JOURNAL
OF SURGICAL
Effects
(1977)
of HI and H2 Histamine Antagonists on the Pulmonary Pressor Response to Alveolar Hypoxia
JOSEPH GIORDANO, Division
22, 392-397
RESEARCH
M.D.,
MICHAEL ZINNER, M.D., ANDNOREEN LYNCH
ALEXANDERGUBA,
of Surgery, Walter Reed Army Institute of Research, and Department George Washington University Hospital, Washington, D.C.
Submitted for publication
The precise mechanism that mediates the pulmonary arterial pressor response to alveolar hypoxia remains unclear. An intensive investigative effort has implicated and then discarded a variety of factors, but to date no consensus has developed suggesting a dominant role for any mechanism. Recently emphasis has been placed on humeral agents, in particular histamine, that are stored and released in the lung. The evidence supporting the hypothesis that histamine mediates the pressor response is impressive. Histamine is a potent pulmonary vasoconstrictor that is synthesized and stored in pulmonary mast cells. Aviado ef al. [I] and Haas and Bergofsky [5] reported an increase in the histamine content of blood from veins draining hypoxic lobes. Haas and Bergofsky [Sl showed that mast cells become degranulated following periods of alveolar hypoxia. Hauge and Staub [8] pretreated animals with a histamine releasing agent and prevented the pressor response. Kay et al. [lo] reported pulmonary mast cell hyperplasia in animals after prolonged exposure to air with low oxygen content. However, efforts to prevent the pressor responses with antihistamines have produced contradictory results. Susmano and Carleton [ 121 reported that chlorpheniramine, an H1 histamine antagonist, blocked the pressor response. Hauge [7] was able to abolish the response with four different H, histamine antagonists. Hales and Kazemi [6] were unable to even attenuate the
M.D.,
of Surgery,
November 9, 1976
pressor response with large doses of chlorpheniramine, findings consistent with those reported by Barer in 1963 [2] and Barer and McCurrie in 1969 [3]. These studies have used only H, histamine antagonists. The physiologic actions of histamine are due to stimulation of both H1 and Hz receptors. H, receptors have been identified in the canine pulmonary vascular system [9, 131. This study investigates the effect of H, and H, histamine antagonists on the pulmonary arterial pressor response to alveolar hypoxia. METHODS AND MATERIALS
Twenty-four adult mongrel dogs of either sex weighing approximately 25 kg were anesthetized with intravenous pentobarbital (30 mg/kg). The left femoral artery was cannulated and connected to a pressure transducer (Statham, Oxnard, CaIif.) for the monitoring of arterial blood pressure. The right femoral artery was isolated and a noncannulating transducer (In Vivo Metric Systems, Los Angeles, Calif.) of a gated sine wave electromagnetic flowmeter (Biotronex Laboratory, Silver Spring, Md.) was placed on it. A branch of the right femoral artery distal to the flow probe was cannulated with PE 90 tubing (Clay Adams, Parsippany, N.J.). A Swan Ganz catheter with a thermistor probe (Edwards Laboratory, Santa Ana, Calif.) was inserted through the external jugular vein and positioned in the pulmonary artery for the 392
Copyright 0 1977 by Academic Press, Inc. AII rights of reproduction in any form reserved.
ISSN 0022-48Q4
GIORDANO
ET AL. : HISTAMINE
AND PULMONARY
PRESSOR RESPONSE
393
40-
-I -! A 252 g,'
20-
8 0 15d a-" IO -
5-
CONTROL
BENADRYL
METIAMIDE
BENADRYL METIAMIDE
FIG. 1. Percentage of pulmonary blood flow to the left lower lobe (LLL) during ventilation of the left lung with 100% 0, (open bars) and with 5% 0, (shaded bars). The effects of the histamine antagonists on the pressor response to alveolar hypoxia are compared to the control response. Values are expressed as means k SEM.
