microsphere analysis of β2-adrenergic control of resistance in different vascular areas after...

Acta Physiol Scand 1984, 121: 119-126

Microsphere analysis of 1S,-adrenergic control of resistance in different vascular areas after hemorrhage

DAVID GUSTAFSSON,’ LENA ANDERSSON,’ LENA MARTENSSON3 and JAN LUNDVALL‘ ‘Department of Physiology and Biophysics, ’Department of Radiation Physics, and ’Department of Zoophysiology, University of Lund, Sweden

GUSTAFSSON, D., ANDERSSON, L., MARTENSSON, L., & LUNDVALL, J.: Mi- crosphere analysis of &-adrenergic control of resistance in different vascular areas after hemorrhage. Acta Physiol Scand 1984, 121: 119-126. Received 20 June 1983. Accepted 11 Jan. 1984. ISSN 0001-6772. Department of Physiology and Biophysics, Department of Radiation Physics, and Department of Zoophysiology, University of Lund, Sweden.

In cats exposed to bleeding (exsanguination of 15 mlxkg bwt-I) the microsphere technique was used to determine regional vascular resistances in a large number of tissues before and after i.v. administration of the ‘selective’ B2-adrencceptor antagonist ICI 118,551. b2-blockade significantly raised vascular resistance in the stomach (+26%), small (+25%) and large (+38%) intestine, pancreas (+29%), kidney (+39%), omental(+33%) and subcutaneous (+26%) fat, ‘white’ skeletal muscle (+19%), and skin (+24%). These findings indicate that, with intact p-adrenoceptors, &adrenergic dilator interaction counteracted the hemorrhage evoked vasoconstrictor influences. &blockade also evoked quite a strong increase of total peripheral resistance (19%) and led to some redistribution of cardiac output. It is concluded that &adrenergic inhibition of vascular tone significantly seems to improve tissue perfusion during bleeding in several vascular areas. Such effects may be of special significance during severe hemorrhage. In the intestine, pancreas, and adipose tissue, for example, protection against excessive vasoconstriction may serve to minimize the severe metabolic disturbances with secondary release of toxic factors into the circulation reported during hemorrhagic shock.

Key words: &adrenergic, p2-blockade, peripheral resistance, cardiac output, distribution of cardiac output, microspheres

It has been known for several decades that j3-adrenoceptors are present in the resistance vessels of most vascular beds, but few if any studies in the past have been able do demonstrate a clear-cut and well defined role for these receptors in the integrat- ed, reflex circulatory control. Recent studies strongly indicate, however, that vascular Bz-adrenoceptors can mediate an important control of the peripheral circulation in bleeding. These investiga- tions revealed a potent #I-adrenergic dilator interaction with the hemorrhage-induced vasoconstrictor influences in several hemodynamically important vascular areas, viz. in skeletal muscle, small intestine, skin, and also, to some extent, in the kidney (Lundvall & Hillman 1978, Hillman & Lundvall

1980, Lundvall & Gustafsson 1981, Gustafsson & Lundvall 1982). It was concluded that the j3-adrenergic inhibitory influence on vascular tone in the resistance vessels, most likely exerted by the blood-borne catecholamines, might significantly improve tissue perfusion (nutrition) in bleeding. It might also have beneficial influences on central hemodynamics since the regional effects were reflected in the total peripheral resistance of the systemic circulation (see Gustafsson et al. 1982, Gus- tafsson & Lundvall 1984).

The aim of the present study was- to obtain a more detailed picture of the vascnlar areas respon- sible for the Pz-adrenergic effect on total peripheral resistance in hemorrhage and, further, to investi-

Acta Physiol Scand 121

120 D . Gustafsson et al.

gate whether the p2-adrenergic resistance control may result in a redistribution of cardiac output. For this purpose the microsphere technique was used in order to permit simultaneous atraumatic measure- ment of arterial blood flows to a large number of tissues.

