Pathophysiology of acute pancreatitis: Evaluation of the effects and mode of action of indomethacin in experimental pancreatitis in dogs

Prostaglandins are known to affect vascular flow and the inflammatory response. Since acute pancreatitis involves both of these phenomena, we undertook studies using anesthetized mongrel dogs to investigate changes in blood pressure, cardiac output and pancreatic arterial flow for 6 hr in both normal animals (10 dogs) and following induction of acute pancreatitis (15 dogs). Indomethacin (5 mg/kg), which inhibits synthesis of prostaglandins, was then injected intravenously, and the animals were subsequently monitored for 2 hr. Results showed: (1) A significant fall in pancreatic arterial flow, relative to cardiac output, over the first 6 hr of the disease in the acute pancreatitis animals (P < 0.001). (2) A further significant decrease in relative pancreatic arterial flow following indomethacin in these animals (P < 0.001). A similar reduction in pancreatic arterial flow was observed following indomethacin administration in the control animals (P < 0.001). Conclusions: (1) Relative pancreatic arterial flow falls during experimental acute pancreatitis. (2) Indomethacin reduces both basal and compromised pancreatic arterial flow in the anesthetized dog; this suggests that prostaglandins may participate in the maintainance of basal acid-compromised pancreatic blood flow in the anesthetized dog.     

Indomethacin and pancreatic blood flow. An experimental study in pigs

Indomethacin has been reported to decrease pancreatic blood flow. The drug has been used as an analgesic in acute pancreatitis. As decreased blood flow to the pancreas may detrimentally affect the outcome of acute pancreatitis, we investigated the effects of indomethacin on blood flow in the normal porcine pancreas. Regional blood flows, with special reference to the pancreatic flow, were studied with radioactively labelled microspheres in ketamine-anesthetized pigs before and after intravenous administration of indomethacin 2 mg/kg during 10 min. A transient decrease of cardiac output was seen during the infusion. Basal pancreatic blood flow was significantly increased 10 and 30 min after administration of indomethacin. No significant changes were found in small-intestinal or renal blood flow. We conclude that indomethacin does not reduce blood flow in normal porcine pancreas.     

Pathophysiology of acute pancreatitis: Evaluation of the effect and mode of action of steroids in experimental pancreatitis in dogs

Three experiments were performed to evaluate the effects and hemodynamic changes brought about by steroids in experimental pancreatitis in dogs. The results show (1) a significant improval in survival in steroid-treated groups, (2) no difference in cardiac output or mean blood pressure between groups, (3) a decrease in relative pancreatic arterial blood flow in the untreated animals, and (4) an increase in arterial flow to the pancreas after steroid therapy. The experiments suggest that the reversal of reduced pancreatic flow may be important in improving the prognosis.     

Effects of indomethacin on hemodynamics of dogs in refractory hemorrhagic shock.

We examined the effects of indomethacin upon anesthetized control dogs and dogs in refractory hemorrhagic shock. Systemic arterial pressure, central venous pressure, cardiac output, and blood flow to the kidney, the heart, the brain, a small intestinal segment, and a piece of skeletal muscle were measured. Systemic vascular resistance and resistances of the vascular beds of the kidney, the heart, the brain, a small intestinal segment, and a piece of skeletal muscle were calculated. Blood flow distribution within the renal cortex was also examined. Indomethacin treatment had little effect upon dogs that were not in shock. Blood flow to the skeletal muscle was decreased. There was also a redistribution of blood flow within the renal cortex with a greater proportion of renal cortical flow going to the outer cortex. However, systemic vascular resistance, cardiac output, and blood flow to the heart, kidneys, brain, and small intestine were unchanged.The refractory shock state was characterized by low systemic arterial pressure and cardiac output with vascular resistance identical to control. Blood flow to the kidney and brain appears to be decreased while coronary flow is maintained. In addition, the ratio of outer renal cortical blood flow to inner renal cortical blood flow, which in the control dog was about 1.5, decreases to 1.Indomethacin treatment largely reversed the hypotension of refractory shock. The increase in arterial pressure following indomethacin treatment is the result of an increase in systemic vascular resistance. Indomethacin treatment had no effect upon cardiac output. The vascular resistances of the kidney, heart, brain, and small intestine increased following treatment of dogs in refractory shock with indomethacin. Renal blood flow was decreased 57%. The renal cortical blood flow distribution was shifted toward the outer cortex as in the controls.Substances dependent upon prosta glandin synthetase may be involved in the hypotension that is characteristic of refractory hemorrhagic shock and may be important in maintaining blood flow to the kidneys and gut.     

