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Clinical Science ( 1990)79,13 1-1 38 131 Haemodynamic and metabolic effects of infused adenosine in man ANDERS EDLUND', ALF SOLLEVI* AND BIRGITTA LINDE' 'Department of Clinical Physiology, Huddinge and Karolinska Hospital, Huddinge, and *Departmentof Anaesthesiology, Sodersjukhuset, Stockholm, Sweden (Received 31 January 1990; accepted 23 March 1990) SUMMARY 1. Haemodynamic and metabolic effects of intravenous infusion of adenosine, an endogenous vasodilator, were studied in healthy humans. 2. Catheters were inserted into pulmonary and brachial arteries and into the hepatic and subclavian veins. Cardiac output was determined according to the Fick principle, and splanchnic blood flow was measured by using extraction of Indocyanine Green. Skin blood flow was estimated by a laser Doppler technique, calf blood fiow by venous occlusion plethysmography and skeletal muscle and adipose tissue blood flow by a local isotope clearance technique. 3. Adenosine (infused in steps from 40 to 80 pg min-' kg- into a central vein) elicited a gradual reduction in the peripheral vascular resistance to less than 50% of the basal level. There was a slight increase in the systemic blood pressure, but the pulmonary arterial and the ventricular filling pressures were unchanged. Cardiac output was doubled, accomplished by a combination of a positive chronotropic effect and an increase in stroke volume, which may be secondary to diminished peripheral resistance. 4. Skin blood flow increased by 100% at 50 pg of adenosine min-' kg-', whereas splanchnic blood flow rose sigmficantly at 60 ,ug of adenosine min-' kg-'. Blood flow in the calf, gastrocnemius muscle and adipose tissue did not change significantly. 5. Arterial concentrations of noradrenaline and adrenaline increased by 62 and 43%, respectively, during infusion of adenosine. Arterial levels of glycerol were depressed by more than 50%, but those of glucose and pyruvate were unchanged. 6. In conclusion, exogenous adenosine caused a marked systemic vasodilatation, with different responsiveness in the investigated vascular beds. The vasodilata- ' Correspondence: Dr Anders Edlund, Department of Clinical Physiology,Karolinska Hospital, S- 10401 Stockholm,Sweden. tion occurred in the presence of an increase in generalized sympathetic activity. Adipose tissue blood flow was unaltered despite a considerable reduction in fat mobilization. Key words: adenosine, cardiac output, catecholamines, glycerol, regional circulation. INTRODUCTION Adenosine is mainly formed by dephosphorylation of 5'adenosine triphosphate or hydrolysis of S-adenosylhomocysteine [l, 21. Due to cellular uptake and enzymatic degradation, adenosine is effectively eliminated from the blood in humans with a half-life of less than 10 s [31. The cardiovascular effects of adenosine were first recognized in 1929 by Drury & Szent-Gyorgyi [4], who reported a general vasodilator effect and negative inotropic, chronotropic and dromotropic effects in the isolated heart. Later, adenosine has been demonstrated to dilate most vascular beds: in heart [S], skeletal muscle [6, 71, intestine [8]and brain [9, 101. The renal circulation may be an exception as transient vasoconstriction has been reported in the dog [ 111. Adenosine also has a wellknown anti-lipolytic effect in animals [ 12, 131. In nervous tissue adenosine antagonizes neurotransmission [ 14, 151, but in man there are reports of increased or unchanged levels of circulating catecholamines [16, 171. Depending on the dose and mode of administration, both bradycardia with atrioventricular-block (bolus administration) [18, 191 and tachycardia [17, 201 have been reported in man. Systemic infusion of low doses of adenosine to healthy man caused a minor increase in cardiac output, paralleled by a decrease in peripheral vascular resistance, the arterial blood pressure being unchanged [21]. To what extent different vasculatures were dilated was not analysed. Thus, knowledge of the effects of adenosine mostly derives from isolated tissues or from experiments in intact 132 A. Edlund et al. animals, with relatively few studies of the effects in man. Information about regional circulatory effects as well as metabolic effects of adenosine in humans is of importance, since the compound has been recently introduced as a vasodilator compound in different clinical situations [7, 221. The aim of the present study was therefore to investigate in conscious healthy humans the effects of intravenous adenosine, up to the highest tolerable dose, on central and regional haemodynamics