METHODS Material and anaesthesia. Cats of both sexes (2.1-2.9 kg) anaesthetized with chloraiose (60 mgxkg bwt-I) and urethane (100 mgxkg bwt-I) were used in the study. The animals were tracheotomized and breathed spontaneously throughout the experiment. Body temperature was main- tained at 38+0.5"C. Heparin (lo00 IUxkg bwt-') was given before intravascular instrumentation.

Surgical and experimental procedures. A polyethylene catheter (0.d. 0.96 mm and i.d. 0.58 mm) for microsphere injection was inserted via the left common carotid artery and its tip gently advanced into the left cardiac ventricle as evidenced by the abrupt fall in diastolic blood pressure when passing the aortic valves. The placement of the catheter in the ventricle was confirmed at autopsy. Anoth- er catheter in the left brachial artery was used for bleeding and for sampling of reference blood (see below). A third catheter in the right brachial artery was used for determination of mean arterial blood pressure (MAP) and heart rate (HR). HR, triggered by the arterial pulse using a Grass tachograph model 7P4D, and MAP were recorded on a Grass polygraph.

Regional blood flows, cardiac output (CO), as well as the fractional distribution of CO to the various tissues were determined with the radioactive microsphere technique originally described by Rudolph & Heymann in 1967 (see also reviews by Hales 1974 and Heymann et al. 1977). The microspheres were labelled with either I4'Ce or '03Ru to permit two determinations in each animal. The animals were subjected to standardized, rapid ( t 2 min) withdrawal of 15 ml of bloodxkg bwt-' (-30% of total blood volume, cf. Hillman et al. 1982). Five cats were used to investigate the effect of hemorrhage per se on regional vascular resistance, and in these animals the first microsphere injection was performed 5 rnin prior to bleeding and the second one 25 min after completed exsanguination. Nine cats were used to study the &adrenergic dilator interaction with the vasoconstrictor influence on the resistance vessels in hemorrhage. This was done by comparing the resistance before and after acute blockade of the vascular Bz-adrenoceptors. The first microsphere injection in these experiments was performed 25 min after completed exsanguination. After this, the vascular /Iz- adrenoceptors were blocked (see below) and a second microsphere injection performed 10 rnin later, i.e. about 35 rnin after the exsanguination. The B2-adrenergic resistance effect is known to be fully developed 25 min after exsanguination (Gustafsson & Lundvall 1984). Five cats not subjected to Bz-blockade served as controls to study possible resistance alterations during the time period 25 to 35 rnin after hemorrhage, demonstrating that such were minor (see Results).

Blockade of the /?2-adrenoceptors was accomplished by i.v. administration of the highly 'selective' (O'Donnell & Wanstall 1980, Bilski et al. 1983) &blocking agent ICI 118,55 1 [erythro-dl-l-(7-methylindan-4-yloxy)-3-isopro- pylaminobutan-2-ol, Imperical Chemical Industries Ltd., England] in a dose of 80 pgxkg bwt-'. This dose of the blocker has been shown to cause effective vascular B2- adrenoceptor blockade within few rnin after application (Gustafsson & Lundvall 1984) without interfering with the P1-adrenoceptors of the heart (Johns 1981, Smith et al. 1983, Bilski et al. 1983).

Microspheres with a diameter of 15+ 1 pm (mean f SD; New England Nuclear, Boston, Mass.), prelabelled at a specific activity of 10 mCixg-' with I4'Ce and '03Ru, respectively, were used. Before injection they were sus- pended in 10% Ficoll-NaC1 solution, containing 0.01 % polyoxyethyl sorbitan monooleate (Tween 80) as an anti- aggregant agent, and mechanically and ultrasonically agi- tated for 10-15 min. 1.5 ml of the solution, containing approximately 3 x lo6 microspheres, was injected into the left ventricle of the heart over a period of 45 s and the catheter was immediately flushed with saline. The injections were not associated with changes in heart rate or blood pressure. Arterial reference blood was withdrawn by a pump at the rate of 1.74 mlxmin-', beginning 15 s before injection and continuing for a total of 120 s. Sam- pled reference blood was compensated for by transfusion. Five min after the microsphere injections, an arterial blood sample was withdrawn for analysis of possible pres- ence of microspheres in the circulating blood. No microspheres could be demonstrated in the blood.