measurement of pulmonary arterial and wedge pressures. Cardiac output was determined by the thermal dilution technique (Columbus Instruments, Columbus, Ohio). These data were collected on a multichannel recorder (Sanborn, Waltham, Mass.). A double lumen endotracheal tube was positioned through a tracheotomy to ventilate right and left lungs separately. The inflated balloon of the tube to the left lung obstructed the orifice of the left apical and cardiac lobes. During the two test periods, ventilation of the left lung was to the left lower lobe only. Dead space of 100 cc was added to each lumen of the endotracheal tube and both lumens were connected to a dual constant volume respirator. The animals were ventilated with a tidal volume of 25 cc/kg. The left lung received 40% and the right lung 60% of this volume. The aterial pC0, was maintained at approximately 35 mm Hg by varying the respiratory rate from 18 to 24 per minute. Samples of gas were taken during inspiration from each endotracheal
tube to verify the 0, content delivered to each lung. Radioactively tagged microspheres (Tracer Microspheres Nuclear Products, 3M Company, St. Paul, Minn.) were injected into the right atrium for determination of the distribution of pulmonary blood flow. Microspheres of two different energy levels were used so that pulmonary blood flow distribution could be determined at two different times in the same animal. In all animals, the balloons of the endotracheal tube were inflated and the left lower lobe and the right lung were ventilated with 100% 0,. The hemodynamic measurements were recorded and 141Ce tagged microspheres were injected into the right atrium to determine pulmonary blood flow distribution (Period 1). The animals were then divided into four groups. In Group 1 (control, n = 6), the left lower lobe was ventilated with 5% O,-95% NP, the right lung with 100% 0, and 51Cr tagged microspheres were injected into the right atrium to document the distribution of pulmonary blood flow. In the remain-
394
JOURNAL
OF SURGICAL
RESEARCH:
ing 18 animals, histamine (1O-3 to 10-l pg/kg) was injected into the right femoral artery and the femoral arterial blood flow was recorded. Diphenhydramine hydrochloride (5 mg/kg; Benadryl, Parke, Davis & Company, Detroit, Mich.) (Group 2, n = 6), Metiamide (7.5 mg/kg) (Group 3, n = 6), and both drugs (Group 4, n = 6) were injected intravenously. Fifteen minutes later the histamine injections .into the femoral artery were repeated and the attenuated responses of femoral arterial blood flow verified effective histamine block. The animals were then ventilated exactly as in the control group (Period 2) and YJr tagged microspheres were injected into the right atrium. The animals were sacrificed and the lungs were removed. The left lung was separated into three regions, corresponding to its anatomical lobes: apical, cardiac, and lower or diaphragmatic lobes. The right lung was separated into three regions: apical lobe, cardiac and intermediate lobes, and diaphragmatic or lower lobe. Sections of the heart were also taken. Tissue sections comprising the entire lung were then counted in a gamma well scintillation counter (Packard Instruments, Downers Grove, Ill.). The results of the scintillation counting were processed through a CDC 3500 computer in an existing program to calculate pulmonary blood flow distribution.
The radioactive counts in the heart sections were not above background, verifying that all the microspheres were trapped in the lung. The distribution of pulmonary blood flow was then determined by dividing the radioactive counts in each lobe by the total counts in the lung. The distribution of pulmonary blood flow in the left lower lobe was compared during the hypoxic and nonhypoxic periods. Significance was assessed by the t test for paired data. RESULTS
In the control group, the left lower lobe received 32.20 2 2.4% of the pulmonary blood flow during Period 1. Ventilation with 5% O2 (Period 2) reduced the proportion of pulmonary blood flow to 24.30 + 2.7%, approximately a 25% reduction from Period 1. Benadryl (Group 2), Metiamide (Group 3), and both drugs (Group 4) did not change the response to alveolar hypoxia. In Group 2, the proportion of pulmonary blood flow to the left lower lobe decreased from 30.08 + 1.8 to 22.4 -t 2.5, in Group 3 from 31.05 + 1.5 to 20.75 2 1.5, and in Group 4 from 32.99 & 1.0 to 21.98 + 1.8. In all four groups, the decrease in the distribution of pulmonary blood flow was significant (P < O.OOl), but the magnitude of the decrease was the same. These data are illustrated in Fig. 1 and the distribution pattern for the entire lung is summarized in Table 1.
TABLE REGIONAL
DISTRIBUTION
Control Period
L apical L cardiac L lower R apical R cardiac and intermediate
R lower
II t t f e
0.8 0.5 2.4 I.1
14.61 2 0.9 26.22 2 I.4
1
OF PULMONARY
BLOOD
7.57 4.11 24.30 16.38
II
I k ? k +
I.5 0.9 2.7 1.4
17.04 2 I.5 30.50 r 0.9
e Values are the percentage of total pulmonary lung ventilated with 100% 02, left apical and cardnc of the lung was ventilated as in Period I.
