The role of leukocyte function-associated antigen-1 in animal models of inflammation.

Both preclinical and clinical data have identified leukocyte function-associated antigen-1 (LFA-1) as an important component of inflammatory disease states. We evaluated small molecule inhibitors of this glycoprotein in several animal models in which the inflammatory process is dependent on human or non-human primate LFA-1. (R)-5(4-bromobenzyl)-3(3,5-dichlorophenyl)-1,5-dimethylimidazolidine-2,4-dione, BIRT 377, effectively suppressed the production of human immunoglobulin (IgG) following reconstitution of severe combined immunodeficient (SCID) mice with human peripheral blood mononuclear cells. The BIRT 377 analog, BIX 642, inhibited the cellular infiltrate and increase in skin thickness associated with the delayed-type hypersensitivity reaction in previously immunized squirrel monkeys challenged with antigen. BIX 642 also inhibited the trans-vivo delayed-type hypersensitivity response in the footpads of SCID mice injected with human peripheral blood mononuclear cells and donor-sensitive antigen. These results demonstrate the efficacy of small molecule inhibitors of LFA-1 in preclinical models of inflammation dependent on human or non-human primate LFA-1.

Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy.

A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development.

Captopril-induced hypotension is inhibited by the bradykinin blocker HOE-140 in Na(+)-depleted marmosets.

Inhibition of angiotensin-converting enzyme (ACE) inhibits formation of angiotensin II and, by inhibition of kinin metabolism, may also increase vascular bradykinin. The present experiments were done in sodium-depleted, conscious, unrestrained marmosets (n = 5-11) to examine the contribution of bradykinin to ACE inhibitor-induced hypotension. Aortic blood pressure and heart rate (HR) were monitored via telemetry. After sodium depletion (low-sodium diet and furosemide), captopril (1 mg/kg po) caused a significant (P < 0.05) decrease in mean arterial blood pressure (MABP) (-34 +/- 3 mmHg, maximally, from 79 +/- 2 mmHg) but no change in HR compared with vehicle treatment. The bradykinin receptor antagonist HOE-140 (1 mg/kg sc) significantly inhibited the hypotensive response to captopril and caused marked tachycardia (+133 +/- 14 beats/min from 214 +/- 8 beats/min). HOE-140 (1 mg/kg sc) followed by vehicle administration had no effect on MABP but increased HR similarly. The hypotensive response to captopril was inhibited by HOE-140 regardless of the order of administration or the route of captopril administration (by mouth vs. subcutaneously). The hypotensive response to a renin inhibitor, A-72517 (3 mg/kg sc), was not inhibited by prior HOE-140 administration despite a similar HOE-140-induced tachycardia. These data suggest that the hypotensive effect of captopril in sodium-depleted, conscious marmosets is dependent on functional bradykinin B2 receptors. Also, blockade of B2 receptors uncovers marked tachycardia in this model, suggesting a tonic effect of bradykinin on control of HR in marmosets.

Sodium depletion in conscious cynomolgus monkeys attenuates baroreflex sensitivity independently of prostaglandins.

We tested the hypothesis that baroreflex attenuation during sodium depletion is due to increased prostaglandin (PG) levels. We studied baroreflex sensitivity before and after PG synthesis inhibition in conscious cynomolgus monkeys. Arterial pressure and pulse interval (PI) were measured during intravenous infusions of phenylephrine (1-20 micrograms.kg-1.min-1, n = 6) and nitroprusside (1-10 micrograms.kg-1.min-1, n = 7). Infusions were repeated 30 min after indomethacin (Indo, 6 mg/kg iv). The slope (in ms/mmHg) of the mean arterial blood pressure-PI plot was used as an index of baroreflex sensitivity. Plasma renin activity (PRA) was elevated (47.9 +/- 9.7 vs. 8.8 +/- 3.3 ng angiotensin I.ml-1.h-1) after sodium depletion (P < 0.05). Baroreflex sensitivity to hypotension and hypertension was significantly (P < 0.05) attenuated by sodium depletion (3.69 +/- 0.9 vs. 0.9 +/- 0.1 ms/mmHg and 7.38 +/- 0.6 vs. 5.04 +/- 0.9 ms/mmHg, respectively). Indo decreased PRA to 28.6 +/- 5.7 ng angiotensin I.ml-1.h-1 (P < 0.05) in sodium-depleted monkeys and decreased heart rate -21 +/- 3.7 from a baseline of 166 +/- 9.40 beats/min in normal monkeys and -22 +/- 2.9 from a baseline of 191 +/- 7.9 beats/min in low-sodium monkeys (P < 0.05). Indo did not significantly change baroreflex sensitivity in either group. Thus the baroreflex was attenuated in conscious nonhuman primates during sodium depletion; acute PG synthesis blockade did not improve baroreflex sensitivity. Indo decreased heart rate without changing arterial pressure; suggesting that PGs caused a downward resetting of the pressure-heart rate relationship.

