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Effect of antihistaminic drugs on hypoxic pulmonary hypertension
EXPERIMENTAL STUDIES
Effect of Antihistaminic Drugs on Hypoxic Pulmonary
ARMANDO RICHARD
SUSMANO. MD A. CARLETON, MD,
FACC
Chicago, Illinois
From the Section of Cardio-Respiratory Diseases, Department of Medicine, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, III. This work was supported in part by U. S. Public Health Service Training Grant HE 05714 from the National Heart and Lung Institute of the National Institutes of Health. Manuscript received May 26. 1972; revised manuscript received November 11, 1972. accepted December 11,1972. Address for reprints: Armando Susmano. MD, Rush-Presbiterian-St. Luke’s Medical Center, 1753 W. Congress Parkway, Chicago, III. 60612.
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During exposure to 8 percent oxygen inhalation, 18 dogs experienced an average increase of 5.4 mm Hg in mean pulmonary arterial pressure. The administration of promethazine and chlorpheniramine during an initial exposure to hypoxia significantly decreased the pulmonary hypoxic pressor response; the administration of diphenhydramine did not. However, these 3 antihistaminic agents prevented the development of pulmonary hypertension during a second exposure to hypoxia (P = 0.3 X lo- 6). Five dogs received progressive doses of chlorpheniramine, thus showing thai the effectiveness of this drug can be demonstrated at a dose of less than 0.3 mg/kg body weight. The amounts of diphenhydramine and promethazine needed to achieve effectiveness equivalent to that of chlorpheniramine are sufficiently great as to restrict their applicability to man in acceptable doses. This study lends further support to the hypothesis that histamine mediates hypoxic pulmonary hypertension.
The biochemical mediation of pulmonary hypertension induced by hypoxia has been unclear for many years. The work of Hauge et al:‘+2 in isolat.ed rat or cat lungs lent support to the hypothesis that histamine may be this mediator. Subsequently, work conducted in our laboratory”.4 lent strong support to this hypothesis by demonstrating that chlorpheniramine (Chlor-Trimeton@) abolished pulmonary hypertension induced by hypoxia and prevented the appearance of pulmonary hypertension with the institution of hypoxia. However, in that study. 2 other antihistaminic agents failed to abolish the pulmonary vascular pressor response to hypoxia. This paradox led to the present studies. to determine whether the antihistaminic properties of chlorpheniramine were those being demonstrated in the prevention or inhibition of hypoxic pulmonary hypertension or whether other properties, not shared by promethazine (Phenergan@‘) and diphenhydramine (Renadryl@), were responsible for the effect. Promethazine has potent antiserotonin properties5 in addition to antihistaminic effects. Diphenhydramine also possesses other pharmacologic effects in addition to its antihistaminic activity.” Conversely, chlorpheniramine has relatively pure antihistaminic effects. Thus, in testing the hypothesis that histamine mediates hypoxic pulmonary hypertension, it became important to determine whether diphenhydramine and promethazine, with their antihistaminic properties, lack the ability to prevent hypoxic pulmonary hypertension or whether an insufficient dose had been utilized in the previous study. Accordingly, we tested the reaction of the pulmonary vascular bed to hypoxia in the presence of differing amounts of the 3 antihistaminic agents. Material
and Methods
‘I’wenty-three mongrel dogs of both sexes (weight range 11.2 to 24.2 kg; mean 17.6) were divided into 1 group of 5 dogs and 3 groups of 6 dogs. Each
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dog was anesthetized
with a mixture of 6.0 mg/kg body weight of droperidol and 0.12 mg/kg body weight of fentanyl (Innovar-Vet, McNeil Laboratories, Fort Washington, Pa.). Small supplemental doses were administered as necessary. Atropine sulfate was also given in a dose of 0.4 mg. Each dog had a cuffed endotracheal tube inserted to ensure a leak-free means of administering a hypoxic gas mixture. A no. 7F catheter was placed in the thoracic aorta from the femoral artery. The distal lumen of a no. 8F double-lumen catheter was placed in a pulmonary arterial wedge position; the proximal lumen was in the main pulmonary artery. Pressures were recorded at a paper speed of 10 mm/set by use of Statham P23Db strain gauges and the carrier amplifiers of an oscillographic recorder (Hewlett-Packard recorder model 7712B). Mean pressure values were obtained by electronic damping. Cardiac output was calculated by the Hamilton methodr after the injection of 2.5 mg of indocyanine green dye into the pulmonary artery and withdrawal of aortic blood through a densitometer (Gilford densitometer, model 1031R). Systemic and pulmonary vascular resistance levels were calculated in the centimeter-gram-second system using the mean aortic and the mean pulmonary arterial minus pulmonary arterial wedge pressure values, respectively. Spontaneous respiration through the cuffed endotracheal tube was permitted throughout. The inspired gas mixture was changed at will from room air to a reservoir containing a mixture of 8 percent oxygen and 92 percent nitrogen, A l-way valve prevented rebreathing and accumulation of carbon dioxide. Each set of measurements included measurement of cardiac output, heart rate, pulmonary arterial and pulmonary arterial wedge pressure, aortic pressure and arterial pH, POz and PC02 (Instrumentation Laboratories, blood gas analyzer, model 113, Boston, Mass.). Procedures: The initial group (5 dogs) was studied to determine the dose-response relation of the effectiveness of chlorpheniramine in the inhibition of pulmonary hypertension. Each dog was subjected to 8 consecutive sequences of 2 minutes of hypoxia and 5 minutes of breathing room air. The first 4 trials were utilized to determine the reproducibility of the pulmonary pressor response to identical degrees of hypoxia. The second 4 trials were utilized to determine the