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A Quantitative Study of Pancreatic Blood Flow in Experimental Pancreatitis
Vol. 51, No.4 Printed in U.S.A.
GASTROENTEROLOGY
Copyright© 1966 by The Williams & Wilkins Co.
A QUANTITATIVE STUDY OF PANCREATIC BLOOD FLOW IN EXPERIMENTAL PANCREATITIS M. PAPP, M.D ., C.Sc., G. B. MAKARA, M.D., B. H~\JTMAN, M.D., M.D.
AND
L. Cs.{Kr,
Department of Pathophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
Panum 1 was the first to call attention to a possible role of vascular factors in the causation of pancreatitis. Later, Knape 2 showed that pancreas extract or trypsin solution, applied to the surface of the organ, slowed down pancreatic blood flow and led to capillary stasis and ecchymoses. Smyth3 produced pancreatitis by injecting mercury droplets, and Pfeffer et al., 4 microspheres, into the pancreatic artery. Popper et al.5 demonstrated the great significance of a decrease in the blood supply of the organ as a causative factor of acute pancreatitis. They found that simultaneous ligation of the accessory duct and stimulation of pancreatic secretion produced pancreatic edema which progressed to a type of hemorrhagic pancreatitis when the gastroduodenal artery was compressed. Compression of this vessel in the nonedematous state of the gland produced no pancreatitis. These findings have since been confirmed. 6 - 8 Examining the pancreas with transillumination, Thal 9 observed that bile produced stagnation of blood flow when injected into the parenchyma of the pancreas. The work here described was undertaken to supplement the scant data published on changes in the amount of blood flowing through the gland in acute pancreatitis. Materials and Methods Dogs of either sex, deprived of food for 12 hr, were used in three series of experiments. Received October 22, 1965. Accepted May 16, 1966. Address requests for reprints to: Dr. M. Papp, Pathophysiology Department, Institute of Experimental Medicine, VIII, Szigony U. 43, Budapest, Hungary.
In the first series, 42 animals were subjected to aseptic laparotomy under Narkothion anesthesia (Sanabo, Vienna) and in 8 of them acute pancreatitis was induced by injecting into the pancreas, under pressure, and through the duct of Santorini, 10 ml of bile obtained from the gall bladder/" and in another 7 about 10 ml of a 1o/o trypsin solution (Trypsin, Kobanyai Gy6gyszerarugyar, Budapest). In 10 animals, laparotomy was followed by traction and tugging of the pancreas (sham operation). An additional 17 intact animals were used as controls. Pancreatic blood flow determinations were made under . chloralose with the method of Sapirsteinu 24 hr after the pancreatitis-inducing injections and sham operations, respectively; the control animals were likewise anesthetized with chloralose for this purpose. For cardiac output and organ fraction determinations 30 p.c of Rb"" and 18 mg of Evans blue were injected, in 4-ml volumes, into the femoral vein. Every 2 sec blood was withdrawn through a polyethylene cannula from the femoral artery, and the animals were killed between the 45th and 50th sec after injection of isotopic rubidium, by thoracotomy and clamping the heart. In the second experimental series, two groups of 6 animals each were treated as the first two groups in the first series. Another 6 animals, sham-operated as the 10 animals in the first series, made up the controls. In this series, unlike in the first, after determination of the cardiac output a polyethylene cannula was introduced against the blood flow into the vein draining the tail and the body of the pancreas, and Rb"" was injected at once into the femoral vein. Following the administration of isotopic rubidium, blood was collected at 15-sec intervals from the femoral artery and the pancreatic vein. At the end of the eighth interval the animals were killed by thoracotomy and clamping the heart. In both experimental series cardiac output was calculated according to Stewart and Hamilton.12 Blood pressure was measured in the
524
PANCREA'l'IC BLOOD FLOW
October 1966
femoral artery. In the animals with bile-induced pancreatitis, gross inspection revealed severe pancreatic edema, extensive intra- and extrapancreatic fat necrosis, and occasional parenchymal necrosis varying in severity and extent. In trypsin-induced pancreatitis, the macroscopic lesions were variably severe edema, extravasation, and hemorrhagic and fat necroses. In the first series, statistical analyses were performed with the Kruskal-Wallis analysis of variance and the Mann-Whitney test. All values for the pancreatitic groups were related to those for t he sham-operated animals (table 1) .
