Relationship between systemic blood pressure, airway blood flow and plasma exudation in guinea-pig

Relationship between systemic blood pressure, airway

blood ¯ow and plasma exudation in guinea-pig

Z . - H . C U I , H . A R A K A W A , I . K A W I K O V A , B . - E . S K O O G H and J . L OÈ T V A L L

Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, GoÈteborg University, Gothenburg, Sweden

ABSTRACT

Plasma exudation in the airways is mainly dependent on microvascular permeability of the

tracheobronchial circulation and may be affected by local blood flow. Aortic blood pressure provides

the major inflow pressure to tracheobronchial circulation. Therefore, systemically administered

vasoconstrictors, in doses enough to increase systemic blood pressure, may theoretically increase

the blood flow in the tracheobronchial circulation by enhancing inflow pressure. Consequently, this

may influence plasma exudation induced by inflammatory mediators in the airways. To test this

hypothesis, we used guinea-pigs to study: (1) the effects of i.v. vasoconstrictors (methoxamine and

angiotensin II) on blood flow in the tracheal mucosa and in the leg skeletal muscle (Laser-Doppler

flowmetry); (2) the effects of i.v. vasoconstrictors on plasma exudation induced by tracheal

administration of the inflammatory mediator bradykinin (150 nmol). We found that i.v. methoxamine

and angiotensin II significantly increase tracheal mucosa blood flow and systemic blood pressure. The

increase in tracheal mucosa blood flow was, in the case of angiotensin II, found to be significantly

related to the increase in systemic blood pressure. In separate experiments, pre-treatment with i.v.

methoxamine and angiotensin II significantly potentiates Evan's Blue dye exudation induced by

bradykinin in the trachea and main bronchi. We conclude that i.v. methoxamine and angiotensin II

potentiate bradykinin-induced plasma exudation in the guinea-pig airways, possibly by increasing the

local blood flow. The increase in the local blood flow is most likely induced by enhanced systemic

blood pressure (inflow pressure), owing to a redistribution of the total body blood flow.

Keywords asthma, blood ¯ow, bradykinin, plasma exudation, vasoconstrictor.

Received 12 February 1997, accepted 21 September 1998

Increased plasma exudation in the airways and subse-

quent airway wall oedema formation have been sug-

gested to be important in asthma (Persson 1986, Barnes

et al. 1988, Chung et al. 1990). Plasma exudation is

mainly a result of increased microvascular permeability

of the tracheobronchial circulation and the degree of

plasma exudation has been suggested to be modi®ed by

local blood ¯ow (Williams & Peck 1977).

In most species, the aorta blood pressure is the most

important in¯ow pressure for the tracheobronchial

circulation. In more peripheral intrapulmonary airways,

the pulmonary circulation can also contribute to the

bronchial blood ¯ow. The bronchial circulation drains

mainly through the low-pressure pulmonary vascular

bed into the left atrium and also to some extent

through tracheal veins into the right atrium (Deffebach

et al. 1987, Barman et al. 1988). These characteristics

make the tracheobronchial circulation a unique

vasculature. It was earlier suggested that the bronchial

arterial blood ¯ow increases as a consequence of in-

creased systemic blood pressure (Aramendia et al.

1962). Therefore, intravenous vasoconstrictors may

increase the local blood ¯ow in the tracheobronchial

circulation as a consequence of increased systemic

blood pressure.

Generally, in¯ammatory mediators with the capacity

to induce plasma exudation are also vasodilators (Wil-

liams 1979, Brain & Williams 1985, Barnes et al. 1988).

Furthermore, in¯ammatory mediator-induced plasma

exudation in skin can be potentiated by vasodilators, by

increasing the local blood ¯ow (Williams 1979, Brain &

Williams 1985). In contrast, vasoconstrictors can at-

tenuate plasma exudation in the skin by decreasing the

local blood ¯ow at the in¯ammatory site (Beets & Paul

1980). However, such synergism in the skin may not be

relevant to the airways, because of the unique

Correspondence: Dr Jan LoÈtvall, Associate Professor, Lung Pharmacology Group, Sahlgrenska University Hospital, Guldhedsgatan 10 A, 413 46

GoÈteborg, Sweden.

