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Effects of acute administration of isoproterenol on the systemic and regional blood flow in the dog
Resuscitation, 3, 285-294
Effects of acute administration of isoproterenol on the systemic and regional blood flow in the dog
H. IN-NAM&T. KAWASHIMAf
KAWAGUCHI*, I. KOSUGI?, Y. YAMAGUCHI?, and H. YAMAMURA
K. OKADAt,
Y.
Department of Anaesthesiology. *Tokyo Teishin I-lospital, f Teikyo University School of Medicine, $Faculty ofMedicine, Universty of Tokyo, Hong0 7-3-1, Bunkyoku, Tokyo, Japan
Summary The effects of isoproterenol on cardiac output and the blood flow to various parts of the body have been investigated in pentobarbital-anaesthetized dogs, by the microsphere method. Arterial and venous catheterizations were performed for haemodynarnic measurements, drug infusions and blood samples. After a stabilization period, control measurements were carried out on the cardiac output, heart rate, blood pressure, expiratory minute volume and blood gases. Radioactive microspheres of 50 pm diameter, labelled with either 8SSr or 141Ce, were then injected into the left ventricle. Thereafter the intravenous infusion of isoproterenol (0.5 pg min-1 kg-l) was started. Fifteen minutes after initiation of the drug infusion, the same parameters as in the control period were measured and the injection of radioactive microspheres into the left ventricle was repeated. At the end of the experiment, various organs and tissues were removed and weighed and their radioactivity was determined. The fractional distribution of cardiac output and the blood flow to various organs and tissues were calculated by the method after Rudolph & Heymann (1967). The infusion of isoproterenol resulted in an increase of 57% in cardiac output but changes in regional blood flow varied. The fraction of cardiac output to the myocardium, skeletal muscle and skin were increased, whereas that to the kidney, pancreas and brain decreased. The fraction to the bronchial arteries and splanchnic organs except for the pancreas remained unchanged. The uneven distribution of cardiac output to the various areas may be due mainly to the differences in direct and indirect responses of individual vascular beds to isoproterenol. Introduction lsoproterenol has been widely employed as an agent for circulatory resuscitation (Aviado 1970), but the effect of this amine on the fractional distribution of cardiac output to various organs and tissues has not been fully clarified. The development of radioactive microspheres has made it feasible to determine the fractional distribution of cardiac output to various parts of the body (Rudolph & Heymann, 1967). This study was per285
286 H.IN-NAMIANDOTHERS
formed to investigate the effect of isoproterenol on the fractional distribution of cardiac output to various organs and tissues in dogs, by using radioactive microspheres. Materials and methods Eight male mongrel dogs weighing 9-16 kg were utilized. Al1 the dogs were starved for lo-15 h before the experiments but they had free access to water. Each dog was anaesthetized with pentobarbital sodium (25 mg/kg, intravenously) and was allowed to breathe room air spontaneously through an endotracheal tube throughout the study. The room temperature was kept at 25’C and the oesophageal temperature of each dog c was maintained within 37 * SD 15°C with an electric heater. Polyethylene catheters were inserted into the thoracic aorta and into the inferior vena cava, througlY the left femoral artery and vein respectively. A Cournand cardiac catheter was inserted into the left ventricle through the left common carotid artery and a Swan-Ganz catheter was also passed through a jugular vein into the pulmonary artery. These catheters were used for haemodynamic measurements, drug infusions and blood sampling. Heparin (4 mg/kg) was used as an anticoagulant. Sodium bicarbonate was injected intravenously, if necessary, to keep the base-excess within the normal range before performing the control measurement. After a stabilization period of at least 30 min, the control measurement was made on cardiac output, blood pressure, heart rate, respiratory minute volume and frequency. The first bolus of radioactive microspheres was then injected into the left ventricle, and blood samples were taken for the analysis of POT,Pco~,pH and haemoglobin. Thereafter, the intravenous infusion of isoproterenol was started with an infusion pump. Isoproterenol was freshly prepared for each experiment, being diluted with isotonic sodium chloride solution (saline) into a stock solution of 5 kg/ml. The infusion rate of this agent was kept at 0.5 pg min-1 kg- I. Fifteen minutes after initiation of the drug infusion, the measurements of haemodynamic and respiratory parameters and the blood sampling were repeated, and .the second bolus of radioactive microspheres labelled with a different kind of nucleide was injected into the left ventricle. At the end of the. experiment each dog was killed by bleeding. Nine organs, as shown in Table 1, were then removed and samples of the skin (500 cm2) and the skeletal muscle (4% of the body weight) were excised from the extremities and trunk in each dog. Large organs and tissues such as the liver, gastrointestinal tract and skeletal muscle were cut into two to four parts, and specimens weighing under 100 g were used for the measurement of radioactivity. Arterial and venous blood pressures were measured with strain-gauge transducers coupled to amplifier units,-and were recorded on a direct-writing polygraph (Nihon Kohden Kohgyo Co., Tokyo). The mean blood pressure was obtained by electrical integration with reference to the level of the heart. Cardiac output was determined by the dye-dilution method, with a Gilford apparatus (Gilford Instrument Laboratories Inc., Oberlin, Ohio). Indocyanine Green dye was injected through the Swan-Ganz catheter into the pulmonary artery, and arterial blood was withdrawn from the arterial catheter by a constant-withdrawal pump into the cuvette of a densitometer. Arterial and mixed venous POZ, PCO~ and pH were measured with a microelectrode assembly (Radiometer Co.; Copenhagen). Haemoglobin concentration was determined by the cyanmethaemoglobin’method. Base excess and oxygen saturation (SO2) of blood were calculated by using a blood-gas calculator of Severinghaus (1966). Oxygen
ISOPROTERENOL AND BLOOD FLOW
287
content of blood (Ca,02:arterial; G,02: mixed venous) and oxygen consumption were derived from the following equations.
