Pfliigers Arch. 358, 89--100 (1975) 9 by Springer-Verlag 1975

Dynamics of Canine Pancreatic Blood Flow and of Insulin Secretion during an Intravenous Glucose Load U w e Fischer, H a r t m u t H o m m e l , a n d E w a l d S c h m i d Zentralinstitut fiir Diabetes ,,Gerhardt Katseh", Karlsburg, GDI~ Received September 24, 1974

Summary. Blood flow through the superior pancreaticoduodenal artery of anaesthetized dogs increases immediately after an i.v. glucose load and parallels to gIyeemia, but not to insulin output. Flow of superior mesenteric, and femoral arteries as well as of portal vein are also enhanced after rapid i.v. injections of glucose or manni~oI. Extent and duration of all flow increases are dose-dependent and strongly related to the alterations of arterial plasma osmolality (maximum increase 24 mosmoles/kg). Heart rate, mean arterial blood pressure, and hematocrit remain unchanged after the first test minute. There is a considerable decrease of peripheral vascular resistance in the circulatory regions investigated. Flow through aorta ascendens is augmented for a short time. Possible mechanisms of vasodilatation are refexes produced by osmoreceptors and/or local effects of osmolality on the tonus of vascular muscle. Within the physiological range pancreatic perfusion does not determine the amount of insulin released. Key words: Blood Flow -- Pancreas -- Blood Glucose -- Insulin Secretion -Osmolality -- Peripheral Vascular Resistance -- Vasodila~tion -- Glucose -Mannitol. P a n c r e a t i c a r t e r i o v e n o u s difference of i m m u n o r e a c t i v e insulin activi t y ( I R I ) a n d p a n c r e a t i c b l o o d flow p r o v i d e t h e p o s s i b i l i t y for a n e x a c t d e t e r m i n a t i o n of t h e n e t p a n c r e a t i c insulin o u t p u t . As a rule, conclusions are d r a w n f r o m I I ~ I a n a l y s e s o n t o t h e a m o u n t of insulin released. This applies to u n c h a n g e d p a n c r e a t i c perfusion. L a c y a n d Greider (1972) showed no a l t e r a t i o n of t h e islet perfusion u n d e r t h e influence of insulinogenic stimuli (vitalmieroscopy). Vance (1970), however, d e m o n s t r a t e d b y t h e m i c r o s p h e r e t e c h n i q u e a considerable flow increase t h r o u g h t h e islets w h e n insulin secretion is s t i m u l a t e d . B y several m e t h o d s (direct m e a s u r e m e n t of v e n o u s outflow, h y d r o g e n gas clearance, e l e c t r o m a g n e t i c flowmcter) some a l t e r a t i o n of t h e whole p a n c r e a t i c flow has been shown d u r i n g a glucose l o a d ( K a n a z a w a et al., 1968, S e m b et al., 1971, F i s c h e r et al., 1973). I n a p r e v i o u s p a p e r (Fischer etal., 1974) we d e s c r i b e d a n e x p e r i m e n t a l a r r a n g e m e n t for t h e e s t i m a t i o n of t h e a c t u a l n e t insulin o u t p u t of t h e whole p a n c r e a s in a n a e s t h e t i z e d dogs. I t includes t h e r e g i s t r a t i o n of flow

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through arteria pancreaticoduodcnalis sup. by an electromagnetic flowmeter. In this report the mechanism for the increased pancreaticoduod e n a l flow in d e p e n d e n c e o n h y p e r g l y c e m i a will be i n v e s t i g a t e d in d e t a i l . M a t e r i a l and M e t h o d s Experimental Design. 34 Alsation dogs of both sexes in intubation anaesthesia with artificial breathing were used after starvation for 20 hrs. They got 25 mg/kg hexobarbital sodium, 60 mg ~yorelaxin | (additional doses in dependence on the effect) and N~O/O~ 4:1 v/v, 10 l/rain. Arterial PO 2 has been controlled. :No heparin has been given. After a laparotomy they were prepared in the following way: A non-cannulating flowprobe of an electromagnetic flowmeter was placed at the superior pancreaticoduodenal artery behind the onset of the A. gastroepiploiea. Additional probes were used at one of the following vessels: femoral artery, trunk of the portal vein, superior mesenteric artery, aorta ascendens (catheter-tip probe). Indwelling catheters were introduced into the splenic artery up to the A. coeliaca for recording blood pressure, and into femoral artery, saphenic, intestinal and portal veins for drawing blood specimen. Blood glucose and plasma I R I concentrations from these specimen and arterial plasma osmolality (Halbmikro-0smometer Fa. Knauer, West-Berlin) were analyzed. Blood flow (square-wave fiowmeter Nycotron A/S, Drammen, :Norway), heart rate and mean arterial blood pressure (Biometer BM 101 RFT, VEB Megger~tewerk ZwSnitz, GDR) were continuously recorded (Motorkompensator MK, VEB Medizinger~itewerk Erich Weinert, magdeburg, GDR). Operation procedures and analytic methods are described in detail by Fischer et al. (1974). Tests. On the average 180 rain after anaesthesia 1.25 ml/kg of 0.9o/0 NaC1 were injected intravenously within 25 sec. From this test up to the end of the experiment the animals were infused with saline (2.0 ml/min). 30 rain after the injection of saline one of the following tests was performed: intravenous injection within 25 see of 1.25 ml/kg of a solution containing 10, 20 or 40 g glucose or mannitol in 100 ml water; i.e. 0.70, 1.39 or 2.78 mmoles/kg under the assumption of 180 as a molecular wt. of both substances. 2.78 mmoles/kg mannitol were applicated as 2.5 ml/kg of a solution with 20 g/100 ml. Each animal got 2 injections (glucose and mannitol in the same dosage) in an alternating order. 4 dogs were additionally injected with 5.56 mmoles/kg of either glucose or mannitol. In all tests the end of application is indicated as "0 min". The interval between the injections was 60 to 120 rain. Because of technical difficulties not all data could be obtained on each test (cf. number of animals in the figures). They were evaluated as long as blood pressure was stable. Some characteristics of the experimental groups are given in Table 1. Evaluation. BIood flow, mean arterial blood pressure, and heart rate were taken from the curves at fixed times. Any alteration shorter than 1 rain was not taken into consideration. The mean -- SEM is given in the tables and figures. Linear correlations were estimated. As a level of significance we used p < 0.01. Peripheral vascular resistance (R) was estimated according to Roddie (1970), except that mean arterial blood pressure was taken as a rough parameter for the arteriovenous pressure gradient. All estimates were done by the computer Cellatron 8205 (VEB Kombinat Centronik, Meiningen, GDR).

