pulmonary microembolism: attenuated pulmonary vasoconstriction with prostaglandin inhibitors and...

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Pulmonary Microembolism: Attenuated Pulmonary Vasoconstriction with Prostaglandin Inhibitors and Antihistamines

Alan Tucker, Ph.D. E. Kenneth Weir, M.R.C.P.

John T. Reeves, M.D. Robert F. Grover, M.D., Ph.D.

Cardiovascular Pulmonary Research Laboratory Division of Cardiology, Department of Medicine

Univeristy of Colorado Medical Center

(Abstract) The mechanism(s) involved in the pulmonary vascular and airway

responses to pulmonary microembolism have not been clearly defined. Therefore, we determined the effects of specific prostaglandin and histamine blockade on the hemodynamic and arterial blood gas tension responses to particulate microembolism (200 u glass beads) in intact anesthetized dogs. The marked increases in pulmonary arterial pressure and pulmonary vascular resistance observed in the untreated dogs were attenuated, but not abolished, following both prostaglandin blockade (with either meclofenamate or polyphloretin phosphate) and histamine blockade (with chlorpheniramine and metiamide) at 5 minutes, and were still attenuated 30 minutes post embolization. Combined prostaglandin and histamine blockade further attenuated, but again did not abolish, the pulmonary vascular responses. Cardiac outputs and systemic arterial pressures were unchanged from control by embolism. The alveolar hypoventilation (decreased arterial oxygen tension and increased carbon dioxide tension) observed in the untreated embolized dogs was prevented only with the prostaglandin inhibitors. Pulmonary microembolism in intact dogs, therefore, appears to induce vasoconstriction mediated partially by prostaglandin and histamine action, and alveolar hypoventilation mediated by prostaglandin, but not histamine, action.

This work was supported by NIH grants HL 14985 and HL 1798. The as- sistance of D. Jackson, S. Hofmeister, R. Glas, M. Munroe, E. Toyos, B. Kaplan, and S. Merino is gratefully acknowledged. Sodium meclofenamate was kindly provided by Parke Davis & Co., Detroit, MI; polyphloretin phosphate by Leo, Helsingborg, Sweden; and metiamide by Smith Kline & French Labs., Philadelphia, PA. Chlorpheniramine (Chlor- Trimeton) was obtained from Schering Corp., Bloomfield, NJ.

Address for mailing proofs: Dr. Alan Tucker Cardiovascular Pulmonary Research

Laboratory University of Colorado Medical Center 4200 East Ninth Avenue Denver, Colorado 80220

12-29-75

JANUARY 1976 VOL. 11 NO. 1 31

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Introduction

Particulate embolisation of lungs has been shown to induce the release of prostaglandins and histamine into the pulmonary venous effluent (l-4). However, the role of these two agents in the hemodynamic and airway responses to embolism has not been elucidated. Nakano and McCloy (5), using an antagonist of prostaglandin synthesis, were able to block the embolism-induced increase in tracheal pressure, but were unable to prevent the pulmonary hypertension. These results suggested that prostaglandins were involved in the airway, but not the hemodynamic, responses to embolism. Histamine has also been implicated in the airway response (6, 7), but little evidence is available regard- ing the role of histamine in the vascular responses to pulmonary microembolism (8). Since the actions of the prostaglandins and histamine released during embolisation are unclear, this study was conducted to clarify their role in the hemodynamic and arterial blood gas tension responses to particulate pulmonary embolism, by employing specific prostaglandin and histamine antagonists.

Methods ,-

Thirty-four dogs of either sex (mean weight 19.9 + 0.6 kg) were anestietized with sodium pentobarbital (30 mg/kg), intubated with a cuffed endotracheal tube, and allowed to breathe 30% oxygen spontane- ously (PIG* = 175 ImnHg). Polyethylene catheters were positioned in the main pulmonary artery and in the abdominal aorta for pressure de- terminations, and an infusion catheter was placed in the superior vena cava. Pulmonary arterial wedge pressure was determined using a Swan-Gans catheter. Mean blood pressures, heart rate, cardiac output (dye dilution), pulmonary vascular resistance (mean pulmonary arterial- pulmonary arterial wedge pressure/cardiac output), and total systemic resistance (mean systemic arterial pressure/cardiac output) were com- puted as previously described (9), using an on-line computer system. Systemic arterial oxygen and carbon dioxide tensions and pH were measured with appropriate electrodes (Radiometer, Copenhagen, Denmark) and corrected to the animals' body temperature.

Particulate pulmonary microembolism was produced by rapid injection of 200 u (150 - 250 U) glass beads (0.15 ml/kg) in saline into the right ventricular outflow tract, thus ensuring equal embolisation of both lungs. Cardiac output and pulmonary and systemic vascular resistances were obtained prior to and at 5. 10, 20, and 30 minutes post embolisation. Mean blood pressures and heart rate were measured at one minute intervals. Arterial blood samples for analysis were drawn prior to and at 5 and 30 minutes post embolization.

The animals were divided into five drug treatment groups. Eight dogs, comprising the control group, were embolized with no prior drug treatment. Sodium meclofenamate (2 nag/kg intravenous bolus injection followed by an infusion of 2 mg/kg/hr) was administered to another group of eight dogs in order to block prostaglandin synthesis (10).