The interaction of the Bainbridge and Bezold-Jarisch reflexes in the conscious dog.

Experiments were undertaken to determine the efferent path of the Bainbridge reflex and to investigate the interaction of the Bainbridge reflex with the Bezold-Jarisch reflex in conscious, chronically instrumented dogs. The Bainbridge reflex was elicited by distending the left atrium by inflating a chronically implanted balloon catheter. The Bezold-Jarisch reflex was elicited using chemical stimulation of left ventricular receptors with infusions of veratridine (0.1-0.8 micrograms/kg/min) into the left circumflex coronary artery. Heart-rate responses to left atrial balloon inflation were compared before and after either beta-1 antagonism with metoprolol or cholinergic antagonism with atropine, and before and during left ventricular receptor stimulation with intracoronary veratridine. Left atrial balloon inflation alone caused a significant increase in heart rate (70.1 +/- 5 bpm), left atrial pressure (14 +/- 3 mmHg) and mean arterial blood pressure (10 +/- mmHg). Heart-rate responses to left atrial distension were inhibited, but not abolished by either cholinergic or beta-1 antagonism. Left atrial distension after both cholinergic and beta-1 antagonism abolished the heart-rate response to balloon inflation. These results indicate that the efferent component of the Bainbridge reflex has both a vagal and a sympathetic component in conscious dogs. Left atrial distension during simultaneous left ventricular receptor stimulation resulted in a significantly decreased tachycardia than did left atrial distension alone (26 +/- 3 bpm compared to 68 +/- 8 bpm in the control experiments). In addition, the slope of the heart rate vs left atrial pressure relationship was significantly inhibited by left ventricular receptor stimulation (1.8 +/- 0.2 bpm/mmHg compared to 5.7 +/- 0.3 bpm/mm Hg in the control experiments). There were no significant differences in either the left atrial pressure or arterial blood pressure changes between the two groups. These data suggest an interaction between these two reflexes that may be occurring in the central nervous system.

Collateral development after carotid artery occlusion in Fischer 344 rats.

Mortality following permanent occlusion of both common carotid arteries decreases as the time between the first and second occlusions increases in Fischer 344 rats. Our goal was to examine the possibility that collaterals develop after unilateral carotid artery occlusion. During temporary occlusion of both carotid arteries in nine ketamine-anesthetized male rats, mean +/- SEM blood flow in both parietal cortices was 23 +/- 4% of the preocclusion (control) blood flow (120 +/- 7 ml/min/100 g) measured by laser Doppler flowmetry (p less than 0.05). After permanent occlusion of one carotid artery for either 1-2 days (n = 10) or 6 weeks (n = 7), mean +/- SEM blood flow was 16 +/- 2% and 30 +/- 3% of control, respectively, during a temporary test occlusion of the other carotid artery. During the test occlusion, blood flow in the cortex ipsilateral to the 6-week occlusion was 170% that in the contralateral cortex (which was similar to the blood flow immediately after temporary occlusion of both carotid arteries) and twice that after 1-2 days of occlusion. Mean luminal diameter of the basilar-carotid anastomosis ipsilateral to the 6-week occlusion was 186% that of the contralateral anastomosis, which showed only minimal change, and 145% that after 1-2 days of occlusion. We conclude that during 6 weeks of permanent carotid artery occlusion the anastomosis enlarges and its blood flow or reserve increases. Thus, collaterals developed ipsilateral to, but not contralateral to, the 6-week carotid artery occlusion, which suggests the possibility of greater collateral protection on the permanently occluded side.

