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Blood Flow Regulation as a Factor in Regulation of Tissue O2 Delivery
14TH ANNUAL ASPEN CONFERENCE ON RESEARCH IN EMPHYSEMA act promptly with little energy cost. More sluggish in its response and yet an essential part of compensation to altered 0 2 supply is a change in Hb concentration. This erythropoietin-mediated response occurs with a decreased Hb concentration, a decreased 0 2 saturation of Hb and an increased Hb affinity for o2 but not with changes in cardiac output. Other components of 0 2 supply are ventilation and cardiac output. Ventilation responds to
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body needs for gas exchange of both Coo and 0 2 . The response to hypoxia is therefore compromised by the associated effect of respiratory alkalosis on o2 cardiac output does not appear to respond to hypoxia until other compensatory mechanisms have failed. Collectively these various responses when capable of reacting provide an inkgrated defense against hypoxia.
Blood Flow Regulation as a Factor in Regulation of Tissue
0
2
Delivery
N . Sheldon Skinner, Jr., M.D.' hile the amount of 0 2 delivered to any tissue depends upon a variety of factors, the 0 2 content of blood and blood flow to tissues are prime determinants of 0 2 delivery. This presentation concentrated only on some facets of blood flow regulation. As a general rule, the vascular dimensions of various tissues are tailored to allow a blood flow that will meet the maximal metabolic requirements of that tissue. Exceptions to this rule are frequent. For example, skeletal muscle, a tissue with an enormous ability to increase its level of metabolism (ie, increase 0 2 uptake from a resting value of 0.15 to 12-16 m11100 g of tissuelmin) appears to have a vascular bed that is underdimensioned relative to its maximal metabolic requirements. Some compensation is offered through the relatively high anaerobic metabolic potential of skeletal muscle. In contrast, the cutaneous bed and the kidney, both of which subserve specific physiologic functions (ie, temperature control and fluid balance) have vascular beds with dimensions that allow for a blood flow far in excess of that needed to meet their maximal metabolic requirements. Hence, these tissue have an overdimensioned vasculature. These vascular dimensions would also appear to be influenced by large changes in cell size and cell number per unit of tissue such as exists in subcutaneous adipose tissue.' Further consideration of specific tissue blood flow reveals that a discrepancy exists between maximal cardiac pump capacity and potential maximal blood flow demands of all of the tissues; ie, the vasculature of all the tissues appears to be overdimensioned relative to the maximum cardiac output that we a ~ h i e v e d .It~ appears that if the vascular bed of all tissues were maximally vasodilated, the amount of blood flow that would be required to 'From the Division of Clinical Physiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
sustain a normal blood pressure of approximately 100 mm Hg would be in the range of 40 to 50 Llmin. In contrast, the maximal cardiac pump capacity is approximately 25 Llmin. These considerations indicate that the responsibility for adjusting the distribution of the cardiac output rests largely on peripheral vascular mechanisms. As such, intravascular shunting becomes an important mechanism whereby the distribution of cardiac output can be manipulated to best satisfy blood flow requirements for individual tissues and, simultaneously, maintain the integrity of the organism by maintaining a satisfactory perfusion pressure or blood pressure. This intravascular shunting appears to be accomplished through a complex interaction between local vasodilator and central vasoconstrictor influences acting on the basal myogenic tone of vascular smooth muscle. The effects of local vasodilator influences were described as interactions among "nonspecific" vasodilator materials rather than a single vasodilator substance.= Finally, examples of the competition between local and neurogenic influences for control of vascular resistance was shown and related to physiologic and pathologic situations that invoke simultaneously an increase in the concentrations of local vasodilator factors, as well as increased sympathetic vasoconstrictor nerve activity. Attempts were also made to illustrate the relative potencies of local vasodilator and central vasoconstrictor factors. While central factors may overcome the powerful local vasodilator substances for a brief period of time, it was concluded that at least in skeletal muscle, the largest mass of tissue in the body, local vasodilator metabolites, will ultimately gain control of resistance These considerations were briefly integrated into the physiologic setting of muscular exercise and the clinical situation of shock in which
CHEST, VOL. 61, NO. 2, FEBRUARY 1972 SUPPLEMENT
14TH ANNUAL ASPEN CONFERENCE ON RESEARCH IN EMPHYSEMA
14s
there occurs simultaneously a large increase in sympathetic vasoconstrictor nerve activity and increased production of local vasodilator metabolites.