dose-response relation of chlorpheniramine. Before the fifth trial, each dog received 5 mg of chlorpheniramine. An additional 5 mg of chlorpheniramine was given before each of the subsequent 3 exposures to hypoxia to permit measurement of the pul.nonary pressor response in the presence of 5, 10, 15 and 20 mg of chlorpheniramine (cumulative dose). The remaining 3 groups (6 dogs in each) were subjected to a similar sequence of measurements. Initial measurements were made while the dogs breathed room air. The endotracheal tube was then connected to the reservoir containing the hypoxic gas mixture. Pulmonary arterial and aortic pressures were measured at 1 minute intervals after the onset of hypoxia. All measurements were repeated after 10 minutes of stable hypoxia and pulmonary hypertension. The antihistaminic agent was then administered over 30 seconds into the main pulmonary artery while hypoxia was maintained. Each of the first group of 6 dogs received 100 mg of diphenhydramine (Benadrylq Parke, Davis & Co., Detroit, Mich.). The second group of 6 dogs each received 50 mg of promethazine (Phenergan@, Wyeth Laboratories, Philadelphia, Pa.), and the last group of 6 dogs each received 20 mg of chlorpheniramine
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(Chlor-Trimetona, Schering Corp., Bloomfield, N.J.). Pulmonary arterial and aortic pressures were then measured at 1 minute intervals. Cardiac output and the other measurements were repeated 15 minutes after the administration of the antihistaminic agent. Each dog was then permitted to breathe room air for 10 minutes. A second period of hypoxia was then begun to determine whether the previously administered antihistaminic agent would prevent the appearance of hypoxic pulmonary hypertension. Statistical analyses of the data were performed by paired comparisonss between groups. Analysis of variance was used to determine the consistency of response within and between groups and the significance of changes induced by hypoxia and those attributable to antihistamine administration. Results Effect of chlorpheniramine: The results in the initial group of dogs are illustrated in Figure 1. Each
of the 4 initial episodes of hypoxia before administration of chlorpheniramine produced significant and equivalent degrees of pulmonary hypertension, with an average increase in the mean pulmonary arterial pressure of 4.5 mm Hg. No significant differences were present among the 4 trials before antihistamine administration (P = 0.99). Although the average level of pulmonary arterial mean pressure was slightly lower after the 20 mg dose of chlorpheniramine than after the 5 mg dose, there were no significant differences (P = 0.94) in the ability of 5, 10, 15 or 20 mg (cumulative doses) to modify the appearance of hypoxic pulmonary hypertension. Thus, even relatively small doses of chlorpheniramine significantly prevented the appearance of hypoxic pulmonary hypertension (P = 0.1 X 1O-s). Comparison of diphenhydramine, promethazine and chlorpheniramine: The original values ob-
tained with the dogs breathing room air and the changes induced by hypoxia in each of the other 3 groups of dogs are summarized in Table IA (diphenhydramine), IB (promethazine) and IC (chlorpheniramine) under the “Before” column. Analysis of the changes induced by hypoxia demonstrated a highly significant decrease in arterial POz (P = 0.8 x lo-11) and PC02 (P = 0.2 X lo-*), and a significant increase in arterial pH (P = 0.1 X 10-8). There were no significant differences in these re6r MEAN
CHANGE IN
PULM
4
f
ARTERY
01
5MG %iToRoL *
IOMG
15MG
20MG
CHLORPHENIRAMINE FIGURE 1. The average changes in pulmonary arterial mean pressure 2 minutes after the onset of hypoxia are shown before chlorpheniramine administration (average of 4 consecutive hypoxic episodes) and after 5, 10. 15 and 20 mg of chlorpheniramine, respectively.
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I
Initial Values and Changes Produced by Shifting from 20.9 Percent to 8 Percent Inspired Oxygen Concentrations (Before) and Subsequent Changes Noted 15 Minutes after Antihistaminic Agent Administration During Constant Hypoxia RoomAir no.
Mean
8% Oxygen* Range
Before
After
A. Diphenhydramine Arterial POP (mm Hg) Arterial PCOz (mm Hg) Arterial pH Cardiac output (liters/min) Heart rate (beats/min) Mean PA pressure (mm Hg) Wedge pressure (mm Hg) Mean aortic pressure (mm Hg) Resistances (dyne set cm-6) Systemic Pulmonary vascular
5 6 6 5 6 6 6 6 5 5
92.3 41.2 7.32 3.37 100 11.5 3.0 106
88.4-102.5 30.9-45.5 7.25-7.37 2.59-3.77 85-125 10-14.5 1.5-5 89-134
2447
2143-3089 133-262
190
-54.7 f -13.9 f 0.13 f 0.93 k 37 i 5.4 f 0.75 i 9*8
6.3 2.6 0.005 0.61 35 2.6 0.9
-274 i 225 38 % 53
-2.9 f -1.0 i -0.03 i -0.10 III 35 f -1.7 * -0.4 * -8=t20 -2.8 -4.4
4.1 2.2 0.03 0.55 28 4.0 1.2
f 380 It 53
-___
._~~.
B. Promethazine Arterial POZ (mm Hg) Arterial PCOZ (mm Hg) Arterial pH Cardiac output (liters/min) Heart rate (beats/min) Mean PA pressure (mm Hg) Wedge pressure (mm Hg) Mean aortic pressure (mm Hg) Resistances (dyne-set-cm-6) Systemic Pulmonary vascular
6 6 6 6 6 6 6 6 6 6
85.3 41.2 7.31 3.25 108 8.5 2.9 122 3028 142
80-95 38.5-45.2 7.24-7.35 2.63-3.94 76-180 7-9.5 2-3.5 88-151
-52.2 f -14.6 i0.14 It 0.91 f 60 + 4.7 f -0.4 It 6.0+
5.0 2.8 0.02 0.9 49 2.6 0.4 8
-4.5 f -0.7 f -0.02 f 0.31 III 56 ;t -2.3 f 0.4 + -11 rt
1.3 0.6 0.02 0.59 20 1.6 0.8 11
2072-3650 91-182
-508 f 79 f
475 57
-376 i -70 f
590 41
C. Chlorpheniramine Arterial PO* (mm Hg) Arterial PCOZ (mm Hg) Arterial pH Cardiac output (liters/min) Heart rate (beats/min) Mean PA pressure (mm Hg) PA wedge pressure (mm Hg) Mean aortic pressure (mm Hg) Resistances (dyne set cm+) Systemic Pulmonary vascular PA = pulmonary arterial. * Mean change +95 percent
confidence
84 39.7 7.34 3.46 99 9.5 2.5 106 5 6
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-49.4 i 6.9 -13.3 i 3.0 0.14 f 0.03 0.65 i 0.34 70 + 55 6.0 ZII 2.8 -1.5 f 2.0 2+ 13
1390-3784 131-201
-275 +I 410 126 i 218
-3.0 =!,I 2.3 1.6 f 1.8 -0.02 Zt 0.003 -0.34 f 0.39 -13 f 40 -5.7 i 3.8 1.2 f 2.3 -16 f 25 -42 f -122 *
605 114
limits of change.