6.75 4.25 30.08 14.56
f 2 + k
1.0 0.4 I.8 2.1
16.54 C I.6 27.83 + 0.6 blood lobes
FLOWS Benadryl and metiamide
Metmmlde
Benadryl
I 8.53 4.94 32.20 13.50
VOL. 22, NO. 4, APRIL 1977
7.02 4.85 22.24 16.87
I k 2 + k
1.2 0.3 2.5 2.3
19.09 + 2.3 29.94 z I.5
6.59 3.69 31.05 15.81
II * ? 2 *
0.7 0.4 1.5 1.0
14.23 2 I.2 2X.96 k 1.0
3.89 2.89 20.75 IX.31
I k 2 + 2
0.5 0.5 1.5 0.5
17.59 f I.1 36.57 ? 2.2
5.25 3.56 32.99 17.13
II + 0.9 t 0.9 -+ 1.0 t 1.0
14.67 ? 1.0 26.39 -c I.1
4.53 2.44 21.9x IX. 19
r i 2 2
0.7 0.4 1.x 3.3
18.40 * 1.7 34.44 2 2.9
flow in each lung region expressed as means c SEM. I. left lower lobe and right were not ventilated; II. left lower lobe was ventdated wtth 54 0, and the remainder
GIORDANO
AL.: HISTAMINE
ET
AND
PULMONARY
TABLE
PRESSOR
395
RESPONSE
2
HEMODYNAMICANDBLOODGASDATA" COlltIOl
Benadryl
1 PA pressure (mm Hg) Wedge pressure (mm Hg) Cardiac output (litersimin) Systemic arterial
II
I5 k 2
Metiamide
1
I8 ? 2
62-1
8+1
3.62 f 0.5
3.50 + 0.4
Benadryl
and m&amide
II
I
II
20 ? 2
24 -r 2
20 + 2
21 2 I
24 k 2
26 t 2
IO?
II f
II + I
IO + I
12 f I
I2 + I
4.65 -t 0.87
4.43 k 0.78
3.97 + 0.80
3.80 2 0.50
I
4.27 k 0.38
I
4.06 + 0.38
I
11
P
(mm Hg) PH PO2
PCO, Inspired 0, R lung (mm Hg) Inspired O2 LLL (mm Hg)
I48 7.342 35X 34
2 + + i
I3 .02 56 2
548 2 I6 602 + 40
142 7.317 130 38
k 2 -’ f
7 .02 I4 2
561 2 22 33 f
* Values are expressed as means t SEM. 5% 02; the right lung with 100% 0,.
I
I48 7.386 409 36
+ + * +
6 .Ol I5 I
141 7.325 I28 41
588 + 18 616 + 9 In Group
I both
+ + r +
4 .04 20 3
139 7.387 395 33
DISCUSSION
H1 and H, histamine antagonists alone or in combination failed to alter the pulmonary arterial pressor response to alveolar hypoxia. The decrease in the percentage of pulmonary blood flow to the
5 .Ol 34 I
I28 7.313 II8 38
+ k f *
4 .02 I2 2
584 f 33
551 + 19
554 2 24
30 f 2
575 ? 46
30 2 1
lungs were ventilated
Ventilation of the left lower lobe with 5% O2 did not cause hypoxemia. In each group, the hemodynamic data obtained during the hypoxic period did not change significantly from the data obtained while both lungs were being ventilated with 100% OZ. The ph and the pC0, remained in a physiologic range in both periods for all four groups. These data are summarized in Table 2. The intra-arterial injections of histamine (10e3 to 10-l /.&kg) caused a dosedependent increase in femoral arterial blood flow. Benadryl, Metiamide, and both drugs completely blocked the effects of histamine at a dose of low3 p.g/kg. At the 10e2 pg/ kg dose, Benadryl reduced the increase in flow by 92%, Metiamide by 43%, and both drugs by 100%. At the 10-l hg/ kg dose, Benadryl decreased the response to histamine by 64%, Metiamide by 22%, and both drugs by 82%.
+ f f f
on 100% 0%. In Group
147 7.385 362 36
2 + ? f
7 .02 I8 I
544 z 28 571 + IX II the LLL
145 7.332 95 39
1: + t f
4 .02 5 I
600 + 25 28 f
was ventilated
I with
hypoxic left lower lobe in the control group and its redistribution to the right lung indicate an increase in vascular resistance in the hypoxic lobe and confirm the well-known pulmonary arterial pressor response to alveolar hypoxia originally described by Liljestrand [ 111. In the groups treated with the antihistamine, a hypoxic stimulus of similar intensity caused a reduction of blood flow to the left lower lobe. The magnitude of the decrease was not different from that observed in the control group. The inability of the histamine antagonists to influence the pressor response occurred despite the demonstration of adequate blockade to intra-arterial injections of histamine. Histamine elicits a potent vasoconstrictor response in the canine pulmonary vascular system [9, 131. H1 histamine antagonists abolish this constrictor response and convert the effect of histamine to vasodilatation [9]. This designates the H, receptor site as the mediator of the vasoconstrictor response and suggests that other receptor sites are capable of vasodilatation in response to histamine. H2 histamine antagonists augment the vasoconstrictor effect of histamine, providing evidence that
396
JOURNAL
OF SURGICAL
RESEARCH:
Hz histamine receptors mediate vasodilatation in the canine pulmonary vascular system [13]. A combined H, and H, receptor blockade completely abolishes the pulmonary vascular effects of histamine [9, 131. Tucker et al. [14] reported that the H2 receptor blockade potentiated the pressor response to alveolar hypoxia. He suggested that histamine is released by the hypoxic lung, stimulates the H2 receptors, and therefore actually opposes the pressor response. Our study did not confirm these findings. The H, receptor blockade either alone or in combination with H, antagonists did not significantly change the degree of vasoconstrictor response to alveolar hypoxia. The results of this study are similar to the report of Hales and Kazemi [6] in an experimental model similar to ours. Howard et al. [9] in 1975, Barer in 1963 [2], and Barer and McCurrie in 1969 [3] were also unable to block the hypoxic response with antihistamines. However, Hauge reported that four different antihistamines blocked the response in an isolated rat lung model. in addition to the obvious species difference, his experimental model involved denervation of the lung. Although most investigators exclude the sympathetic nervous system as the prime mechanism of the pressor response, its subtle participation cannot be ruled out [4]. Susmano and Carleton [12] reported that chlorpheniramine, an H, histamine antagonist, reversed the pulmonary arterial pressure increases associated with alveolar hypoxia. In that study, both lungs were ventilated with 8% 0, and hypoxemia occurred. Interpretation of the pulmonary hemodynamic changes becomes more difficult since hypoxemia causes well-known systemic responses that include increases in cardiac output, systemic arterial pressure and pulse rate. The question in that model is the extent to which changes in pulmonary arterial pressure are due to the systemic effects of hypoxia or to the direct
VOL. 22, NO. 4, APRIL 1977
effects of alveolar hypoxia on the pulmonary circulation. Our experimental preparation was a closed chest model and the innervation of the lungs remained intact. Hypoxemia did not develop and the pulmonary pressures, systemic arterial pressures, and cardiac output did not change from period 1 to Period 2. The increase in vascular resistance in the left lower lobe was a response only to the alveolar hypoxia of that lobe. The absence of any change in the pressor response to alveolar hypoxia following the administration of antihistamines makes it unlikely that histamine mediates that response. REFERENCES 1.
2.
3.
4.
5. 6.
Aviado, D. M., Samanek, M., and Dalle, L. F. Release of histamine during inhalation of cigarette smoke and anoxemia in the heart lung and intact dog preparation. Arch. Environ. Health 12: 705, 1966. Barer, G. R. The mechanism of the increased vascular resistance caused by hypoxemia in both collapsed and ventilated lungs. J. Physiol. (London) 167: 102, 1963. Barer, G. R., and McCurrie, J. R. Pulmonary vasomotor response in the cat; the effect and interrelationships of drugs, hypoxia and hypercapnia. Amer. J. Exp. Physiol. 54: 156, 1969. Bergofsky, E. H. Mechanism underlying vasomotor regulation of regional pulmonary blood flow in normal and disease states. Amer. J. Med. 57: 378, 1974. Haas, F., and Bergofsky, H. Role of the mast cell in the pulmonary pressor responses to hypoxia. J. Clin. Invest. 51: 3154, 1972. Hales, C. A., and Kazemi, H. Role of histamine in the hypoxia vascular response of the lung. Resp.
Physiol.
24: 81, 1975.
7. Hauge, A. Role of histamine in hypoxic pulmonary hypertension in the rat. Circ. Res. 22: 371, 1968. 8. Hauge, A., and Staub, N. Prevention of hypoxic vasoconstriction in cat lung by histamine releasing agent 48180. J. Appl. Physiol. 26: 693, 1969. 9. Howard, P., Barer, G. R., Thompson, B., Warren, P. M., Abbott, C. J., and Mungall, I. P. F. Factors causing and reversing vasoconstriction in unventilated lung respimtion. Resp. Physiol. 24: 325, 197.5. 10. Kay, J. M., Waymire, J. C., and Grover, R. F.
GIORDANO
ET AL.
: HISTAMINE
AND PULMONARY
Lung mast cell hyperplasia and pulmonary histamine forming capacity in hypoxic rats. Amer. J. Physiol. 226: 178, 1974. 11. Liljestrand, G. Regulation of pulmonary arterial blood pressure. Arch. Intern. Med. 81: 162, 1948. 12. Susmano, A., and Carleton, R. A. Prevention of hypoxic pulmonary hypertension by chlorpheniramine. J. Appl. Physiol. 31: 531, 1971.
PRESSOR RESPONSE
397
13. Tucker, A., Weir, E. K., Reeves, J. T., and Grover, R. F. Histamine H, and H, receptors in pulmonary and systemic vasculature of the dog. Amer. J. Physiol. 229: 1008, 1975. 14. Tucker, A., Weir, E. K., and Grover, R. F. Histamine release during hypoxia opposes pulmonary vasoconstriction in intact dogs. Clin. Res. 23: 118A, 1975.