Acta Physiol Scand 1999, 165, 121±127

Ó 1999 Scandinavian Physiological Society 121

characteristics in the tracheobronchial circulation. In

fact, it has been found that a vasodilating neuropeptide

(CGRP) does not potentiate substance P-induced

plasma exudation in guinea-pig airways (Rogers et al.

1988), and a2-adrenoceptor agonists, such as oxy-

metazoline, do not reduce histamine-induced airway

plasma exudation (Svensson et al. 1992).

The aim of the present study is therefore to evaluate

the effects of systemically administered vasoconstric-

tors on blood ¯ow and plasma exudation in the airways.

To do this, we used guinea-pigs to test the effects of i.v.

methoxamine (a1-adrenoceptor agonist) and angioten-

sin II on tracheal blood ¯ow (doppler ¯owmetry) in

one series of experiments and on bradykinin-induced

airway Evan's Blue dye exudation in another.

MATERIALS AND METHODS

Animal preparation

All experiments in the present study were approved by

the Animal Ethics Committee in GoÈteborg. Sixty-one

Dunkin Hartley guinea-pigs were used. The animals

were anaesthetized with ketamine (50 mg kg)1, i.m.)

and xylazine (5 mg kg)1, i.m.), placed on a body tem-

perature-regulating heat blanket (Harvard model 50±

7061, Harvard Apparatus, Edenbridge, UK) to keep

body temperature at 37 °C. Animals were tracheos-

tomized, and ventilated by a constant volume me-

chanical ventilator (Harvard model 50±1718, Harvard

Apparatus Ltd) with a tidal volume of 10 mL kg)1 and

a frequency of 60 breaths min)1. The left carotid artery

was cannulated to monitor mean systemic blood pres-

sure with a pressure transducer (model P23XL, Viggo-

Spectramed, Helsingborg, Sweden). The right external

jugular vein was cannulated for the administration

of drugs. All animals were pre-treated with sux-

amethonium (5 mg i.v.) 10 min before measurement to

avoid artefacts induced by spontaneous breath. Addi-

tional ketamine and xylazine were given during the

experiments to maintain appropriate anaesthesia.

Measurements

Blood ¯ow

Tracheal mucosa and skeletal muscle (right hind limb)

blood ¯ow was measured by Laser-Doppler ¯owmetry

(LDF, Peri¯ux 4001 Master, Perimed, Sweden). A hole

was made in the anterior tracheal wall by the tip of a

25G needle and a stainless steel laser probe (1 mm

outer diameter) was inserted through the hole and

positioned so that the probe tip pointed perpendicularly

to the posterior tracheal mucosa. No macroscopical

bleeding was induced by this procedure and no air

leakage was seen through the hole after insertion of the

probe. A small piece of black plastic was placed be-

tween the trachea and oesophagus to avoid any laser-

Doppler signal from the underlying tissues (Samuet

et al. 1988). Another probe was inserted through the

lumen of a 25G needle into the right hindlimb vastus

medialis muscle. The probes were adjusted to a position

to get proper laser-Doppler signals and then ®xed with

micromanipulators and maintained in position during

any experimental measurement, and were repositioned

as necessary between interventions (Cor®eld et al.

1991). The change in blood ¯ow was expressed as

Perfusion Unit (PU). One PU is an arbitrary value

which is an analogue output of 10 mV. The stable

signals of blood pressure and PU before each dose were

recorded as baseline for this dose.

Lung resistance and Evan's Blue dye exudation

Lung resistance was calculated from transpulmonary

pressure (Ptp) and air¯ow by the method of Von

Neergaard, V. & Wirz, K. (1927). Ptp was measured

with a pressure transducer (Model FCO40;

�1000 mmH2O; Furness Controls, Bexhill, Sussex,

UK), with one port connected to a catheter inserted

into the right pleural cavity and the other port con-

nected to the intratracheal cannula. The ventilatory

circuit had a total volume of 18 mL. Air¯ow was

measured with a pneumotachygraph (Model F1L; G.M.

