Influence of primary prostaglandins, prostacyclin and arachidonic acid on mesenteric hemodynamics in the pig

Prostaglandins

and

Medicine

2:

83-95,

1979

INFLUENCE OF PRIMARY PROSTAGLANDINS, PROSTACYCLIN NIC ACID ON MESENTERIC HEMODYNAMICS IN THE PIG

AND ARACHIDO-

A. Houvenaghel, E. Schrauwen, L. Wechsung. Laboratory of Veterinary Physiology, University of Antwerp, State University Center, Slachthuislaan, 68, B-2000 Antwerp, Belgium.(reprint requests to AH) ABSTRACT In anesthetized young pigs the influence of intraarterial infusion of prostaqlandin E2" prostacyclin, prostaglandin F2ct, and arachidonic acid on mesenteric vascular resistance was studied. Infusion of PGE2 and prostacyclin induced a dose-dependent diInfusion of PGF2cl resulted in a rect decrease in resistance. Infusion of lower dodose-dependent difference in response. ses provoked a decrease in mesenteric vascular resistance, whereas infusion of higher doses resulted in an increase. Lower doses of arachidonic acid induced a gradual decrease in resistance, while higher doses provoked biphasic or triphasic responses. After previous blockade of the PG synthetase and lipoxygenase pathways with indomethacin and ETA, arachidonic acid The results only provoked a decrease in vascular resistance. suggest a possible role of prostaglandins and their precursors in autoregulation of mesenteric blood flow in the pig. INTRODUCTION The effects on mesenteric hemodynamics of close intraarterial administration of prostaglandins (PG) El, E2 and F2cl have previously been studied in several species (6,7,8,15,28,32). PGEl and PGE2 invariably induced a vasodilation in the canine and feline intestinal circulation (6,7,28,32). For PGF2a, however, species variability in response was observed since this PC, induces a vasodilation in human mesenteric vasculature and a vasoconstriction in dog and rat intestinal beds (8,15,32). Paustian et al. (28) indicated that the stable PC712 analog, 13,14dehydroprostacyclin methyl ester, is a potent vasodilator in the feline intestinal vascular bed. 83

In the present study, the influence of intraarterial infusion of PGE2r PGF2a, prostacyclin (PGI2) and, the precursor fatty acid, arachidonic acid (AA) on mesenteric circulation has been studied in anesthetized pigs. The influence of the PC- synthetase inhibitors, indomethacin and ETA (5,8,11,14-eicosatetraynoic acid), has also been investigated. To our knowledge, the influence of these substances on intestinal circulation has not been investigated previously in this species. As claimed by several authors, pigs correspond best to humans in cardiovascular and gastrointestinal physiology (3). Some of our premiminary results with PGE2 and PGF2a have recently been presented at the Belgian Physiological and Pharmacological Society (17). MATERIALS AND METHODS The experiments were performed from May till November on 31 younq pigs (Belgian Landrace) of both sexes, weighing between 15 and 24 kg (mean f SEM:19+0.4). Animals were fasted for 24 hours before the experiments. Anesthesia was induced with sodium pentobarbitone (Nembutal B, Abott), 15 mg/kg intraperitonially, followed by an intravenous injection of 20 mg/kg after an interval of 20 minutes. Endotracheal intubation was performed and the animals were kept on artificial respiration (tidal volume: 10 ml/kg; frequency: 15 min) with a positive-negative pressure respirator (Pulmomat, Drggerwerk, Liibeck). Anesthesia was maintained by ventilation with nitrous oxide in oxygen (ratio 3/l) and by a continuous intravenous infusion of pentobarbitone, 5 mg/ kg/hr, diluted in 100 ml 5 8;glucose. Mus le relaxation was induced by gallamine triethiodide (Flaxedil 6 Specia), 4 mg/kg intravenously, and maintained by a continuo;s infusion of 5 mg/ kg/hr. Body temperature was controlled by table heaters. Saline-filled polyethylene catheters, connected to Statham pressure transducers (P23dB), were introduced into the carotid artery and into the portal vein via a branch of the splenic vein. Intra-luminal jejunal pressure was monitored by a balloon-tipped, fluid-filled Foley catheter connected to a Statham transducer or by a catheter tip pressure transducer (Gaeltec, type 16 CT). Pressure transducers were calibrated manometrically at the start of each experiment, The superior mesenteric artery (SMA) was approached retroperitoneally and a well fitting electro-magnetic flow probe (internal diameter: 2.5-3.5 mm) was placed around the vessel. Continuous flow measurements were made using a square wave electromagnetic flowmeter. The phasic flow was integrated using an electronic integrator. Flow and pressure data were registered simultaneously on a multichannel recorder (Beckman-Dynograph, R 411). Zero blood flow was determined electrically and the accuracy of the electrical zero was checked at the start and at the end of each experiment by mechanical occlusion of the artery distal to the flow probe. The mesenteric artery was cannulated and a continuous infusion of heparinised saline, 0.4 ml/ min, was performed. The PGs and AA were infused into the artery at the same rate for 10 minutes. Following each infusion a reco84