(pO2)
Blood 02 content
= (Hb X 1.34 XSO2/100) + O.OO3PO2
V02 = (Ca,02 - cF,O2) X IO&
where bt is cardiac output (l/min). The respiratory expired minute volume (VE) was measured with a Wright respirometer (British Oxygen Ltd London). Radioactive microspheres (Minnesota Mining and Manufacturing Co., St Paul, Minnesota) used were 50 ,um mean diameter +I0 w SD, and were labelled with either 85Sr or 141Ce. The sequence of injection of the two nucleides was varied from experiment to experiment. As a single bolus, approximately 8.000 microspheres per kg body weight were injected into the left ventricle. The injection of microspheres was carried out by the method described by Kaihara, van Heerden, Migita & Wagner (1968). The radioactivity of the’excised organs and tissues was measured with an Aloka universal scintillation counter (Nihon Musen Co., Tokyo). A crystal scintillation dual detector [Nal (Tl) 5 in. $ X 2 in.] was placed 30 cm from the specimen. The window of the pulse-height analyser was adjusted to 50-200 Kev for 141Ce and 400-m Kev for 85Sr. The fractional distribution of cardiac output and the blood flow to each organ and tissue were calculated by the method of Rudolph & Heymann (1967). Statistical analysis was carried out by using Student’s r-test for paired observations. Results Table 1 summarizes the haemodynamic. respiratory and acid-base parameters during the control period and the period of isoproterenol infusion and changes in systemic circulatory parameters by this agent are illustrated in Fig.1. Cardiac output increased significantly from 2.14 + 0.65 to 3.27 f 0.95 l/min (P < 0.01) during the drug infusion. The increase in cardiac output was produced by increments in both heart rate and stroke volume. The mean aortic blood pressure fell significantly from 149 t 13 to 101 + 24 mmHg (P < 0.001). The total peripheral vascular resistance was reduced significantly. lsoproterenol infusion evoked significant rises in PE, fand v02. The Pa,02 and acid-base parameters during the control period were within normal ranges. The Pa,02 increased significantly from 76.6 to 83.9 mmHg (P < 0.05) whereas Pa,cQ decreased significantly from 44.4 to 37.9 mmHg (P < 0.05), reflecting a slight hyperventilation. There was a slight fall in base excess. The haemoglobin concentration, haemotocrit and oesophageal temperature remained unchanged. The fraction of cardiac output and the blood flow to individual organs and tissues during both the control and the isoproterenol infusion periods are shown (Table 2). and the percentage changes from the control value in the cardiac output and regional blood flow indicated (Fig.2). Cardiac output increased by 57% from the control value after the isoproterenol infusion, and a redistribution of the increased cardiac output was observed (Fig.2). Organs and tissues can be divided roughly into three groups according to the change in the fraction of cardiac output.
288
H. IN-NAM1 AND OTHERS
Table 1. Effects of intravenous isoproterenol on the systemic haemodynamics, respiration and acidbase state. Each result is the mean value *SD of eight dogs. UE = Expiratory minute volume,f= respiratory frequency, vO2 = oxygen consumption. Pvalues (*
Cardiac output i (Urnin) 1
I
2.14 + 0.65 198 * 14 11.5 +2.8 149*13 2.8 * 1.4 5444 f 1358 15.0 + 3.4 0.75 f 0.31
-
3.48 f 0.93 16k8 8.1 * 1.8 76.6 f 12.9 39.1 k 2.3 44.4 f 6.8 50.5 It 6.5 7.381 * 0.036 7.357 f 0.039 0.7 f 1.8 14.1 + 2.1 42.5 f6.8 37.3 a 1.0
Isoproterenol 3.27t f 0.95 227$ f8 16.0t f4.3 101$+24 3.2 f 1.8 2222t+484
15.2 f4.2 0.48* f0.16 5.29t f 0.65 26tf9
11.4t f3.1 83.9* + 7.5 43.7* +4.5 37.9* f5.3 44.3* f 6.3 7.380 + 0.057 7.346 * 0.055 -2.4* f 2.1 14.2 5 2.6 43.4 +7.4 37.0 f0.9
-------I
240
Heart rate (beats/min)
f:: 3 20
Stroke volume ,I (ml/beat) IO 3 100 140
Mean aortic blood pressure ::: ImmHg) soI 7000
TPR 5004 (dyness-’ cm-?::::
1
Control
I
lsoproterenol
Fii.1. Effects of isoproterenol on systemic circulatory parameters. Each result is the mean value fSD of eight dogs. All changes caused by the infusion of isoproterenol are significant (P < 0.05). TPR, total peripheral resistance.
ISOPROTERENOL AND BLOOD FLOW
289
Table 2. Effect of intravenous isoproterenol on-the fraction of cardiac output and the blood flow to individual organs and tissues. Each result is the mean value MD of eight dogs. P values are denoted by asterisks and daggers as described in Table 1.
Fraction of cardiac output (%)
Brain Heart Lungs Kidneys Adrenals Liver Pancreas Spleen G-1 tracts Skeletal muscles Skin
Weight (g)
Control
Isoproterenol
Control
Isoproterenol
12.1 101.3 114.2 67.1 2.0 313.2 29.4 42.7 424.2 416.2
1.97 5.96 5.33 17.40 0.38 9.10 0.94 4.50 17.64 1.95
1.27% kO.28 8.25” f 2.26 3.88 f 1.40 10.32t f 2.67 0.33 + 0.18 9.24 + 2.97 0.53t f0.41 3.97 + 1.94 18.55 +5.60 2.66* + 0.99
55.8 128.8 97.5 560.3 424.7 59.2 66.2 228.6 88.9 9.1
55.0 f 7.6 270.1$ f81.7 108.6 + 34.4 501.9 + 90.8 560.6 dz347.8 92.6t + 16.9 55.4 dz39.1 324.6 + 140.9 140.9* k53.2 18.4t +6.6
+ 1.9 f 30.3 +41.4 f 29.8 * 0.8 f 65.7 * 1.2 * Il.3 f 36.6 f 165.5
60.4 f 16.6
Skin Skeletal
Blood flow (ml rnif;l 100 g wet tissue )
t
i i,
Cardiac muscle [
0.21* to.09
0.13 f0.05
I
muscle1
f 0.44 + 1.38 +2.28 f5.30 _+0.16 +4.81 f 0.42 + 1.99 + 6.04 +0.72
/
f 10.7 f43.5 f 38.3 * 208.3 * 187.0 zb29.3 + 29.8 f 88.9 +43.6 f 4.3
4.4 f 2.1
11.4t +5.9
1I 4
Liver I-G-i Tract
~I_:I
Cardiac output
-+-+
J, 1
Lung
I I( t n
Brain
+
j ( /
Adrenal+ Spleen
,I
Kidney ++Pancreas-50
c
1 I
50
lsoproterenol (0.5 fig min-1
kg-11
100
200
150
Change in blood flow (%)
Fig.2. Percentage changes from the control value in both cardiac output and blood flow to individual organs and tissues after administration of isoproterenol. Each value is the mean value &SD of eight dogs. Each of the control values is expressed as zero. The shift towards the right indicates increase and that towards the left decrease. Isoproterenol infusion produced an increase in cardiac output of 57%, but the resultant changes in regional blood flow were varied. For further details see the text.
The first group consists of the skin, skeletal muscle and myocardium. The fraction of cardiac output to these regions increased significantly (P < 0.05) (Table 2). Accordingly, the percentage increase in blood flow to the first group was greater than the percentage increase in cardiac output (Fig.2). The second group is composed of the liver (hepatic artery), gastrointestinal tract, adrenal, spleen and lung (bronchial artery). The fraction to the second group remained unchanged, and the blood flow to these organs increased in proportion to the increase in cardiac output.