Instruments, UK) connected to a transducer (Model

FCO40; �20 mmH2O; Furness Controls). All signals

were digitalized with a 12-bit analogue digital board

(National Instruments, Austin, TX, USA) connected to

a Macintosh II computer (Apple computer, Cupertino,

CA, USA) and analysed with a software (LabView,

National Instrumentsä). For the study of the effect of

vasoconstrictors per se, animals were given i.v. Evan's

Blue dye (20 mg kg)1) over 1 min. Two minutes later,

animals were intravenously injected with saline, met-

hoxamine or angiotensin II rapidly, and then mean

systemic blood pressure and lung resistance were re-

corded during the following 6 min. The animals were

then disconnected from the ventilatory circuit and the

airway tissue was dissected out as indicated below. For

the study of the effect of vasoconstrictors on plasma

exudation induced by bradykinin, Evan's Blue dye was

administered 4 min after pre-treatment with i.v. vehicle

(saline) or methoxamine or 2 min after angiotensin II.

Another minute later, bradykinin (150 nmol) was in-

stilled by ¯ushing 50 lL bradykinin with 1 mL air be-

hind the drug in a syringe directly into the tracheal

lumen through the tracheostomy. In a preliminary

study, we have demonstrated that tracheally instilled

Evan's Blue dye rapidly distributes from trachea to

distal intrapulmonary airways (lungs taken out within

minutes after instillation and dye found macroscopically

also in intrapulmonary airways). Systemic blood pressure

Airway blood ¯ow and plasma exudation � Z -H Cui et al. Acta Physiol Scand 1999, 165, 121±127

122 Ó 1999 Scandinavian Physiological Society

and lung resistance were monitored for 6 min. Animals

were then disconnected from the ventilator and the

thoracic cavity was opened. The systemic and pulmo-

nary circulation were perfused via the left ventricle and

the pulmonary artery, respectively, with 50 mL saline to

remove Evan's Blue dye in the bronchial circulation.

The trachea, main bronchi and proximal intrapulmo-

nary airway (PIA) and distal intrapulmonary airway

(DIA) were carefully dissected out. All airway tissues

were freeze dried (MicroModulyo, Edwards High

Vacuum International, West Sussex, UK) for 24 h and

were then weighed and Evan's Blue dye was extracted

in 2 mL formamide in a 40 °C water bath for 24 h.

Absorption at 620 nm was measured with a spectro-

photometer (Beckman DB, IngenioÈrs®rma Hugo Till-

quist, Stockholm, Sweden). The extracted Evan's Blue

dye was quanti®ed by interpolation on a standard curve

of Evan's Blue dye concentrations in the range of 0±

16 lg mL)1 and expressed as ng per mg dry tissue.

Evan's Blue dye exudation has been previously shown

to highly correlate with the exudation of radio labelled

albumin in guinea-pig airways (Rogers et al. 1989).

Protocols

Protocol 1: effects of i.v. vasoconstrictors on blood pressure

and local blood ¯ow

The effects of increasing dose of i.v. methoxamine

(0, 0.5, 2 and 8 mg kg)1, n � 6) or angiotensin II (0, 1,

3, 10 and 30 ng kg)1, n � 6) on systemic blood

pressure and blood ¯ow in the tracheal mucosa and leg

skeletal muscle were studied. After a recovery period of

30 min after the animal preparation, drugs were given

in 30-min intervals. The effects of the vasoconstrictors

on the blood pressure and blood ¯ow were evaluated

every 30 s for 10 min.

Protocol 2: synergism between vasoconstrictors and bradykinin

on airway Evan's Blue dye exudation and lung resistance

The synergism between vasoconstrictors and brady-

kinin on Evan's Blue dye exudation in airway and lung

resistance was studied in 7 groups. Firstly, the effects of

i.v. methoxamine (2 mg kg)1, n � 5), angiotensin II

(10 ng kg)1, n � 6) and vehicle (saline, n � 5) per se

were studied in three separate groups. In an additional

series of experiments, the effects of i.v. vasoconstric-

tors on bradykinin-induced airway plasma exudation

and bronchoconstriction were studied in four groups:

pre-treatment with i.v. vehicle (saline) and saline in-

stillation into the tracheal lumen (n � 6); pre-treat-

ment with vehicle (n � 15), methoxamine (2 mg i.v.

kg)1, n � 6) and angiotensin II (10 ng i.v. kg)1,

n � 6), respectively, followed by bradykinin instilla-

tion.