The effect of somatostatin analogue (SMS 201-995) on pancreatic blood flow

The effect of somatostatin analogue SMS 201-995 on pancreatic blood flow was studied. In 24 dogs all vessels to the pancreas, except for the pancreaticoduodenal artery and vein, were divided. A flow probe was placed around the pancreaticoduodenal artery. The animals were divided into four groups. Control animals received a subcutaneous injection of 0.5 ml of normal saline solution. Treated animals received 0.002, 0.02, and 0.2 mg/kg of SMS 201-995 at the outset of the experiment. Mean systemic arterial blood pressure, cardiac output, and serum amylase values were monitored, in addition to pancreaticoduodenal blood flow. SMS 201-995 produced a prompt and sustained decrease in pancreatic blood flow in all treated groups compared with control animals without alteration of systemic hemodynamics. This suggests that SMS 201-995 decreases local vascular resistance, which results in decreased pancreatic blood flow.     

Renal haemodynamics and prostaglandin synthesis in partial unilateral ureteric obstruction

Haemodynamic changes in partial unilateral ureteric obstruction (PUUO) may be related to altered prostaglandin synthesis. In 12 dogs the left ureter was partially obstructed for 5 weeks. In six dogs the ureter was reimplanted into the bladder and to investigate the effect of this procedure on the contralateral side the other six animals underwent ipsilateral nephroureterectomy. Renal blood flow (RBF) was measured by the distribution of radiolabelled microspheres. Changes in urinary prostaglandin (PG) concentrations were validated by renin activity using angiotensin I. Reduced left RBF during obstruction was associated with increased thromboxane A₂ synthesis (P<0.01). Increased RBF to the nonobstructed side was associated with elevated PGE₂ formation (P<0.05). Elevated angiotensin I levels (P<0.01) corresponded to maximal increases in PG synthesis. Reimplantation of the obstructed kidney did not exert a direct effect on contralateral RBF or PG concentration. Haemodynamic changes in PUUO in vivo are associated with alterations in renal PGs.     

Contribution of endogenous vasoactive compounds to renal vascular resistance in neonatal chronic partial ureteral obstruction

To evaluate the relative contribution of endogenous vasoactive compounds to maintenance of increased renal vascular resistance in neonatal obstructive nephropathy, cardiac output and renal blood flow were measured using radioactive microspheres in 25 +/- 3 day-old guinea pigs subjected to unilateral partial ureteral constriction within the first two days of life. Mass and renal blood flow of the obstructed kidney were significantly lower than those of the contralateral kidney. Following a control period, thromboxane synthesis was blocked by infusion of OKY-046, after which prostaglandin synthesis was inhibited by indomethacin. In a separate group of animals, angiotensin converting enzyme inhibitor, MK-422, was infused before or after administration of OKY-046. While neither OKY-046 nor indomethacin had a consistent effect on vascular resistance, infusion of MK-422 resulted in selective reduction of renal vascular resistance of the obstructed kidney compared to resistance in the intact kidney and other vascular beds. Removal of the contralateral kidney at the time of ureteral constriction in an additional group of animals resulted in hypertrophy and vasodilation of the obstructed kidney which was not altered by thromboxane or cyclooxygenase inhibition. We conclude that in the neonatal kidney subjected to ipsilateral chronic partial ureteral obstruction, vasoconstriction is mediated at least in part by angiotensin II, but not by thromboxane. Furthermore, vasodilation of the obstructed kidney resulting from contralateral nephrectomy is not dependent on prostaglandin synthesis. Renal vascular resistance of the kidney with prolonged partial ureteral constriction in early development thus appears to be inversely related to renal growth and is not significantly mediated by endogenous prostanoids.     

