The role of prostacyclin (PGI2) in metabolic hyperemia

PROSTAGLANDINS

THEROLEOF PROSTACYCLIN (PGI2) IN METABOLIC IjYPEREMIA Joseph D. Fondaoaro and Eugene D. Jacobson Department of Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 ABSTRACT We explored the possibility that prostacyclin might be the dilator metabolite of postprandial hyperemla. In canine free-flow preparations, effects of prostacyolln were compared with effects of actively absorbed nutrients on hemodynamic and metabolic parameters Prostacyclln was infused directly into the in the small intestine. superior mesenteric artery for 10 minutes at 1.0 nanograms/kg-min. In absorptive study an isosmotic solution of glucose (1.0 g/l) dissolved in 0.9% NaCl was perfused through the gut lumen for 20 minutes. Prostacyclin increased total blood flow to the intestinal segment and decreased oxygen extraction, while not significantly changing either oxygen consumption or PS-product. Active cotransport of glucose and sodium Increased total blood flow, oxygen extraction, oxygen consumption and PS-product. In constant flow canine gut preparations, intraarterial prostacyclin infusion decreased arterial pressure, oxygen extraction, oxygen consumption and mesenteric vascular resistance but increased venous pressure. Absorption of glucose and sodium inoreased oxygen extraction but decreased mesenteric vascular resistance while not affecting other parameters significantly. Since responses to prostacyclin did not coincide with responses to metabolically dependent transport of glucose and sodium, we conclude that the dilator metabolite of postprandial hyperemia is probably not prostacyclin. INTRODUCTION Blood flow to the small intestine increases during stimulation of Of particular interest has been the organ function ( 1,2). hyperemic response of the mesenteric circulation to activation of absorption (3-8). This metabolically induced hyperemia is coincident with a charaateristio rise in oxygen extraction, such that increases in calculated oxygen consumption exceed proportional augmentation of either blood flow or oxygen extraction (8). Although metabolic hyperemia itself has been well documented, the mechanism by which intestinal absorption causes these changes is unclear. Among several meohanisms proposed (2), a likely explanation is the release of a dilator metabolite during the Since dilator prostaglandins are naturally absorptive process, present in intestinal tissue (9), they may mediate metabolic hyperemia. Several prostaglandins (PC) are potent dilators of the mesenteric PGE1 has been circulation when administered intraarterially. reported to significantly increase mesenteric blood flow in the dog

SUPPLEMENT TO VOL. 21

PROSTAGLANDINS

(lo-121 and human (13) when infused directly into the superior mesenteric artery in doses as low as 100’nanogram.e per kg-min. Both PGD2 (14) and PGE2(9) have been shown to dilate this is an even more potent dilator vascular bed. pG12 (prostacyclin) in the mesenteric circulation when given either as a bolus (9,151 or by constant intraarterial infusion (8, 14). PG12 also increased the fractional blood flow to the mucosal-submucosal compartment of the intestinal wall (14) suggesting that this substance alters distribution of blood flow between intestinal tissues. The present study was performed to ascertain whether or not PG12 may be the dilator metabolite of postprandial metabolic hypereda since pG12 may have a physiological Pole in PegUlatiOn of intestinal blood flow.

MATERIALS ANDMETHODS Experiments were conducted on mongrel dogs of either sex, weighing 18-25 kg. Animals, fasted for 24 hr before each experiment, were anesthetized with intravenous sodium pentobarbital (30mg/kd. All animals were intubated with a cuffed endotrachial tube and were maintained on a positive-pressure respirator (Harvard Apparatus). In free-flow experiments, measurements were performed on systemic arterial pressure, mesenteric blood flow (BF), and arteriovenous oxygen content difference (A-V02)(16). Oxygen consumption (~0~) was calculated as the product of BF x A-V02. The density of perfused capillaries was expressed as the product of permeability and #rface area (PS-product), and was calculated from measurements of Rb clearence as described previously Using a compact infusion pump (Harvard Apparatus) PC12 was (17). administered directly into the superior mesenteric artery via a side branch cannula. Metabolic hyperemia was induced by intraluminal perfusion of an isosmotic solution of glucose (1.0 g/l) dissolved in 0.9% NaCl. In constant flow experiments, the surgical preparation and the measurements of systemic arterial pressure, mesenteric arterial pressure (Pa), mesenteric venous pressure (Pv), BF and A-V02 were performed as previously described (18). Mesenteric resistance (r,) was calculated as(Pa-Pv)-BF. V02 was calculated as Both pG12-induced and metabolically-induced described above. hyperemias were achieved by methods utilized in the free flow PG12 dissolved in saline was infused at 1.0 experiments. nanograms/kg-min for 10 min. Isosmotic glucose-saline solution was perfused through the gut lumen for 20 min. Data from all experiments were statistically evaluated using Student’s t-test for paired observations. Alterations from control were expressed as percentage change. Significance of these changes was assumed at p less than 0.05. RESULTS In the initial two series of experiments, the effects of PG12 on hemodynamic and metabolic parameters of small bowel during free