OF SURGICAL
Effects
(1977)
of HI and H2 Histamine Antagonists on the Pulmonary Pressor Response to Alveolar Hypoxia
JOSEPH GIORDANO, Division
22, 392-397
RESEARCH
M.D.,
MICHAEL ZINNER, M.D., ANDNOREEN LYNCH
ALEXANDERGUBA,
of Surgery, Walter Reed Army Institute of Research, and Department George Washington University Hospital, Washington, D.C.
Submitted for publication
The precise mechanism that mediates the pulmonary arterial pressor response to alveolar hypoxia remains unclear. An intensive investigative effort has implicated and then discarded a variety of factors, but to date no consensus has developed suggesting a dominant role for any mechanism. Recently emphasis has been placed on humeral agents, in particular histamine, that are stored and released in the lung. The evidence supporting the hypothesis that histamine mediates the pressor response is impressive. Histamine is a potent pulmonary vasoconstrictor that is synthesized and stored in pulmonary mast cells. Aviado ef al. [I] and Haas and Bergofsky [5] reported an increase in the histamine content of blood from veins draining hypoxic lobes. Haas and Bergofsky [Sl showed that mast cells become degranulated following periods of alveolar hypoxia. Hauge and Staub [8] pretreated animals with a histamine releasing agent and prevented the pressor response. Kay et al. [lo] reported pulmonary mast cell hyperplasia in animals after prolonged exposure to air with low oxygen content. However, efforts to prevent the pressor responses with antihistamines have produced contradictory results. Susmano and Carleton [ 121 reported that chlorpheniramine, an H1 histamine antagonist, blocked the pressor response. Hauge [7] was able to abolish the response with four different H, histamine antagonists. Hales and Kazemi [6] were unable to even attenuate the
M.D.,
of Surgery,
November 9, 1976
pressor response with large doses of chlorpheniramine, findings consistent with those reported by Barer in 1963 [2] and Barer and McCurrie in 1969 [3]. These studies have used only H, histamine antagonists. The physiologic actions of histamine are due to stimulation of both H1 and Hz receptors. H, receptors have been identified in the canine pulmonary vascular system [9, 131. This study investigates the effect of H, and H, histamine antagonists on the pulmonary arterial pressor response to alveolar hypoxia. METHODS AND MATERIALS
Twenty-four adult mongrel dogs of either sex weighing approximately 25 kg were anesthetized with intravenous pentobarbital (30 mg/kg). The left femoral artery was cannulated and connected to a pressure transducer (Statham, Oxnard, CaIif.) for the monitoring of arterial blood pressure. The right femoral artery was isolated and a noncannulating transducer (In Vivo Metric Systems, Los Angeles, Calif.) of a gated sine wave electromagnetic flowmeter (Biotronex Laboratory, Silver Spring, Md.) was placed on it. A branch of the right femoral artery distal to the flow probe was cannulated with PE 90 tubing (Clay Adams, Parsippany, N.J.). A Swan Ganz catheter with a thermistor probe (Edwards Laboratory, Santa Ana, Calif.) was inserted through the external jugular vein and positioned in the pulmonary artery for the 392
Copyright 0 1977 by Academic Press, Inc. AII rights of reproduction in any form reserved.
ISSN 0022-48Q4
GIORDANO
ET AL. : HISTAMINE
AND PULMONARY
PRESSOR RESPONSE
393
40-
-I -! A 252 g,'
20-
8 0 15d a-" IO -
5-
CONTROL
BENADRYL
METIAMIDE
BENADRYL METIAMIDE
FIG. 1. Percentage of pulmonary blood flow to the left lower lobe (LLL) during ventilation of the left lung with 100% 0, (open bars) and with 5% 0, (shaded bars). The effects of the histamine antagonists on the pressor response to alveolar hypoxia are compared to the control response. Values are expressed as means k SEM.