An evaluation of blood flow and perfusion in the canine pancreas

This study evaluates pancreatic blood flow in the anaesthetised dog. Total flow was measured with an electromagnetic flowmeter and tissue perfusion using a Krypton-85 (85Kr) clearance technique. Cardiac output was also monitored with an electromagnetic flow probe placed on the ascending aorta. The flow and tissue perfusion in the pancreas were measured before and after devascularisation of the duodenum from the pancreas. The results show that the two techniques give similar values after pancreaticoduodenal devascularisation. If these vessels are left intact, however, electromagnetic measurements overestimate pancreatic flow by approximately 35%. Pancreatic blood flow in the dog is considered to have a normal value of 60-65 ml/min/100 g, or 25 ml/min, approximately 1.7% of the cardiac output being distributed to the gland.     

Elevated intra-abdominal pressure and renal function.

The effect of increased intra-abdominal pressure on cardiac output and renal function was investigated using anesthetized dogs into whom inflatable intraperitoneal bags were placed. Hemodynamic and renal function measurements were made at intra-abdominal pressures of 0, 20, and 40 mmHg. Renal blood flo and glomerular filtration rate decreased to les than 25% of normal when the intra-abdominal pressure was elevated to 20 mmHg. At 40 mmHg intra-abdominal pressure, three dogs became anuric, and the renal blood flow and glomerular filtration rate of the remaining dogs was 7% of normal, while cardiac output was reduced to 37% of normal. Expansion of the blood volume using Dextran-40 easily corrected the deficit in cardiac output, but renal blood flow and glomerular filtration rate remained less than 25% of normal. Renal vascular resistance increased 555% when the intra-abdominal pressure was elevated from 0 to 20 mmHg, an increase fifteen-fold that of systemic vascular resistance. This suggests that the impairment in renal function produced by increased intra-abdominal pressure is a local phenomenon caused by direct renal compression and is not related to cardiac output.     

The role of prostaglandins in human hypertension

A large body of evidence supports the concept that prostaglandins (PG) are importantly involved in arterial pressure regulation. Various PGs, especially PGE2 and prostacyclin (PGI2) may influence blood pressure through control of vascular tone, sodium excretion, and renin release. Inhibition of PG synthesis by nonsteroidal antiinflammatory drugs (NSAID) augments the vasoconstrictor response to exogenous pressors such as angiotensin II, arginine vasopressin (AVP), and fludrocortisone. The acute administration of NSAID to either normotensive or untreated hypertensive subjects results in an increase in arterial pressure and peripheral resistance; long-term administration, however, is associated with little or no change in blood pressure, possibly because of a reduction in cardiac output. Although NSAID have little influence on blood pressure in normotensive subjects or untreated hypertensives, inhibition of PG synthesis blunts or abolishes the antihypertensive effect of most antihypertensive agents. NSAID antagonize the vasodepressor action of diuretics, beta-adrenoreceptor antagonists, vasodilators, and converting enzyme inhibitors. Consequently, potent NSAID should be used with caution, if at all, during treatment of hypertensive patients. Numerous studies have examined renal PG production in essential hypertension (EH). The majority have demonstrated reduced basal and stimulated urinary PGE2 excretion in EH compared to normotensive subjects, but there is substantial overlap. Nevertheless, renal PGE2 synthesis is significantly decreased in approximately one-third of patients with EH. A recent innovative approach to arterial pressure regulation has focused on dietary supplementation with polyunsaturated fatty acids (PUFA), especially linoleic acid and eicosapentaenoic acid. Several groups have demonstrated that long-term dietary supplementation with PUFA reduces blood pressure in both normotensive individuals and in patients with EH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of halothane on renal hemodynamics during normovolemia and acute hemorrhagic hypovolemia