sponses among the 3 groups (p = 0.13, 0.21, 0.32, respectively). The cardiac output and heart rate also increased significantly with the advent of hypoxia (P = 0.01 and P = 0.9X 10p6), again without significant differences among the 3 groups (P = 0.94). The mean aortic pressure and the total systemic resistance did not change significantly during hypoxia (P = 0.43 and 0.15, respectively). Each dog experienced at least a 1.5 mm Hg increase in the mean pulmonary arterial pressure during hypoxia. The average increase for the 3 groups of 6 dogs was 5.4 mm Hg (P = 0.1 X 10-5). Pulmonary arterial systolic and diastolic pressures changed in parallel to the changes observed in the mean pres-
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72-95.4 24.4-46.5 7.29-7.42 2.41-4.87 87-117 8-11.5 l-4.5 70-132
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sures, and they are not reported. The pulmonary arterial wedge pressure was not significantly altered by hypoxia in any of the groups (P = 0.57). This response was not different between groups (P = 0.16). Accompanying these changes, hypoxia induced a significant increase in the average pulmonary vascular resistance (P = 0.006). Administration of the 3 antihistaminic agents to the corresponding groups of dogs, as shown in Table I, A to C, under the “After” column, produced no significant changes in the level of arterial POs (P = 0.14), PC02 (P = 0.57), pH (P = 0.13), cardiac output (P = 0.95)or mean aortic pressure (P = 0.09). The wedge pressure was not significantly affected
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FIGURE 2. The average mean pulmonary arterial pressure measured while 18 dogs breathed room air and the changes induced by hypoxia are shown. The solid circles and solid lines reflect data obtained before administration of the designated antihistaminic agent, and the open circles and dashed lines represent data obtained after administration of the designed antihistaminic agent.
8
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after administration of the antihistaminic agents (P = 0.29); however, a reliable wedge pressure could not be recorded in 2 dogs in the group receiving chlorpheniramine. The average heart rate did increase in 2 of the 3 groups after administration of the corresponding antihistaminic agent. Diphenhydramine, administered during the initial period of hypoxia, decreased the mean pulmonary arterial pressure in 3 of the 6 dogs. The pulmonary arterial pressure increased slightly in the other 3 dogs; the average pressure decreased by 1.7 mm Hg (not significant, P = 0.31). The pulmonary arterial pressure decreased in 5 of the 6 dogs that received promethazine and was unchanged in 1; the mean change of -2.3 mm Hg was significant (P = 0.01). Administration of chlorpheniramine to the third group of dogs resulted in a marked decrease in pulmonary arterial pressure in 5 dogs and no change in the sixth dog. The average reduction was -5.7 mm Hg, which was also significant (P = 0.01). Correspondingly, a significant decrease in the pulmonary vascular resistance was observed in this group of dogs (P = 0.04) as well as in the dogs receiving promethazine (P = 0.006). The pulmonary vascular resistance was not significantly altered by the administration of diphenhydramine (P = 0.85). The total systemic resistance was not significantly affected by the administration of antihistamines (P = 0.45). Effect of antihistaminic agents during second hypoxic period: All measured variables returned to the initial level within 10 minutes after the termination of the initial hypoxic period. The second period of exposure to hypoxia was begun approximately 25 to 30 minutes after the antihistaminic agents had
CHLORPHENIRAMINE
50mq
IOOmg
20mg
been administered. However, the advent of pulmonary hypertension was significantly attenuated (P = 0.3 X 10-6) in each group of dogs (Fig. 2). The average mean pulmonary arterial pressure increased by 1.6 mm Hg in the group of dogs that received diphenhydramine. The corresponding values were 1.4 and 1.0 mm Hg in the dogs that received promethazine and chlorpheniramine, respectively. Each of these changes in the mean pulmonary arterial pessure was significantly different from the degree of pulmonary hypertension that had developed with hypoxia in the absence of the 3 antihistaminic drugs. Moreover, there were no significant differences in the effectiveness of any of the 3 agents in the prevention of hypoxic pulmonary hypertension.
Discussion Effect of antihistaminic agents on hypoxic pulmonary hypertension: Many types of parenchymal and pulmonary vascular disorders modify the partial pressure of oxygen in alveolar air or in the sector of the pulmonary microvascular bed, which Bergofsky et al.9 have suggested is the anatomic site for production of hypoxic pulmonary hypertension. It is postulated that hypoxia in this region may augment or perpetuate pulmonary hypertension initiated by factors other than hypoxia. For this reason, it is important to elucidate the nature of the mediators of hypoxic pulmonary hypertension and to seek agents that will attenuate or abolish any element of pulmonary vasoconstriction induced by this mediator. Previous work has suggested that histamine may be an important step in this mediation.l-* However, our previous studies had left a major area of uncer-
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tainty by demonstrating that 2 agents with known antihistaminic properties failed to modify significantly pulmonary hypertension induced by hypoxia. The data from our previous study4 demonstrated that chlorpheniramine, a strong antihistaminic agent, in a dose of 20 mg was capable either of abolishing or of preventing hypoxic pulmonary hypertension when administered during or before hypoxia, respectively. The data from the present study confirm these observations concerning chlorpheniramine in a separate group of experimental dogs. Moreover, this study has demonstrated that the effectiveness of chlorpheniramine can be demonstrated at doses of less than 0.3 mg/kg body weight. The corresponding dose in a 70 kg man would therefore be in a highly acceptable range. Conversely, doses of 2.8 mg/kg body weight of diphenhydramine or 1.4 mg/kg body weight of promethazine had not demonstrated an appreciable effect in the abolition of pulmonary hypertension in our previous study.4 The present study utilized t.wice these doses and demonstrated that these agents also are capable of preventing hypoxic pulmonary hypertension. Thus, the present data demonstrate that any of the 3 antihistaminic agents, when given in sufficient dosage, specifically modify the pulmonary vascular response to an hypoxic stimulus. The amounts of diphenhydramine and promethazine needed to achieve effectiveness equivalent to that exhibited by chlorpheniramine are sufficiently great to restrict their applicability to man in acceptable doses. Moreover, the dose-response characteristics with chlorpheniramine provide a basis for extending to man observations to clarify the role of histamine and of focal hypoxia in pulmonary hypertension of diverse causes. These studies lend further support to the notion that histamine mediates hypoxic pulmonary hypertension. Effects of adrenergie blockade and cateeholamine depletion: It has been shown that neither alpha adrenergic blockade nor tissue catecholamine depletion prevents the hypoxic pulmonary pressor response.lO,ll The potential effect of serotonin in the production of hypoxic pulmonary vasoconstriction has also been previously ruled out.” Ot,her drugs have been used in an attempt to modify the hypoxic pulmonary pressor response. Tolazoline (Priscoline@), for instance, has been observed to reduce transiently the pulmonary arterial pressure elevated for reasons other than hypoxia.12 It has also been observed that it decreases the hypoxic pressor response.1” Tolazoline is a substituted imidazoline and has a wide range of pharmacologic actions, including alpha adrenergic blocking, parasympathomimetic and systemic histamine-like activity. Responses that are mediated by beta receptors are unaffected.14 Tolazoline is a peripheral vasodilator, probably because of a direct effect. on vascular smooth muscle. Since its pharmacologic activity is so varied, it is difficult to define its mechanism of action during hypoxic vasoconstriction. Dipyridamole is another drug that has been ob-