measurement of pulmonary arterial and wedge pressures. Cardiac output was determined by the thermal dilution technique (Columbus Instruments, Columbus, Ohio). These data were collected on a multichannel recorder (Sanborn, Waltham, Mass.). A double lumen endotracheal tube was positioned through a tracheotomy to ventilate right and left lungs separately. The inflated balloon of the tube to the left lung obstructed the orifice of the left apical and cardiac lobes. During the two test periods, ventilation of the left lung was to the left lower lobe only. Dead space of 100 cc was added to each lumen of the endotracheal tube and both lumens were connected to a dual constant volume respirator. The animals were ventilated with a tidal volume of 25 cc/kg. The left lung received 40% and the right lung 60% of this volume. The aterial pC0, was maintained at approximately 35 mm Hg by varying the respiratory rate from 18 to 24 per minute. Samples of gas were taken during inspiration from each endotracheal
tube to verify the 0, content delivered to each lung. Radioactively tagged microspheres (Tracer Microspheres Nuclear Products, 3M Company, St. Paul, Minn.) were injected into the right atrium for determination of the distribution of pulmonary blood flow. Microspheres of two different energy levels were used so that pulmonary blood flow distribution could be determined at two different times in the same animal. In all animals, the balloons of the endotracheal tube were inflated and the left lower lobe and the right lung were ventilated with 100% 0,. The hemodynamic measurements were recorded and 141Ce tagged microspheres were injected into the right atrium to determine pulmonary blood flow distribution (Period 1). The animals were then divided into four groups. In Group 1 (control, n = 6), the left lower lobe was ventilated with 5% O,-95% NP, the right lung with 100% 0, and 51Cr tagged microspheres were injected into the right atrium to document the distribution of pulmonary blood flow. In the remain-
394
JOURNAL
OF SURGICAL
RESEARCH:
ing 18 animals, histamine (1O-3 to 10-l pg/kg) was injected into the right femoral artery and the femoral arterial blood flow was recorded. Diphenhydramine hydrochloride (5 mg/kg; Benadryl, Parke, Davis & Company, Detroit, Mich.) (Group 2, n = 6), Metiamide (7.5 mg/kg) (Group 3, n = 6), and both drugs (Group 4, n = 6) were injected intravenously. Fifteen minutes later the histamine injections .into the femoral artery were repeated and the attenuated responses of femoral arterial blood flow verified effective histamine block. The animals were then ventilated exactly as in the control group (Period 2) and YJr tagged microspheres were injected into the right atrium. The animals were sacrificed and the lungs were removed. The left lung was separated into three regions, corresponding to its anatomical lobes: apical, cardiac, and lower or diaphragmatic lobes. The right lung was separated into three regions: apical lobe, cardiac and intermediate lobes, and diaphragmatic or lower lobe. Sections of the heart were also taken. Tissue sections comprising the entire lung were then counted in a gamma well scintillation counter (Packard Instruments, Downers Grove, Ill.). The results of the scintillation counting were processed through a CDC 3500 computer in an existing program to calculate pulmonary blood flow distribution.
The radioactive counts in the heart sections were not above background, verifying that all the microspheres were trapped in the lung. The distribution of pulmonary blood flow was then determined by dividing the radioactive counts in each lobe by the total counts in the lung. The distribution of pulmonary blood flow in the left lower lobe was compared during the hypoxic and nonhypoxic periods. Significance was assessed by the t test for paired data. RESULTS
In the control group, the left lower lobe received 32.20 2 2.4% of the pulmonary blood flow during Period 1. Ventilation with 5% O2 (Period 2) reduced the proportion of pulmonary blood flow to 24.30 + 2.7%, approximately a 25% reduction from Period 1. Benadryl (Group 2), Metiamide (Group 3), and both drugs (Group 4) did not change the response to alveolar hypoxia. In Group 2, the proportion of pulmonary blood flow to the left lower lobe decreased from 30.08 + 1.8 to 22.4 -t 2.5, in Group 3 from 31.05 + 1.5 to 20.75 2 1.5, and in Group 4 from 32.99 & 1.0 to 21.98 + 1.8. In all four groups, the decrease in the distribution of pulmonary blood flow was significant (P < O.OOl), but the magnitude of the decrease was the same. These data are illustrated in Fig. 1 and the distribution pattern for the entire lung is summarized in Table 1.
TABLE REGIONAL
DISTRIBUTION
Control Period
L apical L cardiac L lower R apical R cardiac and intermediate
R lower
II t t f e
0.8 0.5 2.4 I.1
14.61 2 0.9 26.22 2 I.4
1
OF PULMONARY
BLOOD
7.57 4.11 24.30 16.38
II
I k ? k +
I.5 0.9 2.7 1.4
17.04 2 I.5 30.50 r 0.9
e Values are the percentage of total pulmonary lung ventilated with 100% 02, left apical and cardnc of the lung was ventilated as in Period I.