290
H. IN-NAM1 AND OTHERS
The third group consists of the pancreas, brain and kidney, to which the fraction decreased significantly (Table 2; P= 0.01-0.001). The blood flow to the third group remained unchanged in spite of the increase in cardiac output. Discussion The usefulness and validity of the microsphere method (Rudolph & Heymann, 1967) for determining the fractional distribution of cardiac output to various parts of the body have been confirmed by many investigators (Kaihara et al., 1968; Neutze, Wyler & Rudolph, 1968; Hoffbrand & Forsyth, 1969; Domenech, Hoffman, Noble, Saunders, Henson & Subijanto, 1969; Sasaki & Wagner, 1971). Effects on general haemodynamics The infusion of isoproterenol resulted in significant increases in cardiac output, heart
rate and stroke volume, and in significant decreases in mean aortic blood pressure and total peripheral vascular resistance. These systemic circulatory changes are consistent with those described by Aviado (1970) and lnnes & Nickerson (1970). Effects on the fractional distribution of cardiac output The intravenous administration of isoproterenol produced a significant increase in car-
disc output (t57%), but the changes in blood flow to individual organs and tissues varied (Fig.3). These variations may be due to the differences in direct and indirect responses of vascular beds of individual organs and tissues to isoproterenol. Isoproterenol has been known as a pure beta-adrenergic stimulant, and its effect on the blood flow to each organ and tissue may reflect the distribution of beta-receptors in each vascular bed. Brain Heart Kidneys Lungs Splanchnic organs
Control
lsoproterenol
Fig.3. Distribution of the cardiac output to regional areas during the control and the isoproterenol infusion periods is summarizecL Isoproterenol produced an increase’in cardiac output of 57% and significant increases in the fraction of cardiac output to the myocardium, skeletal muscle and skin, but significant decreases to the brain, kidney and pancreas. The width of each column indicates the size of cardiac output, and the space of each division in the column signifies the blood flow. The fraction to the splanchnic organs is the sum of values for liver (hepatic artery); spleen, gastrointestinal tracts and pancreas. The total skeletal muscular weight was considered to constitute 40% of the total body weight (I. Kosugi, H. In-Nami, Y. Yamaguchi & K. Okada, unpublished results) and the total area of skin was calculated with the formula of Cowglll & Drabkin (1927).
ISOPROTERENOL
AND BLOOD FLOW
291
A predominance of beta-receptors has been found in blood vessels of the skeletal muscles, and many of them are present in the mesenteric, splenic, cutaneous and cardiac vascular beds (Green & Kepchar, 1959; Koelle, 1970). It has been suggested that beta-receptors are also present in the renal (McNay & Goldberg, 1966; Yeh, McNay & Goldberg, 1969; Mark, Eckstein, Abboud & Wendling, 1969) hepatic (Geumei & Mahfouz, 1968; Greenway & Lawson, 1969) and cerebral arteries (Lowe & Gilboe, 1971) though they may be less active in comparison with those in other vascular beds. In the present experiments the magnitude of the increase in blood flow to each organ and tissue produced by isoproterenol was generally in accord with the distribution of beta-receptors among individual vascular beds (Fig.2). Though total peripheral vascular resistance was diminished by this agent (Fig.1) a relative decrease in the vascular resistance in the skin, skeletal muscle and myocardium was observed, whereas a relative increase in resistance was noted in the pancreas, kidney and brain. The intense and direct dilator response of skeletal muscular blood vessels to isoproterenol has been confirmed by many investigators (Ahlquist, 1948; Allwood, Cobbold & Ginsburg, 1963; Abboud, Eckstein & Zimmerman, 1965). Hence the significant increase in the fraction of cardiac output to the skeletal muscle might be due mainly to stimulation of dominant beta-receptors in the blood vessels, especially in resistance vessels (Abboud et al., 1965). Direct dilator responses of coronary and cutaneous vascular beds to this agent may be less than those of the skeletal muscular vasculature (Mark, Abboud, S&mid, Heistad & Mayer, 1972). In our studies, however, the magnitude of increase in blood flow was essentially similar in the myocardium, skin and skeletal muscle (Fig.2). This suggests that the significant increases in coronary and cutaneous fractions of cardiac output are due not only to direct stimulation of betareceptors but may also be due to other factors. lsoproterenol has been reported to increase the myocardial oxygen consumption (Aviado, 1970); an indirect coronary vasodilatation in response to an increase in myocardial metabolism caused by this agent may be another factor in increasing the coronary fraction. Our findings concerning the changes in the fraction of cardiac output to the skin and skeletal muscle are different from those observed by some investigators (Charbon & Reneman, 1970; Hoffbrand, Forsyth & Melmon, 1973). Charbon & Reneman (1970) observed that the intravenous administration of isoproterenol over a wide dose range (from 0.016 to 0.256 pg/kg) to dogs under nitrous oxide anaesthesia did not alter the femoral arterial blood flow, although it resulted in a dose-related increase in aortic flow. Hoffbrand et al. (1973) in studies with conscious monkeys, reported that infusion of isoproterenol (0.18-0.9 @g min-1 kg-r) produced a reduction in the cutaneous fraction of cardiac output and no change in the skeletal muscular fraction in spite of an increase in cardiac output (+24%). The discrepancy between our findings and the latter studies could be ascribed in part to the difference in the sympatho-adrenal activity in the animal used, because the state of the sympatho-adrenal activity will modify the vascular response to isoproterenol in the skin and skeletal muscle, whose vascular beds have abundant alpha-receptors. The sympatho-adrenal system may be more active both under nitrous oxide anaesthesia (Fukunaga & Epstein, 1974) and in the conscious state (Price, 1960; Millar, Warden, Cooperman & Price, 1970) than under pentobarbital anaesthesia. The magnitude of the increase in blood flow to the second group was essentially the same as that of increase in cardiac output (Fig.2). This indicates that vascular resistances in these regions had decreased proportionally to the fall in total peripheral vascular
292 H.IN-NAMIANDOTHERS