32 JANUARY 1976 VOL. 11 NO. 1

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Polyphloretin phosphate (50 mg/kg intravenous injection over 10 minutes followed by an infusion of 50 mg/kg/hr) was given to four dogs to achieve prostaglandin receptor blockade (11). Another group of eight dogs was treated with antihistamines to block the actions of histamine (12); each animal was given an Hl- receptor antagonist, chlorpheniramine (1 mg/kg), and an H2- receptor antagonist, metiamide (5 mg/kg/min for 35 minutes). The final group of six dogs was administered both meclofenamate and the antihistamines, chlorpheniramine and metiamide, to achieve combined prostaglandin and histamine blockade. At least 30 minutes elapsed, following the initial drug infusions, prior to lung embolisation in all groups of dogs. The animals were then embolized and hemodynamic and blood gas measurements were obtained as described. Comparisons were made between pre- and post-embolism values and evaluated statistically with analysis of variance techniques. Significance was accepted at the P < 0.05 level.

Results

Pulmonary embolism of the untreated animals resulted in marked increases in pulmonary arterial pressure (Figure 1 and Table I), which averaged +23 mmHg above control at 5 minutes post embolization. The pulmonary hypertension was attenuated in all of the drug treated groups, particularly in the prostaglandin receptor blocked and combined prostaglandin and histamine blocked groups. Pulmonary embolism also induced large increases in pulmonary vascular resistance (Figure 2 and Table I). The untreated embolised animals exhibited an average +10.3 unit rise in pulmonary vascular resistance compared to increases of less than 6.5 units, above control, in the treated groups. In all four treated groups, the pulmonary pressor and resistance responses were still attenuated 30 minutes post embolisation. The prostaglandin synthetase blocked and prostaglandin receptor blocked groups exhibited slight increases in cardiac output with embolism (Table I). Systemic arterial pressure and total systemic resistance were unchanged with embolism, except for an increase in pressure in the meclofenamate treated animals.

Alveolar hypoventilation following embolism was demonstrated by the changes in arterial oxygen and carbon dioxide tensions (Table II). In the untreated animals, embolism caused significant reductions in Pa02 (-17.1 nnnHg) and increases in PaC02 (+4.6 mmHg) at 5 minutes post embolization. Histamine receptor blockade had no effect upon these altered blood gas tensions; (PaO2, -20.0 mmHg; PaC02, +5.1 mmHg). How- ever, in the three groups in which prostaglandin inhibitors and blockers were used, the changes in arterial blood gas tensions were attenuated: meclofenamate treated (PaO2, -6.5; PaC02, -0.2 nnnHg); polyphloretin phosphate treated (P,O2, -2.0; P,CO2, +1.3 mmHg); and combined meclofenamate and histamine antagonist treated (P,O2, -5.2;

paC02, +1.8 ImnHg). The changes in arterial blood gas tensions, from control, were similar at 5 and 30 minutes post embolization.


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c

M

H

M+H .-._ .A-.-.-.-.-.-.A_.-.- ._._. -.A

l. I ,,

t

IO 20 MICROEMBOLI

30

INJECTED TIME POST EMBOLIZATION ( Minutes )

Figure 1 -Pulmonary arterial pressor responses to microembolism in control (C), meclofenamate (M), polyphloretin phosphate (P), histamine antagonist (H), and combined meclofenamate and histamine antagonist (M + H) treated dogs. Values are Mean 2 SEM. Control and 5 minute SEM values are shown in Table I.


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TABLE I - Hemodynamic responses at 5 minutes post pulmonary microembolism

Cont Meclo PPP Hist M+H

PAP bmnw) Control

Embolism

PAWP (mmHg) Control

Embolism

PVR (Units) Control

Embolism

f, (L/min) Control

Embolism

SAP tag) Control

Embolism

TSR (Units) Control

Embolism

17+1 -

40+4* -

16+1 -

32+2*

4+1 -

4+1 -

4+.5

3+.5 -

5.3+.7 -

15.6+2-l* -

2.5+.2 -

2.5+.3 -

4.9+.a -

10.6+1.6* -

2.7i.3

127+4

3.0+.4* -

127+5 -

129+6 132+6* - -

54+4 52+5 -

56+6 - 49+5 -

14+1 -

22+2*

2+.5 -

12.5

7.3+1.1 -

11.1+1.2* -

1.7+.1 -

2.02.1*

125+8 -

127+7 -

73+6 -

66+5 -

16+1 -

32+3*

5+1 -

4+1 -

3.8+.3 -

10.3+.9* -

3.W.3 -

2.9+.3

141+5 -

131+10

50+5

47+7 -

15+1 -

27+2* -

6+1 -

521

3.8+.3 -

9.2+1.0* -

2.5+.2 -

2.52.2

124+8

12426

5124

51+4 -

Cont, untreated control; Meclo, meclofenamate treated; PPP, polyphloretin phosphate treated; Hist, histamine antagonist treated; M + H, combined meclofenamate and histamine antagonist treated. PAP, pulmonary arterial pressure: PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; 6, cardiac output; SAP, systemic arterial pressure; TSR, total systemic resistance. All values are mean + SIN. * difference between control and 5 minute embolism values significant at P < 0.05.