as well as on some metabolic variables. METHODS Subjects Ten healthy volunteer subjects, six women and four men, aged 20-35 years, were investigated. Their heights and weights averaged 172 4 cm and 63 k 3 kg, respectively. The investigation was approved by the Ethics Committee of Huddinge Hospital. * Procedure The subjects reported to the laboratory in the morning after an overnight fast, including more than 12 h without tobacco and coffee (or other xanthine-containing beverages). With the subject resting in the supine position, a double-lumen Swan-Ganz catheter was introduced percutaneously into a right antecubital vein and advanced under fluoroscopical control to a position with the tip in the pulmonary artery. A Cournand catheter no. 6 was similarly inserted into a hepatic vein through the right femoral vein. Thin polyethylene catheters were introduced into the brachial artery and subclavian vein. After a resting period of 60 min, infusion of adenosine into the subclavian vein was started at a rate of 40 pg min-' kg- Every 20 min the infusion rate was increased by 10 pg min-' kg-' to a final dose of 80 pg min-l kg-I. Due to side-effects, not all subjects tolerated the highest infusion rates. '. Haemodynamic measurements Heart rate was monitored continuously by a one-lead electrocardiograph. Blood pressure was registered after 16-18 min at each infusion rate in the brachial and pulmonary arteries and the right atrium. Peripheral resistance was calculated as Mean arterial pressure - right atrial pressure cardiac output according to the Fick principle by sampling expired air for 5 min (once during basal conditions and once at each infusion step after 15-20 min of infusion), calculating oxygen uptake and measuring the systemic arterial-pulmonary arterial oxygen concentration difference (blood samples taken at start and end of air sampling, using the mean value for further calculation). Splanchnic blood flow was measured by extraction (arterial-hepatic vein content) of Indocyanine Green [24, 251 basally and every 5 min at each rate of adenosine infusion. A laser Doppler probe, connected to a flowmeter (Periflux; Perimed AB, Stockholm, Sweden [26]), was attached to the skin just below the middle of the clavicle for continuous recording of relative skin blood flow. The flowmeter gives a linear response both to velocities and flux of erythrocytes [27, 281. Flow is expressed as a percentage of the basal value. However, a portion of the instrument signal has its origin in internal tissue motion other than blood flow. Thus, the percentage change in flow signal underestimates the true changes in blood flow. Adipose tissue blood flow was measured continuously by clearance of locally injected 133Xe[29, 301 after bilateral injection of 40 kBq into the abdominal subcutaneous fat. Calf blood flow was determined basally and every 5 min during adenosine infusion by venous occlusion plethysmography as described by Dohn [31], using a distal arterial occlusion to exclude foot circulation. Muscle blood flow was followed in the gastrocnemius muscle in the contralateral leg by the local 133Xeclearance technique [32] after injection of 400 kBq of isotope. Since the disappearance rate from muscle was multi-exponential, it was compared with a control study, performed in another eight healthy subjects, who were not subjected to infusion of adenosine. Blood flow in the adipose tissue and the calf is expressed in ml s - I 1- tissue volume. Blood samples for determination of lactate, pyruvate, glycerol (arterial and hepatic venous), adrenaline and noradrenaline (arterial) were taken basally and at each infusion step after 16-1 8 min of infusion. ' Analytical procedures The oxygen content in blood was analysed according to standard procedures. Adrenaline and noradrenaline were analysed by using h.p.1.c. with electrochemical detection [33]. Lactate, pyruvate and glycerol were determined fluorimetrically as described elsewhere [34, 351. Glucose was analysed in deproteinized plasma with a Glucose Analyzer (Beckman;Palo Alto, CA, U.S.A.). and pulmonary resistance as Data analysis Mean pulmonary arterial pressurepulmonary capillary venous pressure No statistically significant differences were found between determinations made at different times during each infusion step, which is in accordance with the steadystate level of cardiac output and peripheral resistance observed during 15 min of infusion of adenosine by Bush et al. [21]. Therefore, the mean values for each period were used for further calculations and presentations. cardiac output When missing (in five