In the second series, the extraction ratios for the pancreatitic groups and the control groups 11·ere determined on the basis of the formula
f
(Ca - Cv) dt {
Cadt
and integra ted on the basis of the Simpson formula and related to each other with Student's test (table 2). In an attempt to find direct evidence for the validity of the Rb"" clearance as a measure of p ancreatic blood flow a third experimental series was carried out, involving 4 animals, in which, under chloralose anesthesia, the caudal portion of the gland (about half of it) was isolated from the duodenum. The amount of blood flowing through the isolated gland portion was then determined by measuring pancreatic venous outflow, simultaneously with Rb 6" clearance (table 3). Cardiac output and Rb86 clearance values were determined as in the first experimental series. No experiment was evaluated in which the blood pressure was found to be 70 mm Hg or less.
Results and Comments
The results in the first experiment, presented in table I, show that in blood flow per minute through 100 g of pancreas there was no significant difference between the control animals and the sham-operated group. A statistically significant fall was, however, noted in the animals with bile- and trypsin-induced pancreatitis (P < 0.05; P < 0.01). In the weight of the gland, a significant increment above the control and sham-operated levels, was f<:mnd in the bile-induced pancreatitic
525
group (P < 0.05) . Expressed in percentage of body weight, an increment in organ weight was seen both in the bile and in the trypsin-induced pancreatitic animals (P < 0.01). This is evidence of the presence of edema. The value for cardiac output was significantly lower in the group with bileinduced pancreatitis than in any of the other three groups (P < 0.05). The blood pressure was also significantly lower in the two pancreatitic groups as compared with the other two groups (P < 0.01). The results in the second experiment, summarized in table 2, show that the extraction ratios in the controls do not differ significantly from those in diseased animals. The results of the third experiment (table 3) produce evidence of good agreement between venous outflow from the isolated gland and the simultaneously determined Rb 86 clearance of it. This means that Rb 86 clearance may be considered at least an approximate indicator of organ blood flow in pancreatitis. The values found for pancreatic blood flow both in the intact and the shamoperated control groups (75.5 and 73.2 ml per min per 100 g) accord well with earlier data in the literature.11 • 13 - 15 As regards organ blood flow in pancreatitis, its diminution is presumably due to pathological changes in the organ (edema, hemorrhage, necrosis) and to impaired systemic circulation (fall in blood pressure, diminution in cardiac output) . What still demands explanation is the influence which the vasoactive substances (bradykinin, histamine,1 6 etc.), released by the inflamed pancreas, exert upon the local and general circulation. In acute pancreatitis, the concentrations of vasoactive polypeptides in the blood are increased. 17 • 18 Earlier authors have shown that bradykinin, injected into the superior mesenteric artery, induced vasodilation. 19 When given into the arteries supplying the pancreas it caused a significant rise in local blood flow. 20 We found that histamine increases pancreatic blood flow,21 but other workers 1 R have failed to produce confirmatory evidence. One may perhaps speculate that at the initial phase of pancreatitis both substances for some time prevent a diminution
0.01 .
<
P < 0 .05.
b
p
a
Intac t control . .. . Sham -opera t ed co nt rol ... .. . .. . Bil e-indu ced pancreatitis . .. . . . .. Try psin-induced p a ncreatit is . . .. .
T ype of experiment
M ean SE
M ean SE
Organ weight (g)
±0.026
0. 353b
± 4 .5
38 .3
±1.8
11.4-
7
±8 .5
54 .3"
±1.2
12. 9
±0 .035
OA lOb
8
±0 .008
0.216
±3. 8
28 .9
±1.8
13 .5
10
±0.014
0.215
±1.2
15 .3
17
±2 .0
SE
31.1
M ean
Organ weight (% of body weight)
SE
Mean
SE
±7
89 b ± 24 --
166 --
± 8.2 -
22 .4 ±6. 8
23. 0b
±0 .07
0. 61
·-
±3
93b ±12 142" ± 3 .2 15 .9 ±10.1
36. 00"
±0 .19
0 .91
- -
±5
119 ±12 187 ± 3. 7 21.1 ±9.4
73 .2
±0 .08
0.83
-
±3
127 ±9
193 ±2.9
-
Mean
- - --- - - -22 .8
SE
---
M ean
-±8.4
SE
Blood pressure (mmHg)
75 .5
Mean
Cardiac output (mljmin per kg)
±0.09
SE
ml/min per 100 g
mljmin per pancreas
0.81
- --
Mean
% of cardiac output
Pancreatic blood flow
1. PancTeacti c blood flo w m easu T£d with RbS 6
- - --- --- - -- ---
No.