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1 DiGirolamo M, Hanley HG, Sachs RG, et al: Relationship of adipose tissue blood flow to fat cell size and number. Amer J Physiol220:932-937, 1971 2 Mellander S, Johansson B: Control of resistance, exchange and capacitance functions in the peripheral circulation. Pharmacological Rev 20: 117-196, 1968 3 Skinner NS Jr, Powell WJ: Action of oxygen and potassium
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on vascular resistance in dog skeletal muscle. Amer. J Physiol 212 :533-540, 1967 Skinner NS Jr, Costin JC: Tissue metabolites and regulation of local blood flow. Fed Proc 27: 1426-1429, 1968 Skinner NS Jr, Costin JC: Interactions between oxygen, potassium and osmolality in regulation of skeletal muscle blood flow. Circulation Res 28(Suppl.l):73-85, 1971 Skinner NS Jr, Costin JC: Role of & and K+ in abolition of sympathetic va~oconstriction in dog skeletal muscle. Amer J Physiol217:438-444,1969 Costin JC, Skinner NS Jr: Competition between vasoconstrictor and vasodilator mechanisms in skeletal muscle. Amer J Physiol220:462-466, 1971
Effect of Hemoglobin Little Rock on the Physiology of Oxygen Delivery* P. A. Bromberg, M . D.; F . Padillu, M . D.; I. T . Guy and S. P . Balcerzak, M.D."
ncreased blood affinity was found in an Ipercent. asymptomatic 55-year-old man with a Hct of 70 An abnormal hemoglobin was found which 0 2
had greater cathodal mobility than Hb A on agar gel electrophoresis at pH 6.0, but did not separate from Hb A on starch gel electrophoresis at pH 7.0, 7.7 and 8.6. Hb Little Rock was heat stable and normally sensitive to alkali. The p-Little Rock chain is abnormal as indicated by its separation from PA on CMC chromatography of whole hemolysate treated with p-chloromecuribenzoate so as to dissociate the a and p chains. The 0 2 equilibrium of red cells suspended in phosphate buffer at 37OC showed a log of P5002 of 1.03 at pH 7.40 (normal 1.34-1.40), normal Bohr effect, and an "n" value of 1.6. At 0 2 saturations < 20 percent or > 80 percent, however, "n" approached 2.5. The log P5002 of cells depleted of DPG and ATP by an in vitro incubation procedure was 0.80 (normal 1.041.07). The in viuo effects of Hb Little Rock on oxygen delivery were assessed by measuring red cell mass - 51 mllkg; plasma volume - 35 ml/kg; plasma iron turnover-two times normal; urine erythropoietin-high normal; red cell DPG-12.2 pM/g Hb (normal 11.9-18.0); red cell ATP-3.7 pM/g Hb 'From the Ohio State University, Columbus and University of Arkansas, Little Rock.
(normal 3.7-4.6); cardiac output supine at rest (Voe 0.247 L/min) -7.2 L/min and during exercise (Voz 1.015 L/min) - 10.1 L/min. At rest, mixed venous Po2 was 36 mm Hg, pH 7.38 and 0 2 saturation 86 percent. Arterial Po2 was 86 mm with a measured 0 2 saturation of 99 percent. During exercise, mixed venous PO:! was 26 mm, pH 7.30 and 0 2 saturation 66 percent. Arterial Po2 was 86 mm with measured 0 2 saturation 99 percent. Mean pulmonary artery pressure at rest was 16 mm Hg and rose during exercise to 35 rnrn Hg. Following phlebotomies totalling 1000 ml blood, urine erythropoietin increased to supranormal levels. These studies describe a new Hb with an abnormal p-chain, not detectable by electrophoresis at pH 8.6, and causing increased blood 0 2 affinity with unusual "n" values and apparently normal interaction with organic phosphates. Adaptation to Hb Little Rock's functional abnormality is achieved by a marked increase in red cell mass mediated by erythropoietin. Although compensation is not quite complete (low mixed venous Po2 values), red cell generation of DPG and ATP is not stimulated, presumably because of high blood 0 2 saturation. This study emphasizes that adaptation to tissue hypoxia is not stereotyped and is modi6ed by the disease process producing the defect in oxygen delivery.