Drugs and chemicals

The following drugs and chemicals were used: Ket-

amine hydrochloride (Park-Davis S.A., Barcelona,

Spain), Xylazine chloride (Bayer Sverig AB, GoÈteborg,

Sweden), Suxamethonium chloride (KabiVitum AB,

Stockholm, Sweden), Methoxamine, Angiotensin II,

and Bradykinin (Sigma Chemical, St Louis, USA), Ev-

an's Blue dye (Aldrich Chemical, Milwaukee, USA).

Methoxamine, angiotensin II, bradykinin and Evan's

Blue dye were dissolved in saline.

Data analysis

Data are reported as mean � SEM. The effects of the

vasoconstrictors on the blood ¯ow were expressed as

the Area Under the Curve (AUC) for 0±3 min after the

administration of saline or drugs. The Mann±Whitney

U-test was used to test the signi®cance between groups

and treatments for effects of vasoconstrictors. If more

than two groups were involved, the Kruskal±Wallis test

was used ®rst to be sure that signi®cance exists among

groups evaluated. Spearman Rank Correlation (RS) was

used to test for any relationship between the systemic

blood pressure and the blood ¯ow in trachea as well as

leg skeletal muscle, not including control animals (sa-

line), but all animals from active treatment. A P-value

less than 0.05 was considered to be signi®cant. Data

were analysed by a Macintosh computer using standard

statistical packages (StatView).

RESULTS

Blood pressure and local blood ¯ow

Increasing doses of intravenously administered vaso-

constrictors methoxamine and angiotensin II increase

mean systemic blood pressure �20±40 mmHg above

baseline (Table 1, Figs 1a and 2a). The time course of

these two vasoconstrictors was different. Thus, met-

hoxamine produced a prolonged enhanced systemic

blood pressure over the 10 min observation period,

whereas the blood pressure increase by angiotensin II

declined towards baseline immediately after �3 min.

The tracheal mucosa Perfusion Unit (PU) increased

signi®cantly after intravenous methoxamine and an-

giotensin II, except after the lowest dose of angiotensin

II (Table 1, Figs 1b and 2b), with a similar time-course

as blood pressure in the case of angiotensin II. A sta-

tistically signi®cant relationship was found between the

increase in systemic blood pressure (DmBp) and the

increase in tracheal mucosa PU (DPU) after angiotensin

II (RS � 0.60, P < 0.01) but not after methoxamine

(RS � 0.31; NS). Right hindlimb vastus medialis muscle

PU decreased signi®cantly after the highest dose of

methoxamine (Table 1).


Acta Physiol Scand 1999, 165, 121±127 Z -H Cui et al. � Airway blood ¯ow and plasma exudation

Synergism of vasoconstrictors and bradykinin

Intravenous administration of a single dose of met-

hoxamine (2 mg kg)1) and angiotensin II (10 ng kg)1)

did not have any signi®cant effect on lung resistance or

Evan's Blue dye levels in unchallenged guinea-pig air-

ways compared with saline (Table 2).

Instillation of bradykinin (150 nmol) into tracheal

lumen produced a signi®cant increase in lung

resistance (Table 3) and Evan's Blue dye exudation in

saline pre-treated animals (Figs 3b and 4b). The

pre-treatment of guinea-pigs with methoxamine

(2 mg kg)1, i.v.) and angiotensin II (10 ng kg)1, i.v.)

increased mean systemic blood pressure signi®cantly

from a baseline 47 � 4 and 39 � 2 mmHg, respec-

tively, to a maximum 75 � 4 and 72 � 5 mmHg, re-

spectively (Table 3, Figs 3a and 4a). The mean

systemic blood pressure in the two vasoconstrictor

groups was still signi®cantly higher compared with the

saline pre-treatment group at 2.5 min after instillation

of bradykinin (P < 0.05, Figs 3a and 4a). The pre-

treatment of guinea-pigs with both i.v. vasoconstrictors

signi®cantly potentiated exudation of Evan's Blue dye

induced by instillation of bradykinin, at the levels of

trachea and main bronchi (Figs 3b and 4b), but not in

intrapulmonary airways (data not shown). Pre-treat-

ment of guinea-pigs with i.v. vasoconstrictors did not

signi®cantly increase lung resistance induced by instil-

lation of bradykinin (Table 3).