The effects of halothane on renal hemodynamics under both normovolemic and hypovolemic conditions were investigated in chronically instrumented conscious dogs whose homeostatic mechanisms were not altered by the presence of preexisting drugs. Renal blood flow and aortic pressure were assessed by prior implantation of Doppler ultrasonic flow probes on the renal artery and a catheter in the descending aorta. Administration of halothane to conscious normovolemic dogs (Group HN) resulted in 11-26% decreases in renal vascular resistance with no significant changes occurring in renal blood flow. In a second group of animals made hypovolemic while awake (Group AH), 30% of the blood volume was removed over one-half hour. In response to hemorrhage, these conscious animals' renal blood flow did not significantly change from the normovolemic control, and renal vascular resistance significantly decreased. With no further intervention, renal vascular resistance and renal blood flow remained unchanged from the level achieved after the 30% hemorrhage. A third group of animals (Group HH) was hemorrhaged in a manner similar to that of Group AH. They also showed no significant changes in renal blood flow and a significant decrease in renal vascular resistance in response to hemorrhage. Thereafter, administration of halothane, as in Group HN, to this group produced 11-23% decreases in renal vascular resistance with no significant decline in renal blood flow from the hypovolemic control levels established after hemorrhage. The author concludes the following: administration of halothane to normovolemic conscious dogs does not decrease renal blood flow; a moderate degree of acute hemorrhagic hypovolemia does not decrease renal blood flow in conscious dogs; and administration of halothane to acutely hypovolemic conscious dogs does not impair renal perfusion.     

Hemodynamic function in dogs with chronic obstructive jaundice: effects of radiocontrast medium

Chronic obstruction of the biliary tract alters circulatory function. The effects of radiocontrast medium (iothalamate meglumine) on systemic and renal hemodynamics were studied in normal dogs and dogs with chronic common bile duct ligation (CBDL). After intravenous injection of radiocontrast, cardiac output and stroke volume were not altered in normal and CBDL dogs; arterial pressure was stable in normal dogs but decreased significantly in CBDL dogs and was accompanied by reduced systemic vascular resistance. In normal and CBDL dogs the renal hemodynamic responses to radiocontrast medium were characterized by initial vasoconstriction (independent of renal renin release) and later vasodilation. This vasodilatation in CBDL dogs was particularly striking as it occurred despite reduced renal perfusion pressure and the augmented renin-angiotensin system. Inhibition of prostaglandin synthesis with indomethacin in CBDL dogs abolished both the hypotensive and the renal vasodilator responses to radiocontrast medium. We conclude that enhanced prostaglandin activity contributes to the labile hemodynamic function noted in obstructive jaundice.     

Effect of steroids on the cardiac output and renal changes of bacteremia

The effects of methyl prednisolone pretreatment in dogs prior to a bacterial infusion were measured in relation to cardiac output, blood pressure, intrarenal blood flow, and glomerular filtration rate. In dogs not pretreated with steroid, cardiac output fell 61.1 per cent 30 min postbacterial infusion and remained depressed for the balance of the experiment. Pretreated animals showed a similar 61 per cent depression in cardiac output immediately following bacterial infusion, but then experienced recovery of cardiac output and blood pressure to levels not significantly different from controls at the conclusion of the experiment. Changes in outer cortical bloodflow and glomerular filtration rate were not affected by steroid pretreatment. Based on the above data, the author concludes that the salutary effect of steroid pretreatment on cardiovascular dynamics occurs independently of changes in renal function.     