very period of 20 minutes was to return to control levels.

allowed

to permit

all parameters

Flow changes are expressed in percentages, the integrated control flow being taken as 100 %. Changes in mesenteric vascular resistance are also expressed in percentage of control resistance and calculated as the quotient of arterial-venous pressure differential and blood flow, both of which are expressed as percentaae of their control values. For these calculations, blood flow as well as arterial and portal pressures are always measured at the point of maximal change in blood flow. PGF2a-Tham salt (Prostin F2 alp a Upjohn) and PGE2, prepared in absolute ethanol (Prostin E2o@, Upjohn) were diluted with saline immediately before use and infused in doses of 0.03; 0.1; 0.3; 1; 3; 10; 30 and 100 Dg/animal/min for PGF~cY (free acid) PGI2-"oand 0.03; 0.1; 0.3; 1; 3 and 10 pg/animal/min for PGE2. dium salt was diluted in 0.05 M tris buffer and stored at O'C. In these conditions no loss of biological activity was observed for 48 hours (5). The infused doses of PGI2, free acid, amounSodium salts ted to 0.03; 0.1; 0.3; 1; 3 and 10 pg/animal/min. of AA (99 % pure, Sigma) were made by mixing 10 mg AA with 0.1 ml of 95 8 ethanol and 0.08 ml of 0.5 M sodium carbonate and diluting the mixture with saline (29). The infused doses of AA-sodium salt amounted to 0.1; 0.3; 1 and 5 mg/animal/min. As a control, the corresponding amounts of Tham-salt, ethanol, tris buffer and the ethanol and sodium carbonate solvent for AA were frequently infused. In a few additional experiments the influence of indomethacin and ETA on the effects of AA was examined. Indomethacin solution was prepared by adding a warm solution (5O'C) of 50 mg sodium bicarbonate in 5 ml saline to 50 mg indomethacin dissolved in 1.7 ml 90 % ethanol (1). Sodium salts of ETA were prepared as described for AA. Following intraarterial infusions of AA, 1 and 5 rng/ min, indomethacin, 50 mg, was delivered intravenously over a 5 minute period. After an interval of 20 minutes the infusions of AA were repeated. ETA, 75 mg, was then infused intravenously over a 5 minute period and an intraarterial infusion of AA, 5 ma/ min, was again performed. The influence of the solvents for indomethacin and ETA, was also investigated. Data were Student's

expressed as means t test was used.

+ SEM.

For

statistical

analysis,

RESULTS The most PGE2

important

results

are summarized

in Table

I.

and PG12

Intraarterial se-dependent

infusion of PC-E2 and PC-I2 invariably induced a doincrease in SMA flow (Fig. 1). The minimal effecti85

z

$19 f 2 p
NS

424 + 3 pco.001

NS

0.1 - 0.3 pg/min

+42 it 8 pco.01

4 1 f 0.3 pco.01

+53 t 6 p
+12 + 2 p
3 - 10 ~g/min

I

I

I

I

I

NS

f0.8f0.2 pco.005

641 f 7 p
r-19+ 3 p
NS

+43 f 5 p
45 t 1 p
30 - 100 ~lg/min

+137 f 17 pco.001

$0.36 20.09 p
CL

PGF,a 0.3 - 1 ug/min

+71 zk 14 125 + 5 p
$11 * 2 p
3 - 10 ~g/min

--I-

J-11 + 3 p
NS

+13 k 4 p
NS

3.1 - 0.3 pg/min

PG12 1

432 + 5 p
NS

450 f 11 p
NS

mg/mir

AA

r55k 3.4 p
+70 - m p
+16+ 1 p
+97+ 29 p
+79+ 13 p
s25+ 6 p
4 6+ 1.3 p
5 mg/min

TABLE I. Chancres in arterial blood pressure (ABP), superior mesenteric artery blood flow (SWBF), venous portal pressure (PP) and mesenteric vascular resistance (R) in the anesthetized pig during infusion of PGE2, PG12, PGF2a and arachidonic acid (AA) into the mesenteric artery. NS = not significant. + = increase; J- = decrease.