Results According to our preliminary measurements of vascular diameters m o r e t h a n 900/0 o f t h e s u p e r i o r p a n c r e a t i c o d u o d e n a l flow r e a c h e s t h e

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Dynamics of Canine Pancreatic Blood Flow and of Insulin Secretion Table 1. Data on the animals of the different experimental groups Dose [mmoles/kg] of glucose and mannitol Number of animals Age [mths] Body wt. [kg] Pancreatic wet wt. [g] Peripheral venous concentrations before anaesthesia BG [mg/100 ml] I g I [~zU/ml] Time from anaesthesia up to the first test [min] the end of the experiment [rain]

0.70

1.39

2.78

Mean

SEM

Mean

SE)/I

Mean

SEM

5 29 27.4 52.0

4 2.4 3.0

8 24 27.0 51.3

3 1.4 2.9

21 26 25.3 46.8

3 1.0 2.7

76 32

4 8

77 24

4 8

81 37

4 4

169 472 a

7 23

203 355 e

8 14

193 271 b

11 13

These animals were additionally injected with 5.56 mmoles/kg glucose or manni~l. b Part of these animals did not get any mannitol injection. c Two of these animals got an additional injection of 0.70 mmoles/kg glucose.

p a n c r e a s . 58 4- 2 ~ of t h e p a n c r e a t i c wet wt. are s u p p l i e d b y this a r t e r y (injections of China ink, n = 28 animals). W i t h r e s p e c t t o these figures t h e specific b l o o d flow t h r o u g h t h e p a n c r e a t i c p a r e n c h y m a a m o u n t s to 2.0 4- 0.1 m l / m i n - g in general a n a e s t h e s i a before a n y t e s t ( d a t a from 69 animals). I m m e d i a t e l y a f t e r i.v. i n j e c t i o n of glucose t h e flow t h r o u g h t h e s u p e r i o r p a n c r e a t i e o d u o d e n a l a r t e r y is significantly e n h a n c e d (Fig. 1). The r e l a t i v e a n d a b s o l u t e e n h a n c e m e n t s seem to be r e l a t e d to t h e dose a n d to t h e h y p e r g l y c e m i c level, respectively. N o r m a l i z a t i o n of b l o o d flow parallels t h a t of BG. I n c o n t r a s t to this, in a first phase p o r t a l venous I g I increases i n d e p e n d e n t l y of BG. I t s e n h a n c e m e n t lasts cons i d e r a b l y longer t h a n t h a t of b l o o d glucose c o n c e n t r a t i o n a n d of b l o o d flow. F u r t h e r o b s e r v a t i o n s should show w h e t h e r t h e increase of p a n c r e a t i c perfusion is due to a specific effect of glucose on t h e p a n c r e a t i c v a s c u l a r bed. D u r i n g h y p e r g l y c e m i a p o r t a l v e n o u s flow increases w i t h t h e s a m e r e a c t i o n p a t t e r n t o o (Fig.2). Similar recordings eoutd be o b t a i n e d on t h e s u p e r i o r m e s e n t e r i e a r t e r y a f t e r t h e a d m i n i s t r a t i o n of glucose or m a n n i t o l : f r o m t h e b a s a l level (225--240 m l / m i n ) t h e flow increases to 2 8 0 - - 3 1 0 m l / m i n d u r i n g t h e first 5 m i n a f t e r t h e i n j e c t i o n of 2.78 m m o l e s / k g ; n o r m a l i z a t i o n needs 2 0 - - 3 0 rain. F e m o r a l a r t e r i a l b l o o d s t r e a m is also a u g m e n t e d c o n s i d e r a b l y (Fig.4). B u t i t normalizes m o r e r a p i d l y : t h e s t a r t i n g levels are r e a c h e d a g a i n a f t e r 5 min. F l o w t h r o u g h a o r t a a s c e n d e n s was c o n s i d e r e d as a r o u g h figure of cardiac o u t p u t . I t was r e g i s t e r e d b y a c a t h e t e r - t i p flowprobe which could n o t be c a l i b r a t e d in

U. Fischer et al.

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