resistance. lsoproterenol has been shown to produce vasodilatation in the hepatic artery (Ross & Kurrasch, 1969), superior mesenteric artery (Charbon & Reneman, 1970), splenic artery (Ross, 1967; Opdyke, 1970), gastrointestinal artery (Scholtholt, Lochner, Renn & Shin&hi, 1967) and vessels of portal organs (Myers, Paul & Julian, 1968). The fraction of cardiac output to the third group diminished significantly during the isoproterenol infusion. The reduction in the renal fraction by isoproterenol has also been observed in dogs under nitrous oxide anaesthesia (Charbon & Reneman, 1970) in dogs under haemorrhagic shock (Okada, Yamaguchi, In-Nami, Yamamura & Kosugi, 1972) and in conscious monkeys (Hoffbrand et al., 1973). In man, it has been reported that intravenous administration of this amine (l-4 g/min) to patients with congestive heart failure produced only a slight increase in renal blood flow of 20%, compared with a greater increase in cardiac index of 56%, suggesting a reduction in the renal fraction (Sandler, Dodge & Murdaugh, 1961). Furthermore, Rosenblum, Berkowitz & Lawson (1968) observed that, in patients with or without cardiac diseases, infusion of this agent (0.9-2.6 /& mm ’ ) caused an increase in cardiac index (+56%) and a decrease in the renal fraction (-35%) without increase in renal blood flow. Isoproterenol produces a dose-related increase in renal arterial blood flow when administered into the renal artery (McNay & Goldberg, 1966; Yeh et& 1969; Mark et al., 1969). Intravenous administration of this agent, however, induced only a slight dilatation of the renal artery (Ahlquist, 1948; Spencer, 1956; McNay, McDonald & Goldberg, 1965). This could be ascribed in part to a paucity of beta-receptors in the renal vascular beds. An autoregulatory mechanism is suggested by the fact that this agent produced a decrease in the renal fraction of cardiac output without change in the renal blood flow. The decrease in the fraction to the pancreas and brain has also been found in conscious monkeys (Hoffbrand et al., 1973). An autoregulatory mechanism, a paucity of beta-receptors and a slight fall inPa,coZ (Table 1) might have been involved in the reduction of cerebral fraction. The exact mechanism contributing to the fall in the pancreatic fraction is unclear. In this regard it is worth noticing that isoproterenol inhibits pancreatic exocrine secretion (Hubel, 1970; Rudick, Gonda, Rosenberg, Chapman, Dreiting & Janowitz, 1973), whereas propranolol enhances it (Suda, Robinson & White, 1969). The moderate fall in mean aortic pressure (from 149 to 102 mmHg) did not seem to affect the regional blood flow significantly. However, an enhancement of the sympathetic discharge via a baroreceptor reflex secondary to a fail in aortic pressure (Abboud et al., 1965; King, Mason, Amsterdam & Zelis, 1973) might have beeninvolved in increasing the vascular tonus in those areas where alpha-receptors are predominant. Changes in the I%,~02may affect the fractional distribution of cardiac output in the anaesthetized dog (In-Nami, Kawaguchi & Kosugi, 1972). The slight decrease in the mean Pa,c02(from 44.4 to 37.9 mmHg) due to hyperventilation seems to have contributed slightly to both the decrease in the cerebral fraction and to the rise in the skeletal muscular fraction. The Pa,02 and body temperature remained unchanged, so that the effects of these factors could be ruled out. The effect of renin release provoked by administration of isoproterenol on the regional blood flow (Winer, Chokshi & Walkenhorst, 1971; Reid, Schrier & Earley, 1972) may be neglected in view of the short period of observation after the drug infusion. It remains to be determined whether isoproterenol produces the same pattern of distribution as found in the present study over a wide dose range in the dog, although
ISOPROTERENOL AND BLOOD FLOW
293
a dose-related effect of isoproterenol on the fractional distribution of cardiac output has been reported in the conscious monkey (Hoffbrand et al., 1973). The effect of infusion of this agent for a longer period on the distribution of cardiac output also remains to be studied. Conclusion The intravenous administration of isoproterenol (0.5 Ergmin-1 kg-l) to pentobarbitalanaesthetized dogs produced an increase in cardiac output of 57% and a redistribution of the cardiac output, that is, an increase in the proportion going to the coronary and skeletal muscle circulations and decreases in that going to the cerebral, renal and pancreatic circulations. Acknowledgement The authors are indebted to Miss Yoshiko Fukao for the preparation of the manuscript. References Abboud, F. M., Eckstein, J. W. & Zimmerman, B. C. (1965) Venous and arterial responses to stimulation of beta adrenergic receptors. Amer. J. Physiol. 209, 383-389. AhIquist, R. P. (1948) A study of the adrenotropic receptors. Amer. J. Physiol. 153, 586-600. Allwood, M. J., Cobbold, A. F. & Ginsburg, J. (1963) Peripheral vascular effects of noradrenaline, isopropylnoradrenaline and dopamine. Stir. Med. BUN. 19, 132-136. Aviado, D. M. (1960) Sympathomimetic Drugs, p. 367. Thomas, Springfield, Ill. Charbon, G. A. & Reneman, R. S. (1970) The effects of p-receptor agonists and antagonists on regional blood flow. European J Pharmacol. 9,21-26. Cowgill, D. & Drabkin, D. L. (1927) Determination of a formula for the surface area of the dog together with consideration of formulae available for other species. Amer. J. Physiof. 81, 36-61. Domenech, R. J., Hoffman, J. I. E., Noble, M. I. M., Saunders, K. B., Henson, J. R. & Subijanto, S. (1969) Total and regional coronary blood flow measured by radioactive microspheres in conscious and anaesthetized dogs. Circulation Res. 25,581~596. Fukunaga, A. F. & Epstein, R. M. (1974) Sympathetic excitation during nitrous oxide-halothane anesthesia in the cat. Anesthesiology, 39,23-36. Geumei, A. M. & Mahfouz, M. (1968) The presence of padrenergic receptors in the hepatic vasculature Brit. J. Pharmacol. 32,446-472.
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Price, H. L. (1960) General anesthesia and circulatory homeostasis. Physiol. Reviews, 40,187-218. Reid, I. A., Schrier, R. W; & Earley, L. E. (1972) An effect of extrarenal betaadrenergic stimulation on the release of renin.J. Clin. Invest. 51,1861-1869. Rosenblum, R., Berkowitz, W. D. & Lawson, D. (1968) Effect of acute intravenous administration of isoproterenol on cardiorenal hemodynamics in man. Circulation, 38,158-168. Ross, G. (1967) Effects of catecholamines on splenic blood flow in the cat. Amer. J. Physiol. 213, 107991083. Ross, G. & Kurrasch, M. (1969) Adrenergic responses of the hepatic circulation. Amer. J. Physiol. 216, 1380-1385.
Rudick, J., Gonda, M., Rosenberg, I. R., Chapman, M. L., Dreiling, D. A. & Janowitz, H. D. (1973) Effects of a beta-adrenergic receptor stimulant (isoproterenol) on pancreatic exocrine secretion. Surgery, 74,338-343.
Rudolph, A. M. & Heymann, M. A. (1967) The circulation of the fetus in utero: methods for studying distribution of blood flow, cardiac output and organ blood flow. Circulation Res. 21, 163-184. Sandler, H., Dodge, H. T. & Murdaugh, H. V., Jr (1961) Effects of isoproterenol on cardiac output and renal function in congestive heart failure. Amer. Heurt J. 62,643-65 1. Sasaki, Y. & Wagner, H. N., Jr (1971) Measurement of the distribution of cardiac output in unanesthetized rats. J. Appl. Physiol. 30,879-884. Scholtholt, J., Lochner, W., Renn, H. & Shiraishi, T. (1967) Die Wirkung von Noradrenaline, Adrenalin, Isoproterenol und Adenosin auf die Durchblutung der Leber und des Splanchnicusgebietes des Hundes. Arch. Ges. Physiol. 239, 129-154. Severinghaus, J. W. (1966) Blood gas calculator. J. Appl. Physiol. 21,1108-1116. Spencer, M. P. (1956) The renal vascular responses to vasodepressor sympathomimetics. J. Pharmacol. Exp. Therap. 116,237-244.