26

SUPPLEMENTTO'VOL.21

PROSTAGLANDINS

flow conditionswere examined during direct infusion of this agent into the superior mesenteric artery (Table 1). Table 1: The effects of intraarterialPGIg infusion and intraluminalisosmoticglucose-salineperfusion on hemodynamicand metabolic parameters in the canine free flow mesenteric circulation. All values are expressed as the mean $ change from control (+.S.E.M.)and are statisticallysignificant;(n.c.=no significantchange). PS-product BF A_VO? 3 -1124% . . n.0. PGI +15+32 (n=Z) Glucosesaline (n=6)

+ 9218

+14+1$

+2624$

+18+3%

PG12 significantlyincreased BF, decreased A-V02, and did not alter V02 or PS-product. In the second series of six experiments intraluminalperfusion of the gut with isosmoticglucose-salinein the free flow state also produced a significantrise in BF and vo2. However, the increase in V02 exceeded the increase in BF because of a significantincrease in A-V020 PS-productwas also significantlyelevated. Typical responses from individual experimentsare contrasted in Figure 1.

Figure

/

PG12

Glucose -Saline

J-ZZ-L

150

BF (ml/mid

A-Vo,

I

100 n 50

J

PO mill

c

-

5

A

B

Figure 1. Typical responses of BF and A-V02 in the canine free flow mesenteric circulationto intraarterialinfusion of PC12 (Panel A) and intraluminalperfusion with isosmotic glucose-saline(Panel B).

SUPPLEMENT TO VOL. 21

27

PROSTAGLANDINS In order to further delineate hemodynamicand metabolic effects of these pertubationson the mesenteric vascular bed, two series of experimentswere performed under constant blood flow conditions (Table 2). Table 2: The effects of intraarterialPG12 infusion and intraluminalisosmoticglucose-salineperfusion on hemodynamicand metabolic parameters in the canine constant flow mesenteric circulation. All values are expressedas the mean $ change from control (+ S.E.M.) and are statisticallysignificant;(n.c. = no significantchange; ff= held constant). Pv F -3E6l +142+56$ -+ _ - & - 3&1 PGI (n=8) Glucose- l n.c. n.c. + 1222% + 1324% - 922% saline (n=6) Intraarterialinfusion of PG12 produced a significantdecrease in Pa and an increase in Pv in six experiments,resulting in a signifiant fall in rm, indicativeof vasodilation. More importantly, A-V02 was also significantlyreduced and with constant BF, calculatedV02 was comparablyreduced. With intraluminalperfusion of isosmoticglucose-salinein six experiments,Pa and Pv were not consistentlyaltered in all cases, however, rm was reduced significantly. A_V02 was significantly elevated in all oases, resultingin a comparableincrease in vo2. Typical responses to these stimuli are shown in Figure 2. In all experimentsin both free flow and constant flow series, systemic arterial pressure was unaffected. DISCUSSION Hemodynamicand metabolic responses of canine gut to intraarterialPG12 infusion and to intraluminalglucose-saline perfusion were compared in free flow and constant flow preparations in order to assess the role of PC1 in metabolic hyperemia. In free flow preparations, PG12 elici$ed a significantincrease in blood flow to the gut. These findings suggest that PG12 relaxes arteriolarsmooth muscle but probably does not relax precapillary sphinctericsmooth muscle since oxygen extractionwas decreased and the density of perfused capillaries(PS-product)was unchanged. The vasodilatorresponse to PG12 in this vascular bed is similar to what has been reported previously (9,14,15). Since PG12 reduced oxygen extraction, oxygen consumptionwas not increased. This reduction in A-V02 is typical of dilator-inducedhyperemia and has been a consistant finding with other PCs (9, 10, 14) as well as with chemicallyand pharmacologicallydissimilardilator agents such as histamine (191, glucagon (20), and the calcium antagonists,nifedipineand diltiazem (21). BY contrast, intraluminalglucose-salineperfusion under free flow conditionsproduced a r&ponse typical-ofmetabolic