CHEST, VOL. 61, NO. 2, FEBRUARY 1972 SUPPLEMENT
13s
body needs for gas exchange of both Coo and 0 2 . The response to hypoxia is therefore compromised by the associated effect of respiratory alkalosis on o2 cardiac output does not appear to respond to hypoxia until other compensatory mechanisms have failed. Collectively these various responses when capable of reacting provide an inkgrated defense against hypoxia.
Blood Flow Regulation as a Factor in Regulation of Tissue
0
2
Delivery
N . Sheldon Skinner, Jr., M.D.' hile the amount of 0 2 delivered to any tissue depends upon a variety of factors, the 0 2 content of blood and blood flow to tissues are prime determinants of 0 2 delivery. This presentation concentrated only on some facets of blood flow regulation. As a general rule, the vascular dimensions of various tissues are tailored to allow a blood flow that will meet the maximal metabolic requirements of that tissue. Exceptions to this rule are frequent. For example, skeletal muscle, a tissue with an enormous ability to increase its level of metabolism (ie, increase 0 2 uptake from a resting value of 0.15 to 12-16 m11100 g of tissuelmin) appears to have a vascular bed that is underdimensioned relative to its maximal metabolic requirements. Some compensation is offered through the relatively high anaerobic metabolic potential of skeletal muscle. In contrast, the cutaneous bed and the kidney, both of which subserve specific physiologic functions (ie, temperature control and fluid balance) have vascular beds with dimensions that allow for a blood flow far in excess of that needed to meet their maximal metabolic requirements. Hence, these tissue have an overdimensioned vasculature. These vascular dimensions would also appear to be influenced by large changes in cell size and cell number per unit of tissue such as exists in subcutaneous adipose tissue.' Further consideration of specific tissue blood flow reveals that a discrepancy exists between maximal cardiac pump capacity and potential maximal blood flow demands of all of the tissues; ie, the vasculature of all the tissues appears to be overdimensioned relative to the maximum cardiac output that we a ~ h i e v e d .It~ appears that if the vascular bed of all tissues were maximally vasodilated, the amount of blood flow that would be required to 'From the Division of Clinical Physiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
sustain a normal blood pressure of approximately 100 mm Hg would be in the range of 40 to 50 Llmin. In contrast, the maximal cardiac pump capacity is approximately 25 Llmin. These considerations indicate that the responsibility for adjusting the distribution of the cardiac output rests largely on peripheral vascular mechanisms. As such, intravascular shunting becomes an important mechanism whereby the distribution of cardiac output can be manipulated to best satisfy blood flow requirements for individual tissues and, simultaneously, maintain the integrity of the organism by maintaining a satisfactory perfusion pressure or blood pressure. This intravascular shunting appears to be accomplished through a complex interaction between local vasodilator and central vasoconstrictor influences acting on the basal myogenic tone of vascular smooth muscle. The effects of local vasodilator influences were described as interactions among "nonspecific" vasodilator materials rather than a single vasodilator substance.= Finally, examples of the competition between local and neurogenic influences for control of vascular resistance was shown and related to physiologic and pathologic situations that invoke simultaneously an increase in the concentrations of local vasodilator factors, as well as increased sympathetic vasoconstrictor nerve activity. Attempts were also made to illustrate the relative potencies of local vasodilator and central vasoconstrictor factors. While central factors may overcome the powerful local vasodilator substances for a brief period of time, it was concluded that at least in skeletal muscle, the largest mass of tissue in the body, local vasodilator metabolites, will ultimately gain control of resistance These considerations were briefly integrated into the physiologic setting of muscular exercise and the clinical situation of shock in which
CHEST, VOL. 61, NO. 2, FEBRUARY 1972 SUPPLEMENT
14TH ANNUAL ASPEN CONFERENCE ON RESEARCH IN EMPHYSEMA
14s
there occurs simultaneously a large increase in sympathetic vasoconstrictor nerve activity and increased production of local vasodilator metabolites.