Table 1 Effects of i.v. methoxamine (mg kg)1) and angiotensin II (ng kg)1) on the systemic blood pressure and Perfusion Unit (PU) in tracheal

mucosa and leg skeletal muscle

Bp (mmHg) Perfusion Unit (AUC of PU, 0±3min)

Drug Dose Baseline Maximum Increase Trachea Leg

Me Saline 57 � 5 59 � 5 2 � 1 )1 � 7 5 � 9

0.5 57 � 4 91 � 14 35 � 11 115 � 52* 41 � 27

2 77 � 3 119 � 9## 33 � 10 84 � 19** 6 � 11

8 78 � 2 104 � 7## 27 � 7 71 � 13** )74 � 15

A II Saline 58 � 3 61 � 4 4 � 1 )3 � 4 20 � 42

1 57 � 3 64 � 4 7 � 2 10 � 15 15 � 13

3 55 � 3 66 � 5 12 � 2 62 � 24* 29 � 11

10 54 � 6 84 � 7# 30 � 3 147 � 47** § 54 � 33

30 54 � 5 81 � 6# 28 � 5 151 � 78** §§ 42 � 19

The systemic blood pressure and tracheal mucosa Perfusion Unit increased after i.v. methoxamine (Me) and angiotensin II (A II), whereas leg

skeletal muscle Perfusion Unit did not change or even decreased (after methoxamine 8 mg kg)1). #P < 0.05, ##P < 0.01 vs. baseline Bp;

*P < 0.05, **P < 0.01 vs. saline; §P < 0.05, §§ P < 0.01 vs. 1 ng kg)1; P < 0.01 vs. saline, 0.5 and 2 mg kg)1 (n = 6).

Figure 1 Time course of systemic blood pressure (a) and percentage

change of tracheal mucosa Perfusion Unit (PU) from baseline in the

trachea (b) after the administration of i.v. methoxamine in guinea-

pig. Data are shown as means. For statistical evaluation, see Table 1.

Figure 2 Time course of systemic blood pressure (a) and percentage

change of tracheal mucosa Perfusion Unit (PU) from baseline in the

trachea (b) after the administration of i.v. angiotensin II in guinea-

pig. Data are shown as means. For statistical evaluation, see Table 1.



DISCUSSION

This study shows that i.v. administration of the vaso-

constrictors methoxamine and angiotensin II signi®-

cantly increase systemic blood pressure and the tracheal

mucosa blood ¯ow in guinea-pig, whereas skeletal

muscle blood ¯ow remains unchanged or decreased.

The increase in tracheal mucosa blood ¯ow parallels the

increase in systemic blood pressure. Intravenous met-

hoxamine and angiotensin II alone have no effects on

lung resistance and airway plasma exudation in guinea-

pig. However, pre-treatment with i.v. methoxamine and

angiotensin II signi®cantly potentiates plasma exuda-

tion in central airways induced by intratracheal instil-

lation of bradykinin.

The increases in systemic blood pressure and tra-

cheal mucosal blood ¯ow in the guinea-pig were shown

to be dose-dependent after angiotensin II, but dose-

dependence was not documented for methoxamine

(Table 1, Figs 1 and 2). The long duration of effect of

methoxamine increased the baseline blood pressure and

tracheal blood ¯ow before the highest doses used (2 and

8 mg kg)1; Table 1). Thus, the magnitude of the ana-

lysed change from baseline in Perfusion Units (DPU)

may have been smaller at the highest doses of met-

hoxamine than otherwise expected. Thus, the protocol

used in this series of experiments can alone explain why

the observed effects of methoxamine were not evi-

dently dose-dependent.