subjects), the pulmonary capillary venous pressure was replaced by the diastolic pulmonary arterial pressure (cf. [23]).Cardiac output was determined Haemodynamic effects of intravenous adenosine Statistics Results are means fSEM. For calculation of statistical differences, one-way analysis of variance with the Fisher test was used. but increased markedly at higher infusion rates (Table 1, Fig. 3),being almost doubled at the highest rate. The basal skin blood flow showed small oscillations around a stable mean level. During infusion the mean RESULTS The basal uptake of oxygen was 2 1 8 f l l ml/min. Infusion of adenosine did not significantly alter the consumption of oxygen, which measured 243 f 16 ml/ min at the highest infusion rate. The respiratory Guotient and ventilatory volume did not change significantly from the basal values (0.80 f 0.03 and 7.3 f0.2 I/min, respectively) during infusion of adenosine. All subjects experienced symptoms such as cutaneous flushing, chest oppression, palpitations, headache, abdominal pain or anxiety. Due to these sensations only five subjects accepted the dose of 80 pg min-' kg-I. 133 SVR 2olT Central haemodynamics Cardiac output displayed a gradual, marked increase during adenosine infusion (Fig. l), being twice the basal output at the highest infusion rate (5.0f 0.3 and 9.6 f0.7 I/min, respectively). Heart rate increased gradually from 6 0 f 2 beats/min, reaching a maximum of 9 0 f 6 beats/ min at 80 p g of adenosine min-' kg-I (Fig. 2). Stroke volume increased at the lowest infusion rate with a only minor further increase at higher infusion rates (Fig. 2). As a consequence of the increased cardiac output, during unchanged whole body oxygen uptake, the arterialpulmonary artery concentration difference for oxygen decreased markedly, from 44 f 2 ml/l in the basal state to 2 6 f 2 ml/l at an infusion rate of 80 pg of adenosine min- kg - I (P<0.00 1), indicating a hyperkinetic circulation. Systolic blood pressure and pulse pressure amplitude showed gradual increases from 1 2 9 f 3 and 5 9 f 3 mmHg, respectively, to 1 4 2 f 5 and 8 3 f 4 mmHg ( P < O . O l and 0.001, respectively) at 80 pg of adenosine min-' kg-I, whereas diastolic pressure did not change sigdicantly ( 6 9 f 2 and 6 0 f 3 mmHg, respectively). Mean arterial pressure was not sigmficantly altered. Pulmonary artery pressure (21 f 1 mmHg systolic, 9 f 1 mmHg diastolic), right atrial pressure (5f 1 mmHg) and pulmonary capillary venous pressure (9 f 1 mmHg) did not change. During infusion there was a gradual decrease in the systemic vascular resistance, amounting to more than 50% at the highest infusion rates (Fig. 1).The decrease in pulmonary vascular resistance, from the basal level of 0.7f0.1 to 0.5f0.1 mmHg min-' I-' at the highest infusion rate, did not reach statistical significance. Basal I I I I i 40 50 60 70 80 Adenosine (pgmir-' kg-') Fig. 1. Cardiac output (CO) and systemic vascular resistance (SVR) in the basal state and during infusion of adenosine (40-80 pg min-' kg-l intravenously). Statistical sigmficance:*P< 0.05, **P< 0.01, ***PC 0.001 compared with basal. Values are means f SEM. 120 80 40 " 1 HR I I I I I I Basal 40 50 60 70 80 Adenosine (pg mir-'kg-') Peripheral haemodynamics The basal blood flow in the splanchnic region measured 1.4 f 0.1 I/min. Flow remained unchanged at infusion rates of 40 and 50 pg of adenosine min-' kg-I, Fig. 2. Stroke volume (SV) and heart rate (HR) in the basal state and during infusion of adenosine (40-80 pg &-I kg- intravenously). Statistical significance: *P<0.05, **P< 0.01, ***P< 0.001 compared with basal. Values are means f SEM. 134 A. Edlund et al. amplitude of the Doppler signal was doubled at an infusion rate of 50 pg of adenosine min-l kg-' (Table 1, Fig. 3) and the oscillations were magnified (Fig. 4). Furthermore, even at the lowest infusion rate there were repeated blood flow peaks of variable magnitude, amounting at most to twice the mean level and lasting a few minutes each (a typical response is shown in Fig. 4). After discontinuation of the infusion of adenosine, skin blood flow gradually returned towards the basal level, which was not reached until after 10-20 min. This is in contrast to other effects of adenosine, such as the increase in heart rate and the subjective symptoms (e.g. chest oppression, abdominal discomfort), which disappeared within a few minutes. Blood flow in the adipose tissue and the calf (plethysmographic measurement) did not change significantly during adenosine infusion (Table 1).The disappearance curves for 133Xefrom the gastrocnemius muscle during adenosine