Body weight (kg)
TABLE
~'-:)
Cll
..,_
0
~
""._
~
-.:::
t-<
;:,..
>-'J
t>;j
'\j '\j
'\j
;:,..
0>
October 1966
527
PANCREATIC BLOOD FLOW T ABLE
2. Rb 86 extmction mtios in experimental pancreatitis Extraction ratio (%)
Groups
No.
30 sec Mean
90 sec
60 sec SE
Mean
SE
Mean
120 sec SE
---
Control .. _. . .. - 0 - ..... Pancreatitic .. -- · ......
95.25 95.20
6 10
±0.80 ±1.07
3. Pancreatic blood flow measured simu ltaneously with venous outflow and Rb8 6 cleamnce
TABLE
Pancreatic blood flow (mljmin per 100 g of gland)
Rb86 clearance
Venous efflux
Mean
26.6
SE
Mean
SE
±5.2
27.9
±5 .6
in local blood flow, but later are conducive to the development of edema, which, in turn, may impair the blood circulation in the organ. On the other hand, it is not at all improbable that having entered the general circulation these vasoactive substances have a major role to play in producing the shock that accompanies pancreatitis and reduces the supply of blood to the pancreas. Su m m ary
Pancreatic blood flow, measured by the Rb 86 method, decreased in dogs with acute bile- and trypsin-induced pancreatitis. Cardiac output decreased in the former situation and blood pressure decreased in both types of experimental pancreatitis. Decreased organ blood flow is believed to be due to pathological changes in the pancreas as well as to impaired systemic circulation, and to play a part in well established pancreatitis. REFERENCES 1. Panum, P. L. 1862. Experimentelle Beitrage zur Lehre von der Embolie . Virchows Arch. P ath. Anat. 25 : 308-338. 2. Knape, W. 1912. Untersuchungen tiber Pankreashamorrhagie, Pankreas- und Fettgewebsnekrose. Virchow. Arch. Path. Anat. 207 : 277-320.
82.23 88.06
±2.17 ±3.51
73.79 82 .17
±2.15 ±5.24
Mean
SE
--69.25 77 . 74
±2 .20 ± 6.21
3. Smyth, C. J. 1940. Etiology of acute hemorrhagic pancreatitis with special reference to the vascular factors. Arch. P ath. 30: 651669. 4. Pfeffer, R. G., A. Lazzarini-Robertson, J r., D . Safadi, G. Mixter, Jr., C. F. Secoy, and J . W. Hinton. 1962. Gradations of pancreatitis, edematous through hemorrhagic, experimentally produced by controlled injection of microspheres into blood vessels in dogs. Surgery 51 : 764-769. 5. Popper, H. L., H. Necheles, and K. C. Russel. 1948. Transition of pancreatic oedema into pancreatic necrosis. Surg. Gynec. Obstet. 87: 79-82. 6. Block, M. A., K. G. Wakim, and A. H. Baggenstoss. 1954. Experimental studies concerning factors in the pathogenesis of acute pancreatitis. Surg. Gynec. Obstet. 99 : 83- 90. 7. Nestel, P. I. 1957. Vascular factors in experimental acute pancreatitis. M ed. J. Aust. 44: 86-88. 8. Paulino-Netto, A., and D. A. Dreiling. 1960. Chronic duodenal obstruction: a mechanovascular etiology of pancreatitis. Amer. J. Dig. Dis. 5 : 1006-1018. 9. Thal, A. P. 1954. Studies on pancreatitis IV. P athogenesis of bile pancreatitis. Surg. Forum 5: 391. 10. Blumenthal, H. T., and I. G. Probstein. 1959. Pancreatitis. Charles C Thomas, Springfield, Ill. 11. Sapirstein, L. A. 1958. Regional blood flow by fractional distribution of indicators. Amer. J . Physiol. 193: 161-168. 12. H egglin, R., W. Rutishauer, G. Kaufman, E . Luthy, and H. Scheu. 1962. Kreislaufdiagnostik mit der Farbstoffverdiinnungsmethode. Thieme Verlag, Stuttgart. 13. Delaney, J. P., and E . Grim. 1964. Drug influences on pancreatitic blood flow. Fed. Proc. 23 : 252. 14. Delaney, J . P., and J. Custer. 1965. Gastrointestinal blood flow in the dog. Circ. Res. 17: 394-402. 15. Steiner, S., a.nd G. Mueller. 1961. Distribution
528
PAPP ET AL.