Hepatic and renal clearances of lidocaine in conscious and anesthetized sheep

Sheep were implanted with cannulae to study blood flow through, and drug extraction by, the lungs, kidneys, liver, and gut. Lidocaine, infused to a steady state in conscious sheep, caused no significant changes in cardiac output or regional blood flow, and was cleared principally by the liver, where the extraction ratio usually exceeded 0.9, and by the kidneys, where the extraction ratio was 0.1-0.2. There was no detectable clearance by lungs or gut. Under general anesthesia with 1.5% halothane, the cardiac output and renal and hepatic blood flows were decreased to means of 77, 44, and 79% of mean control values, respectively, but hepatic and renal extraction ratios of lidocaine were not systematically altered, so that regional clearances of lidocaine were not significantly different from those in conscious animals. There was evidence that the total body clearance of lidocaine exceeded the sum of the directly measured regional clearances in both control and general anesthesia studies. These equivocal findings of the effects of general anesthesia on lidocaine clearance are at variance with unequivocal findings of reduced regional clearances of other drugs tested in this preparation.     

The effect of electrical vagal stimulation on canine pancreatic exocrine function.

The effect of electrical vagal stimulation on canine pancreatic exocrine function was studied in conscious dogs by stimulating intact thoracic vagus nerves, the distal ends of cut vagus nerves in animals with intact gastric denervation, and the distal ends of cut vagus nerves in dogs whose stomachs had been previously selectively denervated. The effectiveness of the stimulus was confirmed by monitoring gastric hydrogen ion output. The results indicate that stimulation of intact nerves produced minimal alteration in pancreatic output and bicarbonate and protein secretion while significantly increasing gastric fistula hydrogen ion output. Stimulation of the distal ends (efferent fibers) of cut vagus nerves in dogs with intact gastric innervation significantly increased the volume and protein output of the pancreas and the acid output of the stomach. Stimulation of the distal ends of cut right and both vagus nerves in dogs whose stomach had been denervated previously, again, significantly increased the volume and protein output of the pancreas without stimulation of stomach hydrogen ion output. The data presented in this study suggest that the canine pancreas is innervated directly by vagal fibers, which when stimulated produce an increase in protein (enzyme) output and volume of secretion. Maintenance of the pancreatic response following denervation of the stomach suggests that the response is primarily the result of direct vagal innervation and is not produced by gastrin released from the antrum.     

Paradoxical increase of renal blood flow in anesthetized hypertensive dog treated with indomethacin.

To evaluate the effect of prostaglandin inhibition on the renal blood flow of the ischemic kidney, we administered indomethacin to 10 anesthetized dogs with renal artery stenosis and contralateral nephrectomy. Following the operation to produce renal ischemia, there was an increase of blood pressure associated with an increase of renin and the prostaglandins F1 (PGF1), and E (PGE). The administration of indomethacin to the intact, normotensive animals caused the anticipated decrease of prostaglandin E, renin, and renal blood flow. However, in the hypertensive dogs, indomethacin caused a paradoxical 45 per cent increase in the renal blood flow, despite a 44 per cent decrease of prostaglandin E. PGF1, PGE, renin, and erythropoietin exhibited the anticipated decreased levels. The study suggests that prostaglandins may not be the sole important factor in the regulation of renal blood flow in the presence of ischemia. Other important factors likely include the renin-sensitive angiotensin, the adrenergic, and the kallikrein-kinin systems.     

Canine renal and systemic hemodynamic measurements after 4 weeks of a magnesium deficient diet

To probe renal hemodynamic measurements in relation to simultaneous systemic hemodynamic measurements in normal, adult, conscious dogs on a magnesium-deficient diet, 6 experimental animals were given 4 weeks of a magnesium-deficient diet compared to 9 animals whose dietary magnesium was normal. Systemic hemodynamics were estimated using a thermodilution catheter, and renal hemodynamics were estimated by standard renal clearance techniques. Electrolytes and hormones were also surveyed in these same animals at the time of hemodynamic measurements. Heart rate was significantly higher in magnesium-deficient dogs, but there were no other systemic hemodynamic differences between the two groups of dogs. Renal blood flow, effective renal plasma flow, and urinary osmolality were significantly higher in the magnesium-deficient animals. Whole-blood ionized calcium and potassium, serum magnesium, and fractional excretion of magnesium were lower in the magnesium-deficient dogs. We conclude that the renal circulation is more sensitive than the systemic circulation to disturbances in magnesium balance. Disturbances of other electrolytes accompanying magnesium deficiency were also confirmed.     

