recently been used to study biologic or physiologic homeostatic systems in order to relate a system's closed-loop behavior to the responses of its individual components (11, 17, 18, 19). The mammalian cardiovascular system has been described by Grodins (10) as a very complex hydrodynamic system whose many parameters are continuously operated upon by neural and humoral controlling signals. Korner (17) has decircul a tory control system in the scribed the neural circulatory intact animal. Guy ton et al. (12) in a recent description of o f the overall regulation regul a tion of the circulati tion, on, discussed the local response to decreased oxygen and modification of this response by complex o f the cardiovascular integration of neural control of system. Gregg (9) has recently discussed the relationship between coronary blood flow and metabolic changes and the coronary flow responses to natural stresses. He reports that any theory of coronary vasodilation should explain the complex and massive dilation of the coronary circulation which occurs during the stresses of everyday life. Kontos et al. (13) have compared the circulatory responses to systemic hypoxic hypoxia in man and in the unanesthetized dog. The physiologic responses to CO have also been previously described (5, 13, 18, 20), including some of the effects on the heart and cardiovascular system (2, 3). HETHODS Forty-three dogs were surgically instrumented under anesthesia with different transducers to evaluate the effects of hypoxic hypoxia and CO on coronary blood flow, cardiac dynamics, myocardial metabolism, and regional blood flow. Cardiac output,
left circumflex coronary artery, left renal artery, superior mesenteric artery, and terminal aortic blood flow were measured with Doppler or electromagnetic flow transducers. Left ventricular pressure was determined with a solid-state pressure transducer. Piezoelectric crystals were implanted on the endocardial surface of the left ventricle to measure the transverse internal diameter. Arterial pressure was measured in an exteriorized carotid artery. Catheters were placed in the left atrium and coronary sinus of the heart in order to measure left atrial pressure and to determine.blood gases, pH, and the oxygen saturation of arterial and coronary venous blood. Arterial oxygen saturation was also continuously monitored by reflection oximetry to evaluate the dynamic response to hypoxic hypoxia. RESULTS AND DISCUSSION The coronary and cardiac responses to hypoxic hypoxia were investigated in 24 conscious dogs exposed to low-oxygen atmospheres, 10% or 5% oxygen, through a permanent tracheostomy or in an environmental chamber. A summary of the results is given in Table 1. Exposure to hypoxic hypoxia resulted in a significant decrease in both arterial and coronary venous oxygen tensions and saturations (7). l.Jith With 5% 5% oxygen, there were significant increases in heart rate, cardiac output, coronary blood flow, myocardial oxygen consumption, and left ventricular dP/dt. Left atrial pressure did not change with hypoxia, but there was a decrease in left ventricular end systolic internal diameter, with little change in end diastolic diameter (4). These responses suggest an increase in autonomic activity to the heart, represented by both a positive inotropic and positive chronotropic effect (Figure 1). Tachycardia, hypertension, and increased cardiac output associated with this type of hypoxia is considered due to chemoreceptor stimulation (15, 16). Betaadrenergic blockade with propranolol attenuated the response in these variables, suggesting that the myocardial response to hypoxia was associated with chemoreceptor stimulation and increased betaa drenergic sympathetic activity. The increase in adrenergic heart rate and left ventricular dP/dt during hypoxia after beta-adrenergic blockade was attributed to a decrease in parasympathetic activity (Figure 1). An increase in ventilation rate and hypocapnia also support a change in vagal activity. The response in coronary blood flow may be primarily associated with myocardial oxygen requirements. Neural influences may modify the direct effects of
315
TABLE 1.
EFFECTS OF HYPOXIC HYPOXIA AND CARBON MJNOXIDE ON CARDIOVASCULAR FUNCTION
Art. POZ (mm (rmn Hg) Art. Oz Sa t. ((%) %) Cor. Ven. Ve n . Poz (mm (rmn Hg) Cor. Ven. 02 Oz Sat. A-V Diff. in 02 Oz Sa to t. (%) Heart Rate (b/m) Cor. B. F. (ml/min) LV dP/dt (mm Hg/Sec) LV O Oz2 Cons. (ml/min) Cardiac Output (ml/kg/min)
CONTROL 97 95 20 19 76 88 38 3259 4.6 149
20% COHb -24 +10 -34 +18 +23 +142 -1. 3 +15
10% 10% OXYGEN -53 -25 -7 -6 -19 +14 +22 +478 +1.4 +22
10% OXYGEN 10% B-BLOCKADE -SO -19 -6 -8 -11 +4 +17 +526 +1.4 +20
5% OXYGEN -73 -51 -12 -12 -39 +22 +62 +1202 +2.1 +42
5% OXYGEN 5% B-BLOCKADE
-71
-so -12 -14 -36 +10 +43 +620 +0.4 +34
sumption. The myocardial response to CO may be primarily under local control; but neural components appear to play a role since the heart rate response is attenuated following the administration of propranolol (1).
vasodilating substances like oxygen and act as simultaneous defense mechanisms to provide a reflex change in blood flow or flow distribution. Neurogenic modification of of local control in the peripheral circulation has been implied in the recent reviews by Guy ton et al. (12) and Korner (17), but it may also apply to the coronary circulation.