The local blood ¯ow in the tracheal mucosa in-

creases after both vasoconstrictors and a signi®cant

relationship was found between the increase in sys-

temic blood pressure and tracheal mucosa blood ¯ow

after angiotensin II. Furthermore, blood ¯ow in the leg

skeletal muscle concomitantly decreases after a high

dose of methoxamine. These data together suggest that

Table 2 Effects of i.v. saline, methoxamine and angiotensin II on lung resistance (RL) and Evans Blue dye exudation (EBD) in trachea and main

bronchi

RL (cmH2O mL s)1) EBD [ng (mg dry tissue))1]

Drug (n) Dose Body (g) Baseline Maximum Trachea m. bronchi

Saline 5 1 mL kg)1 580 � 11 0.16 � 0.03 0.19 � 0.04 60 � 8 44 � 9

Me 5 2 mg kg)1 594 � 8 0.22 � 0.03 0.29 � 0.04 67 � 13 39 � 11

A II 6 10 ng kg)1 608 � 8 0.13 � 0.01 0.16 � 0.01 66 � 12 44 � 4

i.v. methoxamine (Me) and angiotensin II (A II) per se have no effects on RL and EBD exudation in the trachea and main bronchi.

Table 3 The synergism of vasoconstrictors and bradykinin on the systemic blood pressure (Bp) and lung resistance (RL)

Bp (mmHg) RL (cmH2O mL)1 s)1)

Drug Body (g) Baseline Maximum Baseline Maximum

Saline + BK 417 � 5 46 � 3 45 � 1 0.33 � 0.01 1.55 � 0.02*

Me + BK 420 � 10 47 � 4 75 � 4* 0.30 � 0.02 2.11 � 0.28*

A II + BK 418 � 19 39 � 3 72 � 5* 0.33 � 0.02 2.25 � 0.42*

Pretreatment with i.v. methoxamine (Me) and angiotensin II (A II) increased systemic blood pressure. Instillation of bradykinin (BK) into tracheal

lumen increased lung resistance (RL). *P < 0.01 vs. baseline.

Figure 3 (a) Time course of systemic blood pressure after i.v. met-

hoxamine or saline in guinea-pigs (mean � SEM). Methoxamine

signi®cantly increased blood pressure (P < 0.05). (b) Bradykinin in-

stillation (150 nmol) produced exudation of Evan's Blue dye com-

pared with saline instillation. i.v. methoxamine signi®cantly enhanced

exudation of Evan's Blue dye induced by bradykinin instillation,

*P < 0.01. S � Saline (0.9%); Me � Methoxamine: Bk � Brady-

kinin; i.t. � intratracheally.



the systemic blood pressure is of great importance for

the tracheal blood ¯ow and that systemic vasocon-

strictors redistributes blood from other vascular beds

to the airways. We cannot exclude that the cardiac

output to a minor degree is increased by the vaso-

constrictors and therefore could contribute to the

increased airway blood ¯ow. However, systemic blood

pressure and the resistance of the vascular bed are

generally considered to be important factors for local

blood ¯ow.

The importance of the systemic blood pressure for

airway blood ¯ow is supported by an older study in the

heart-lung-bronchial preparation, demonstrating that

increase in aortal blood pressure can dramatically in-

crease bronchial arterial blood ¯ow (Aramendia et al.

1962). The importance of the systemic blood pressure

for local blood ¯ow is also seen in other tissues, such as

the cochlea and tongue, in which increased local blood

¯ow is found in response to i.v. vasoconstrictors

(Hasegawa et al. 1989, Fazekas et al. 1991). Thus, it is

likely that the constrictive potency and ef®cacy of a

vasoconstrictor varies between different vascular beds.

We would therefore suggest that the vasoconstrictive

response in the leg skeletal muscle and other peripheral

tissue is strong, resulting in unchanged or decreased

local blood ¯ow. In contrast, the vasoconstrictive

response in the tracheobronchial circulation seems to

be comparatively weaker, suggesting that a slight

vasoconstriction in this vascular bed is opposed by a

pronounced elevated systemic blood pressure. This

would cause the local blood ¯ow to increase in the

tracheobronchial tissue despite mild vasoconstriction

(Gilman et al. 1990). In contrast, local administration of

vasoconstrictors into the tracheobronchial circulation,

at doses not affecting systemic blood pressure, in-

creases tracheobronchial vascular resistance, resulting

in decreased local blood ¯ow and attenuate in¯amma-

tory mediator-induced plasma exudation in the airways

(Charan et al. 1985, Larrazet et al. 1994).

