Hexnodynamic Changes of Adenosine Diphosphate, Adenosine Triphosphate, and Thrombin in Relation to Their Platelet-Aggregating Activity J. SWEDENBORG, G. TAYLOR & P. OLSSON Surgical Research Laboratory, Thoracic Clinics, Karolinska Sjukhuset, Stockholm, Sweden

Swedenborg, J., Taylor, G. & Olsson, P. Hemodynamic Changes of Adenosine Diphosphate, Adenosine Triphospate, and Thrombin in Relation to Their Platelet-Aggregating Activity. Scand. 1. d i n . Lab. Invest. 27, 21 3-219, 1971.

ADP and ATP were infused into the systemic and pulmonary circulation of dogs. Thrombin was infused into the pulmonary circulation. All the agents caused a decreased platelet count. ADP and ATP caused an increase in cardiac output. Pulmonary vascular resistance as well as total peripheral vascular resistance were decreased. Thrombin caused an increase in pulmonary vascular resistance and a decrease in total peripheral vascular resistance. Key-words: ADP; ATP; hemodynamics; platelet aggregation; thrombin 1. Swedeizborg, M.D. , Surgical Research Laboratory, Thoracic Clinics, Karu- linska Sjukhuset, 104 01 Stockholm 60, Sweden

Since the publication of Fleisch’s works (13) adenosine compounds have been known to exert hemodynamic effects. Both ADP and ATP have been reported t o be strong peripheral vasodilators (11, 12, 14, 18, 19). ATP has, in addition, been reported to be a pulmonary vasoconstrictor (lo), and its release from intracellular sources has been put forward as one possible explanation for the increased pulmonary vascular resistance seen in, e. g., hemorrhagic shock (2).

Thrombinemia - the prerequisite for dissemin- ated intravascular coagulation-gives rise to decre- ased peripheral vascular resistance and increased pulmonary vascular resistance (23). The decrease in peripheral vascular resistance induced by throm- bin has been explained by release of ADP and ATP from the platelets (27). Whether the release of ADP and ATP could also, a t least t o some extent, explain the increase. in pulmonary vascular resistance seen in thrombinemia is, however, un- known.

Thrombinemia further causes platelet aggre- gation. Mechanical blocking of the pulmonary capillaries by platelet agreggates has been ad- vanced as one explanation for the increased pul-

monary vascular resistance seen in, e. g., dis- seminated intravascular coagulation (25). ADP - and t o some extent ATP - also have platelet- aggregating properties i vitro (4, 15) as well as in vivo (5, 8, 22).

The purpose of this investigation was to study the effects on the pulmonary and the peripheral circulation of physiological amounts of ADP and ATP, i. e., amounts that theoretically could be released from cells, as well as t o evaluate the effect of platelet aggregation upon pulmonary vascular resistance.

METHODS

Twelve mongrel dogs weighing between 17 and 35 kg were used. The dogs were intubated endo- tracheally and ventilated with a n Engstrom respi- rator (LKB Medical, Sweden). Anesthesia was induced and maintained with sodium pento- barbital. A leftsided or a transverse thoracotomy was performed. A catheter was advanced into the pulmonary artery through a stab wound in the outflow tract of the right ventricle. Catheters were also placed in the left atrial appendage and

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214 J . Swedenborg, G. Taylor & P . Olsson

one carotid artery. These three catheters were connected to strain gauge transducers for pressure measurements. Cardiac output was measured by a flow probe of a square wave electromagnetic flowmeter (Nycotron, Norway) placed around the main pulmonary artery. Zero reference levels were obtained by occlusions of the main pul- monary artery. Recordings were made on an ultraviolet recorder (Oscillofil, Siemens, West- Germany).

Right-sided infusions were made through a catheter inserted into one jugular vein and with its tip in the right atrium. Left-sided infusions were made through a catheter inserted into onq femoral artery and with its tip in the root of the aorta. All catheters used were made of poly- ethylene. Infusions were made with a constant speed infusion pump. Infusion rate was 1-10 ml/min, and infusion time was 2 minutes. Arterial blood samples for platelet counts were taken through a catheter placed in one femoral artery.