Acute baroreflex resetting and its control of blood pressure in an open loop model.

Acute baroreflex resetting has been quantitatively studied in anesthetized dogs. Carotid sinuses were isolated bilaterally and carotid sinus conditioning pressure (CPcsp) was set at nine different levels for 20 min over a range of from 40 to 200 mm Hg. Over this range of 160 mm Hg in CPcsp, the magnitude of baroreflex resetting of set point pressure (Psp), threshold pressure (Pth) and BP50 was 32.0 +/- 5, 43.3 +/- 6 and 39.6 +/- 6 mm Hg, respectively. The extent of resetting was a non-linear function of the level of CPcsp. There is less resetting at high CPcsp. The average extent of resetting is only about 25%. In contrast to this small degree of resetting, a profound inverse relationship between the baseline pressure and the conditioning pressure was observed at the end of the conditioning period for each CPcsp. In addition, we also observed an attenuation in the buffering capacity of the baroreflex at very high or very low CPcsp. Vagotomy and aortic section did not alter baroreflex resetting. This data indicates that the baroreflex is capable of monitoring the absolute level of blood pressure during acute resetting in addition to buffering transient disturbances in arterial pressure. Based upon the results of the present experiments, the concept that acute baroreflex resetting results in an inability of the baroreflex to monitor the absolute level of arterial pressure does not appear to be valid.

A central mechanism of acute baroreflex resetting in the conscious dog.

The role of the central nervous system in the mechanism(s) involved in acute carotid baroreflex resetting was studied in six conscious, chronically instrumented, aortic-denervated dogs. Dogs were prepared for reversible vascular isolation of the carotid sinuses. Acute baroreflex resetting was induced by holding the left carotid sinus pressure (LCcsp) at a given value for 20 minutes using a pulsatile pressure control system while at the same time keeping the right carotid sinus pressure (RCSP) at a subthreshold level (approximately 40 mm Hg). At the end of the 20 minutes, the LCcsp) was reduced to approximately 20 mm Hg, and a baroreflex (RCSP-mean arterial pressure [MAP]) curve was generated on the right carotid sinus using static-step increases in carotid sinus pressure. At the control LCcsp of 100 mm Hg, the RCSP-MAP baroreflex had a threshold pressure (Pth) of 86.6 +/- 3.1 mm Hg and a set point pressure (Psp) of 104.7 +/- 2.5 mm Hg. Increasing LCcsp) to 140 mm Hg for 20 minutes caused these parameters for the right carotid baroreflex to increase. Pth and Psp increased by 18.4 +/- 4.0 and 14.2 +/- 3.0 mm Hg, respectively (p less than 0.05). The baroreflex curve, therefore, was shifted upward and to the right. Decreasing LCcsp to 60 mm Hg caused Pth and Psp to decrease by 24.7 +/- 5.0 and 18.1 +/- 2 mm Hg, respectively (p less than 0.05). The baroreflex curve was therefore shift downward and to the left. The percent of resetting of Pth and Psp was 46 +/- 9% and 36 +/- 8%, respectively, when LCcsp was 140 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Baroreflex inhibition during coronary occlusion is mediated by prostaglandins.