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served to lessen, but not to abolish, hypoxic pulmonary vasoconstriction. l5 It is a potent vasodilator, and is known to alter platelet aggregation by interference with adenosine metabolism. The effects of adenosine on the pulmonary vessels have not been tested. However, dipyridamole effectively antagonizes the spasm of intestinal smooth muscle induced by barium and also inhibits the bronchospasm induced by either histamine or acetylchoiine.15 Richardson et a1.l” have shown that bet.a adrenergic blocking agents can significantly reduce the systemic effects produced in man by the acute inhalation of 7.5 percent oxygen for periods of less than 10 minutes. However, the effects of these agents in the pulmonary circulation are different. There are discrepancies in the published reports as to whether the administration of beta adrenergic blocking agents (propranolol) to man produces an increase or no change in the mean pulmonary arterial pressure and in total pulmonary resistance. With reference to hypoxia, it has been shown that. t.he pulmonary pressor response to the inhalat.ion of 13 percent. oxygen is not blocked by beta blockade with propranolol.12 It has recently been demonstrat,ed in anesthetized cats17 that histamine acts primarily by constricting the pulmonary blood vessels. Subsequent pulmonary vasodilatation probably depends on epinephrine released from the adrenal glands by the action of histamine. After beta receptor blockade with propranol01. histamine had the same pressor effect as in adrenalectomized cats, but the histamine-induced increase in pulmonary vascular resistance was prolonged. It appears that the effect of alveolar hypoxia is due to the local release of histamine. Recent histochemical studies performed in isolated lung preparations have presented direct evidence that histamine is important in the response to alveolar hypoxia. The histamine concentration in lung tissue has been shown to change appropriately during the different phases of the pulmonary pressor response.‘s Many substances and drugs can result in hist,amine release; among these is morphine. The peripheral vasodilator action of morphine has been attributed to histamine release: however, this action is only partially blocked by antihistamines.14.20 The major decrease in systemic blood pressure that occurs aft~er toxic doses of morphine is largely related to hypoxia, both from central respiratory depression and from bronchoconstriction.” This combination may well produce alveolar hypoventilation; the associated hypoxia may in turn cause histamine release. However. recent studies of the hemodynamic effects of small doses of morphine in patients with coronary artery disease have shown no changes in the mean pulmonary arterial pressure or in pulmonary vascular resistance.*9 It is not known whether larger doses directly affect the pulmonary vasculature. Clinical implication: Histamine probably has an important effect on the local vasoregulatior~ of flow in the lung in areas that have alveolar hypoxia. Whether hypercapnia or acidosis acts through the same mediator remains to be clarified. Demonstra-
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tion of the effect of antihistaminic agents on hypoxic pulmonary vasoconstriction may provide another therapeutic approach to the altered physiologic and hemodynamic status of patients with chronic obstructive lung disease.
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Acknowledgments We are grateful to Mr. Mitchell Passovoy for his assistance with the statistical analyses, and to Mrs. Shirley Williams for her secretarial assistance.
References 1
2.
3.
4.
5.
6. 7.
a. 9.
10.
KL: Role of histamine in hypoxic Hauge A. Melmon in the rat. 2. Depletion of pulmonary hypertension catecholamines. Circ Res serotonin and histamine. 44: 385-392. 1968 Hauge A, Staub NC: Prevention of hypoxic vasoconstriction in cat lung by histamine-releasing agent 48/80. J Appl Physiol26: 693-699,1969 Susmano A, Carleton RA: Inhibition of hypoxic pulmonary hypertension by antihistamines (abstr). J Lab Clin Med 76: 855-856. 1970 Susmano A. Carleton RA: Prevention of hypoxic pulmonary hypertension by chlorpheniramine. J Appl Physiol 31: 531535,197l Stone CH, Wenger HC, Ludden CT, et al: Antiserotonin-antihistaminic properties of cyproheptadine. J Pharmacol Exp Ther 131: 73-84. 1961 Goth A: Medical Pharmacology, third edition. St. Louis. Missouri. CV Mosby. 1966. p 179.280 Hamilton WF, Riley RL, Attyah AM, et al: Comparisons of the Fick and dye injection methods of measuring the cardiac output in man. Amer J Physiol 153: 309-321, 1948 Snedecor GW: Statistical Methods (fifth edition). Ames. Iowa. Iowa State University Press, 1957. p 257-260 Bergofsky EH, Lehr DE, Fishman AP: The effects of changes in hydrogen ion concentration on the pulmonary circulation. J Clin Invest 41: 1492-1505. 1962 Silove ED, Grover RF: Effects of alpha adrenergic blockade and tissue catecholamine depletion on pulmonary vascular response to hypoxia. J Clin Invest 47: 274-285. 1968
11. Goldring RA, Turin0 GM, Cohen G, et al: The catecholamines in the pulmonary pressor response to acute hypoxia. J Clin Invest41: 1211-1221. 1962 12 Grover RF, Reeves JT, Blount Jr SG: Tolazoline hydrochloride (Priscoline): an effective pulmonary vasodilator. Amer Heart J 61: 5-14. 1961 13 Vogel JHK. Blount SG Jr: Modiflcatlon of cardiovascular responses by propranolol. Brit Heart J 29: 310-316. 1967 14. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics, third edition. New York, Macmillan, 1965, p 255, 556. 744 of hy15. Lynch FP. Rosenkrantz JG. Vogel JHG: Modification poxic pulmonary hypertension by dipyridamole. Advances Cardiol 5: 154-l 58. 1970 16. Richardson DW, Kontos HA, Raper AJ, et al: Modification by beta-adrenergic blockade of the circulatory responses to acute hypoxia in man. J Clin Invest 46: 77-85. 1967 17. Colebatch HJH: Adrenergic mechanisms in the effects of histamine in the pulmonary circulation of the cat. Circ Res 26: 379-396, 1970 18. Berkov S, Sirbu R, Melmon KL: Histamine: a mediator of increased pulmonary vascular resistance during alveolar hypoxia (abstr). Clin Res 18: 146.‘1970 19. Alderman EL, Barry WH, Graham AF, et al: Hemodynamic effects of morphine and pentazocine differ in cardiac patients. New Eng J Med 287: 623-627, 1972 20. Eckenhoff JE, Steffen RO: The effects of narcotics and antagonists upon respiration and circulation in man. Clin Pharmacol Ther 1: 483-524. 1960
June 1973
The American
Journal of CARDIOLOGY
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723
Effect of Antihistaminic Drugs on Hypoxic Pulmonary
ARMANDO RICHARD
SUSMANO. MD A. CARLETON, MD,
FACC
Chicago, Illinois
From the Section of Cardio-Respiratory Diseases, Department of Medicine, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, III. This work was supported in part by U. S. Public Health Service Training Grant HE 05714 from the National Heart and Lung Institute of the National Institutes of Health. Manuscript received May 26. 1972; revised manuscript received November 11, 1972. accepted December 11,1972. Address for reprints: Armando Susmano. MD, Rush-Presbiterian-St. Luke’s Medical Center, 1753 W. Congress Parkway, Chicago, III. 60612.