Since blood flow in the main pulmonary artery and the pressure gradient across the lung were known, it was possible to calculate pulmo- nary vascular resistance (P. V. R.). P. V. R. =

PPA - PLA . Total peripheral vascular resistance QPA

(T. P. V. R.) was calculated as aortic blood

pressure divided by cardiac output (g:) on

the assumption that right atrial pressure was negligible compared to aortic pressure.

The initial intravascular concentrations of the substances to be tested were calculated as in- jected amount divided by the cardiac output at the start of the infusions. This method of calcu- lation was used for both right-sided and left- sided infusions.

Samples for platelet count were taken before and 1, 2, 3 and 5 minutes after the start of the infusions. At thesanie time P. V. R. and T. P. V. R. were calculated.

sodium salt: Fluka A. G., Buchs, Switzerland. All reagents were dissolved in isotonic saline be- fore used. The solutions were kept in crushed ice between injections.

RESULTS

Infirsions of ADP

Thirty-two injections of ADP, 22 on the right side and 10 on the left side, were given to 12 dogs. The calculated intravascular concentra- tions ranged between 0.7 and 20.0 pg/ml for right- sided infusions, mean 5.5 pg/ml; and 1.7 and 17.7 pg/ml for left-sided infusions, mean 6.4 pg/ml. Infusions of ADP into the right atrium usually caused an increase in pulmonary blood flow, i. e., an increased cardiac output. This was accompanied by a minor increase in pulmonary arterial pressure and usually a decrease in aortic blood pressure. Left atrial pressure was largely unaffected. Left-sided infusions produced essen- tially the same changes, but the effects were more marked (Table 1).

Fig. 1 A shows the simultaneous changes in platelet count, P. V. R., and T. P. V. R. after right-sided infusions. After 2 minutes the mean platelet count was 83 per cent of the initial value while P. V. R. was 91 per cent and T. P. V. R. 65 per cent. The platelet count and T. P. V. R. then returned towards the preinfusion values, while P. V. R. was normalized somewhat later. The maximum decreases in platelet count, P. V. R., and T. P. V. R. were also noted for each infusion irrespective of time. The mean platelet count decreased to 70 per cent of the initial value (p < 0.001), the mean P. V. R. to 89 per cent (0.02 < p < 0.05), and the mean T. P. V. R. to 64 per cent (p < 0.001).

Infusions of ADP into the root of the aorta seemed to produce a more pronounced fall in platelet count. Fig. 1 B shows the simultaneous changes in platelet count, P. V. R., and T. P. V. R. upon left-sided infusions. After 2 minutes the mean platelet count was 64 per cent, the mean P. V. R. 83 per cent, and the mean T. P. V. R 31 per cent of the initial values. The maximum changes irrespective of time showed a lowering of the mean platelet count to 60 per cent (p < 0.001),

REAGENTS

Thrombin: Parke Davies & Company, Detroit, Mich., USA. ADP, Adenosine-5’-diphosphate, sodium salt and ATP, Adenosine-5’-triphosphate,

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Vmoactivity of ADP, ATP and Thrombin 215

Table I. Hemodynamic effects of infusions of ADP into the pulmonary circulation and the systemic circula- tion in 12 dogs

Maximum or minimum value during or

Before infusion after infusions

Pulmonary arterial pressure mm Hg Aortic pressure

Infusions into the mm Hg right atrium Left atrial pressure

mm Hg Cardiac output ml/min

18 (S.D. = 4)

125 (S.D. = 22)

4 (S.D. = 2)

1370 (S.D. = 620)

20 (S.D. = 5)

95 (S.D. = 30)

4 (S.D. = 3)

1670 (S.D. = 700)

Pulmonary arterial pressure mm Hg Aortic pressure

Infusions into the mm Hg root of aorta Left atrial pressure

mm Hg Cardiac output ml/min

18 (S.D. = 3)

126 (S.D. = 28)

4 (S.D. = 1)

1360 (S.D. = 700)

22 (S.D. = 5)

56 (S.D. = 27)

4 (S.D. = 1)

21 60 (S.D. = 980)

of P. V. R. to 81 per cent (0.01 < p < 0.001), and of T. P. V. R. to 33 per cent (p < 0.001) of the initial value.