infusion and control were congruent, suggesting that there was no change in muscle blood flow during these doses of adenosine infusion. Metabolic variables The arterial concentrations of glycerol showed a gradual decrease (Table 2), whereas those of pyruvate, lactate and glucose were unchanged. The hepatic exchange of these metabolites did not show any significant changes, except for a transient increase in lactate uptake (Table 2). Arterial plasma catecholamines From a basal level of 0.90 f 0.15 nmol/l, arterial noradrenaline increased and reached 1.46 f0.18 nmol/l at the highest infusion rate (Table 2). Arterial adrenaline was slightly elevated already in the basal state, measuring 0.53 f 0 . 1 2 nmol/l, but increased further during adenosine infusion, reaching a maximal level of 0.75f0.18 nmol/l at 60 pg of adenosine min- I kg- I (Table 2). DISCUSSION This investigation is the first to present data on simultaneous central and regional haemodynamic responses to, as well as some metabolic effects of, systemic adenosine administration in healthy volunteers. Previous studies in conscious subjects have only examined the influence of adenosine on systemic blood pressure, heart rate [ 17,201 and central haemodynamics [211. Central haemodynamics The stepwise increase in the adenosine infusion rate from 40 to 80 pg min-' kg-I was associated with a dosedependent decrease in peripheral vascular resistance to a value as low as half the basal one at the highest dose level. This vasodilatation was accompanied by a major increase in cardiac output, which was doubled at 80 pg of adenosine min-l kg-l. The systemic blood pressure was only slightly affected, showing a minor increase in systolic pressure and pulse pressure at the higher infusion rates. The maintenance of the systemic blood pressure and the increased heart rate in our conscious volunteers is in agreement with previous clinical investigations [ 17, 20, 2 11. The systemic vasodilatory effect of adenosine (reduction in systemic vascular resistance) is thus paralleled by a reflex increase in cardiac output, resulting in unaffected mean arterial blood pressure with increased pulse pressure. This is in contrast to the effects during anaesthesia, when infusion of adenosine causes dosedependent hypotension, due to an inadequate reflex increase in cardiac output [16, 361. Furthermore, in patients with sympathetic autonomic dysfunction, infusion of adenosine causes reduction in blood pressure, supporting the view that baroreceptor activation is involved in the maintenance of blood pressure during intravenous administration in conscious healthy subjects ~71. In the present study, the responses of heart rate and blood pressure were of the same magnitude as those in the study of Biaggioni et af. [17], although our maximal infusion rate was only 80 pg min-l kg-l as compared with 140 pg min-' kg- in the latter study. Bush et af. [21] found less pronounced effects on peripheral vascular resistance and heart rate than those seen in this study at a comparable dose level. These discrepancies in the reported effects of adenosine may be explained by the different sites of infusion. Due to the extremely rapid inactivation of adenosine in the circulation (half-life less than 10 s [3]), a more peripheral venous infusion site results in more degradation before the arterial circulation is reached. Table 1. Blood flow in the splanchnic region (dye extraction), the skin (laser Doppler technique), the calf (venous occlusion plethysrnography) and in the abdominal subcutaneous fat (isotope clearance) during infusion of adenosine (40-80 pg min- kg- intravenously) in healthy subjects Values are means fSEM.Statistical significance: *P< 0.05, **P< 0.01, ***P< 0.001 compared with basal. Dose of adenosine (pgmin ~ I kg- I ) . .. Basal ( n= 10) Splanchnic blood flow (l/min) 1.40 f0.13 Skin blood flow (arbitrary units) 23f3 Calf blood flow (mls - I I - ' ) 0.24f0.02 Adiposetissuebloodflow(mls-'l-~) 1.2fO.2 ( n = 10) 40 50 ( n= 10) 60 ( n=9) 1.46 f 0.14 33+6 0.24f0.02 1.3f0.2 1.50 k0.18 50 f 16* 0.23+0.03 1.3 f 0.2 1.97+0.33* 4 8 f 12* 0.23f0.03 1.4f0.3 70 ( n =6) 2.22 f 0.52** 48 f 12* 0.20f0.03 1.3f0.2 80 ( n= 5 ) 2.18 f 0.38*** 46+11* 0.17 f 0.03 1.1 f 0 . 