After the second microsphere injection the animals were killed by an i.v. overdose of pentobarbitone and tissue samples removed, weighed, and placed in gamma- scintillation counting tubes (maximum 5 g in each tube). Some of the organs (tissues) were distributed into several counting tubes. The entire cerebrum, cerebellum, brain- stem, parotid and submaxillary glands (analyzed together), adrenal glands, kidneys, urinary bladder, gastrocnemius muscle, soleus muscle, and pads of the hind limb paws were removed. Multiple tissue samples were taken from the stomach, small intestine, large intestine, liver, subcutaneous fat and from the skin of the hind limbs and the back. Single samples were taken from the pancreas (mainly its tail), and from the omentum. No measurements were made on the myocardium since accurate determination of coronary blood flow with the microsphere technique requires left atrium injection (Wicker & Tarazi 1982).

Tissue and reference sample radioactivity was counted in a 2"X2" welltype NaI(Tl)-scintillation counter (Selec- tronik 45-22) with appropriate window settings. The cross-channel interference of I4'Ce and '03Ru as well as the geometrical effects caused by varying amounts of tissue in the counting tubes were corrected for. Injected activity (pre-injection minus residual activity in the sy- ringe) was measured in a well-type ionization chamber (Capintec CRC 4). There was a minimum of 400 spheres in each tissue sample and a minimum of 2000 spheres in each reference blood sample implying that the counting errors were below 20 % at 95 % confidence level (Buck- berg et al. 1971, Dole et al. 1982). The radioactivity in the

Acru Physiol S a n d I21

j32-adrenergic vasodilatation in hemorrhage 121

adrenal gland, on the other hand, showed a clear-cut decrease of resistance (-46%). The raised resistance in the individual tissues was reflected in total peripheral resistance (TPR) which increased by 28%. Concomitantly there was a decrease of both cardiac output (CO; -36%) and of mean arterial blood pressure (MAP; -22%). Although these data refer to a limited number of experiments the observed vascular resistances in the control period as well as the effects evoked by hemorrhage are in agreement with previous reports in the literature (for ref. see Mellander 62 Johansson 1968, Slater et al. 1973). As shown by the results below, however, the observed resistance response in several of the studied tissues seems to depict the net effect of hemorrhage evoked vasoconstrictor and concomitant Bz-adrenergic vasodilator influences.

Table 2 summarizes (9 animals) the observed effects on regional vascular resistances and on central hemodynamics caused by B2-adrenoceptor blockade instituted during hemorrhagic hypovolemia. The data with intact B-adrenoceptors were obtained 25 min after rapid withdrawal of 15 ml

left and right kidney did not differ by more than 1 5 % in any animal, signifying adequate mixing of the microspheres in the arterial blood after injection. CO has pre- viously been determined by the indicator dilution technique (Gustafsson et al. 1982, Gustafsson & Lundvall 1984). The effects on CO of bleeding and of &blockade were similar in the present and in the previous studies, although the magnitude of CO was somewhat smaller in the previous studies.

Calculations of circulatory functions. Organ sample activity (OSA; Bq), organ sample weight (OSW; g), reference sample activity (RSA; Bq), reference sample rate (RSR; mlxmin-I), injected activity (IA; Bq), body weight (bwt; kg) were used to calculate the following functions.