6.75 4.25 30.08 14.56
f 2 + k
1.0 0.4 I.8 2.1
16.54 C I.6 27.83 + 0.6 blood lobes
FLOWS Benadryl and metiamide
Metmmlde
Benadryl
I 8.53 4.94 32.20 13.50
VOL. 22, NO. 4, APRIL 1977
7.02 4.85 22.24 16.87
I k 2 + k
1.2 0.3 2.5 2.3
19.09 + 2.3 29.94 z I.5
6.59 3.69 31.05 15.81
II * ? 2 *
0.7 0.4 1.5 1.0
14.23 2 I.2 2X.96 k 1.0
3.89 2.89 20.75 IX.31
I k 2 + 2
0.5 0.5 1.5 0.5
17.59 f I.1 36.57 ? 2.2
5.25 3.56 32.99 17.13
II + 0.9 t 0.9 -+ 1.0 t 1.0
14.67 ? 1.0 26.39 -c I.1
4.53 2.44 21.9x IX. 19
r i 2 2
0.7 0.4 1.x 3.3
18.40 * 1.7 34.44 2 2.9
flow in each lung region expressed as means c SEM. I. left lower lobe and right were not ventilated; II. left lower lobe was ventdated wtth 54 0, and the remainder
GIORDANO
AL.: HISTAMINE
ET
AND
PULMONARY
TABLE
PRESSOR
395
RESPONSE
2
HEMODYNAMICANDBLOODGASDATA" COlltIOl
Benadryl
1 PA pressure (mm Hg) Wedge pressure (mm Hg) Cardiac output (litersimin) Systemic arterial
II
I5 k 2
Metiamide
1
I8 ? 2
62-1
8+1
3.62 f 0.5
3.50 + 0.4
Benadryl
and m&amide
II
I
II
20 ? 2
24 -r 2
20 + 2
21 2 I
24 k 2
26 t 2
IO?
II f
II + I
IO + I
12 f I
I2 + I
4.65 -t 0.87
4.43 k 0.78
3.97 + 0.80
3.80 2 0.50
I
4.27 k 0.38
I
4.06 + 0.38
I
11
P
(mm Hg) PH PO2
PCO, Inspired 0, R lung (mm Hg) Inspired O2 LLL (mm Hg)
I48 7.342 35X 34
2 + + i
I3 .02 56 2
548 2 I6 602 + 40
142 7.317 130 38
k 2 -’ f
7 .02 I4 2
561 2 22 33 f
* Values are expressed as means t SEM. 5% 02; the right lung with 100% 0,.
I
I48 7.386 409 36
+ + * +
6 .Ol I5 I
141 7.325 I28 41
588 + 18 616 + 9 In Group
I both
+ + r +
4 .04 20 3
139 7.387 395 33
DISCUSSION
H1 and H, histamine antagonists alone or in combination failed to alter the pulmonary arterial pressor response to alveolar hypoxia. The decrease in the percentage of pulmonary blood flow to the
5 .Ol 34 I
I28 7.313 II8 38
+ k f *
4 .02 I2 2
584 f 33
551 + 19
554 2 24
30 f 2
575 ? 46
30 2 1
lungs were ventilated
Ventilation of the left lower lobe with 5% O2 did not cause hypoxemia. In each group, the hemodynamic data obtained during the hypoxic period did not change significantly from the data obtained while both lungs were being ventilated with 100% OZ. The ph and the pC0, remained in a physiologic range in both periods for all four groups. These data are summarized in Table 2. The intra-arterial injections of histamine (10e3 to 10-l /.&kg) caused a dosedependent increase in femoral arterial blood flow. Benadryl, Metiamide, and both drugs completely blocked the effects of histamine at a dose of low3 p.g/kg. At the 10e2 pg/ kg dose, Benadryl reduced the increase in flow by 92%, Metiamide by 43%, and both drugs by 100%. At the 10-l hg/ kg dose, Benadryl decreased the response to histamine by 64%, Metiamide by 22%, and both drugs by 82%.