4 5
1 DiGirolamo M, Hanley HG, Sachs RG, et al: Relationship of adipose tissue blood flow to fat cell size and number. Amer J Physiol220:932-937, 1971 2 Mellander S, Johansson B: Control of resistance, exchange and capacitance functions in the peripheral circulation. Pharmacological Rev 20: 117-196, 1968 3 Skinner NS Jr, Powell WJ: Action of oxygen and potassium
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7
on vascular resistance in dog skeletal muscle. Amer. J Physiol 212 :533-540, 1967 Skinner NS Jr, Costin JC: Tissue metabolites and regulation of local blood flow. Fed Proc 27: 1426-1429, 1968 Skinner NS Jr, Costin JC: Interactions between oxygen, potassium and osmolality in regulation of skeletal muscle blood flow. Circulation Res 28(Suppl.l):73-85, 1971 Skinner NS Jr, Costin JC: Role of & and K+ in abolition of sympathetic va~oconstriction in dog skeletal muscle. Amer J Physiol217:438-444,1969 Costin JC, Skinner NS Jr: Competition between vasoconstrictor and vasodilator mechanisms in skeletal muscle. Amer J Physiol220:462-466, 1971
Effect of Hemoglobin Little Rock on the Physiology of Oxygen Delivery* P. A. Bromberg, M . D.; F . Padillu, M . D.; I. T . Guy and S. P . Balcerzak, M.D."
ncreased blood affinity was found in an Ipercent. asymptomatic 55-year-old man with a Hct of 70 An abnormal hemoglobin was found which 0 2
had greater cathodal mobility than Hb A on agar gel electrophoresis at pH 6.0, but did not separate from Hb A on starch gel electrophoresis at pH 7.0, 7.7 and 8.6. Hb Little Rock was heat stable and normally sensitive to alkali. The p-Little Rock chain is abnormal as indicated by its separation from PA on CMC chromatography of whole hemolysate treated with p-chloromecuribenzoate so as to dissociate the a and p chains. The 0 2 equilibrium of red cells suspended in phosphate buffer at 37OC showed a log of P5002 of 1.03 at pH 7.40 (normal 1.34-1.40), normal Bohr effect, and an "n" value of 1.6. At 0 2 saturations < 20 percent or > 80 percent, however, "n" approached 2.5. The log P5002 of cells depleted of DPG and ATP by an in vitro incubation procedure was 0.80 (normal 1.041.07). The in viuo effects of Hb Little Rock on oxygen delivery were assessed by measuring red cell mass - 51 mllkg; plasma volume - 35 ml/kg; plasma iron turnover-two times normal; urine erythropoietin-high normal; red cell DPG-12.2 pM/g Hb (normal 11.9-18.0); red cell ATP-3.7 pM/g Hb 'From the Ohio State University, Columbus and University of Arkansas, Little Rock.
(normal 3.7-4.6); cardiac output supine at rest (Voe 0.247 L/min) -7.2 L/min and during exercise (Voz 1.015 L/min) - 10.1 L/min. At rest, mixed venous Po2 was 36 mm Hg, pH 7.38 and 0 2 saturation 86 percent. Arterial Po2 was 86 mm with a measured 0 2 saturation of 99 percent. During exercise, mixed venous PO:! was 26 mm, pH 7.30 and 0 2 saturation 66 percent. Arterial Po2 was 86 mm with measured 0 2 saturation 99 percent. Mean pulmonary artery pressure at rest was 16 mm Hg and rose during exercise to 35 rnrn Hg. Following phlebotomies totalling 1000 ml blood, urine erythropoietin increased to supranormal levels. These studies describe a new Hb with an abnormal p-chain, not detectable by electrophoresis at pH 8.6, and causing increased blood 0 2 affinity with unusual "n" values and apparently normal interaction with organic phosphates. Adaptation to Hb Little Rock's functional abnormality is achieved by a marked increase in red cell mass mediated by erythropoietin. Although compensation is not quite complete (low mixed venous Po2 values), red cell generation of DPG and ATP is not stimulated, presumably because of high blood 0 2 saturation. This study emphasizes that adaptation to tissue hypoxia is not stereotyped and is modi6ed by the disease process producing the defect in oxygen delivery.
CHEST, VOL. 61, NO. 2, FEBRUARY 1972 SUPPLEMENT