1. Organ blood flow (mlxmin-'X100 g tissue-') - - OSAxRSRxlOO

RSAx OSW

2. Cardiac output (mlxmin-' kg bwt-') - RSRXIA -

RSAxbwt '

3. Stroke volume (mlxkg bwt-I) - co -~

HR ' bloodxkg bwt-' and the data after the subsequent i.v. administration of the 'selective' j3z-blocking agent ICI 118,551 10 min later. It can be seen that &blockade caused a statistically significant increase in resistance in several tissues, viz. in the

- - MAP stomach (+26%), small (+25%) and large (+38%) intestine, pancreas (+29%), kidney (+39%), omental (+33%) and subcutaneous (+26%) fat, gastrocnemius muscle (+19%), and skin (+24%). TPR also increased significantly (+ 19 %), whereas CO decreased (-15%). mainly due to a decline in

4. Fractional distribution of CO (% X 100 g tissue-') - - OSAx l00x 100

IAxOSW

5 . Regional resistance (mmHgxminx 100 gxml-')

organ blood flow

6. Total peripheral resistance (mmHgxmin

xkg bwtxml-I) =MAP. co ,,

Statistics. Spread of data in Results is given as standard error of the mean (SE) and the statistical significances were calculated according to Student's t-test for paired observations.

stroke volume (sv). The most likely explanation for these findings is that bleeding with intact 82-

adrenoceptors is associated with a quite strong Pz-

RESULTS

The pattern of vascular resistance response evoked by hemorrhage in cats with intact 8-adrenoceptors was investigated by determination of regional vascular resistances in the prehemorrhage control period and 25 min after completed exsanguination of 15 mlxkg bwt-' (Table 1; n=5). Most tissues tended to increase vascular resistance in response to bleeding and this effect was especially marked in the pancreas (+133 %), urinary bladder (+97%), omen- tai (+106%) and subcutaneous (+145%) fat, skin (+%%), and in the pad of the paw (+106%). The

adrenergic dilator interaction with the hemorrhage induced vasoconstrictor influence (see Discussion). Control experiments without B2-blockade (5 animals), in which observations were made 25 and 35 min after bleeding (15 mlxkg bwt-I), showed no or only small increases in resistance with time. In the tissues showing a significant effect in response to &-blockade (Table 2) the following average resistance alterations were found in these control experiments: Stomach +6%, small intestine +6%, large intestine -2%, pancreas, +6%, kidney +lo%, omental fat +O%, subcutaneous fat -9%, gastrocnemius muscle +3 %, skin -3 %. TPR increased by 3 % and CO was unchanged. Only in the kidney was


122 D . Gustafsson et al.

Table 1. Regional resistances (mmHgxminx 100 gxml-') and central hemodynamics in the control period prior to bleeding and 25 min after exsanguination of 15 mlxkg bwt-' (n=5)

Control period 25 min after prior to bleeding exsanguination Difference

Cerebrum Cerebellum Brain stem Spinal cord Salivary gland Stomach Small intestine Large intestine Liver (arterial) Pancreas Adrenal gland Kidney Urinary bladder Omentum Subcutaneous fat Gastrocnemius muscle Soleus muscle Skin Pad of the paw Total peripheral resistance

Cardiac out ut

Stroke volume

Heart rate

Mean arterial blood pressure

(mmHg xmin x kg bwt xml- ')

(mlxmin- P xkg bwt-I)

(mlxkg bwt-I)

(beats xmin-I)

(mmHg)

2.7k0.4 2.2k0.4 2.7k0.3 4.6f0.7 4.5k0.5 6.421.6 2.7f0.5 3.0k0.6 2.8f0.9 2.0 k 0.5