The present study was undertaken to determine whether the baroreflex control of renal sympathetic nerve activity (RSNA) was attenuated by an acute coronary artery occlusion and if so, what was the role played by cardiac prostaglandins in this attenuation. Arterial pressure was lowered with an infusion of sodium nitroprusside before and during a 5- to 10-min occlusion of the left circumflex coronary artery. The protocol was repeated 30 min after indomethacin (5 mg/kg) had been given. In addition, this study was carried out in a group of vagotomized dogs and in a group of thoracic-sympathectomized dogs. In intact dogs, coronary occlusion reduced the slope of the mean arterial pressure-RSNA relationship by 75% from -7.7 +/- 1.8% change in RSNA per millimeter Hg before indomethacin treatment. After indomethacin, there was no inhibition of the baroreflex slope during coronary occlusion. The reduction in the slope during coronary occlusion was abolished in dogs that were vagotomized but preserved in thoracic-sympathectomized dogs. In this latter group, indomethacin inhibited the attenuation of the slope during coronary occlusion. These data provide strong support for the notion that some cyclooxygenase product (most likely a prostaglandin) is released during coronary ischemia and stimulates or sensitizes cardiac vagal afferent endings, which, in turn, attenuate the baroreflex-mediated increase in RSNA during lowered arterial pressure.

PGE2 and arachidonate inhibit the baroreflex in conscious dogs via cardiac receptors.

Prostaglandin (PG) I2 and PGE2 are known to stimulate left ventricular receptors with nonmyelinated vagal afferents. The present experiments were performed to determine the effects of intracoronary infusion of PGE2 (10-50 ng.kg-1.min-1) and arachidonic acid (50-100 micrograms.kg-1.min-1) on the baroreflex control of heart rate in conscious dogs. Dogs were anesthetized with pentobarbital sodium and were instrumented using sterile surgical techniques. After recovery, baroreflex pressure-heart rate curves were constructed by varying arterial pressure with partial occlusions of the descending aorta or inferior vena cava. Intracoronary infusion of PGE2 significantly inhibited the maximum heart rate achieved during unloading of baroreceptors, attenuated the heart rate range, and decreased the maximum slope of the baroreflex curve; PGE2 had no significant effect on the minimum heart rate during hypertension. Intravenous infusion of PGE2 did not cause significant baroreflex inhibition, and pericoronary nerve block in three dogs prevented the effects of intracoronary PGE2. Intracoronary infusion of arachidonic acid had effects on the baroreflex control of heart rate similar to those of PGE2. The effects of arachidonic acid infusion were prevented by cyclooxygenase blockade. Thus intracoronary PGE2 and arachidonic acid inhibit the baroreflex control of heart rate most likely via stimulation of left ventricular receptors with vagal C-fiber afferents. The effects of arachidonic acid were secondary to synthesis of prostaglandins.

Intracoronary infusion of prostaglandin I2 attenuates arterial baroreflex control of heart rate in conscious dogs.

Prostaglandin I2 (PGI2) is known to stimulate ventricular C fiber receptors resulting in a Bezold-Jarisch-like reflex. Also, cardiac receptor stimulation is known to interact with the expression of arterial baroreflexes. Therefore, experiments were performed to determine the effects of left circumflex coronary artery infusion of PGI2 on the baroreflex control of heart rate in conscious instrumented dogs. Dogs were instrumented chronically with an aortic catheter for the measurement of mean aortic pressure, hydraulic occluder cuffs on the descending aorta and inferior vena cava, a left ventricular catheter for the measurement of left ventricular pressure and heart rate, and a nonocclusive catheter in the left circumflex coronary artery. At the time of experimentation, arterial pressure was altered randomly in steps by partially inflating the occluders. Mean arterial pressure-heart curves (baroreflex curves) were constructed by fitting the data to a logistic curve by nonlinear regression. PGI2 infused into the left circumflex coronary artery at doses of 10, 20, and 50 ng/kg/min caused significant (p less than 0.05) inhibition of the maximum heart rate, heart rate range, and maximum slope of the curve compared to the control baroreflex curve obtained during intracoronary infusion of PGI2 vehicle. PGI2 had no significant effect on the minimum heart rate during hypertension. Since PGI2 is known to stimulate left ventricular receptors, these effects were most likely produced via stimulation of cardiac receptors. In additional experiments using beta 1-blockade with metoprolol or cholinergic blockade with atropine methyl bromide, it was shown that PGI2 attenuates baroreflex-mediated tachycardia by preventing parasympathetic withdrawal completely and by attenuating sympathetic stimulation by approximately 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

PGI2 attenuates baroreflex control of renal nerve activity by a vagal mechanism.