ADP was more active in lowering T. P. V. R. when infused on the left side. Amaximum response was rapidly reached and increasing the dose had little effect. This was not true for right-sided in- fusions.

Thus, infusions of ADP, both on the right and the left side of the heart, give rise to an increased cardiac output. There is a concomitant decrease in pulmonary vascular resistance and platelet count. ADP has a stronger effect when injected on the left side of the heart as judged both by fall in platelet count and decrease in T. P. V. R.

Infusions of ATP

Twenty-one infusions of ATP were made in the same way as for ADP in 7 dogs, 13 on the right side and 8 on the left side, and the data were treated analoguously. The mean intravasular concentration was 6.4 pg/ml for right-sided in- fusions, range 1.6-16.6, and 5.2 pg/ml for the left-sided infusions, range 1.4-19.6. Infusions of ATP gave rise to essentially the same changes as ADP, i. e., an increase in cardiac output concomi-

tant with a slight increase in pulmonary arterial pressure, no change in left atrial pressure, and usually a decrease in aortic blood pressure. As with ADP, left-sided infusions produced more marked changes (Table 11).

The following changes were noted upon right- sided infusions. After 2 minutes the mean platelet count was 88 per cent of the initial value, and P. V. R. decreased to a minimum of 91 per cent after 3 minutes. T. P. V. R. reached its minimum value after 2 minutes (70 per cent). All parameters normalized rapidly. Upon left-sided infusions the platelet count decreased to 91 per cent and P. V. R. to 88 per cent, both figures after 3 minutes. T. P. V. R. reached its minimum after 2 minutes (38 per cent). The mean P. V. R. irrespective of time went down to 93 per cent (n. s.) upon right- sided and to 85 per cent (0.001 < p < 0.01) upon left-sided infusions. The minimum platelet count was 88 per cent (n. s.) after right-sided infusions, and 92 per cent (0.02 < p < 0.05) after left-sided infusions. As with ADP, left-sided infusions gave the most pronounced fall in T. P. V. R. The mean T. P. V. R. fell to 71 per cent (p < 0.001) and to 32 per cent (p < 0.001) on right- and left-sided infusions respectively.

Apparently, ATP was less potent than ADP

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216 J . Swedeizborg, G. Taylor & P . Olssori

1 % . of control T

1004

75- A.

501

0 TC PVR

6 TPVR

251 min 0 I

0 1 2 3 4 5

i % of control

looh 75

affected, Cardiac output showed an initial increase from 1750 ml/min. (S. D. = 900) to 1910 ml /min. (S. D. = 800) and then decreased to 1690 ml/min. (S. D. = 920). Fig. 2 shows the changes in platelet count, P. V. R. and T. P. V. R. minute by minute. After 3 minutes the mean platelet count was 29 per cent of the initial value. At the same time the maximum value of P. V.R. ( I 55 per cent) and the. minimum value of T. P. V. R. (75 per cent) were reached. If the maximum changes caused by each injection were used for the calculations, there was an increase of the mean P. V. R. to 165 per cent of the initial value (0.02 < p < 0.05) and a decrease of the mean platelet count to 23 per cent (p < 0.001).

Thus, after infusions of thrombin into the right atrium, a rise in P. V. R. was seen at the same time as the platelet count dropped. The fall in platelet count was more marked than after in- fusions of ADP while the lowering of T. P. V. R. was of the same order of magnitude.