0.7820.19 0.60f0.08

10k2 31k6 48k 17 29k6 22k3 11f2 10f2

0.70k0.05

1902 11

0.97f0.04

197f15

131k5

2.9k0.3 2.1k0.2 2.7k0.2 4.2k0.3 5.3f0.4 9.4k 1.2 4.0f0.4 3.8k0.7 2.2k0.4 4.7t0.8

0.43k0.16 0.64k0.09

2022 64+ 14

118k29 40t5 26k5 21k3 21k3

0.90k0.16

121218

0.56f0.08

215f7

lOlklO

+0.2+0.3 -0.1 f0.4 0.0f0.5

-0.4k0.9 +0.8+0.4 +3.0+1.0 + 1.3k0.4 +0.7+0.3 -0.6f0.6 +2.7k0.3

-0.36k0.08 +0.04~0.11 + 10f2

+33+11 +70k 16 +11+4 +4+4

+ 10k2 +11+2

0.20t0.12

-69214

-0.4150.09

+18f8

-30210

(+6%) ( -5 %) (0 %I (-9%) (+18%) (+48%) (+51%) (+25%) (-22%) (+133%) (-46 %) (+6%) (+97%) (+106%) (+ 145 %) (+37%) (+ 18 %) (+96%) (+ 106 %)

(+28 %)

(-36%)

(-42 %)

(+9%)

(-22%)

- - - - - p<0.05 p<0.05 p<0.05

p<O.Ol p<O.Ol

p<O.Ol p<0.05 p<0.05

p<O.Ol p<o.o1

-

-

- -

-

p<O.Ol

p<0.05

-

~ ~ 0 . 0 5

the effect significant (p<O.OS) but the observed resistance increase was clearly smaller @<0.05, un- paired t-test) than that exerted by Brblockade.

The consequences of &blockade for the fractional distribution of CO are shown in Table 3. Note that the data are presented per 100 g tissue in analogy with the results in Tables 1 and 2, and not per whole organ (see Methods). As expected, the tissues showing a significant increase of regional resistance in response to &blockade (see Table 2) tended to decrease their fraction of CO, but this effect was significant only for the kidney (17% less than the fraction of CO distributed to the kidney with intact Pz-adrenoceptors). In several other tissues B2-blockade instead caused a 'passive' increase in the received fraction, significant in the adrenal gland and in the soleus muscle (12 and 23 % more than the fractions of CO distributed to these tissues with intact B-adrenoceptors). The interpre- tation of these results may be aided by considering the fact that the distribution of CO can be ex- pressed as TPWregional resistance instead of the

Acra Physiol Scand 121

conventional expression, regional blood flowKO. It follows that only those tissues in which the relative change (%) of regional resistance in response to &blockade markedly differed from the concomitant relative change in TPR (Table 2) will show clear-cut alterations in the fractional distribution of CO (Table 3, figures for %-change, far right). It should be pointed out, however, that the determination of regional resistance was based on the reference sample method and the determination of CO- distribution on injected activity (see Methods). Therefore, relative changes in CO-distribution esti- mated from the ratio TPWregional resistance may differ somewhat from those in Table 3.

DISCUSSION

The present results suggest that bleeding is associated with a signifcant j32-adrenergic dilator interaction with the hemorrhage-evoked constrictor influences in several tissues, viz. in the kidney, gastrointestinal tract, pancreas, adipose tissue, skin, and

P2-adrenergic vasodilatation in hemorrhage 123

Table 2 . Regional resistances (mmHgxminx100 gxml-') and central hemodynamics with intact and blocked P2-adrenoceptors 25 and 35 min, respectively, after exsanguination of 15 mlxkg bwt-' (n=9)

Intact Blocked adrenoceptors &adrenoceptors Difference

Cerebrum 2.1f0.2 2.3k0.2 +0.2+0.3 (+lo%) - Cerebellum 1.9f0.2 1.9f0.2 O.Ok0.2 (+2%) - Brain stem 2.2f0.3 2.320.3 +0.1+0.2 (+4%) - Salivary gland 4.9f0.7 4.8k0.7 -0.1f0.6 (-2%) - Spinal cord 4.0f0.7 3.6k0.5 -0.4f0.5 (-10%) - Stomach 7.2k0.6 9.1 50.7 +1.9+0.5 (+26%) pt0.01 Small intestine 2.650.2 3.3k0.3 +0.6+0.2 (+25%) pt0.01 Large intestine 1.8f0.2 2.5f0.4 +0.7f0.2 (+38%) p<O.O1