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During exposure to 8 percent oxygen inhalation, 18 dogs experienced an average increase of 5.4 mm Hg in mean pulmonary arterial pressure. The administration of promethazine and chlorpheniramine during an initial exposure to hypoxia significantly decreased the pulmonary hypoxic pressor response; the administration of diphenhydramine did not. However, these 3 antihistaminic agents prevented the development of pulmonary hypertension during a second exposure to hypoxia (P = 0.3 X lo- 6). Five dogs received progressive doses of chlorpheniramine, thus showing thai the effectiveness of this drug can be demonstrated at a dose of less than 0.3 mg/kg body weight. The amounts of diphenhydramine and promethazine needed to achieve effectiveness equivalent to that of chlorpheniramine are sufficiently great as to restrict their applicability to man in acceptable doses. This study lends further support to the hypothesis that histamine mediates hypoxic pulmonary hypertension.
The biochemical mediation of pulmonary hypertension induced by hypoxia has been unclear for many years. The work of Hauge et al:‘+2 in isolat.ed rat or cat lungs lent support to the hypothesis that histamine may be this mediator. Subsequently, work conducted in our laboratory”.4 lent strong support to this hypothesis by demonstrating that chlorpheniramine (Chlor-Trimeton@) abolished pulmonary hypertension induced by hypoxia and prevented the appearance of pulmonary hypertension with the institution of hypoxia. However, in that study. 2 other antihistaminic agents failed to abolish the pulmonary vascular pressor response to hypoxia. This paradox led to the present studies. to determine whether the antihistaminic properties of chlorpheniramine were those being demonstrated in the prevention or inhibition of hypoxic pulmonary hypertension or whether other properties, not shared by promethazine (Phenergan@‘) and diphenhydramine (Renadryl@), were responsible for the effect. Promethazine has potent antiserotonin properties5 in addition to antihistaminic effects. Diphenhydramine also possesses other pharmacologic effects in addition to its antihistaminic activity.” Conversely, chlorpheniramine has relatively pure antihistaminic effects. Thus, in testing the hypothesis that histamine mediates hypoxic pulmonary hypertension, it became important to determine whether diphenhydramine and promethazine, with their antihistaminic properties, lack the ability to prevent hypoxic pulmonary hypertension or whether an insufficient dose had been utilized in the previous study. Accordingly, we tested the reaction of the pulmonary vascular bed to hypoxia in the presence of differing amounts of the 3 antihistaminic agents. Material
and Methods
‘I’wenty-three mongrel dogs of both sexes (weight range 11.2 to 24.2 kg; mean 17.6) were divided into 1 group of 5 dogs and 3 groups of 6 dogs. Each
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dog was anesthetized
with a mixture of 6.0 mg/kg body weight of droperidol and 0.12 mg/kg body weight of fentanyl (Innovar-Vet, McNeil Laboratories, Fort Washington, Pa.). Small supplemental doses were administered as necessary. Atropine sulfate was also given in a dose of 0.4 mg. Each dog had a cuffed endotracheal tube inserted to ensure a leak-free means of administering a hypoxic gas mixture. A no. 7F catheter was placed in the thoracic aorta from the femoral artery. The distal lumen of a no. 8F double-lumen catheter was placed in a pulmonary arterial wedge position; the proximal lumen was in the main pulmonary artery. Pressures were recorded at a paper speed of 10 mm/set by use of Statham P23Db strain gauges and the carrier amplifiers of an oscillographic recorder (Hewlett-Packard recorder model 7712B). Mean pressure values were obtained by electronic damping. Cardiac output was calculated by the Hamilton methodr after the injection of 2.5 mg of indocyanine green dye into the pulmonary artery and withdrawal of aortic blood through a densitometer (Gilford densitometer, model 1031R). Systemic and pulmonary vascular resistance levels were calculated in the centimeter-gram-second system using the mean aortic and the mean pulmonary arterial minus pulmonary arterial wedge pressure values, respectively. Spontaneous respiration through the cuffed endotracheal tube was permitted throughout. The inspired gas mixture was changed at will from room air to a reservoir containing a mixture of 8 percent oxygen and 92 percent nitrogen, A l-way valve prevented rebreathing and accumulation of carbon dioxide. Each set of measurements included measurement of cardiac output, heart rate, pulmonary arterial and pulmonary arterial wedge pressure, aortic pressure and arterial pH, POz and PC02 (Instrumentation Laboratories, blood gas analyzer, model 113, Boston, Mass.). Procedures: The initial group (5 dogs) was studied to determine the dose-response relation of the effectiveness of chlorpheniramine in the inhibition of pulmonary hypertension. Each dog was subjected to 8 consecutive sequences of 2 minutes of hypoxia and 5 minutes of breathing room air. The first 4 trials were utilized to determine the reproducibility of the pulmonary pressor response to identical degrees of hypoxia. The second 4 trials were utilized to determine the dose-response relation of chlorpheniramine. Before the fifth trial, each dog received 5 mg of chlorpheniramine. An additional 5 mg of chlorpheniramine was given before each of the subsequent 3 exposures to hypoxia to permit measurement of the pul.nonary pressor response in the presence of 5, 10, 15 and 20 mg of chlorpheniramine (cumulative dose). The remaining 3 groups (6 dogs in each) were subjected to a similar sequence of measurements. Initial measurements were made while the dogs breathed room air. The endotracheal tube was then connected to the reservoir containing the hypoxic gas mixture. Pulmonary arterial and aortic pressures were measured at 1 minute intervals after the onset of hypoxia. All measurements were repeated after 10 minutes of stable hypoxia and pulmonary hypertension. The antihistaminic agent was then administered over 30 seconds into the main pulmonary artery while hypoxia was maintained. Each of the first group of 6 dogs received 100 mg of diphenhydramine (Benadrylq Parke, Davis & Co., Detroit, Mich.). The second group of 6 dogs each received 50 mg of promethazine (Phenergan@, Wyeth Laboratories, Philadelphia, Pa.), and the last group of 6 dogs each received 20 mg of chlorpheniramine