2 Haemodynamiceffects of intravenousadenosine The increase in cardiac output was accomplished by a combined elevation of stroke volume and heart rate. The increase in stroke volume may be due primarily to the decrease in peripheral resistance. Whether or not changes in inotropy also contributed cannot be determined from the present study. Adenosine-induced enhancement in * * *- T T * 135 inotropy has not been reported, but in isolated hearts adenosine exerts negative inotropic effects in the atria [37].Since the end-diastolic volumes were not measured, one cannot tell whether an increased preload may have contributed to the increase in stroke volume, but the ventricular f i i g pressures (right atrial pressure, diastolic pulmonary artery pressure and pulmonary capillary venous pressure) were not affected. The positive chronotropic response to adenosine infusion has been suggested to be caused by a combination of vagal withdrawal and sympathetic activation [20].The latter is indicated in our study by the slightly elevated levels of circulating noradrenaline. It is worth noting that in vitro and after bolus injections in humans, adenosine exerts dose-dependent and transient (seconds)negative chronotropiceffects [ 181. The discrepancy between the present situation in vivo on the one hand and previous bolus injections in vivo and studies in vitro on the other hand could possibly be explained by the much higher adenosine concentrations that were reached in the latter situations and the lack of reflex adjustmentsin those cases. Splanchnic Peripheral haemdynamics -100 -+ Basal I I I I 40 50 60 70 I 80 Adenosine (pg min- kg- I ) Fig. 3. Percentage change in blood flow in the skin and the splanchnic region during infusion of adenosine (40-80 pg min- kg- intravenously).Statistical significance: *P<0.05, **P< 0.01, ***P< 0.001 compared with basal. Values are means f SEM. ' .I 100, $ 1 0 1 /- ' 1 min Basal Infusion of adenosine Fig. 4. Skin blood flow, as measured by the laser Doppler technique, in one healthy subject in the basal state and during infusion of adenosine (80 pg min-' kg-' intravenously),showing a typical response. The basal flow was low, with small oscillations.During adenosine infusion the mean blood flow increased, the oscillations were greatly magdied and peaks of high blood flow of a few minutes duration occurred. Flow is expressed as a percentage of the maximal response of the instrument. The regional vascular effects of adenosine suggest that the skin is the most sensitive of the four tissues studied. This is illustrated by the fact that skin flow started to increase at 40 p g of adenosine min-' kg-' and was maximal at 50 pg of adenosine min-I kg-I, whereas splanchnic flow did not increase until 60 pg of adenosine min-' kg-l (Fig. 3). On the other hand, skeletal muscle and adipose tissue did not show any vasodilatation at all at adenosine doses of up to 80 pg min-' kg-I. The doseindependent and long-lasting effect of adenosine on skin blood flow differs markedly from other cardiovascular responses, e.g. the increases in heart rate and coronary blood flow ([38];A. Edlund et al., unpublished work).We therefore speculate that, in the skin, adenosine may release some long-lasting vasodilator, possibly a peptide such as calcitonin-gene-related peptide [39]. With respect to the different regional flow responses, it is possible that the rapid elimination of adenosine causes the plasma concentration during exogenous administration to be higher in arterial blood reaching a proximal vascular bed, such as the coronary circulation, than in more distal tissues. However, the transit time and, consequently, the blood concentration of adenosine is unlikely to differ much between three of the peripheral tissues studied. the skin (thoracic region), adipose tissue (abdomen)and the splanchnic area. Skeletal muscle blood flow, on the other hand, was studied more peripherally (the calf), and possibly the adenosine concentrations may have been somewhat lower at the effector sites of the vasculature in this tissue. A rough estimate of the increases in blood flow in the skin and splanchnic region cannot account for the total increase in cardiac output. The cerebral [lo] and coronary [ 5 ] vasculatures are also known to dilate in response to adenosine infusion, but probably other regions are dilated as well. 136 A. Edlund et al. Sympathetic activation . . The plasma levels of catecholamines, especially noradrenline, were elevated during adenosine infusion, indicating sympathetic activation. This is in contrast to fiidings in vitro, where adenosine inhibits the release of noradrenaline [14, 401. The increase in circulating noradrenaline in this study, in agreement with the findings of Biaggioni et al. [17], indicates that sympathetic reflex mechanisms overcome this possible inhibitory effect. Increased sympathetic activity during adenosine infusion in man has in fact been found by a direct recording technique [41]. This