Pancreas 4.5f1.2 5.8f1.6 +1.3+0.4 (+29%) p<0.05 Liver (arterial) 2.8k0.7 2.9f0.6 +O.lk0.2 (+2%) -

Adrenal gland 0.37k0.09 0.36f0.09 -0.01k0.02 (-2%) - Kidney 0.53f0.06 0.74 f 0.07 +0.21+0.04 (+39%) p<O.Ol Urinary bladder 18f2 20k3 +2+2 (+lo%) - Omentum 44f8 58f11 +14+4 (+33%) p<0.05 Subcutaneous fat 86522 109f24 +22k6 (+26%) p<O.Ol Gastrocnemius muscle 36f4 43 5 4 +7+1 (+19%) p<O.Ol Soleus muscle 31f3 30f3 - 1 f 2 (-3%) - Skin 22f6 27f6 + 5 f 2 (+24%) pt0.05

Total peripheral resistance (mmHgx min x kg bwt x I&') 0.90f0.08 1.07fO.07 +0.17+0.03 (+19%) p<O.Ol

Cardiac out ut

Pad of the paw 18k4 21f4 +3+2 (+15%) -

(mlxmin- P xkg bwt-') 123k10 105k5 -18f6 (-15%) p<0.05 Stroke volume (mlxkg bwt-') 0.50f0.05 0.44f0.03 -0.06f0.03 (-12%) -

Heart rate

Mean arterial blood pressure (beatsxmin-') 251f13 242f 12 -9k3 (-3%) p<0.05

(mmHg) 10526 110f7 +5+3 (+4%) -

Table 3.Fractional distribution of cardiac output (%xlOO g tissue-') with intact and blocked /&- adrenoceptors 25 and 35 min, respectively, after exsanguination of I S mlxkg bwt-' (n=9)

Intact Blocked adrenoceutors B,-adrenoceptors Difference

Cerebrum Cerebellum Brain stem Spinal cord Salivary gland Stomach Small intestine Large intestine Liver (arterial) Pancreas Adrenal gland Kidney Urinary bladder Omentum Subcutaneous fat Gastrocnemius muscle Soleus muscle Skin Pad of the paw

18f2 19k2 21k3 2453 19k3 21k3 12k3 15f3

8 . 5 f 1 .o I l k 1 5.2k0.6 4.8k0.4 14+1 14k1 2424 22f4 16f3 15f4

156k58 73f7

2.420.5 1.520.6

0.66f0.16 1.1kO.1 1.2k0.1 2.2k0.3 2.6f0.7

18f2 1252

175f58 60+5

2.7k0.5 1.1 f0.3

0.54f0.09 ~.l+O.l i Sk0.1 2.2f0.3 2.6f0.5

+1+2 +3k2 +2+1 + 3 f l +2+1

-0.4k0.3 O f 1

-2k2 +1+1 -3k2

+ 19k6 -1324 0.3k0.2

-0.4f0.3 -0.11 f0.07

O.OfO.1 +0.3k0.1

0.0+0.1 O.Of0.3

(+4%) (+12%) (+ 13 %) (+25 %) (+25%) (-7%) (-3 %) (-7 %) (+8%) (-20%) (+12%) (-17%) (+12%) (-25 %) (-17%) (-2%)

(-2%) (-3%)

(+23%)

- pCO.05 p<O.OS -

Acts Physiol Scand I21

124 D . Gustafsson et a/.

Table 4. Skeletal muscle blood flow (mlxmin-’xlOO g-’) with intact and blocked B- adrenoceptors at different hemorrhagic hypotension levels Mean values calculated from a series of expts reported by Hillman & Lundvall(1980)