28

SUPPLEMENTTOVOL.21

* i-\s

PROSTAGLANDINS

Figure 2

90

Pa (mmtlg)

PV (mmHg)

80

70

IS

lo 5

30

BF hl/min)

- _

‘O IO f--

5 J

Figure 2.

Typical responses of Pa, Pv, BF and A-V02 in the canine constant flow mesenteric circulation to intraarterial intraarterial infusion of PC12 (Panel A) and intraluminal perfusion with isosmotic glucose-saline (Panel B).

hyperemia (due to cotransport of glucose and sodium) and one that differed from the PG12-induced response. BF was significantly elevated by absorption of glucose and sodium. More importantly, however, A-V02 increased (Table 1 and Figure 1, panel B) resulting in augmentation of calculated ~02 which exceeded the rise in either BF or A-V02. This rise in A-V02 indicates that intestinal tissue is extracting more 02 since metabolic function It is likely and, therefore, oxygen demand have been increased. that much of the augmented flow is being routed through capillaries near metabolically active cells resulting in extraction of more oxygen. The increase in PS-product indicates that this metabolic

SUPPLEMENT TO VOL. 21

29

PROSTAGLANDINS

hyperemia is further characterized by an increase in the density of perfused capillaries and that precapillary sphincters are the sites responsible for these changes. In these free flow experiments the dilation induced by PGI2 differed from that evoked by absorption of intraluminal glucose-saline. Whereas both manipulations produced hyperemia, the response of the measured metabolic parameter (A-V02) was increased during active absorption and decreased by the drug. Since calculated changes in VO2 reflect changes in both blood flow and oxygen extraction in the free flow preparation, we also utilized the constant flow preparation, which permitted differentiation between metabolic and hemodynamic factors on vo29 When PG12 was infused intraarterially in constant flow experiments, A_V02 decreased (Table 2) as in the free flow state and to approximately the same degree. Furthermore, although blood flow was held constant, we know that vasodilation occurred since rm was significantly reduced. Therefore, the response of the mesenteric vasculature to PG12 is similar in free flow ami constant flow conditions, that is, vasodilation with a significant reduction in oxygen extraction. VO2, however, was reduced under Furthermore, constant flow conditions, since A-V02 was reduced. when glucose-saline was perfused through the lumen of the constant flow segments, A-V02 increased to nearly the same magnitude as in the free flow condition. Vasodilation also occurred with absorption of glucose and saline since ‘m was reduced by 9%. These experiments serve to emphasize the metabolic character of the dilation observed with glucose-saline in the free flow state. If PG12 were the dilator metabolite responsible for the effects of active cotransport of glucose and sodium upon the mesenteric circulation, one would anticipate that PG12-induced hyperemia would be associated witi changes similar to those seen during the absorptive state, particularly those most closely related to its metabolic aspects, namely, an increase in A-V02. Such changes did not occur with PGI2. In either free flow or constant flow studies one would be hardpressed to invoke stimulation of metabolism by PG12 as the mechanism by which this substance increases blood flow. On this basis we conclude that PC12 is not the dilator metabolite in postprandial hyperemia. ACKNOWLEDGEMENTS The authors acknowledge the technical assistance of Mrs. Christine Eldon and Mrs. Sheryl Birdseye. This study was supported by a Grant-in-Aid from the American Heart Association with funds provided in part by the American Heart Association, Southwest Ohio. REFERENCES 1. Bynum, T.E., and E.D. Jacobson. Blood flow and gastrointestinal function. Gastro. 60: 325, 1971. 2. Granger, D.N., P.D.I. Richardson, P.RFKvietys, and M.A. Mortillaro. Intestinal blood flow. Gastro. s: 837, 1980.