sympathetic discharge may be secondary to baroreceptor activation due to the pronounced peripheral vasodilatation, but an activation through afferent myocardial receptors may also occur [42]. This sympathetic reflex may thereby counteract a direct vasodilating effect of adenosine. The vasculature in skeletal muscle is indeed sensitive to the vasodilating effect of adenosine, since a threefold increase in leg blood flow has been demonstrated during - local infusion of adenosine into the femoral artery (19 pg/min or about 0.3 pg min-l kg-l) [43]. However, such infusion probably provides higher local plasma concentrations of the drug and possibly without enhancing sympathetic reflex discharge to the leg tissues. The feelings of discomfort experienced by the volunteers at ;he highest dose(s) of adenosine may have induced physiological effects by themselves. However, although the rises in the catecholamine levels are of similar magnitude, the haemodynamic and metabolic response patterns during mental stress and adenosine infusion are markedly different. Thus, despite the fact that a considerable increase in cardiac output occurred during intense mental stress, the reduction in the peripheral resistance was less pronounced, and the systemic blood pressure rose markedly [44]. Vasodilatation occurred primarily in skeletal muscle and adipose tissue [45], which were unaffected by adenosine. Furthermore, lipolysis increased markedly during mental stress. In addition, effects of adenosine were found at doses too low to elicit any subjective discomfort. Therefore, it seems unlikely that physiological stress factors would contribute sigmficantly to the haemodynamic and metabolic responses found in this study. Metabolic effects Adenosine produces powerful anti-lipolytic effects in animal models both in vitro and in vivo [ 12, 13, 461 and has been proposed to be a physiological regulator of Table 2. Arterial concentrations, arteriovenous concentration differences and splanchnic uptake of glycerol, pyruvate, lactate and glucose, and arterial concentrations of adrenaline and noradrenaline, in the basal state and during infusion of adenosine (40-80 c(g min- * kg- intravenously) in healthy subjects Values are means f SEM.Statistical significance: *P< 0.05, **P< 0.01 compared with basal. Dose of adenosine (pgmin-l kg-l)... Glycerol Arterial concn. (pnol/l) (Arterial-hepatic vein) concn. difference (pmol/l) Splanchnic uptake (pmol/min) Pyruvate Arterial concn. (pmol/l) (Arterial-hepatic vein) concn. difference (pmol/l) Splanchnic uptake (pmol/min) Lactate Arterial concn. (pmol/l) (Arterial-hepatic vein) concn. difference (pmol/l) Splanchnic uptake (pmol/min) Basal ( n= 10) 40 ( n= 10) 50 (n=lO) 60 (n=9) 70 ( n=6) 80 (n=5) 64f9 47 f 7 61f10 45f6 54f4 39f7 40 f 5* 26 f 8* 37 f 6** 25f5* 28 f 7** 17f6** 57fll 67f22 57f12 41 f 9 46f13 47f19 53f6 6f 5 52f5 7f4 52f4 14f2 49f4 14f 1 50f4 6f3 49f5 7f2 6f7 11 f 6 22f6 27f9 14f6 16f5 434 f 36 126 f 12 431 f 26 148fll 406 f 20 159f18 392 f 28 138f 16 386 f 25 112f17 387 f 30 75fll* 147 f 25 192 f 27. 217 37* * 243 45* * 188f34 167f33 4.29 f 0.1 1 - 0.60 f 0.43 4.26 f 0.27 - 0.43 f 0.36 4.36 f 0.27 - 0.23 f 0.09 4.09 f 0.22 -0.63 f0.13 4.20 f 0.25 -0.16 f 0.16 - 0.6 1 f 0.50 - 0.40 f 0.43 -0.28f0.11 -0.89 f 0.23 -0.13 f 0.18 Glucose 4.36 f 0.26 Arterial concn. (mmol/l) (Arterial-hepatic vein) concn. - 0.12 f 0.15 difference (mmol/l) -0.18 f0.18 Splanchnic uptake (mmol/min) Adrenaline Arterial concn. (nmol/l) 0.53 f0.12 0.45 f0.09 0.59f0.14 0.75 f0.18* 0.72 f0.18* 0.76 f0.18* Noradrenaline Arterial concn. (nmol/l) 0.90 f 0.15 0.82 f 0.09 0.98 f 0.08 1.32f0.16* 1.32 f 0.14** 1.46 f0.18** Haemodynamic effects of intravenous adenosine lipolysis [46]. In t h e present subjects, the arterial glycerol concentration decreased by more than 50% without any concomitant increase in the hepatic uptake of glycerol, suggesting reduced lipolysis. This reduction was not mediated by an adenosine-induced depression of sympathetic activity, which was, on the contrary, slightly elevated. The results therefore suggest that exogenous adenosine causes an inhibition of lipolysis but a maintained blood flow in adipose tissue. Whether the inhibition of lipolysis is a local direct effect or also involves interactions with regulatory hormones still remains to be elucidated. This inhibition of the lipolytic rate may be a factor that counteracts a direct vasodilatory effect of exogenous adenosine in adipose tissue, since enhanced lipolysis is known t o be associated with an augmented blood flow [46]. 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