-
Suda, Y., Robinson, L. A. & White, T. T. (1969) The effects of adrenergic blocking agents on Pancreatic secretion in dogs. Ann. Surg. 169,625-630. Yeh, B. K., McNay, J. L. & Goldberg, L. I. (1969) Attenuation of dopamine renal and mesenterk vasodilation by haloperidol: evidence for a specific dopamine receptor. J. Pharmacol. Exp. Therap. 168,303-309.
Winer, N., Chokshi, D. S. & Walkenhorst, W. G. (1971) Effects of cyclic AMP, sympathomimetic amines, and adrenergic receptor antagonists on renin secretion. Circulation Res. 29,239-248.
Effects of acute administration of isoproterenol on the systemic and regional blood flow in the dog
H. IN-NAM&T. KAWASHIMAf
KAWAGUCHI*, I. KOSUGI?, Y. YAMAGUCHI?, and H. YAMAMURA
K. OKADAt,
Y.
Department of Anaesthesiology. *Tokyo Teishin I-lospital, f Teikyo University School of Medicine, $Faculty ofMedicine, Universty of Tokyo, Hong0 7-3-1, Bunkyoku, Tokyo, Japan
Summary The effects of isoproterenol on cardiac output and the blood flow to various parts of the body have been investigated in pentobarbital-anaesthetized dogs, by the microsphere method. Arterial and venous catheterizations were performed for haemodynarnic measurements, drug infusions and blood samples. After a stabilization period, control measurements were carried out on the cardiac output, heart rate, blood pressure, expiratory minute volume and blood gases. Radioactive microspheres of 50 pm diameter, labelled with either 8SSr or 141Ce, were then injected into the left ventricle. Thereafter the intravenous infusion of isoproterenol (0.5 pg min-1 kg-l) was started. Fifteen minutes after initiation of the drug infusion, the same parameters as in the control period were measured and the injection of radioactive microspheres into the left ventricle was repeated. At the end of the experiment, various organs and tissues were removed and weighed and their radioactivity was determined. The fractional distribution of cardiac output and the blood flow to various organs and tissues were calculated by the method after Rudolph & Heymann (1967). The infusion of isoproterenol resulted in an increase of 57% in cardiac output but changes in regional blood flow varied. The fraction of cardiac output to the myocardium, skeletal muscle and skin were increased, whereas that to the kidney, pancreas and brain decreased. The fraction to the bronchial arteries and splanchnic organs except for the pancreas remained unchanged. The uneven distribution of cardiac output to the various areas may be due mainly to the differences in direct and indirect responses of individual vascular beds to isoproterenol. Introduction lsoproterenol has been widely employed as an agent for circulatory resuscitation (Aviado 1970), but the effect of this amine on the fractional distribution of cardiac output to various organs and tissues has not been fully clarified. The development of radioactive microspheres has made it feasible to determine the fractional distribution of cardiac output to various parts of the body (Rudolph & Heymann, 1967). This study was per285
286 H.IN-NAMIANDOTHERS
formed to investigate the effect of isoproterenol on the fractional distribution of cardiac output to various organs and tissues in dogs, by using radioactive microspheres. Materials and methods Eight male mongrel dogs weighing 9-16 kg were utilized. Al1 the dogs were starved for lo-15 h before the experiments but they had free access to water. Each dog was anaesthetized with pentobarbital sodium (25 mg/kg, intravenously) and was allowed to breathe room air spontaneously through an endotracheal tube throughout the study. The room temperature was kept at 25’C and the oesophageal temperature of each dog c was maintained within 37 * SD 15°C with an electric heater. Polyethylene catheters were inserted into the thoracic aorta and into the inferior vena cava, througlY the left femoral artery and vein respectively. A Cournand cardiac catheter was inserted into the left ventricle through the left common carotid artery and a Swan-Ganz catheter was also passed through a jugular vein into the pulmonary artery. These catheters were used for haemodynamic measurements, drug infusions and blood sampling. Heparin (4 mg/kg) was used as an anticoagulant. Sodium bicarbonate was injected intravenously, if necessary, to keep the base-excess within the normal range before performing the control measurement. After a stabilization period of at least 30 min, the control measurement was made on cardiac output, blood pressure, heart rate, respiratory minute volume and frequency. The first bolus of radioactive microspheres was then injected into the left ventricle, and blood samples were taken for the analysis of POT,Pco~,pH and haemoglobin. Thereafter, the intravenous infusion of isoproterenol was started with an infusion pump. Isoproterenol was freshly prepared for each experiment, being diluted with isotonic sodium chloride solution (saline) into a stock solution of 5 kg/ml. The infusion rate of this agent was kept at 0.5 pg min-1 kg- I. Fifteen minutes after initiation of the drug infusion, the measurements of haemodynamic and respiratory parameters and the blood sampling were repeated, and .the second bolus of radioactive microspheres labelled with a different kind of nucleide was injected into the left ventricle. At the end of the. experiment each dog was killed by bleeding. Nine organs, as shown in Table 1, were then removed and samples of the skin (500 cm2) and the skeletal muscle (4% of the body weight) were excised from the extremities and trunk in each dog. Large organs and tissues such as the liver, gastrointestinal tract and skeletal muscle were cut into two to four parts, and specimens weighing under 100 g were used for the measurement of radioactivity. Arterial and venous blood pressures were measured with strain-gauge transducers coupled to amplifier units,-and were recorded on a direct-writing polygraph (Nihon Kohden Kohgyo Co., Tokyo). The mean blood pressure was obtained by electrical integration with reference to the level of the heart. Cardiac output was determined by the dye-dilution method, with a Gilford apparatus (Gilford Instrument Laboratories Inc., Oberlin, Ohio). Indocyanine Green dye was injected through the Swan-Ganz catheter into the pulmonary artery, and arterial blood was withdrawn from the arterial catheter by a constant-withdrawal pump into the cuvette of a densitometer. Arterial and mixed venous POZ, PCO~ and pH were measured with a microelectrode assembly (Radiometer Co.; Copenhagen). Haemoglobin concentration was determined by the cyanmethaemoglobin’method. Base excess and oxygen saturation (SO2) of blood were calculated by using a blood-gas calculator of Severinghaus (1966). Oxygen
ISOPROTERENOL AND BLOOD FLOW
287
content of blood (Ca,02:arterial; G,02: mixed venous) and oxygen consumption were derived from the following equations.