of blood flow in the digestive tract of the rat. Cir. Res. 9 : 99-102. 16. Bernard, A. 1959. La pancn§atite aigue: toxemie enzymatique. Presse Med. 67: 23512353. 17. Katz, W., M. Silverstein, E. Kobold, and A. P. Thai. 1964. Trypsin release, kinin
production and shock. Arch. Surg. (Chicago) 89: 322-328.
18. Thai, A. P., E. E. Kobold, and M. I. Hollenberg. 1963. The release of vasoactive sub-
stances in acute pancreatitis. Amer. J. Surg. 105: 708-713. 19. Chou, C. C., E. D. Frohlich, and E. C.
Vol. 51, No . 4
Texter, Jr. 1965. A comparative study of the effects of bradykinin, kallidin II, and eledoisin on segmental superior mesenteric resistance. J . Physiol. (London) 176: 1-11. 20. Papp, M., G. B. Makara, and B. Varga. 1966. Effet de Ia bradykinine, de Ia kallidine, de Ia serotonine et de !'histamine sur le flux sanguin de pancreas. Arch. Int. Pharmacodyn. In press. 21. P app, M., B. Varga, Zs. Acs, I. Krasznai, and J. Foldes. 1966. Pharmacological effects on pancreatic blood flow. Arch. Int. Pharmacodyn. 161: 61-67.
GASTROENTEROLOGY
Copyright© 1966 by The Williams & Wilkins Co.
A QUANTITATIVE STUDY OF PANCREATIC BLOOD FLOW IN EXPERIMENTAL PANCREATITIS M. PAPP, M.D ., C.Sc., G. B. MAKARA, M.D., B. H~\JTMAN, M.D., M.D.
AND
L. Cs.{Kr,
Department of Pathophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
Panum 1 was the first to call attention to a possible role of vascular factors in the causation of pancreatitis. Later, Knape 2 showed that pancreas extract or trypsin solution, applied to the surface of the organ, slowed down pancreatic blood flow and led to capillary stasis and ecchymoses. Smyth3 produced pancreatitis by injecting mercury droplets, and Pfeffer et al., 4 microspheres, into the pancreatic artery. Popper et al.5 demonstrated the great significance of a decrease in the blood supply of the organ as a causative factor of acute pancreatitis. They found that simultaneous ligation of the accessory duct and stimulation of pancreatic secretion produced pancreatic edema which progressed to a type of hemorrhagic pancreatitis when the gastroduodenal artery was compressed. Compression of this vessel in the nonedematous state of the gland produced no pancreatitis. These findings have since been confirmed. 6 - 8 Examining the pancreas with transillumination, Thal 9 observed that bile produced stagnation of blood flow when injected into the parenchyma of the pancreas. The work here described was undertaken to supplement the scant data published on changes in the amount of blood flowing through the gland in acute pancreatitis. Materials and Methods Dogs of either sex, deprived of food for 12 hr, were used in three series of experiments. Received October 22, 1965. Accepted May 16, 1966. Address requests for reprints to: Dr. M. Papp, Pathophysiology Department, Institute of Experimental Medicine, VIII, Szigony U. 43, Budapest, Hungary.