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(Chlor-Trimetona, Schering Corp., Bloomfield, N.J.). Pulmonary arterial and aortic pressures were then measured at 1 minute intervals. Cardiac output and the other measurements were repeated 15 minutes after the administration of the antihistaminic agent. Each dog was then permitted to breathe room air for 10 minutes. A second period of hypoxia was then begun to determine whether the previously administered antihistaminic agent would prevent the appearance of hypoxic pulmonary hypertension. Statistical analyses of the data were performed by paired comparisonss between groups. Analysis of variance was used to determine the consistency of response within and between groups and the significance of changes induced by hypoxia and those attributable to antihistamine administration. Results Effect of chlorpheniramine: The results in the initial group of dogs are illustrated in Figure 1. Each
of the 4 initial episodes of hypoxia before administration of chlorpheniramine produced significant and equivalent degrees of pulmonary hypertension, with an average increase in the mean pulmonary arterial pressure of 4.5 mm Hg. No significant differences were present among the 4 trials before antihistamine administration (P = 0.99). Although the average level of pulmonary arterial mean pressure was slightly lower after the 20 mg dose of chlorpheniramine than after the 5 mg dose, there were no significant differences (P = 0.94) in the ability of 5, 10, 15 or 20 mg (cumulative doses) to modify the appearance of hypoxic pulmonary hypertension. Thus, even relatively small doses of chlorpheniramine significantly prevented the appearance of hypoxic pulmonary hypertension (P = 0.1 X 1O-s). Comparison of diphenhydramine, promethazine and chlorpheniramine: The original values ob-
tained with the dogs breathing room air and the changes induced by hypoxia in each of the other 3 groups of dogs are summarized in Table IA (diphenhydramine), IB (promethazine) and IC (chlorpheniramine) under the “Before” column. Analysis of the changes induced by hypoxia demonstrated a highly significant decrease in arterial POz (P = 0.8 x lo-11) and PC02 (P = 0.2 X lo-*), and a significant increase in arterial pH (P = 0.1 X 10-8). There were no significant differences in these re6r MEAN
CHANGE IN
PULM
4
f
ARTERY
01
5MG %iToRoL *
IOMG
15MG
20MG
CHLORPHENIRAMINE FIGURE 1. The average changes in pulmonary arterial mean pressure 2 minutes after the onset of hypoxia are shown before chlorpheniramine administration (average of 4 consecutive hypoxic episodes) and after 5, 10. 15 and 20 mg of chlorpheniramine, respectively.
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I
Initial Values and Changes Produced by Shifting from 20.9 Percent to 8 Percent Inspired Oxygen Concentrations (Before) and Subsequent Changes Noted 15 Minutes after Antihistaminic Agent Administration During Constant Hypoxia RoomAir no.
Mean
8% Oxygen* Range
Before
After
A. Diphenhydramine Arterial POP (mm Hg) Arterial PCOz (mm Hg) Arterial pH Cardiac output (liters/min) Heart rate (beats/min) Mean PA pressure (mm Hg) Wedge pressure (mm Hg) Mean aortic pressure (mm Hg) Resistances (dyne set cm-6) Systemic Pulmonary vascular
5 6 6 5 6 6 6 6 5 5
92.3 41.2 7.32 3.37 100 11.5 3.0 106
88.4-102.5 30.9-45.5 7.25-7.37 2.59-3.77 85-125 10-14.5 1.5-5 89-134
2447
2143-3089 133-262
190
-54.7 f -13.9 f 0.13 f 0.93 k 37 i 5.4 f 0.75 i 9*8
6.3 2.6 0.005 0.61 35 2.6 0.9
-274 i 225 38 % 53
-2.9 f -1.0 i -0.03 i -0.10 III 35 f -1.7 * -0.4 * -8=t20 -2.8 -4.4
4.1 2.2 0.03 0.55 28 4.0 1.2
f 380 It 53
-___
._~~.
B. Promethazine Arterial POZ (mm Hg) Arterial PCOZ (mm Hg) Arterial pH Cardiac output (liters/min) Heart rate (beats/min) Mean PA pressure (mm Hg) Wedge pressure (mm Hg) Mean aortic pressure (mm Hg) Resistances (dyne-set-cm-6) Systemic Pulmonary vascular
6 6 6 6 6 6 6 6 6 6
85.3 41.2 7.31 3.25 108 8.5 2.9 122 3028 142
80-95 38.5-45.2 7.24-7.35 2.63-3.94 76-180 7-9.5 2-3.5 88-151
-52.2 f -14.6 i0.14 It 0.91 f 60 + 4.7 f -0.4 It 6.0+
5.0 2.8 0.02 0.9 49 2.6 0.4 8
-4.5 f -0.7 f -0.02 f 0.31 III 56 ;t -2.3 f 0.4 + -11 rt
1.3 0.6 0.02 0.59 20 1.6 0.8 11
2072-3650 91-182
-508 f 79 f
475 57
-376 i -70 f
590 41
C. Chlorpheniramine Arterial PO* (mm Hg) Arterial PCOZ (mm Hg) Arterial pH Cardiac output (liters/min) Heart rate (beats/min) Mean PA pressure (mm Hg) PA wedge pressure (mm Hg) Mean aortic pressure (mm Hg) Resistances (dyne set cm+) Systemic Pulmonary vascular PA = pulmonary arterial. * Mean change +95 percent
confidence
84 39.7 7.34 3.46 99 9.5 2.5 106 5 6
2544 168
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-49.4 i 6.9 -13.3 i 3.0 0.14 f 0.03 0.65 i 0.34 70 + 55 6.0 ZII 2.8 -1.5 f 2.0 2+ 13
1390-3784 131-201
-275 +I 410 126 i 218
-3.0 =!,I 2.3 1.6 f 1.8 -0.02 Zt 0.003 -0.34 f 0.39 -13 f 40 -5.7 i 3.8 1.2 f 2.3 -16 f 25 -42 f -122 *
605 114
limits of change.