, , , , min, 0 0 1 2 3 4 5

Fig. 1 . Relative changes in platelet count (TC), pulmonary vascular resistance (PVR), and total peripheral vascular resistance (TPVR) upon in- fusions of ADP into the right atrium (A) and the root of the aorta (B). Infusion time was 2 minutes. The bars represent standard error of the mean.

both in lowering the platelet count and the pulmonary vascular resistance. Like ADP it had a stronger effect on T. P. V. R. when injected on the left side of the heart.

Infusions of thrombin

The effects of infusions of ADP and ATP were compared to infusions of thrombin into the right atrium. Six infusions were made in 6 dogs. The calculated intravascular concentrations ranged between 0.04 and 0.15 NIH units/ml (mean 0.08). Thrombin infusions caused a rise in pulmonary arterial pressure from 18 mm Hg ( S. D. = 4) to 27 mm Hg (S. D. = 6). Aortic blood pressure was lowered from 140 mm Hg (S. D. = 27) to 110 mm Hg (S. D. = 34). Left atrial pressure was not

DISCUSSION

ADP and ATP both gave rise to an increase in cardiac output accompanied by a rise in pulmo- nary arterial pressure. Left atrial pressure re- mained unchanged. Since cardiac output was increased relatively more than pulmonary arterial pressure, the pulmonary vascular resistance was lowered. The lowering of P. V. R. upon right- sided infusions of ATP was not statistically significant, however. The increased cardiac out- put may well be due to peripheral vasodilatation and systemic hypotension which activates baro- receptors and causes the heart rate to increase. Increased heart rate is reported following in- fusions of ATP (26). The increase in pulmonary flow and pressure tends to increase transmural pulmonary vascular pressure with a passive de- crease in P. V. R. as a result (3, 9). In the concen- trations studied, ADP and ATP themselves have no major effect on the pulmonary vascular bed. The changes observed in the lung circulation are probably secondary to peripheral vascular effects and possibly cardiac effects. This argument is supported by the fact that left-sided infusions of ADP and ATP caused more marked increases in pulmonary blood flow and also more marked

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Vasoactivity of ADP, A T P arid Thrombin 217

Table 11. Hemodynamic effects of infusions of ATP into the pulmonary circulation and the systemic circula- tion in 7 dogs

~

Pulmonary arterial pressure mm Hg Aortic pressure

Infusions into the mm Hg right atrium Left atrial

pressure mm Hg Cardiac output ml/min

Maximum or

Before infusion after infusions minimum value during or

16 18

130 1 02

4 4

1920 2360

(S.D. = 4)

(S.D. = 29)

(S.D. = 3)

(S.D. = 11 10)

(S.D. = 5)

(S.D. = 37)

(S.D. = 2)

(S.D. = 1500)

Pulmonary arterial pressure mm Hg Aortic pressure

Infusions into the mm Hg root of aorta Left atrial

pressure mm Hg Cardiac output ml/min

19 (S.D. = 3)

135 (S.D. = 24)

4 (S.D. = 1)

1960 (S.D. = 1060)

23 (S.D. = 4)

65 (S.D. = 36)

4 (S.D. = 1)

2960 (S.D. = 1500)

decrease in P. V. R., as compared to right-sided infusions.

ATP has by some authors been reported to be a pulmonary vasoconstrictor (10, 17). These studies, however, have been performed by using either an artificial circulation of the lung in situ or isolated perfused lungs. ATP has also been reported to cause pulmonary obstruction in animals with an intact circulation, but this obser- vation was not supported by simultaneous flow and pressure measurements (1 1). Rowe et al. (26), however, observed a decreased pulmonary vascular resistance in the intact dog after infusions of ATP. It is possible that ATP exerts a vasocon- stricting effect in the lung, but this is counter- acted in the whole animal by the increased pulmonary blood flow resulting in a recruitment of closed capillary beds. This might explain why there was a less pronounced lowering of P. V. R. after infusions of ATP than after infusions of ADP. The decreases in peripheral vascular resis- tance were similar when infusions of ADP were compared to infusions of ATP.