The present study was undertaken to determine whether left circumflex coronary artery (ic) administration of prostacyclin (PGI2) caused an inhibition of the baroreflex control of renal sympathetic nerve activity (RSNA). RSNA was recorded in 12 dogs. Baroreflex sensitivity of RSNA was assessed by infusion of either sodium nitroprusside or phenylephrine and by determining the slope of the mean arterial pressure-RSNA relationship. During nitroprusside infusion, intracoronary PGI2 depressed the baroreflex sensitivity by nearly 90% compared with intracoronary tris(hydroxymethyl)aminomethane (Tris) (P less than 0.002). In addition, the peak increase in RSNA during nitroprusside infusion was significantly inhibited during intracoronary PGI2 (57.9 +/- 6.4 vs. 21.2 +/- 3.0 spikes/s, P less than 0.05). There was no significant difference in the inhibition of RSNA during phenylephrine infusion when intracoronary PGI2 was compared with Tris. Both bilateral vagotomy and pericoronary lidocaine blocked the inhibitory effects of PGI2 on the baroreflex increase in RSNA. It is concluded from these data that exogenously administered PGI2 stimulates or sensitizes afferent endings within the supply of the left circumflex coronary artery to inhibit the baroreflex control of RSNA during evoked hypotension. These afferents traverse vagal pathways via the pericoronary nerves. The role of endogenous prostaglandins in modulation of baroreflex function via a cardiac reflex remains to be elucidated.

6-Keto-prostaglandin E1 is a potent coronary vasodilator and stimulates a vagal reflex in dogs.

These studies were performed to examine the effects of 6-keto-prostaglandin E1 (6-keto-PGE1) on coronary artery blood flow and reflex cardiovascular regulation. In seven chloralose-anesthetized dogs 6-keto-PGE1 and prostacyclin (PGI2) were injected as a bolus into the left circumflex coronary artery in doses of 250 to 4000 ng. Coronary artery blood flow significantly increased and coronary artery resistance decreased in a dose-related manner. There were no significant differences observed between 6-keto-PGE1 and PGI2 in the magnitude of the maximum increase in coronary blood flow or decrease in coronary artery resistance. In six additional anesthetized dogs in which the carotid arteries were ligated in order to minimize baroreflexes, intracoronary injection of 6-keto-PGE1 and PGI2 (in doses of 7, 14 and 23 micrograms) caused systemic hypotension and bradycardia. Bilateral vagotomy attenuated the hypotension and abolished the bradycardia induced by these substances. In five conscious dogs, 6-keto-PGE1 and PGI2 were infused (2, 10 and 20 micrograms/min i.v.) for 10 min. 6-keto-PGE1 and PGI2 caused significant decreases in mean arterial pressure; however PGI2 was significantly more potent in this respect. The tachycardia to the highest doses was compared to that induced by infusion of nitroprusside (500 micrograms/min i.v.). 6-keto-PGE1 and PGI2 caused significantly less baroreflex tachycardia per millimeter of mercury decrease in arterial pressure than did nitroprusside. Thus, in anesthetized dogs, 6-keto-PGE1 and PGI2 are equipotent coronary vasodilators. These PGs also stimulate a vagal reflex which results in hypotension, bradycardia and attenuation of baroreflex-mediated tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandins mediate the increased sensitivity of left ventricular reflexes after captopril treatment in conscious dogs.