Gregg (9) has reported that the metabolic activity of the left myocardium, as reflected by its oxygen consumption, correlates closely with left coronary blood flow in various stress states. This appears to be true with hypoxic hypoxia when cardiovascular regulation results from the integration of chemoreceptor and baroreceptor control. During exposure to carbon monoxide, however, this correlation between coronary blood flow and myocardial oxygen consumption is different. different . As coronary blood flow increases, there is a decrease in myocardial oxygen consumption. Chemoreceptor and baroreceptor control during this type of hypoxia are minimal. Cardiovascular regulation is primarily under local control, but seems to be modified by the integration of neural neura l control.
Analysis of the dynamic response to hypoxia showed an increase in coronary flow a few seconds after the initial desaturation of o f oxygen or when the arterial oxygen saturation was approximately 70%. This was primarily a local vasodilation of the cor~ cor~ nary vasculature since there was no increase in heart rate or myocardial contractility. contracti1ity. This response was followed by an increase in heart rate and dP/dt which began about 10-15 sec later. In nine dogs regional vascular changes were investigated in the superior mesenteric, renal, and terminal aortic circulations (14). Severe hypoxia (5% oxygen) resulted in increases in heart rate (60 beats/min), arterial blood pressure (17 mm rmn Hg), renal blood flow (18 ml/min), and terminal aortic blood flow (99 ml/min). Exposure to hypoxia after alpha-adrenergic blockade with phenoxybenzamine still resulted in an increase in heart rate (48 beats/min), beats /min), renal (17 ml/min), m1/min), and terminal aortic (57 ml/min) blood flow; however, there was essentially no change in arterial pressure (-3 mm rmn Hg). This suggests that peripheral periphera l hypertension associmedi a ted through alphaated with hypoxia is mediated adrenergic sympathetic activity.
CONCLUSION In summary, surmnary, cardiovascular dynamics and control during hypoxia have been investigated in the conscious dog, using two different types of hypoxia hypox ia as stressors or inputs to the system. sys tem. This approach has helped to define the overall regulation regul at ion of the circulatory system during exposure to hypoxia. Exposure to carbon monoxide resulted in a decrease a rterial oxygen saturation with little change in the arterial or pH. in oxygen tension, carbon dioxide tension, or Cardiovascular regulation, during exposure to carbon monoxide, appeared to be primarily under local conf actors did modify tre response. respon se. trol; however, neural factors
The physiologic responses to CO were studied in 10 dogs breathing 1500 ppm CO (1) and in 12 dogs breathing 100 ppm CO (8). The response to CO was ic hypoxia or similar to that produced by hypox hypoxic altitude hypoxia; however, there were some major differences. First, the dynamic response to CO was much slower than the response to hypoxic hypoxia. Exposure to CO resulted in no change in arterial or coronary venous oxygen tensions (Table 1). There a rterial oxygen satwas a significant decrease in arterial uration; however, coronary venous oxygen saturation increased by 10% 10% at 20% COHb. This resulted in a decrease in the A-V difference in oxygen saturation which was comparable to breathing 5% 5% oxygen. The increases in heart rate and coronary blood flow at 20% 20% COHb were comparable to breathing 10% 10% oxygen. Arterial blood pressure and maximal left ventricular dP/dt, however, did not increase and there was a significant s ignificant decrease in myocardial oxygen con-
Hypoxic hypoxia, hypox ia, however, resulted in a decrease in bo th arterial a rterial oxygen saturation and tension; there both a lso a decrease in carbon c a r bon dioxide tension te ns ion and was also i nc re ase in pH. Cardiovascular regulation re gu lation during an increase heavil y hypoxic hypoxia appeared to be modified more heavily neura l control, both alphaa lpha by the integration of neural and beta-adrenergic sympathetic activity and pa pararasympathetic activity. Stresses such as hypoxic monox ide alter the input from hypoxia and carbon monoxide Ko rner several cardiorespiratory receptor groups as Korner (17) has suggested, but there tends to be prefereninput . The reflex tial engagement by a particular input. autonomic effects, thus, become a function of the entire input profile that characterizes the disturbance.
316
REFERENCES 1.