%

R

mm Hg

PP

%

SMABF

mm Hg

ABP

DOSES

PGE,L

Fig. 1 Semi-logarithmic relationship between doses of PGE2 and PG12 and % increase in mesenteric blood flow in the pig. The averaqe effect of each dose is shown with SEM.

Fig. 2 Semi-logarithmic relationship between higher doses PGF~cL and % decrease in mesenteric blood flow in the pig. average effect of each dose is shown with SEM.

87

of The

ve dose amounted to 0.03 ug/min for both PGs. With the higher doses, blood flow gradually declined (escape) after a rapid initial flow increase. With the lower doses, maximal flow increase was usually observed near the end of the infusion. During infusion of the lower doses of both PGs, carotid arterial pressure and portal venous pressure did not change significant1Yl whereas a modest decrease in arterial pressure and a rise in portal pressure were observed during infusion of the higher doses. Intestinal tone and motility were usually stimulated during infusion of PGE2 whereas PG12 displayed no effect. All parameters returned to control values within 5-10 minutes after cessation of the infusions. PGF2cl With the SMA blood flow responses to this PC, were variable. higher doses (3-100 pg/min), intraarterial infusion of PGF2a induced a direct dose-dependent decrease in blood flow (Fig. 2). The llescape" from the vasocontrictor influence of PGF2cl was not pronounced and only significant with the highest doses infused (30-100 ug/min). With the lower doses (0.03-l 'Jg/min), a deThis flow inlayed increase in blood flow was often observed. crease started after a latency period of 2-5 minutes, and its maximal effect was usually reached at the end of the infusion. After cessation of the infusion, flow sometimes did not return to control values, but stabilized at a higher level. Within the studied dose range, arterial pressure exhibited no change or just a small decrease with the lower doses. With the higher doses, a modest increase in pressure was observed which Portal venous was maintained until the end of the infusion. pressure increased gradually during infusion of the lower doses. With the higher doses, a transient decrease in portal pressure was observed, followed by a gradual increase. A pronounced stimulation of intestinal tone and motility was sometimes observed during infusion of the lower dose synchronously occuring with the delayed increase in mesenteric blood flow. Tone and motility were usually stimulated with higher doses. However, at times, an inhibition of motility was observed with the highest doses. Arachidonic acid before and after inhibition of the PG synthetase and lipoxygenase pathways. Infusion of AA, in a dose of 1 mg/min, induced a gradual increase in SMA flow with a maximal increase at the end of the infusion. Infusion of lower doses either had no effect on SMA flow or resulted in a slight increase in blood flow. Infusion of a 88

higher dose, 5 mg/min, provoked complex changes in SMA blood flow: usually an initial decrease in blood flow, followed by a gradual increase reaching a maximum at the end, or shortly afWith some inter the end, of the infusion (biphasic effect). fusions the initial decrease was preceded by a short lasting After cessation of the infusion, increase (triphasic effect). flow slowly returned to control level. No significant changes in arterial pressure were observed during infusion of the lower doses of AA. Infusion of 5 mg/min induced a small initial increase in carotid pressure, synchronously occuring with the flow decrease, followed by a more pronounced decrease which corresponded with the flow increase. Portal venous pressure did not change or showed a small increase during infusion of the lower doses. With the higher dose, 5 mg/min, however, a very pronounced increase in portal pressure was observed synchronously occuring with the increase in SMA flow. Infusion of AA was usually without significant influence cn inSometimes, however, an increase in testinal tone and motility. tone and motility was observed. All parameters returned to control level within lo-15 minutes, after cessation of the infusion. Intravenous infusion of indomethacin, 50 mg, over a 5 minutes period, induced a pronounced increase in arterial blood pressure ( 50 mm Hg) which was maintained at a higher level after cessation of the infusion. This PG synthetase inhibitor also provoked a small persistant decrease in SMA blood flow, a transient increase in portal pressure and an increase in mesenteric vascular resistance. Sometimes a small temporary increase in intestinal tone and motility was registered. Intravenous infusion of ETA, 75 mg, after a previous administration of indomethacin,had no significant effect on the studied parameters. The effects of infusion of AA, 5 mg/min, into the SMA were significantly changed after indomethacin. Arterial blood pressure exhibited a small decrease (5+0.5 mm Hg) at the start of the infusion and then returned to control value. SMA blood flow revealed a direct and maintained increase (49+5 %). After cessation of the infusion, flow gradually returned to control level. Venous portal pressure increased modestly (1.5+0.5 mm Her). Intestinal