In this study, i.v. methoxamine (2 mg kg)1) and

angiotensin II (10 ng kg)1) have no effects per se on

lung resistance and plasma exudation at any airway level

in guinea-pig, although local blood ¯ow in the

tracheobronchial circulation is increased. It is possible

to in vitro induce contraction of airway smooth muscle

with methoxamine, but this drug has no reported effect

on lung resistance in vivo (Advenier et al. 1984, Biyah &

Advenier 1995). One study has surprisingly suggested

that six sequential intravenous injections of methox-

amine (25±800 lg kg)1, in 40 min) induces airway

Evan's Blue dye exudation in rat (Larrazet et al. 1994).

The discrepancy with our data may be owing to species

differences, or perhaps more importantly, to the dif-

ferent protocols used.

We have in this study con®rmed that instillation into

the tracheal lumen of the in¯ammatory mediator bra-

dykinin increases lung resistance and causes airway

plasma exudation in guinea-pigs. Pre-treatment of

guinea-pigs with i.v. methoxamine and angiotensin II

both signi®cantly potentiate bradykinin-induced plasma

exudation about 70±90%, whereas no signi®cant en-

hancement of the induced lung resistance is observed.

This suggests that the permeability of the airway mic-

rovasculature is increased by bradykinin, resulting in

plasma exudation, and that the induced plasma exuda-

tion is enhanced by increased local blood ¯ow. Thus, it

seems that the degree of local blood ¯ow in¯uences the

degree of plasma exudation in airways. We chose to

induce plasma exudation with bradykinin, because in

our experience, this mediator is a potent inducer of

plasma exudation, and responses are generally very

reproducible from animal to animal.

No signi®cant enhancement of bradykinin-induced

plasma exudation in intrapulmonary airways were ob-

served after pre-treatment with the vasoconstrictors.

This ®nding may indirectly suggest that the increase in

blood pressure induced by the vasoconstrictors increase

local blood ¯ow and thus plasma exudation only in

more central airways. In the guinea-pig, it is likely that

the contribution of the systemic circulation to local

blood ¯ow in central airways is substantial, but in more

peripheral airways much smaller.

Figure 4 (a) Time course of systemic blood pressure after i.v. ad-

ministration of angiotensin II or saline in guinea-pigs (mean � SEM).

Angiotensin II signi®cantly increased systemic blood pressure

(P < 0.05). (b) Bradykinin instillation (150 nmol) produced exudation

of Evan's Blue dye compared with saline instillation. i.v. angiotensin

II signi®cantly enhanced exudation of Evan's Blue dye induced by

bradykinin instillation, *P < 0.01. S � Saline (0.9%); A

II � Angiotensin II; Bk � Bradykinin; i.t. � intratracheally.



In conclusion, intravenously administered methox-

amine and angiotensin II increase systemic blood

pressure and tracheal mucosa blood ¯ow and potentiate

airway plasma exudation induced by bradykinin instilled

into the tracheal lumen of guinea-pig. The increase of

the blood ¯ow by i.v. vasoconstrictors is probably

caused by a redistribution of total blood ¯ow from

other vascular beds. We strongly suggest that in studies

of airway plasma exudation, the in¯uence of local blood

¯ow in tracheobronchial circulation and systemic blood

pressure should be taken into account. The details of

the relationship between systemic blood pressure, air-

way blood ¯ow and airway plasma exudation in asthma

remains unclear, but would be of great interest to

evaluate when appropriate techniques are available.

This study was supported by the Swedish Heart & Lung Foundation,

the Swedish Medical Research Council, the Swedish Work Environ-

mental Fund, the VaÊrdal Foundation and by Herman Krefting

Foundation Against Asthma-Allergy.

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Relationship between systemic blood pressure, airway blood flow and plasma exudation in guinea-pig

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