sponses among the 3 groups (p = 0.13, 0.21, 0.32, respectively). The cardiac output and heart rate also increased significantly with the advent of hypoxia (P = 0.01 and P = 0.9X 10p6), again without significant differences among the 3 groups (P = 0.94). The mean aortic pressure and the total systemic resistance did not change significantly during hypoxia (P = 0.43 and 0.15, respectively). Each dog experienced at least a 1.5 mm Hg increase in the mean pulmonary arterial pressure during hypoxia. The average increase for the 3 groups of 6 dogs was 5.4 mm Hg (P = 0.1 X 10-5). Pulmonary arterial systolic and diastolic pressures changed in parallel to the changes observed in the mean pres-
720
72-95.4 24.4-46.5 7.29-7.42 2.41-4.87 87-117 8-11.5 l-4.5 70-132
Journal of CARDIOLOGY
sures, and they are not reported. The pulmonary arterial wedge pressure was not significantly altered by hypoxia in any of the groups (P = 0.57). This response was not different between groups (P = 0.16). Accompanying these changes, hypoxia induced a significant increase in the average pulmonary vascular resistance (P = 0.006). Administration of the 3 antihistaminic agents to the corresponding groups of dogs, as shown in Table I, A to C, under the “After” column, produced no significant changes in the level of arterial POs (P = 0.14), PC02 (P = 0.57), pH (P = 0.13), cardiac output (P = 0.95)or mean aortic pressure (P = 0.09). The wedge pressure was not significantly affected
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16
FIGURE 2. The average mean pulmonary arterial pressure measured while 18 dogs breathed room air and the changes induced by hypoxia are shown. The solid circles and solid lines reflect data obtained before administration of the designated antihistaminic agent, and the open circles and dashed lines represent data obtained after administration of the designed antihistaminic agent.
8
DI PtiENHYDRAMlNE
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after administration of the antihistaminic agents (P = 0.29); however, a reliable wedge pressure could not be recorded in 2 dogs in the group receiving chlorpheniramine. The average heart rate did increase in 2 of the 3 groups after administration of the corresponding antihistaminic agent. Diphenhydramine, administered during the initial period of hypoxia, decreased the mean pulmonary arterial pressure in 3 of the 6 dogs. The pulmonary arterial pressure increased slightly in the other 3 dogs; the average pressure decreased by 1.7 mm Hg (not significant, P = 0.31). The pulmonary arterial pressure decreased in 5 of the 6 dogs that received promethazine and was unchanged in 1; the mean change of -2.3 mm Hg was significant (P = 0.01). Administration of chlorpheniramine to the third group of dogs resulted in a marked decrease in pulmonary arterial pressure in 5 dogs and no change in the sixth dog. The average reduction was -5.7 mm Hg, which was also significant (P = 0.01). Correspondingly, a significant decrease in the pulmonary vascular resistance was observed in this group of dogs (P = 0.04) as well as in the dogs receiving promethazine (P = 0.006). The pulmonary vascular resistance was not significantly altered by the administration of diphenhydramine (P = 0.85). The total systemic resistance was not significantly affected by the administration of antihistamines (P = 0.45). Effect of antihistaminic agents during second hypoxic period: All measured variables returned to the initial level within 10 minutes after the termination of the initial hypoxic period. The second period of exposure to hypoxia was begun approximately 25 to 30 minutes after the antihistaminic agents had
CHLORPHENIRAMINE
50mq
IOOmg
20mg
been administered. However, the advent of pulmonary hypertension was significantly attenuated (P = 0.3 X 10-6) in each group of dogs (Fig. 2). The average mean pulmonary arterial pressure increased by 1.6 mm Hg in the group of dogs that received diphenhydramine. The corresponding values were 1.4 and 1.0 mm Hg in the dogs that received promethazine and chlorpheniramine, respectively. Each of these changes in the mean pulmonary arterial pessure was significantly different from the degree of pulmonary hypertension that had developed with hypoxia in the absence of the 3 antihistaminic drugs. Moreover, there were no significant differences in the effectiveness of any of the 3 agents in the prevention of hypoxic pulmonary hypertension.
Discussion Effect of antihistaminic agents on hypoxic pulmonary hypertension: Many types of parenchymal and pulmonary vascular disorders modify the partial pressure of oxygen in alveolar air or in the sector of the pulmonary microvascular bed, which Bergofsky et al.9 have suggested is the anatomic site for production of hypoxic pulmonary hypertension. It is postulated that hypoxia in this region may augment or perpetuate pulmonary hypertension initiated by factors other than hypoxia. For this reason, it is important to elucidate the nature of the mediators of hypoxic pulmonary hypertension and to seek agents that will attenuate or abolish any element of pulmonary vasoconstriction induced by this mediator. Previous work has suggested that histamine may be an important step in this mediation.l-* However, our previous studies had left a major area of uncer-
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tainty by demonstrating that 2 agents with known antihistaminic properties failed to modify significantly pulmonary hypertension induced by hypoxia. The data from our previous study4 demonstrated that chlorpheniramine, a strong antihistaminic agent, in a dose of 20 mg was capable either of abolishing or of preventing hypoxic pulmonary hypertension when administered during or before hypoxia, respectively. The data from the present study confirm these observations concerning chlorpheniramine in a separate group of experimental dogs. Moreover, this study has demonstrated that the effectiveness of chlorpheniramine can be demonstrated at doses of less than 0.3 mg/kg body weight. The corresponding dose in a 70 kg man would therefore be in a highly acceptable range. Conversely, doses of 2.8 mg/kg body weight of diphenhydramine or 1.4 mg/kg body weight of promethazine had not demonstrated an appreciable effect in the abolition of pulmonary hypertension in our previous study.4 The present study utilized t.wice these doses and demonstrated that these agents also are capable of preventing hypoxic pulmonary hypertension. Thus, the present data demonstrate that any of the 3 antihistaminic agents, when given in sufficient dosage, specifically modify the pulmonary vascular response to an hypoxic stimulus. The amounts of diphenhydramine and promethazine needed to achieve effectiveness equivalent to that exhibited by chlorpheniramine are sufficiently great to restrict their applicability to man in acceptable doses. Moreover, the dose-response characteristics with chlorpheniramine provide a basis for extending to man observations to clarify the role of histamine and of focal hypoxia in pulmonary hypertension of diverse causes. These studies lend further support to the notion that histamine mediates hypoxic pulmonary hypertension. Effects of adrenergie blockade and cateeholamine depletion: It has been shown that neither alpha adrenergic blockade nor tissue catecholamine depletion prevents the hypoxic pulmonary pressor response.lO,ll The potential effect of serotonin in the production of hypoxic pulmonary vasoconstriction has also been previously ruled out.” Ot,her drugs have been used in an attempt to modify the hypoxic pulmonary pressor response. Tolazoline (Priscoline@), for instance, has been observed to reduce transiently the pulmonary arterial pressure elevated for reasons other than hypoxia.12 It has also been observed that it decreases the hypoxic pressor response.1” Tolazoline is a substituted imidazoline and has a wide range of pharmacologic actions, including alpha adrenergic blocking, parasympathomimetic and systemic histamine-like activity. Responses that are mediated by beta receptors are unaffected.14 Tolazoline is a peripheral vasodilator, probably because of a direct effect. on vascular smooth muscle. Since its pharmacologic activity is so varied, it is difficult to define its mechanism of action during hypoxic vasoconstriction. Dipyridamole is another drug that has been ob-