+ f f f
on 100% 0%. In Group
147 7.385 362 36
2 + ? f
7 .02 I8 I
544 z 28 571 + IX II the LLL
145 7.332 95 39
1: + t f
4 .02 5 I
600 + 25 28 f
was ventilated
I with
hypoxic left lower lobe in the control group and its redistribution to the right lung indicate an increase in vascular resistance in the hypoxic lobe and confirm the well-known pulmonary arterial pressor response to alveolar hypoxia originally described by Liljestrand [ 111. In the groups treated with the antihistamine, a hypoxic stimulus of similar intensity caused a reduction of blood flow to the left lower lobe. The magnitude of the decrease was not different from that observed in the control group. The inability of the histamine antagonists to influence the pressor response occurred despite the demonstration of adequate blockade to intra-arterial injections of histamine. Histamine elicits a potent vasoconstrictor response in the canine pulmonary vascular system [9, 131. H1 histamine antagonists abolish this constrictor response and convert the effect of histamine to vasodilatation [9]. This designates the H, receptor site as the mediator of the vasoconstrictor response and suggests that other receptor sites are capable of vasodilatation in response to histamine. H2 histamine antagonists augment the vasoconstrictor effect of histamine, providing evidence that
396
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Hz histamine receptors mediate vasodilatation in the canine pulmonary vascular system [13]. A combined H, and H, receptor blockade completely abolishes the pulmonary vascular effects of histamine [9, 131. Tucker et al. [14] reported that the H2 receptor blockade potentiated the pressor response to alveolar hypoxia. He suggested that histamine is released by the hypoxic lung, stimulates the H2 receptors, and therefore actually opposes the pressor response. Our study did not confirm these findings. The H, receptor blockade either alone or in combination with H, antagonists did not significantly change the degree of vasoconstrictor response to alveolar hypoxia. The results of this study are similar to the report of Hales and Kazemi [6] in an experimental model similar to ours. Howard et al. [9] in 1975, Barer in 1963 [2], and Barer and McCurrie in 1969 [3] were also unable to block the hypoxic response with antihistamines. However, Hauge reported that four different antihistamines blocked the response in an isolated rat lung model. in addition to the obvious species difference, his experimental model involved denervation of the lung. Although most investigators exclude the sympathetic nervous system as the prime mechanism of the pressor response, its subtle participation cannot be ruled out [4]. Susmano and Carleton [12] reported that chlorpheniramine, an H, histamine antagonist, reversed the pulmonary arterial pressure increases associated with alveolar hypoxia. In that study, both lungs were ventilated with 8% 0, and hypoxemia occurred. Interpretation of the pulmonary hemodynamic changes becomes more difficult since hypoxemia causes well-known systemic responses that include increases in cardiac output, systemic arterial pressure and pulse rate. The question in that model is the extent to which changes in pulmonary arterial pressure are due to the systemic effects of hypoxia or to the direct
VOL. 22, NO. 4, APRIL 1977
effects of alveolar hypoxia on the pulmonary circulation. Our experimental preparation was a closed chest model and the innervation of the lungs remained intact. Hypoxemia did not develop and the pulmonary pressures, systemic arterial pressures, and cardiac output did not change from period 1 to Period 2. The increase in vascular resistance in the left lower lobe was a response only to the alveolar hypoxia of that lobe. The absence of any change in the pressor response to alveolar hypoxia following the administration of antihistamines makes it unlikely that histamine mediates that response. REFERENCES 1.
2.
3.
4.
5. 6.
Aviado, D. M., Samanek, M., and Dalle, L. F. Release of histamine during inhalation of cigarette smoke and anoxemia in the heart lung and intact dog preparation. Arch. Environ. Health 12: 705, 1966. Barer, G. R. The mechanism of the increased vascular resistance caused by hypoxemia in both collapsed and ventilated lungs. J. Physiol. (London) 167: 102, 1963. Barer, G. R., and McCurrie, J. R. Pulmonary vasomotor response in the cat; the effect and interrelationships of drugs, hypoxia and hypercapnia. Amer. J. Exp. Physiol. 54: 156, 1969. Bergofsky, E. H. Mechanism underlying vasomotor regulation of regional pulmonary blood flow in normal and disease states. Amer. J. Med. 57: 378, 1974. Haas, F., and Bergofsky, H. Role of the mast cell in the pulmonary pressor responses to hypoxia. J. Clin. Invest. 51: 3154, 1972. Hales, C. A., and Kazemi, H. Role of histamine in the hypoxia vascular response of the lung. Resp.
Physiol.
24: 81, 1975.
7. Hauge, A. Role of histamine in hypoxic pulmonary hypertension in the rat. Circ. Res. 22: 371, 1968. 8. Hauge, A., and Staub, N. Prevention of hypoxic vasoconstriction in cat lung by histamine releasing agent 48180. J. Appl. Physiol. 26: 693, 1969. 9. Howard, P., Barer, G. R., Thompson, B., Warren, P. M., Abbott, C. J., and Mungall, I. P. F. Factors causing and reversing vasoconstriction in unventilated lung respimtion. Resp. Physiol. 24: 325, 197.5. 10. Kay, J. M., Waymire, J. C., and Grover, R. F.
GIORDANO
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AND PULMONARY
Lung mast cell hyperplasia and pulmonary histamine forming capacity in hypoxic rats. Amer. J. Physiol. 226: 178, 1974. 11. Liljestrand, G. Regulation of pulmonary arterial blood pressure. Arch. Intern. Med. 81: 162, 1948. 12. Susmano, A., and Carleton, R. A. Prevention of hypoxic pulmonary hypertension by chlorpheniramine. J. Appl. Physiol. 31: 531, 1971.
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13. Tucker, A., Weir, E. K., Reeves, J. T., and Grover, R. F. Histamine H, and H, receptors in pulmonary and systemic vasculature of the dog. Amer. J. Physiol. 229: 1008, 1975. 14. Tucker, A., Weir, E. K., and Grover, R. F. Histamine release during hypoxia opposes pulmonary vasoconstriction in intact dogs. Clin. Res. 23: 118A, 1975.