In the first series, 42 animals were subjected to aseptic laparotomy under Narkothion anesthesia (Sanabo, Vienna) and in 8 of them acute pancreatitis was induced by injecting into the pancreas, under pressure, and through the duct of Santorini, 10 ml of bile obtained from the gall bladder/" and in another 7 about 10 ml of a 1o/o trypsin solution (Trypsin, Kobanyai Gy6gyszerarugyar, Budapest). In 10 animals, laparotomy was followed by traction and tugging of the pancreas (sham operation). An additional 17 intact animals were used as controls. Pancreatic blood flow determinations were made under . chloralose with the method of Sapirsteinu 24 hr after the pancreatitis-inducing injections and sham operations, respectively; the control animals were likewise anesthetized with chloralose for this purpose. For cardiac output and organ fraction determinations 30 p.c of Rb"" and 18 mg of Evans blue were injected, in 4-ml volumes, into the femoral vein. Every 2 sec blood was withdrawn through a polyethylene cannula from the femoral artery, and the animals were killed between the 45th and 50th sec after injection of isotopic rubidium, by thoracotomy and clamping the heart. In the second experimental series, two groups of 6 animals each were treated as the first two groups in the first series. Another 6 animals, sham-operated as the 10 animals in the first series, made up the controls. In this series, unlike in the first, after determination of the cardiac output a polyethylene cannula was introduced against the blood flow into the vein draining the tail and the body of the pancreas, and Rb"" was injected at once into the femoral vein. Following the administration of isotopic rubidium, blood was collected at 15-sec intervals from the femoral artery and the pancreatic vein. At the end of the eighth interval the animals were killed by thoracotomy and clamping the heart. In both experimental series cardiac output was calculated according to Stewart and Hamilton.12 Blood pressure was measured in the
524
PANCREA'l'IC BLOOD FLOW
October 1966
femoral artery. In the animals with bile-induced pancreatitis, gross inspection revealed severe pancreatic edema, extensive intra- and extrapancreatic fat necrosis, and occasional parenchymal necrosis varying in severity and extent. In trypsin-induced pancreatitis, the macroscopic lesions were variably severe edema, extravasation, and hemorrhagic and fat necroses. In the first series, statistical analyses were performed with the Kruskal-Wallis analysis of variance and the Mann-Whitney test. All values for the pancreatitic groups were related to those for t he sham-operated animals (table 1) .
In the second series, the extraction ratios for the pancreatitic groups and the control groups 11·ere determined on the basis of the formula
f
(Ca - Cv) dt {
Cadt
and integra ted on the basis of the Simpson formula and related to each other with Student's test (table 2). In an attempt to find direct evidence for the validity of the Rb"" clearance as a measure of p ancreatic blood flow a third experimental series was carried out, involving 4 animals, in which, under chloralose anesthesia, the caudal portion of the gland (about half of it) was isolated from the duodenum. The amount of blood flowing through the isolated gland portion was then determined by measuring pancreatic venous outflow, simultaneously with Rb 6" clearance (table 3). Cardiac output and Rb86 clearance values were determined as in the first experimental series. No experiment was evaluated in which the blood pressure was found to be 70 mm Hg or less.
Results and Comments
The results in the first experiment, presented in table I, show that in blood flow per minute through 100 g of pancreas there was no significant difference between the control animals and the sham-operated group. A statistically significant fall was, however, noted in the animals with bile- and trypsin-induced pancreatitis (P < 0.05; P < 0.01). In the weight of the gland, a significant increment above the control and sham-operated levels, was f<:mnd in the bile-induced pancreatitic
525
group (P < 0.05) . Expressed in percentage of body weight, an increment in organ weight was seen both in the bile and in the trypsin-induced pancreatitic animals (P < 0.01). This is evidence of the presence of edema. The value for cardiac output was significantly lower in the group with bileinduced pancreatitis than in any of the other three groups (P < 0.05). The blood pressure was also significantly lower in the two pancreatitic groups as compared with the other two groups (P < 0.01). The results in the second experiment, summarized in table 2, show that the extraction ratios in the controls do not differ significantly from those in diseased animals. The results of the third experiment (table 3) produce evidence of good agreement between venous outflow from the isolated gland and the simultaneously determined Rb 86 clearance of it. This means that Rb 86 clearance may be considered at least an approximate indicator of organ blood flow in pancreatitis. The values found for pancreatic blood flow both in the intact and the shamoperated control groups (75.5 and 73.2 ml per min per 100 g) accord well with earlier data in the literature.11 • 13 - 15 As regards organ blood flow in pancreatitis, its diminution is presumably due to pathological changes in the organ (edema, hemorrhage, necrosis) and to impaired systemic circulation (fall in blood pressure, diminution in cardiac output) . What still demands explanation is the influence which the vasoactive substances (bradykinin, histamine,1 6 etc.), released by the inflamed pancreas, exert upon the local and general circulation. In acute pancreatitis, the concentrations of vasoactive polypeptides in the blood are increased. 17 • 18 Earlier authors have shown that bradykinin, injected into the superior mesenteric artery, induced vasodilation. 19 When given into the arteries supplying the pancreas it caused a significant rise in local blood flow. 20 We found that histamine increases pancreatic blood flow,21 but other workers 1 R have failed to produce confirmatory evidence. One may perhaps speculate that at the initial phase of pancreatitis both substances for some time prevent a diminution
0.01 .