tone

and motility

were

not

significantly

influenced.

The effects of intraarterial infusion of AA, 5 mg/min, after additional blockade of the lipoxygenase pathway by ETA, were identical to the responses of the infusion of the fatty acid after indomethacin. 89

Infusion of the solvents of all substances effective.

studied was always in-

DISCUSSION Numerous studies have been conducted to determine the cardiovascular effects of the PGE and PGF compounds in animals and man (20,231. PGs of the E series produce a decrease in total peripheral resistance and systemic arterial pressure and an increase in regional blood flow in all species thus far studied. The cardiovascular effects of the F PGs are more complicated by species variability. They are depressor in cat and rabbit, and pressor in rat, dog, calf, baboon, monkey and man. The mechanism of the cardiovascular effects of the PGF compounds in various animal species is still unclear. The cardiovascular effects of PG12 and AA have not been studied as extensively as those of the primary PGs. However, it may be concluded from the literature that PG12 is a depressor in rat and dog (2,27) and AA in rabbit and dog (18,191. Prostacyclin synthetase, the enzyme which generates PG12 from prostaqlandin endoperoxides, has been shown to be present in the microsomal fractions of several blood vessels: rabbit and pier aorta, pig mesenteric artery, rabbit coeliac and mesenteric artery (4,14,21, 22). The unstable PG12 relaxes strips of rabbit mesenteric and coeliac artery (4,251. In order to reduce as much as possible the systemic cardiovascular effects, we have infused the PGs and their common precursor fatty acid directly into the vascular bed under study. This way, significant changes in mesenteric hemodynamics could be observed, at least during infusion of the lower doses studied, without noThe lack of systemic ticable systemic arterial pressure changes. effects from infusion of the lower doses can be explained by the rapid inactivation of PGF~Q and PGE2 by the lungs and the liver (30,341 and of PG12 by the liver (11). Intraarterial infusion of PGE2 and PG12 induced a dose-dependent This corresponds vasodilation in the pig mesenteric artery. with previous observations in the dog and the cat (6,7,10,28,32). The influence of adrenergic amines on pig mesenteric hemodynamics has recently been studied in our laboratory (31). Compared on a molar basis isoproterenol, PGE2 and PG12 are approximately equipotent vasodilators in the pig mesenteric vasculature. The dose-dependent variability in response to PGF2a of the pig The intestinal vasculature has not been noted in other species. delayed increase in SMA flow, observed with infusion of the lower doses of PGF2~ could be the result of an enzymatic conversion of PGF2cx into PGE2. The presence of such an enzyme has recently .been demonstrated in the kidneys of rabbit and rat (16,261. Another explanation for this phenomenon is the possible liberation of vasodilatory compounds (e.g. PGE2, PG12) by the mesenteric 90