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18-

69

MICROEMBOLI

INJECTED I TIME POST EMBOLIZATION

( Minutes )

Figure 2 -Pulmonary vascular resistance responses to microembolism. See legend to Figure 1 for abbreviations. ?he SEM values

for the M and H groups are similar to, and fall within the SEM bars of the P and M + H groups.


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TABLE II - Arterial blood gas tension and pH responses at 5 minutes post pulmonary microembolism

Pa02 (mmHg) Control

Embolism

PaC02 (ImtQ-Ig) Control

Embolism

pH, (Units) Control

Embolism

Cont Meclo PPP Hist M-FH

84+5 93+5 84+6 101+6 98+8 - - - - -

6?+3* 86+6 82+3 81+5* 92+8 - - - -

46+2 39+3 38+3 36+2 39+5 - - - -

50+3* 38+2 40+3 41+2* 40+5 - - -

7.27+.02 7.34+.03 7.29+.05 - 7.332.01 7.28i.04 - - -

7.24+.02 7.33+.03 7.28+.05 7.29+.02 7.28+.04 - -

Cont, untreated control; Meclo, meclofenamate treated; PPP, polyphloretin phosphate treated; Hist, histamine antagonist; M + H combined meclofenamate and histamine antagonist treated. PaO2, arterial oxygen tension: PaC02, arterial carbon dioxide tension; pHa, arterial

PH. All values are mean + SEM. * difference between control and 5 minute embolism values significant at P < 0.05.

Discussion

Prostaglandins and histamine have been shown to be released into the venous effluent of embolized lungs (l-4). The results of the present study, using specific antagonists, further these observations by suggesting the probable role of prostaglandins and histamine in the pulmonary responses to microembolism. The attenuated pulmonary vascular responses to embolism following blockade of prostaglandin synthesis and histamine blockade, suggested that both vasoconstrictor prostaglandins and histamine are involved in the increased pulmonary vascular resistance. However, Nakano and McCloy (5) observed no reduction in the pulmonary hypertensive response following prostaglandin synthesis inhibition with indomethacin. The reason for this discre- pancy may be related to their use of barium sulfate for lung embolization, whereas we used glass beads. It is possible, despite the low solubility of barium sulfate, that barium ions may have interacted with the pulmonary arterioles causing tonic contractures (13) that could not be blocked by prostaglandin inhibition. Recently, aspirin


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has been shown to reduce the increase in central venous pressure and prevent the.mortality (14), and reduce the pulmonary hypertension (15) induced by pulmonary thromboembolism. However, the protection afforded by aspirin was attributed to inhibition of serotonin release from platelets (13) and to an unknown site and mode of action (15), rather than to its reported inhibition of prostaglandin synthesis (10).

Since combined prostaglandin and histamine blockade did not a- bolish the pulmonary vascular responses to microembolism in the present study , other vasoactive agents, such as serotonin (16-18), and physical obstruction (5, 19, 20) are probably also important in the increased resistance to flow. Neural reflex vasoconstriction has also been suggested as a possible mechanism of the increased pulmonary vascular resistance with microembolism (21-24). However, many investi- gators have not been able to demonstrate the existence of vasomotor reflexes (19, 25-27). The primary factors involved in the increased pulmonary vascular resistance, therefore, appear to be physical obstruction, and release and action of vasoconstrictor agents, such as prostaglandins, histamine, and serotonin.

The previously reported involvement of prostaglandins in the airway response to lung embolism (5) was confirmed in the present study. The alveolar hypoventilation induced by microembolism was suggestive of bronchoconstriction, a response that has been well documented (6, 28, 29). Since prostaglandin, but not histamine, inhibitors attenuated the alveolar hypoventilation, prostaglandins are probably the primary agents responsible for airway constriction with pulmonary microembolism. Nadel et al. (6) reported that the airway constriction with barium sulfate embolism was due to histamine release, since pre- treatment with compound 48/80 reduced the airway response. However, compound 48/80 has many actions other than histamine depletion (30). The evidence, therefore, suggests that histamine may not be as important as other agents in the airway response to embolism.

The site of release of prostaglandins and histamine remains to be determined , although the likely sites are either the vessels and parenchyma surrounding the emboli , or,the platelets that adhere to and aggregate on emboli (4, 7, 8, 15, 31). Lung embolism, produced by platelet aggregates, does produce vascular and airway responses (4, 26) similar to those observed following particulate and thrombotic embolism. Furthermore, reduced pulmonary vascular responses to embolism have been demonstrated in dogs and cats rendered thrombo- cytopenic by treatment with anti-platelet serum (8, 14). Therefore, platelets may be the primary sites of vasoconstrictor and broncho- constrictor agent release. In the present study it could not be de- _ termined if the agents were released from lung tissue or from the platelets adhering to the glass bead emboli. Vaage and Piper (51, however, have suggested that the prostaglandins are released only from platelets and not from lung tissue.


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