Hypotension Intact Blocked level adreno- B-adreno- B-adrenergic (mmHg) ceptors ceptors flow ‘increase’

100 4.9 4.1 0.8 (+20%) 75 3.2 2.4 0.8 (+33%) 50 1.4 0.9 0.5 (+56%)

‘white’ skeletal muscle, with consequent quite strong effects on total peripheral resistance (TPR). The j3-adrenergic effects on the distribution of cardiac output (CO) were small, however, which was explained by the fact that the dilator influence was present in many tissues and that it thereby was reflected in total systemic resistance (TPR). The discussion below will deal with the functional significance of such dilator responses, but the inter- pretation of the findings will first be critically exam- ined.

Our previous studies (see Introduction) have clearly demonstrated a hemorrhage-induced 82- adrenergic inhibitory influence on vascular tone of the resistance vessels in several tissues, viz. the skeletal muscle, small intestine, and in skin. Some effect was observed also in the kidney (cf. below). In those experiments regional B-blockade was performed by La. administration of propranolol and the venous outflow of blood from the studied re- gions was concomitantly sampled and discarded to avoid systemic effects of the blocking agent. The observed marked increase of resistance in response to P-blockade therefore entirely must represent a regional effect, in all probability reflecting a direct interaction with the vascular smooth muscle B- adrenoceptors (cf. Hillman & Lundvall 1980, Hill- man 1983). In the present study, on the other hand, the ,&blocking agent was administered intra-ve- nously and it could be argued that it might have produced a primary direct cardio-depressive effect (decrease in CO) and that the observed increase of resistance was a secondary, reflex phenomenon (cf. Table 2). It has been clearly shown, however, that the Bz-blocking agent ICI 118,551 in the dose used, neither interferes with BI-receptors of the heart (see Methods) nor causes any non-specific negative

inotropic effect (Bilski et al. 1983). The fact that the TPR increase in response to B2-blockade occasion- ally occurs without a concomitant decrease of CO is also of relevance in this context. In one of the present animals TPR thus increased by 21 % concomitantly with an 8% increase in CO. In another series of experiments (Gustafsson & Lundvall 1984) 3 out of 7 animals showed a similar pattern of response to B2-blockade when instituted, as in the present investigation, about 25 min after bleeding (15 mlxkg bwt-I), viz. a clearcut increase of TPR (+ 15 % on the average) without a concomitant decrease of CO (+ 1 % on the average). Such observations, taken together with the above described clearcut evidence for a direct Bz-adrenergic inhibition of vascular smooth muscle tone in individual vascular areas during hemorrhage, seem to warrant the conclusion that the raised resistance after P2- blockade is the primary effect and the decrease of CO a secondary phenomenon. Such secondary decrease of CO might tentatively occur in order to avoid undue, marked increase of blood pressure.

Isoprenaline has been reported to reduce arterio- lar resistance in most vascular beds, but the magnitude of the dilator response varies in different vascular areas and species differences seem to exist. The most pronounced isoprenaline induced inhibition of vascular tone is reported to be evoked in the gastrointestinal tract and in phasic, ‘white’ skeletal muscle (for ref. see Greenway 1981) but also skin can show prominent dilator responses, at least in the dog (Abboud et al. 1965). The present observations are in consonance with those findings. The observed signifcant Bz-adrenergic inhibition of vascular tone in the kidney and in adipose tissue de- serves some additional comments. In the kidney isoprenaline is reported to produce only weak dila- tation (for ref. see Aukland 1976, Greenway 1981) in contrast to the present hemorrhage induced quite pronounced Bz-adrenergic inhibition of vascular tone. Tentatively, this discrepancy might be related to the possibility that the dilator response during isoprenaline infusion might be counteracted by PI- adrenoceptor-mediated (cf. Keeton & Campell 1980, Johns 1981) release of renin-angiotensin. The possible existence of both PI- and &adrenergic vascular effects with opposing influences might also explain why non selective /3-blockade failed to reveal any major renal resistance effect during hemorrhage (Lundvall & Gustafsson 1981). In canine adipose tissue p-adrenergic inhibition of vascular