<
P < 0 .05.
b
p
a
Intac t control . .. . Sham -opera t ed co nt rol ... .. . .. . Bil e-indu ced pancreatitis . .. . . . .. Try psin-induced p a ncreatit is . . .. .
T ype of experiment
M ean SE
M ean SE
Organ weight (g)
±0.026
0. 353b
± 4 .5
38 .3
±1.8
11.4-
7
±8 .5
54 .3"
±1.2
12. 9
±0 .035
OA lOb
8
±0 .008
0.216
±3. 8
28 .9
±1.8
13 .5
10
±0.014
0.215
±1.2
15 .3
17
±2 .0
SE
31.1
M ean
Organ weight (% of body weight)
SE
Mean
SE
±7
89 b ± 24 --
166 --
± 8.2 -
22 .4 ±6. 8
23. 0b
±0 .07
0. 61
·-
±3
93b ±12 142" ± 3 .2 15 .9 ±10.1
36. 00"
±0 .19
0 .91
- -
±5
119 ±12 187 ± 3. 7 21.1 ±9.4
73 .2
±0 .08
0.83
-
±3
127 ±9
193 ±2.9
-
Mean
- - --- - - -22 .8
SE
---
M ean
-±8.4
SE
Blood pressure (mmHg)
75 .5
Mean
Cardiac output (mljmin per kg)
±0.09
SE
ml/min per 100 g
mljmin per pancreas
0.81
- --
Mean
% of cardiac output
Pancreatic blood flow
1. PancTeacti c blood flo w m easu T£d with RbS 6
- - --- --- - -- ---
No.
Body weight (kg)
TABLE
~'-:)
Cll
..,_
0
~
""._
~
-.:::
t-<
;:,..
>-'J
t>;j
'\j '\j
'\j
;:,..
0>
October 1966
527
PANCREATIC BLOOD FLOW T ABLE
2. Rb 86 extmction mtios in experimental pancreatitis Extraction ratio (%)
Groups
No.
30 sec Mean
90 sec
60 sec SE
Mean
SE
Mean
120 sec SE
---
Control .. _. . .. - 0 - ..... Pancreatitic .. -- · ......
95.25 95.20
6 10
±0.80 ±1.07
3. Pancreatic blood flow measured simu ltaneously with venous outflow and Rb8 6 cleamnce
TABLE
Pancreatic blood flow (mljmin per 100 g of gland)
Rb86 clearance
Venous efflux
Mean
26.6
SE
Mean
SE
±5.2
27.9
±5 .6
in local blood flow, but later are conducive to the development of edema, which, in turn, may impair the blood circulation in the organ. On the other hand, it is not at all improbable that having entered the general circulation these vasoactive substances have a major role to play in producing the shock that accompanies pancreatitis and reduces the supply of blood to the pancreas. Su m m ary
Pancreatic blood flow, measured by the Rb 86 method, decreased in dogs with acute bile- and trypsin-induced pancreatitis. Cardiac output decreased in the former situation and blood pressure decreased in both types of experimental pancreatitis. Decreased organ blood flow is believed to be due to pathological changes in the pancreas as well as to impaired systemic circulation, and to play a part in well established pancreatitis. REFERENCES 1. Panum, P. L. 1862. Experimentelle Beitrage zur Lehre von der Embolie . Virchows Arch. P ath. Anat. 25 : 308-338. 2. Knape, W. 1912. Untersuchungen tiber Pankreashamorrhagie, Pankreas- und Fettgewebsnekrose. Virchow. Arch. Path. Anat. 207 : 277-320.