(pO2)
Blood 02 content
= (Hb X 1.34 XSO2/100) + O.OO3PO2
V02 = (Ca,02 - cF,O2) X IO&
where bt is cardiac output (l/min). The respiratory expired minute volume (VE) was measured with a Wright respirometer (British Oxygen Ltd London). Radioactive microspheres (Minnesota Mining and Manufacturing Co., St Paul, Minnesota) used were 50 ,um mean diameter +I0 w SD, and were labelled with either 85Sr or 141Ce. The sequence of injection of the two nucleides was varied from experiment to experiment. As a single bolus, approximately 8.000 microspheres per kg body weight were injected into the left ventricle. The injection of microspheres was carried out by the method described by Kaihara, van Heerden, Migita & Wagner (1968). The radioactivity of the’excised organs and tissues was measured with an Aloka universal scintillation counter (Nihon Musen Co., Tokyo). A crystal scintillation dual detector [Nal (Tl) 5 in. $ X 2 in.] was placed 30 cm from the specimen. The window of the pulse-height analyser was adjusted to 50-200 Kev for 141Ce and 400-m Kev for 85Sr. The fractional distribution of cardiac output and the blood flow to each organ and tissue were calculated by the method of Rudolph & Heymann (1967). Statistical analysis was carried out by using Student’s r-test for paired observations. Results Table 1 summarizes the haemodynamic. respiratory and acid-base parameters during the control period and the period of isoproterenol infusion and changes in systemic circulatory parameters by this agent are illustrated in Fig.1. Cardiac output increased significantly from 2.14 + 0.65 to 3.27 f 0.95 l/min (P < 0.01) during the drug infusion. The increase in cardiac output was produced by increments in both heart rate and stroke volume. The mean aortic blood pressure fell significantly from 149 t 13 to 101 + 24 mmHg (P < 0.001). The total peripheral vascular resistance was reduced significantly. lsoproterenol infusion evoked significant rises in PE, fand v02. The Pa,02 and acid-base parameters during the control period were within normal ranges. The Pa,02 increased significantly from 76.6 to 83.9 mmHg (P < 0.05) whereas Pa,cQ decreased significantly from 44.4 to 37.9 mmHg (P < 0.05), reflecting a slight hyperventilation. There was a slight fall in base excess. The haemoglobin concentration, haemotocrit and oesophageal temperature remained unchanged. The fraction of cardiac output and the blood flow to individual organs and tissues during both the control and the isoproterenol infusion periods are shown (Table 2). and the percentage changes from the control value in the cardiac output and regional blood flow indicated (Fig.2). Cardiac output increased by 57% from the control value after the isoproterenol infusion, and a redistribution of the increased cardiac output was observed (Fig.2). Organs and tissues can be divided roughly into three groups according to the change in the fraction of cardiac output.
288
H. IN-NAM1 AND OTHERS
Table 1. Effects of intravenous isoproterenol on the systemic haemodynamics, respiration and acidbase state. Each result is the mean value *SD of eight dogs. UE = Expiratory minute volume,f= respiratory frequency, vO2 = oxygen consumption. Pvalues (*
Cardiac output i (Urnin) 1
I
2.14 + 0.65 198 * 14 11.5 +2.8 149*13 2.8 * 1.4 5444 f 1358 15.0 + 3.4 0.75 f 0.31
-
3.48 f 0.93 16k8 8.1 * 1.8 76.6 f 12.9 39.1 k 2.3 44.4 f 6.8 50.5 It 6.5 7.381 * 0.036 7.357 f 0.039 0.7 f 1.8 14.1 + 2.1 42.5 f6.8 37.3 a 1.0
Isoproterenol 3.27t f 0.95 227$ f8 16.0t f4.3 101$+24 3.2 f 1.8 2222t+484
15.2 f4.2 0.48* f0.16 5.29t f 0.65 26tf9
11.4t f3.1 83.9* + 7.5 43.7* +4.5 37.9* f5.3 44.3* f 6.3 7.380 + 0.057 7.346 * 0.055 -2.4* f 2.1 14.2 5 2.6 43.4 +7.4 37.0 f0.9
-------I
240
Heart rate (beats/min)
f:: 3 20
Stroke volume ,I (ml/beat) IO 3 100 140
Mean aortic blood pressure ::: ImmHg) soI 7000
TPR 5004 (dyness-’ cm-?::::
1
Control
I
lsoproterenol
Fii.1. Effects of isoproterenol on systemic circulatory parameters. Each result is the mean value fSD of eight dogs. All changes caused by the infusion of isoproterenol are significant (P < 0.05). TPR, total peripheral resistance.
ISOPROTERENOL AND BLOOD FLOW
289
Table 2. Effect of intravenous isoproterenol on-the fraction of cardiac output and the blood flow to individual organs and tissues. Each result is the mean value MD of eight dogs. P values are denoted by asterisks and daggers as described in Table 1.
Fraction of cardiac output (%)
Brain Heart Lungs Kidneys Adrenals Liver Pancreas Spleen G-1 tracts Skeletal muscles Skin
Weight (g)
Control
Isoproterenol
Control
Isoproterenol
12.1 101.3 114.2 67.1 2.0 313.2 29.4 42.7 424.2 416.2
1.97 5.96 5.33 17.40 0.38 9.10 0.94 4.50 17.64 1.95
1.27% kO.28 8.25” f 2.26 3.88 f 1.40 10.32t f 2.67 0.33 + 0.18 9.24 + 2.97 0.53t f0.41 3.97 + 1.94 18.55 +5.60 2.66* + 0.99
55.8 128.8 97.5 560.3 424.7 59.2 66.2 228.6 88.9 9.1
55.0 f 7.6 270.1$ f81.7 108.6 + 34.4 501.9 + 90.8 560.6 dz347.8 92.6t + 16.9 55.4 dz39.1 324.6 + 140.9 140.9* k53.2 18.4t +6.6
+ 1.9 f 30.3 +41.4 f 29.8 * 0.8 f 65.7 * 1.2 * Il.3 f 36.6 f 165.5
60.4 f 16.6
Skin Skeletal
Blood flow (ml rnif;l 100 g wet tissue )
t
i i,
Cardiac muscle [
0.21* to.09
0.13 f0.05
I
muscle1
f 0.44 + 1.38 +2.28 f5.30 _+0.16 +4.81 f 0.42 + 1.99 + 6.04 +0.72
/
f 10.7 f43.5 f 38.3 * 208.3 * 187.0 zb29.3 + 29.8 f 88.9 +43.6 f 4.3
4.4 f 2.1
11.4t +5.9
1I 4
Liver I-G-i Tract
~I_:I
Cardiac output
-+-+
J, 1
Lung
I I( t n
Brain
+
j ( /
Adrenal+ Spleen
,I
Kidney ++Pancreas-50
c
1 I
50
lsoproterenol (0.5 fig min-1
kg-11
100
200
150
Change in blood flow (%)
Fig.2. Percentage changes from the control value in both cardiac output and blood flow to individual organs and tissues after administration of isoproterenol. Each value is the mean value &SD of eight dogs. Each of the control values is expressed as zero. The shift towards the right indicates increase and that towards the left decrease. Isoproterenol infusion produced an increase in cardiac output of 57%, but the resultant changes in regional blood flow were varied. For further details see the text.
The first group consists of the skin, skeletal muscle and myocardium. The fraction of cardiac output to these regions increased significantly (P < 0.05) (Table 2). Accordingly, the percentage increase in blood flow to the first group was greater than the percentage increase in cardiac output (Fig.2). The second group is composed of the liver (hepatic artery), gastrointestinal tract, adrenal, spleen and lung (bronchial artery). The fraction to the second group remained unchanged, and the blood flow to these organs increased in proportion to the increase in cardiac output.