B2-adrenergic vasodilatation in hemorrhage 125

1957, Haglund 1973) and pancreas (cf. Lefer 1982) are critical organs in hemorrhagic shock insofar as they may release toxic factors into the circulation. B-adrenergic protection against excessive vasoconstriction may therefore be of special importance in these tissues. This may be true also with regard to adipose tissue, in which severe flow restriction in hypovolemia has been reported to produce vascular damage with secondary consequences for lipid me- tabolism in the tissue itself and in the whole organ- ism (cf. Rosell & Belfrage 1979). With regard to skeletal muscle, it is possible that the /?-adrenergic augmentation of blood flow, besides improving tissue nutrition, may serve over-all circulatory ho- meostasis insofar that the vital, compensatory absorption of tissue fluid from skeletal muscle into the blood in hemorrhage has been shown to be serious- ly impeded in states of excessive vasoconstriction (Lundvall & Gustafsson 1982).

tone is reported to be mediated by the PI- rather than by the j32-adrenoceptor type (Rosell & Bel- frage 1979). The present 8.2-adrenergic resistance effect in the cat adipose tissue indicates that species differencies exist with regard to the type of vascular B-adrenoceptors present in this tissue. A recent report suggests that also in man significant dilator responses can be evoked in subcutaneous fat- via activation of B2-adrenoceptors (Hjemdahl & Linde 1983). It cannot be excluded, however, that this effect, as well as the present one in the cat, at least partly could represent an indirect, metabolic inhibition of vascular tone secondary to /?-adrenergic lipolysis.

A B2-adrenergic dilator interaction with the constrictor mechanisms in hemorrhage must obviously be of importance for tissue perfusion, even if this dilator influence was relatively small in the present experiments (Table 2). In ‘white’ skeletal muscle, for example, the resistance increase evoked by j32- blockade was about 20%, but the relative importance of the /?-adrenergic mechanism can be much larger in severe hemorrhage (Hillman & Lundvail 1980). The data in Table 4 have been recalculated from the latter investigation on the lower leg mus- cles of the cat and refer to blood flow values observed with intact and blocked B-adrenoceptors at the hemorrhagic hypotension levels of 100, 75 and 50 mmHg. It can be seen that /I-blockade caused clear-cut decreases in blood flow at all three hypotension levels and it is reasonable to assume that these effects can be taken to reflect a corresponding /?-adrenergic increase in flow in the preparation with intact adrenoceptors. Although the flow effect, in absolute terms, was no larger at severe (50 mmHg) than at mild and moderate bleeding, these data seem to permit the conclusion that the relative importance of the /3-adrenergic dilator influence for tissue nutrition increases with increasing hemorrhagic stress. Implicit in this statement is that even a small augmentation of blood flow when it is critically reduced as during severe bleeding may be of crucial benefit for tissue nutrition, preventing ischemia and cell damage. It should be stressed that the B-adrenergic increase in the volume flow of blood in hemorrhage has been shown to be associated with a marked B2-adrenergic inhibition of ‘pre- capillary sphincter’ tone (see Hillman 1983), which also significantly can improve tissue nutrition by facilitation of the transcapillary diffusion exchange.

It has been reported that the intestine (Lillehei

This study was supported by grants from the Swedish Medical Research Council (2210) and from the Faculty of Medicine, University of Lund. The /3,-blocking agent, ICI 118,551, was generously supplied from ICI-Pharma AB, Sweden. The authors thank Mrs Anne Bjorkly, Mrs Tora Jinde, and Mrs Eva-Mona Welther for skilled technical assistance.

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