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served to lessen, but not to abolish, hypoxic pulmonary vasoconstriction. l5 It is a potent vasodilator, and is known to alter platelet aggregation by interference with adenosine metabolism. The effects of adenosine on the pulmonary vessels have not been tested. However, dipyridamole effectively antagonizes the spasm of intestinal smooth muscle induced by barium and also inhibits the bronchospasm induced by either histamine or acetylchoiine.15 Richardson et a1.l” have shown that bet.a adrenergic blocking agents can significantly reduce the systemic effects produced in man by the acute inhalation of 7.5 percent oxygen for periods of less than 10 minutes. However, the effects of these agents in the pulmonary circulation are different. There are discrepancies in the published reports as to whether the administration of beta adrenergic blocking agents (propranolol) to man produces an increase or no change in the mean pulmonary arterial pressure and in total pulmonary resistance. With reference to hypoxia, it has been shown that. t.he pulmonary pressor response to the inhalat.ion of 13 percent. oxygen is not blocked by beta blockade with propranolol.12 It has recently been demonstrat,ed in anesthetized cats17 that histamine acts primarily by constricting the pulmonary blood vessels. Subsequent pulmonary vasodilatation probably depends on epinephrine released from the adrenal glands by the action of histamine. After beta receptor blockade with propranol01. histamine had the same pressor effect as in adrenalectomized cats, but the histamine-induced increase in pulmonary vascular resistance was prolonged. It appears that the effect of alveolar hypoxia is due to the local release of histamine. Recent histochemical studies performed in isolated lung preparations have presented direct evidence that histamine is important in the response to alveolar hypoxia. The histamine concentration in lung tissue has been shown to change appropriately during the different phases of the pulmonary pressor response.‘s Many substances and drugs can result in hist,amine release; among these is morphine. The peripheral vasodilator action of morphine has been attributed to histamine release: however, this action is only partially blocked by antihistamines.14.20 The major decrease in systemic blood pressure that occurs aft~er toxic doses of morphine is largely related to hypoxia, both from central respiratory depression and from bronchoconstriction.” This combination may well produce alveolar hypoventilation; the associated hypoxia may in turn cause histamine release. However. recent studies of the hemodynamic effects of small doses of morphine in patients with coronary artery disease have shown no changes in the mean pulmonary arterial pressure or in pulmonary vascular resistance.*9 It is not known whether larger doses directly affect the pulmonary vasculature. Clinical implication: Histamine probably has an important effect on the local vasoregulatior~ of flow in the lung in areas that have alveolar hypoxia. Whether hypercapnia or acidosis acts through the same mediator remains to be clarified. Demonstra-
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tion of the effect of antihistaminic agents on hypoxic pulmonary vasoconstriction may provide another therapeutic approach to the altered physiologic and hemodynamic status of patients with chronic obstructive lung disease.
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Acknowledgments We are grateful to Mr. Mitchell Passovoy for his assistance with the statistical analyses, and to Mrs. Shirley Williams for her secretarial assistance.
References 1
2.
3.
4.
5.
6. 7.
a. 9.
10.
KL: Role of histamine in hypoxic Hauge A. Melmon in the rat. 2. Depletion of pulmonary hypertension catecholamines. Circ Res serotonin and histamine. 44: 385-392. 1968 Hauge A, Staub NC: Prevention of hypoxic vasoconstriction in cat lung by histamine-releasing agent 48/80. J Appl Physiol26: 693-699,1969 Susmano A, Carleton RA: Inhibition of hypoxic pulmonary hypertension by antihistamines (abstr). J Lab Clin Med 76: 855-856. 1970 Susmano A. Carleton RA: Prevention of hypoxic pulmonary hypertension by chlorpheniramine. J Appl Physiol 31: 531535,197l Stone CH, Wenger HC, Ludden CT, et al: Antiserotonin-antihistaminic properties of cyproheptadine. J Pharmacol Exp Ther 131: 73-84. 1961 Goth A: Medical Pharmacology, third edition. St. Louis. Missouri. CV Mosby. 1966. p 179.280 Hamilton WF, Riley RL, Attyah AM, et al: Comparisons of the Fick and dye injection methods of measuring the cardiac output in man. Amer J Physiol 153: 309-321, 1948 Snedecor GW: Statistical Methods (fifth edition). Ames. Iowa. Iowa State University Press, 1957. p 257-260 Bergofsky EH, Lehr DE, Fishman AP: The effects of changes in hydrogen ion concentration on the pulmonary circulation. J Clin Invest 41: 1492-1505. 1962 Silove ED, Grover RF: Effects of alpha adrenergic blockade and tissue catecholamine depletion on pulmonary vascular response to hypoxia. J Clin Invest 47: 274-285. 1968
11. Goldring RA, Turin0 GM, Cohen G, et al: The catecholamines in the pulmonary pressor response to acute hypoxia. J Clin Invest41: 1211-1221. 1962 12 Grover RF, Reeves JT, Blount Jr SG: Tolazoline hydrochloride (Priscoline): an effective pulmonary vasodilator. Amer Heart J 61: 5-14. 1961 13 Vogel JHK. Blount SG Jr: Modiflcatlon of cardiovascular responses by propranolol. Brit Heart J 29: 310-316. 1967 14. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics, third edition. New York, Macmillan, 1965, p 255, 556. 744 of hy15. Lynch FP. Rosenkrantz JG. Vogel JHG: Modification poxic pulmonary hypertension by dipyridamole. Advances Cardiol 5: 154-l 58. 1970 16. Richardson DW, Kontos HA, Raper AJ, et al: Modification by beta-adrenergic blockade of the circulatory responses to acute hypoxia in man. J Clin Invest 46: 77-85. 1967 17. Colebatch HJH: Adrenergic mechanisms in the effects of histamine in the pulmonary circulation of the cat. Circ Res 26: 379-396, 1970 18. Berkov S, Sirbu R, Melmon KL: Histamine: a mediator of increased pulmonary vascular resistance during alveolar hypoxia (abstr). Clin Res 18: 146.‘1970 19. Alderman EL, Barry WH, Graham AF, et al: Hemodynamic effects of morphine and pentazocine differ in cardiac patients. New Eng J Med 287: 623-627, 1972 20. Eckenhoff JE, Steffen RO: The effects of narcotics and antagonists upon respiration and circulation in man. Clin Pharmacol Ther 1: 483-524. 1960
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