30

SUPPLEMENTTO VOL. 21

PROSTAGLANDINS

3. Chou, C.C., C.P. Hsieh, Y.M. Yu, P. Kvietys, and L.C. Yu. Localizationof metabolio hyperemia during digestion in the dog. Am. J. Physiol. 230: 583, 1976. 4. Kvietys, P.R., R.P. Pit&, and C.C. Chou. Contributionof luminal concentrationof nutrients and osmolarity to postprandialintestinalhyperemia in dogs. Proc. Sot. Exp. Biol. Med. 152: 659, 1976. 5. Vatner, SF.,7. Franklin, and R.L. VanCitters. Mesenteric vasoactivityassociatedwith eating and digestion in the conscious dog. Am. J. Physiol. 219: 170, 1970. 6. Vatner, SF., D. Franklin, and R.cVanCitters. Coronary and visceral vasoactivityassociatedwith eating and digestion in conscious dogs. Am. J. Physiol. 219: 1380, 1970. 7. Shepherd, A.P., Intestinalblood flow autoregulationduring foodstuff absorption. Am. J. Physiol. 239: H156, 1980. 8. Pawlik, W.W., J.D. Fondacaro,and E.D. JEbson. Metabolic hyperemia in canine gut. Am. J. Physiol. 239: G12, 1980. 9. Chapnick, B.M., L.P. Feigen, A.L. Hyman, anc.J. Kadowitz. Differentiatedeffects of prostaglandinsin the mesenteric vascular bed. Am. J. Physiol. 235: H326, 1978. 10. Pawlik, W., A.P. Shepherd, and ET Jacobson. Effects of vasoactiveagents on intestinaloxygen consumptionand blood flow in dogs. J. Clin. Invest. 6: 484, 1975. 11. Davis, L.J., J. Anderson, S. Wallace, and E.D. Jacobson. Experimentaluse of prostaglandinEl in nonocclusive mesenteric eschemia. Am. J. Roent. Rad. Ther. Nut. Med. 125: 99, 1975. 12. Davis, L.J., J. Anderson, S. WallaceT. Gianturco,and E.D. Jacobson. The use of prostaglandinEl to enhance the angiographicvisualizationof the splanchniccirculation. Radiol. 114: 281, 1975. 13. Jonsson,K., S. Wallace, E.D. Jacobson, J.H. Anderson, J. Zornoza, and H. Granmayeh. The use of prostaglandinEl for an enhanced visualizationof the splanchniccirculation. Radiol. 125: 373, 1977. 14. Fondacaroz.D., M. Schwaiger,and E.D. Jacobson. Effects of prostacyclin (PC121 and prostaglandinD2 (PGD2) on the ischemic canine mesenteric circulation. Castro. j'&:1134, 1979. 15. Dusting, G.J., S. Mincada, and J. R. Vane. Vascular actions of arachidonicacid and its metabolites in perfused mesenteric and femoral beds of the dog. Euro. J. Pharmacol.49: 65, 1978. 16. Pawlik, W.W., K.M. Walus, and J.D. Fondacaro.?ffects of methionine-enkephalin on intestinalcirculationand oxygen consumption. Proc. Sot. Exp. Bio. Med. 165: 26, 1980. 17. Pawlik, W., D. Mailman, L.L. Shanbour, and.D. Jacobson. Dopamine effects on the intestinal circulation. Am. Heart J. 91: 325, 1976. 18. zepherd, A.P. Intestinalcapillary blood flow during metabolic hyperemia. Am. J. Physiol. 237: E548, 1979.

SUPPLEMENT TO VOL. 2 1

31

PROSTAGLANDINS

19. Pawlik, W., L.L. Tague, B.L. Tepperman, T.A. Miller, and E.D. Jacobson. Histamine H, and H2 receptor vasodilationof canine intestinalcirculation. Am. J. Physiol.233: E219, 1977. 20. Fondacaro, J.D., M. Schwaiger,and E. D. Jacobson. Effects of vasodilatorson mesenteric ischemia and hypoxia. Circ. Shock 6: 255, 1979. 21. Galus, K.M., J.D. Fondacaro,and E.D. Jacobson. Effects of CaCt and Ca*- antagonistson the intestinalvasculature. The Physiologist. 23(4): 185, 1980.

32

SUPPLEMENT TO VOL. 21