PGF2a (6,32). Infusion of PG12 and of lower doses of AA also induces a small increase in portal pressure. During infusion of higher doses of AA, however, an unexpectedly pronounced rise in portal pressure was recorded. This pronounced rise in portal pressure could be the result of a significant increase in portal vascular resistance, induced by venoconstrictor substances (e.g. PG endoperoxides), generated from AA. Goldberg et al. (13) reported that PG endoperoxide analogs were potent venoconstrictors. The inhibition of the AA-induced increase in portal pressure by indomethacin points in favor of this explanation. Intestinal tone and motility were usually stimulated during intraarterial infusion of PGE2 in the pig. Shehadeh et al. (32) and Tiirker znd Onur (33) observed a decrease in intestinal motility in the dog and the cat during intraarterial infusion of PGEl (32,331. Villaneuva et_,al. (35) found that PGE2 given intravenously in cats, stimulated intestinal motility. This variability in response is probably due to differences in the PC- used (PGEl versus PGE21, its route of administration (intraarterially versus intravenously) or dosage. A stimulation of intestinal tone and motility in response to PGF2" was also observed in the dog and the cat (32,351. To our knowledge, no data are available concerning the influence of PG12 on "in viva" intestinal moIn our experiments on pigs, PG12 did not produce any tility. This observation significant effect on intestinal motility. points to the proposed hypothesis that PG12 is the end product in the meta'>olism of AA in the pig intestinal vasculature, since infusion of AA was usually without any significant influence on intestinal motility in this species. The sensitivity of the pig mesenteric vasculature to the studied PGs and their common precursor fatty acid, AA, as well as the observed change in mesenteric hemodynamics after inhibition of the PG synthetase, suggest a possible role of PGs and their precursors in autoregulation of mesenteric blood flow in the pig. ACKNOWLEDGMENTS This work was supported by a grant from the Belgian F.G.W.O. We wish to thank C. De Schepper-Van Hoecke, G. foundation. Drubbel, R. Hens-Sleeckx and P. Staes, for technical assistance. The prostaglandins were kindly supplied by Drs. R. Vandenhende and J. Vanhemelrijk, Upjohn, Puurs (Belgium). Indomethacin was ETA a gift from Dr. Deboeck, Merck, Sharp and Dohme, Brussels. was kindly supplied by Drs. P. Dermaux and J. Werli, Roche, Brussels. REFERENCES 1.

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92

vasculature in response to the infusion of PGF~cx. As already mentioned, the presence of the PG12 synthetase has recently been demonstrated in the pig mesenteric artery (14). Experiments are now in progress for explanation of this unusual effect of PGF2CL. Infusion of the bisenoic PG precursor, AA, in a dose of 5 mg/min/ pig, resulted in a biphasic (decrease followed by a prolonged increase) or triphasic (initial increase followed by a transient decrease and a prolonged increase) response in SMA blood flow. Comparable results have been described in dog renal vascular bed (12). Infusion of AA in a lower dose, 1 mg/min, however, induced a vasodilation only in the pig mesenteric vascular bed. Dusting et al. (10) reported a dose-dependent vasodilation in both femoral and mesenteric vascular beds in the dog in response to close intraarterial injection of AA in doses of loo-550 pg. Feigen et al. (12) postulate that the biphasic or triphasic effects to AA infusions may represent a rather unusual response, provoked by the administration of relatively hicrh doses of AA. The transient vasoconstriction followed by the prolonged vasodilation (biphasic response), observed with most infusions of the higher dose of AA, resemble the effects of endoperoxides observed in other species (10,28). The initial vasoconstriction is possibly provoked by the endoperoxides, whereas the vasodilation can be provoked by a conversion of the unstable endoperoxides to PG12 (9,141. Therefore, infusion of AA in the lower dose range (0.1-l mg/min) may induce vasodilatation in the pig intestinal vascular bed by generation of PG12 without any vasoactive effect of the endoperoxide intermediates. When infused in a higher dose of 5 mg/min, the endoperoxides or AA itself, may exert a transient vasoactive effect resulting in the primary vasoconstriction of the biphasic effects or the secondary vasoconstriction and the primary vasodilation of the triphasic effects. The increase in systemic arterial pressure, as well as in mesenteric vascular resistance induced by administration of indomethacin, has also been reported in other species as rabbit and man (19,241. The direct increase in SMA flow induced by AA, 5 mg/min, after previous administration of indomethacin, can probably be ascribed to an inherent effect of AA itself. Indeed additional blockade of the lipoxygenase pathway by ETA results in an identical response to AA as observed after blockade of the PG synthetase pathway alone. This vasodilator effect of AA can also explain the small primary vasodilation, preceding the vaso?onstrition in the triphasic flow responses observed occasionally during infusion of 5 mg AA. The modest rise in portal pressure during infusion of the primary prostaglandins was also observed in the dog with PGEI and