290
H. IN-NAM1 AND OTHERS
The third group consists of the pancreas, brain and kidney, to which the fraction decreased significantly (Table 2; P= 0.01-0.001). The blood flow to the third group remained unchanged in spite of the increase in cardiac output. Discussion The usefulness and validity of the microsphere method (Rudolph & Heymann, 1967) for determining the fractional distribution of cardiac output to various parts of the body have been confirmed by many investigators (Kaihara et al., 1968; Neutze, Wyler & Rudolph, 1968; Hoffbrand & Forsyth, 1969; Domenech, Hoffman, Noble, Saunders, Henson & Subijanto, 1969; Sasaki & Wagner, 1971). Effects on general haemodynamics The infusion of isoproterenol resulted in significant increases in cardiac output, heart
rate and stroke volume, and in significant decreases in mean aortic blood pressure and total peripheral vascular resistance. These systemic circulatory changes are consistent with those described by Aviado (1970) and lnnes & Nickerson (1970). Effects on the fractional distribution of cardiac output The intravenous administration of isoproterenol produced a significant increase in car-
disc output (t57%), but the changes in blood flow to individual organs and tissues varied (Fig.3). These variations may be due to the differences in direct and indirect responses of vascular beds of individual organs and tissues to isoproterenol. Isoproterenol has been known as a pure beta-adrenergic stimulant, and its effect on the blood flow to each organ and tissue may reflect the distribution of beta-receptors in each vascular bed. Brain Heart Kidneys Lungs Splanchnic organs
Control
lsoproterenol
Fig.3. Distribution of the cardiac output to regional areas during the control and the isoproterenol infusion periods is summarizecL Isoproterenol produced an increase’in cardiac output of 57% and significant increases in the fraction of cardiac output to the myocardium, skeletal muscle and skin, but significant decreases to the brain, kidney and pancreas. The width of each column indicates the size of cardiac output, and the space of each division in the column signifies the blood flow. The fraction to the splanchnic organs is the sum of values for liver (hepatic artery); spleen, gastrointestinal tracts and pancreas. The total skeletal muscular weight was considered to constitute 40% of the total body weight (I. Kosugi, H. In-Nami, Y. Yamaguchi & K. Okada, unpublished results) and the total area of skin was calculated with the formula of Cowglll & Drabkin (1927).
ISOPROTERENOL
AND BLOOD FLOW
291
A predominance of beta-receptors has been found in blood vessels of the skeletal muscles, and many of them are present in the mesenteric, splenic, cutaneous and cardiac vascular beds (Green & Kepchar, 1959; Koelle, 1970). It has been suggested that beta-receptors are also present in the renal (McNay & Goldberg, 1966; Yeh, McNay & Goldberg, 1969; Mark, Eckstein, Abboud & Wendling, 1969) hepatic (Geumei & Mahfouz, 1968; Greenway & Lawson, 1969) and cerebral arteries (Lowe & Gilboe, 1971) though they may be less active in comparison with those in other vascular beds. In the present experiments the magnitude of the increase in blood flow to each organ and tissue produced by isoproterenol was generally in accord with the distribution of beta-receptors among individual vascular beds (Fig.2). Though total peripheral vascular resistance was diminished by this agent (Fig.1) a relative decrease in the vascular resistance in the skin, skeletal muscle and myocardium was observed, whereas a relative increase in resistance was noted in the pancreas, kidney and brain. The intense and direct dilator response of skeletal muscular blood vessels to isoproterenol has been confirmed by many investigators (Ahlquist, 1948; Allwood, Cobbold & Ginsburg, 1963; Abboud, Eckstein & Zimmerman, 1965). Hence the significant increase in the fraction of cardiac output to the skeletal muscle might be due mainly to stimulation of dominant beta-receptors in the blood vessels, especially in resistance vessels (Abboud et al., 1965). Direct dilator responses of coronary and cutaneous vascular beds to this agent may be less than those of the skeletal muscular vasculature (Mark, Abboud, S&mid, Heistad & Mayer, 1972). In our studies, however, the magnitude of increase in blood flow was essentially similar in the myocardium, skin and skeletal muscle (Fig.2). This suggests that the significant increases in coronary and cutaneous fractions of cardiac output are due not only to direct stimulation of betareceptors but may also be due to other factors. lsoproterenol has been reported to increase the myocardial oxygen consumption (Aviado, 1970); an indirect coronary vasodilatation in response to an increase in myocardial metabolism caused by this agent may be another factor in increasing the coronary fraction. Our findings concerning the changes in the fraction of cardiac output to the skin and skeletal muscle are different from those observed by some investigators (Charbon & Reneman, 1970; Hoffbrand, Forsyth & Melmon, 1973). Charbon & Reneman (1970) observed that the intravenous administration of isoproterenol over a wide dose range (from 0.016 to 0.256 pg/kg) to dogs under nitrous oxide anaesthesia did not alter the femoral arterial blood flow, although it resulted in a dose-related increase in aortic flow. Hoffbrand et al. (1973) in studies with conscious monkeys, reported that infusion of isoproterenol (0.18-0.9 @g min-1 kg-r) produced a reduction in the cutaneous fraction of cardiac output and no change in the skeletal muscular fraction in spite of an increase in cardiac output (+24%). The discrepancy between our findings and the latter studies could be ascribed in part to the difference in the sympatho-adrenal activity in the animal used, because the state of the sympatho-adrenal activity will modify the vascular response to isoproterenol in the skin and skeletal muscle, whose vascular beds have abundant alpha-receptors. The sympatho-adrenal system may be more active both under nitrous oxide anaesthesia (Fukunaga & Epstein, 1974) and in the conscious state (Price, 1960; Millar, Warden, Cooperman & Price, 1970) than under pentobarbital anaesthesia. The magnitude of the increase in blood flow to the second group was essentially the same as that of increase in cardiac output (Fig.2). This indicates that vascular resistances in these regions had decreased proportionally to the fall in total peripheral vascular
292 H.IN-NAMIANDOTHERS