Adams, J. D., H. H. Erickson, and H. L. Stone. Myocardial metabolism during exposure to carbon monoxide in the conscious dog. J. Appl. Physiol. 34:238, 1973.
2.
Ayres, S. M., S. Giannelli, and H. Mueller. Myocardial and systemic responses to carboxyhemoglobin. Ann. N. Y. Acad. Sci. 174: 268, 1970.
3.
4.
5.
6.
Ayres, S. M., H. S. Mueller, J. J. Gregory, S. Giannelli, and J. L. Penny. Systemic and myocardial hemodynamic responses to relatively small concentrations of carboxyhemoglobin (COHb). Arch. Environ. Health 18:699, 1969. Brown, B. G., H. L. Stone, and H. H. Erickson. Left ventricular diameter during hypoxic hypoxia. The Physiologist 15:95, 1972 Douglas, C. G., J. S. Haldane, and J. B. S. Haldane. The laws of combination of hemoglobin with CO and 02. J. Physiol., London 44:275, 19l2. 1912. Erickson, H. H., E. L. Fitzpatrick, and H. L. Stone. The transient response in coronary blood flow and left ventricular function to acute hypoxia. Conf. on Engin. in Med. and BioI. Proc. 12:100, 1970.
7.
Erickson, H. H., and H. L. Stone. Cardiac beta-adrenergic receptors and coronary hemodynamics in the conscious dog during hypoxic hypoxia. Aerospace Med. 43:422, 1972.
8.
Erickson, H. H. and D. K. Buckhold. Coronary blood flow and myocardial function during exposure to 100 ppm carbon monoxide. The Physiologist 15:128, 1972.
9.
Gregg, D. E. Relationship between coronary metabo lic changes. Cardiology 56: flow and metabolic 29l, 291, 1971-72.
10.
cardiovascul a r F . S. Integrative cardiovascular Grodins, F. physiology. A mathematical synthesis of cardiac and blood vessel hemodynamics. BioI. 34:93, 1959. Quart. Rev. Biol.
11.
Grodins, F. S. Contrel Theory and Biological Systems. New York: Columbia Univ. Press, 1963.
12.
Guy ton, A. C., T. G. Co leman , and H. J. Granger. Circulation: Overall regulation. Physiol. Rev. 34:13, 1972.
13.
Haldane, J. B. S. The dissociation of oxyhemoglobin in human blood during partial CO poisoning. J. Physiol. London 45:22, 1912-13.
14.
Jones, E. T., A. H. Nelson, H. H. Erickson, and H. L. Stone. Regional blood flow during hypoxia. The Physiologist 15:185, 1972.
15.
Kontos, H. A., J. E. LeVasseur, D. W. Richardson, H. P. Mauck, and J. L. Patterson. Patterson . Comparative circulatory responses to systemic hypoxia in man and in unanesthetized dogs. J. Appl. Physiol. 23:381, 1967.
16.
Kontos, H. A., G. W. Vetrovec, and D. W. Richardson. Role of carotid chemoreceptors in circulatory response to hypoxia in dogs. J. Appl. Physiol. 28:561, 1970.
17.
Korner, P. I. Integrative neural cardiovascular control. Physiol. Rev. 51:312, 1971.
18.
Milhorn, H. T., Jr. Application of Control Theory to Physiological Systems. Philadelphia: W. B. Saunders Co., 1966.
19.
Milsum, J. H. Biological Control System Analysis. New York: McGraw-Hill, 1966.
20.
Root, W. W. Carbon monoxide. In: Handbook of Physiology Respiration. Washington, D. C.: Am. Physiol. Soc. 1965, sect. 3, vol. 11, chapt. 43, p. 1087.
21.
Starling, E. H. The Linacre Lecture on the Law of the Heart. London: Longmans, Green, 19l9. 1919.
The animals involved in this study were maintained in accordance with the "Guide for Laboratory Animal Facilities and Care" as published by the National Academy of Sciences--National Research Council. This work was supported in part by the National Aeronautics and Space Administration under Contract No. A94544.
r-1
AUTONOIIIC CONTROL
BARORECEPTOR SET POINT CHEIIORECEPTOR POINT SET PO'NT
CENTRAl CENTRAL NERVOUS SYSTEII
ARTERiAl Po, Peo , ANO pH
ARTERiAl CHEMORECEPTORS
SYIlPATHETlC SYIIPATHETlC ANO PARASYMPATHETlC
ARTERiAl BARORECEPTORS
CORONARY CIRCULATION IIAND ANO AND ~ OTHER 10NOTROPlC IACTIVITY ORGANS
HEAlT HEART
- ----CHRONOTROPIC
1-----
'-
I I
ARTERiAl PRESSURE
r~
Figure 1 Hechanisms of cardiovascular control during hypoxia.
317