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14. Gryglewski, RJ, Bunting, S, Moncada, S, Flower, RJ, Vane JR. Arterial walls are protected against deposition of platelet thrombi by a substance (prostaglandin X) which they make from prostaqlandin endoperoxides. Prostaglandins 12: 685, 1976. 15. Henrich, H, Lutz, J. Das vasculare Escape-Phgnomen am Intestinalkreislauf und seine Auslijsung durch unterschiedlithe vasoconstrictorische Substanzen. Pfliigers Archiv: European Journal of Physiology 329: 82, 1971. 16. Hoult, JRS, Moore, PK. Pathways of prostaglandin F2cl metabolism in mammalian kidneys. Britisch Journal of Pharmacology 61: 615, 1977. 17. Houvenaghel, A, Wechsung, E. Influence of prostaglandins on blood flow through the superior mesenteric artery in the pig. Archives internationales de Pharmacodynamie et de Therapie 230: 332, 1977. 18. Kadowitz, PJ, Spannhake, EW, Greenbercr, S, Feicren, LP, Hyman, AL. Comparative effects of arachidonic acid, bisenoic prostaglandins, and an endoperoxide analog on the canine pulmonary vascular bed. Canadian Journal of Physiology and Pharmacology 55: 1369, 1977. E. Arachidonic acid lowers and indomet19. Larsson, C, Angg&d, hacin increases the blood pressure of the rabbit. Journal of Pharmacy and Pharmacology 25: 653, 1973. 20. Malik, KU, McGiff, JC. Cardiovascular actions of prostaularrdins. Prostaglandins: Physiological, Pharmacological and Pathological Aspects (S.M.M. Karim, ed.) MTP Press Ltd, Lancaster, 1976. 21. Moncada, S, Gryglewski, R, Bunting, S, Vane, JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263: 663, 1976. 22. Moncada, S, Gryglewski, RJ, Bunting, S, Vane, JR. A lipid peroxide inhibits the enzyme in blood vessel microsomes that generates from prostaglandin endoperoxides the substance (prostaglandin X) which prevents platelet aggregation. Pro% taglandins 12: 715, 1976. 23. Nakano, J. Prostaglandins and the circulation. cepts of cardiovascular disease 40: 49, 1971.

Modern con-

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26. Pace-Asciak, C. Prostaglandin 9-hydroxydehydrogenase activity in the adult rat kidney. Identification, assay, pathway and some enzyme properties. Journal of Biological Chemistry 250: 2789, 1975. 27. Pace-Asciak, C, Carrara, MC, Nicolaou, KC. Prostaglandin I2 has more potent hypotensive properties than prostaglandin E2 in the normal and spontaneously hypertensive rat. Prostaglandins 15: 999, 1978. 28. Paustian, PW, Chapnick, BM, Feiqen, LP, Hyman, AL, Kadowitz, PJ. Effects of 13,14-dehydroprostacyclin methyl ester on the feline intestinal vascular bed. Prostaglandins 14: 141, 1977. 29. Ryan, MJ, Kraft, E, Sugawara, K, Zimmerman, BG. Influence of prostaglandin precursors and synthesis inhibitors in vascular bed perfused without a pump. The Journal of Pharmacology and Experimental Therapeutics 200: 606, 1977. 30. Samuelsson, B, Granstrdm, E, Green, K, Hamberg, M. Metabolism of prostaglandins. Annals of the New York Academy of Sciences 180: 138, 1971. 31. Schrauwen, E, Houvenaqhel, A. Influence of adrenergic amines on mesenteric haemodynamics in the pig. Zentralblat fiir Veterinsr Medicine: Reihe A: Physiologie, Endokrinologie, Biochemie. In press, 1979. 32. Shehadeh, Z, Price, WE, Jacobson, ED. Effects of vasoactive agents on intestinal blood flow and motility in the dou. American Journal of Physiology 216: 386, 1969. 33. Tiirker, RK, Onur, R. Effect of prostaglandin El on intestinal motility of the cat. Archives Internationales de Physiologie et de Biochimie 79: 535, 1971. 34. Vane, JR. Release and fate of vasoactive hormones in circulation. Britisch Journal of Pharmacology 35: 209, 1969. 35. Villanueva, R, Hinds, L, Katz, RL, Eakins, KE. The effect of polyphloretin phosphate on some smooth muscle actions of prostaglandins in the cat. The Journal of Pharmacology and Experimental Therapeutics 180: 78, 1972.

95