resistance. lsoproterenol has been shown to produce vasodilatation in the hepatic artery (Ross & Kurrasch, 1969), superior mesenteric artery (Charbon & Reneman, 1970), splenic artery (Ross, 1967; Opdyke, 1970), gastrointestinal artery (Scholtholt, Lochner, Renn & Shin&hi, 1967) and vessels of portal organs (Myers, Paul & Julian, 1968). The fraction of cardiac output to the third group diminished significantly during the isoproterenol infusion. The reduction in the renal fraction by isoproterenol has also been observed in dogs under nitrous oxide anaesthesia (Charbon & Reneman, 1970) in dogs under haemorrhagic shock (Okada, Yamaguchi, In-Nami, Yamamura & Kosugi, 1972) and in conscious monkeys (Hoffbrand et al., 1973). In man, it has been reported that intravenous administration of this amine (l-4 g/min) to patients with congestive heart failure produced only a slight increase in renal blood flow of 20%, compared with a greater increase in cardiac index of 56%, suggesting a reduction in the renal fraction (Sandler, Dodge & Murdaugh, 1961). Furthermore, Rosenblum, Berkowitz & Lawson (1968) observed that, in patients with or without cardiac diseases, infusion of this agent (0.9-2.6 /& mm ’ ) caused an increase in cardiac index (+56%) and a decrease in the renal fraction (-35%) without increase in renal blood flow. Isoproterenol produces a dose-related increase in renal arterial blood flow when administered into the renal artery (McNay & Goldberg, 1966; Yeh et& 1969; Mark et al., 1969). Intravenous administration of this agent, however, induced only a slight dilatation of the renal artery (Ahlquist, 1948; Spencer, 1956; McNay, McDonald & Goldberg, 1965). This could be ascribed in part to a paucity of beta-receptors in the renal vascular beds. An autoregulatory mechanism is suggested by the fact that this agent produced a decrease in the renal fraction of cardiac output without change in the renal blood flow. The decrease in the fraction to the pancreas and brain has also been found in conscious monkeys (Hoffbrand et al., 1973). An autoregulatory mechanism, a paucity of beta-receptors and a slight fall inPa,coZ (Table 1) might have been involved in the reduction of cerebral fraction. The exact mechanism contributing to the fall in the pancreatic fraction is unclear. In this regard it is worth noticing that isoproterenol inhibits pancreatic exocrine secretion (Hubel, 1970; Rudick, Gonda, Rosenberg, Chapman, Dreiting & Janowitz, 1973), whereas propranolol enhances it (Suda, Robinson & White, 1969). The moderate fall in mean aortic pressure (from 149 to 102 mmHg) did not seem to affect the regional blood flow significantly. However, an enhancement of the sympathetic discharge via a baroreceptor reflex secondary to a fail in aortic pressure (Abboud et al., 1965; King, Mason, Amsterdam & Zelis, 1973) might have beeninvolved in increasing the vascular tonus in those areas where alpha-receptors are predominant. Changes in the I%,~02may affect the fractional distribution of cardiac output in the anaesthetized dog (In-Nami, Kawaguchi & Kosugi, 1972). The slight decrease in the mean Pa,c02(from 44.4 to 37.9 mmHg) due to hyperventilation seems to have contributed slightly to both the decrease in the cerebral fraction and to the rise in the skeletal muscular fraction. The Pa,02 and body temperature remained unchanged, so that the effects of these factors could be ruled out. The effect of renin release provoked by administration of isoproterenol on the regional blood flow (Winer, Chokshi & Walkenhorst, 1971; Reid, Schrier & Earley, 1972) may be neglected in view of the short period of observation after the drug infusion. It remains to be determined whether isoproterenol produces the same pattern of distribution as found in the present study over a wide dose range in the dog, although
ISOPROTERENOL AND BLOOD FLOW
293
a dose-related effect of isoproterenol on the fractional distribution of cardiac output has been reported in the conscious monkey (Hoffbrand et al., 1973). The effect of infusion of this agent for a longer period on the distribution of cardiac output also remains to be studied. Conclusion The intravenous administration of isoproterenol (0.5 Ergmin-1 kg-l) to pentobarbitalanaesthetized dogs produced an increase in cardiac output of 57% and a redistribution of the cardiac output, that is, an increase in the proportion going to the coronary and skeletal muscle circulations and decreases in that going to the cerebral, renal and pancreatic circulations. Acknowledgement The authors are indebted to Miss Yoshiko Fukao for the preparation of the manuscript. References Abboud, F. M., Eckstein, J. W. & Zimmerman, B. C. (1965) Venous and arterial responses to stimulation of beta adrenergic receptors. Amer. J. Physiol. 209, 383-389. AhIquist, R. P. (1948) A study of the adrenotropic receptors. Amer. J. Physiol. 153, 586-600. Allwood, M. J., Cobbold, A. F. & Ginsburg, J. (1963) Peripheral vascular effects of noradrenaline, isopropylnoradrenaline and dopamine. Stir. Med. BUN. 19, 132-136. Aviado, D. M. (1960) Sympathomimetic Drugs, p. 367. Thomas, Springfield, Ill. Charbon, G. A. & Reneman, R. S. (1970) The effects of p-receptor agonists and antagonists on regional blood flow. European J Pharmacol. 9,21-26. Cowgill, D. & Drabkin, D. L. (1927) Determination of a formula for the surface area of the dog together with consideration of formulae available for other species. Amer. J. Physiof. 81, 36-61. Domenech, R. J., Hoffman, J. I. E., Noble, M. I. M., Saunders, K. B., Henson, J. R. & Subijanto, S. (1969) Total and regional coronary blood flow measured by radioactive microspheres in conscious and anaesthetized dogs. Circulation Res. 25,581~596. Fukunaga, A. F. & Epstein, R. M. (1974) Sympathetic excitation during nitrous oxide-halothane anesthesia in the cat. Anesthesiology, 39,23-36. Geumei, A. M. & Mahfouz, M. (1968) The presence of padrenergic receptors in the hepatic vasculature Brit. J. Pharmacol. 32,446-472.
Green, H. D. & Kepchar, J. H. (1959) Control of peripheral resistance in major systemic vascular beds. Physiol. Reviews, 39,617-686.
Greenway, C. V. & Lawson, A. E. (1969) p-Adrenergic receptors in the hepatic arterial bed of the anesthetized cat. Can. J. Physiol. Pharmacol. 47,415-419. Hoffbrand, B. I. & Forsyth, R. P. (1969) Validity studies of the radioactive microsphere method for the study of the distribution of cardiac output, organ blood flow, and resistance in the conscious rhesus monkey. Cardiovasc. Res. 3,426-432. Hoffbrand, B. I., Forsyth, R. P. & Melmon, K. L. (1973) Dose-related effects of isoprenaline on the distribution of cardiac output and myocardial blood flow in conscious monkeys. Cardiovasc. Res. 7,664-669.
Hubel, K. A. (1970) Response of rabbit pancreas in vitro to adrenergic agonists and antagonists. Amer. J Physiol. 219,1590-1594. In-Nami, H., Kawaguchi, T. & Kosugi, I. (1972) The effect of PaCO2 on the fractional distribution of cardiac output and on the blood flow of various organs during general anesthesia in dogs. In: Fifth World Congress of Anaesthesiologists p.45. Excerpta Medica, Amsterdam.
(Excerpta Medica International
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Innes, I. R. & Nickerson, M. (1970) Drugs acting on postganglionic adrenergic nerve endings and structures innervated by them (sympathomimetic drugs). In: The Pharmacological Basis of Therapeutics, 4th edn., p.478. Ed. Goodman, L. S. & Gilman, A. Macmillan, New York. Kaihara, S., van Heerden, P. D., Migita, T. &Wagner, H. N., Jr (1968) Measurement of distribution of cardiac output. J. Appl. Physiol. 25,696-700.
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