ADP and ATP in the concentrations used were obviously inactivated during the passage through the lungs. Right-sided infusions caused much

200 % of control 1

min 0 I

0 1 2 3 4 5 Fig. 2. Relative changes in platelet count (TC), pul- monary vascular resistance (PVR), and total peri- pheral vascular resistance (TPVR) upon infusions of thrombin into the right atrium. Infusion time was 2 minutes. The bars represent standard error of the mean.

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218 1. Swedeirborg, G . Taylor & P. Olsson

less decrease in T. P. V. R. as compared to left- sided infusions. This is in agreement with the studies on ATP by Folkow (12). Brashear & Ross (6), on the other hand, could not demonstrate a significant decrease of injected ADP after passage through the lungs. In the latter study, however, the amounts of ADP infused per unit time were more than a hundred times larger than in our investigation.

Left-sided infusions of ADP as well as ATP showed poor dose-response correlation. This is in agreement with Kovacs et al. (20), who found a maximum effect of ATP with a relatively small dose. A possible explanation for this may be that the active vasodilator is a break-down product of ADP or ATP and that the conversion system gets saturated at a certain amount of the nucleo- tides. In right-sided infusions of ADP there was a better dose-response correlation possibly because smaller amounts than those injected reached the arterial circulation, owing to degradation in the pulmonary circulation.

Blood contains high amounts of ADP and ATP, but most of this is to be found inside theredcells (7) and is not released by thrombin (27). The pool of nucleotides available for thrombin-in- duced release is to be found inside the platelets and constitutes a small fraction of the total amounts of ADP and ATP in blood. In trauma with intravascular coagulation there is probably a release of ADP and ATPfrom theplatelets, and we have mainly been interested in the effects of such amounts. It has been reported that the vasodilatation in the systemic circulation caused by thrombin can be explained by release of ADP and/or ATP from the platelets (24, 27). The present results show that ADP or ATP do not contribute to the increase in P. V. R. seen in thrombinemia.

Platelet aggregation has been claimed to cause obliteration of the pulmonary vessels, thereby in- creasing pulmonary vascular resistance (1 , 25). ADP caused a more pronounced lowering of both P. V. R. and platelet count than ATP did. The pulmonary vessels were obviously able to cope with the platelet aggregates. Infusions of thrombin, however, gave rise to an increase in P. V. R. concomitant with a fall of the amount

It is hard to reconcile that platelet aggregates cause pulmonary obstruction in one case but not in the other. It is true that the fall in platelet count was more dramatic when thrombin was infused, but the smaller platelet-aggregating effect of ADP would have increased P. V. R. if platelet aggregates alone were capable of increasing P. V. R. The decrease in T. P. V. R. was, however, of the same order of magnitude when right- sided infusions of thrombin were compared to right-sided infusions of ADP. We suggest that normal pulmonary vessels are relatively unaffected by mechanical obstruction by platelet aggregates. The effect of mechanical obstruction may, how- ever, be added to an already existing vasocon- striction. This may well be the case when throm- bin is infused. Serotonin (16,21, 29) and possibly other vasoactive compounds are released from the platelets by thrombin. The released amounts of serotonin are capable of increasing pulmonary vascular tone (28).

ADP and ATP have small effects on the pul- monary circulation in concentrations that can be released from blood cells, even though at least ADP causes a significant fall in platelet count. The effect on the peripheral circulation is, how- ever, marked. Thrombin, on the other hand, causes an increase in pulmonary vascular resis- tance at the same time as the platelet count goes down.

ACKNOWLEDGEMENT

These studies were supported by grant B71-14X- 3188-01 from the Swedish Medical Research Council and grants from Karolinska Institutet, Stockholm, Sweden.

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Received 12 January 1971 Accepted 5 March 1971

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