82.23 88.06
±2.17 ±3.51
73.79 82 .17
±2.15 ±5.24
Mean
SE
--69.25 77 . 74
±2 .20 ± 6.21
3. Smyth, C. J. 1940. Etiology of acute hemorrhagic pancreatitis with special reference to the vascular factors. Arch. P ath. 30: 651669. 4. Pfeffer, R. G., A. Lazzarini-Robertson, J r., D . Safadi, G. Mixter, Jr., C. F. Secoy, and J . W. Hinton. 1962. Gradations of pancreatitis, edematous through hemorrhagic, experimentally produced by controlled injection of microspheres into blood vessels in dogs. Surgery 51 : 764-769. 5. Popper, H. L., H. Necheles, and K. C. Russel. 1948. Transition of pancreatic oedema into pancreatic necrosis. Surg. Gynec. Obstet. 87: 79-82. 6. Block, M. A., K. G. Wakim, and A. H. Baggenstoss. 1954. Experimental studies concerning factors in the pathogenesis of acute pancreatitis. Surg. Gynec. Obstet. 99 : 83- 90. 7. Nestel, P. I. 1957. Vascular factors in experimental acute pancreatitis. M ed. J. Aust. 44: 86-88. 8. Paulino-Netto, A., and D. A. Dreiling. 1960. Chronic duodenal obstruction: a mechanovascular etiology of pancreatitis. Amer. J. Dig. Dis. 5 : 1006-1018. 9. Thal, A. P. 1954. Studies on pancreatitis IV. P athogenesis of bile pancreatitis. Surg. Forum 5: 391. 10. Blumenthal, H. T., and I. G. Probstein. 1959. Pancreatitis. Charles C Thomas, Springfield, Ill. 11. Sapirstein, L. A. 1958. Regional blood flow by fractional distribution of indicators. Amer. J . Physiol. 193: 161-168. 12. H egglin, R., W. Rutishauer, G. Kaufman, E . Luthy, and H. Scheu. 1962. Kreislaufdiagnostik mit der Farbstoffverdiinnungsmethode. Thieme Verlag, Stuttgart. 13. Delaney, J. P., and E . Grim. 1964. Drug influences on pancreatitic blood flow. Fed. Proc. 23 : 252. 14. Delaney, J . P., and J. Custer. 1965. Gastrointestinal blood flow in the dog. Circ. Res. 17: 394-402. 15. Steiner, S., a.nd G. Mueller. 1961. Distribution
528
PAPP ET AL.
of blood flow in the digestive tract of the rat. Cir. Res. 9 : 99-102. 16. Bernard, A. 1959. La pancn§atite aigue: toxemie enzymatique. Presse Med. 67: 23512353. 17. Katz, W., M. Silverstein, E. Kobold, and A. P. Thai. 1964. Trypsin release, kinin
production and shock. Arch. Surg. (Chicago) 89: 322-328.
18. Thai, A. P., E. E. Kobold, and M. I. Hollenberg. 1963. The release of vasoactive sub-
stances in acute pancreatitis. Amer. J. Surg. 105: 708-713. 19. Chou, C. C., E. D. Frohlich, and E. C.
Vol. 51, No . 4
Texter, Jr. 1965. A comparative study of the effects of bradykinin, kallidin II, and eledoisin on segmental superior mesenteric resistance. J . Physiol. (London) 176: 1-11. 20. Papp, M., G. B. Makara, and B. Varga. 1966. Effet de Ia bradykinine, de Ia kallidine, de Ia serotonine et de !'histamine sur le flux sanguin de pancreas. Arch. Int. Pharmacodyn. In press. 21. P app, M., B. Varga, Zs. Acs, I. Krasznai, and J. Foldes. 1966. Pharmacological effects on pancreatic blood flow. Arch. Int. Pharmacodyn. 161: 61-67.