Improvement in blood flow through a critical arterial stenosis by defibrination with ancrod.

Using electromagnetic flow probes, cardiac output and hind limb blood flow were measured in dogs in which one hind limb had been rendered ischemic. Four dogs served as controls; seven were defibrinated by intravenous infusion of ancrod, 1 unit/kg, over a 30-minute period. In both groups, hematocrit readings remained constant, but cardiac output fell (this was attributed to barbiturate anesthesia), as did flow in the normal hind limb. In the controls after three hours, flow in the ischemic hind limb had decreased by 34%, but in the treated animals it had increased by 20%. The difference was statistically significant (P less than .001). The selective increase in blood flow in the ischemic limb may be explained by the greater reduction in blood viscosity at low shear rates achieved by defibrination.     

Studies on the mechanism of action of angiotensin converting enzyme inhibitors on the dog kidney]

The effects of angiotensin-converting enzyme (ACE) inhibitors, rampipril, captopril and enalapril, on the renal circulation and function were examined in normotensive dogs, in relation to the renin-angiotensin-aldosterone (R-A-A) and kallikrein-kinin (K-K) systems and prostaglandins (PGs). These inhibitors markedly decreased renal vascular resistance (RVR) in parallel with a reduction in systemic blood pressure, and increased renal blood flow (RBF). Captopril exerted its effects rapidly, but its disappearance was also rapid. The onset of ramipril's effects was slightly delayed, but its antihypertensive and RVR-decreasing effects were fairly prolonged. Ramipril showed more potent and longer-lasting RBF-increasing effect and induced marked Na diuresis. Enalapril had no diuretic effect, and captopril's effect was only temporary. Plasma renin activity was increased similarly by the three inhibitors, but only ramipril significantly decreased plasma aldosterone concentration. This aldosterone secretion inhibition by ramipril may be partly involved in the diuretic effect. Involvement of the K-K system and PGs in ramipril's effects on the dog kidney was examined. When systemic PG biosynthesis was inhibited by indomethacin pretreatment, ramipril-induced increases in RBF and urine volume were inhibited about 50%. Inhibition of the K-K system by aprotinin pretreatment resulted in marked inhibition of urine volume increase, but scarcely affected RBF increase. These results indicate that ramipril produces the most potent effect on the renal circulation and function of the dog among the three ACE inhibitors and that its diuretic action is mostly due to kinins and kinin-induced PGs in the kidney and the RBF increase, due to the R-A-A system and PGs.     

The effect of hemodilution on capillary blood flow and arteriovenous shunt after resuscitation in dogs

The present study was designed to elucidate the adverse effects of temporary circulatory arrest upon the capillary blood flow and arteriovenous shunt and additionally to observe how hemodilution may improve such microcirculatory deterioration. The organ capillary blood flow and organ fraction of cardiac output were measured by the microsphere (phi 9 microns) trapping method in 14 organs. Simultaneously, the arteriovenous shunt rate was measured by continuous collection of drained venous blood at 4.8 ml.min-1 for two minutes from the brain, kidney, liver, splanchnic organs, skeletal muscle of the pelvic limb and all systemic circulatory organs. In five non-hemodiluted dogs (C group), the capillary blood flows decreased in the thyroid gland and pancreas at 30 minutes after circulatory arrest, and in these organs as well as in the brain and stomach at 90 minutes after the arrest. Change in the fraction of cardiac output was similar to that in the capillary blood flow. The arteriovenous shunt rate was unchanged after circulatory arrest. The remaining ten dogs were hemodiluted with dextran-70 solution either before (Pre group, five dogs) or after (Post group, five dogs) circulatory arrest. Both groups of hemodilution maintained the capillary blood flow and showed no alteration of the arteriovenous shunt rate after circulatory arrest, except for an increase in the systemic arteriovenous shunt rate in the Pre group. These results suggest that hemodilution maintains the capillary blood flow at a normal level and ameliorates the oxygen supply into organs after circulatory arrest.