Captopril administration has been shown to result in the release of prostaglandins (PGs) in experimental animals and patients. Also, PGs, particularly prostacyclin (PGI2), have been shown to stimulate left ventricular receptor reflexes. Thus, the hypothesis that captopril administration results in sensitization of left ventricular reflexes via increased circulating levels of PGs was tested in conscious instrumented dogs. Left ventricular reflexes were stimulated by injecting veratridine into the left circumflex coronary artery through a nonocclusive catheter. Under control conditions, injection of veratridine resulted in a decrease in mean arterial pressure of -25 +/- 4.7% from a base line of 97 +/- 4.7 mm Hg and a decrease in heart rate of -28 +/- 3.7% from a base line of 91 +/- 6.6 beats/min. After administration of captopril, veratridine injection resulted in a decrease in mean arterial pressure of -43 +/- 4.9% and a decrease in heart rate of -51 +/- 8.5%, both significantly greater effects than before captopril (P less than .05); N = 7). Subsequent administration of the cyclooxygenase inhibitor, indomethacin (5 mg/kg), in the presence of captopril reversed the potentiation of the response to veratridine. Thus, after indomethacin, injection of veratridine decreased mean arterial pressure -29 +/- 4.4% and decreased heart rate -28 +/- 4.1%; changes not significantly different from the control response. Similar findings were observed in a separate set of experiments in which heart rate was held constant by cardiac pacing (N = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandins participate in the renal vasodilation due to hydralazine in dogs.

The authors studied the effects of bolus injections of hydralazine (500 micrograms) into the renal artery of chloralose-anesthetized dogs. In control dogs, hydralazine injection resulted in an increase in renal artery blood flow of 110 +/- 10.4 ml/min (53 +/- 4.7%) from 214 +/- 28 ml/min. In dogs that were pretreated with the alpha-1 adrenergic antagonist, prazosin (1 mg/kg), hydralazine injection increased renal blood flow by 95 +/- 22 ml/min (37 +/- 7.4%) from 253 +/- 19 ml/min, an increase not different from that found in control dogs. However, in dogs pretreated with indomethacin (5 mg/kg) or sodium meclofenamate (3 mg/kg), inhibitors of cyclooxygenase, hydralazine injection resulted in an increase in renal artery blood flow of only 44 +/- 5.3 ml/min (19 +/- 2.7%) from 235 +/- 23 ml/min, an increase significantly different from that in control dogs (P less than .05). The renal blood flow response to hydralazine injection developed slowly, reached a maximum in 20 min and was maintained for at least 1 hr. Arterial blood pressure, heart rate and descending aortic blood flow were not significantly changed after hydralazine injection. The authors conclude that hydralazine increases renal blood flow in dogs by a mechanism independent of alpha-1 adrenergic receptors and that this increase is, in large part, mediated by prostaglandin release.

Mechanisms of reflex bradycardia and hypotension by metabolites of arachidonic acid in the cat.

In the cat, intravenous injections of arachidonic acid or prostaglandin (PG)F2 alpha caused significant reductions in mean arterial pressure and heart rate which were eliminated or significantly lessened, respectively, by previous administration of indomethacin. The bradycardia to intravenous prostacyclin (PGI2) was unaffected by indomethacin. In cats with bilateral ligation of the carotid arteries to eliminate competition between systemic baroreflexes and cardiopulmonary reflexes, PGI2, PGF2 alpha and arachidonic acid caused significantly greater hypotension and bradycardia than in cats with intact carotid baroreflexes. The bradycardia to PGI2, PGF2 alpha and arachidonic acid was eliminated by bilateral vagal section or atropine. PGE1, PGE2 and nitroprusside caused dose-related falls in mean arterial pressure and a small tachycardia. In a small group of cats (7 of 67) nitroprusside also caused a reduction in heart rate which was eliminated by indomethacin. We conclude that the reflex bradycardia to PGF2 alpha, like that to arachidonic acid is, at least in part, the result of the stimulation of synthesis of another prostaglandin, most likely PGI2.

Nitroglycerin and nitroprusside increase coronary blood flow in dogs by a mechanism independent of prostaglandin release.

The hypothesis that local release of vasodilator prostaglandins mediates, in part, the decrease in coronary resistance after nitroglycerin (NG) administration was tested. NG (60 micrograms/min) and nitroprusside (NP) (30 micrograms/min) were infused for 10 minutes into the left circumflex coronary artery of 9 open-chest, chloralose-anesthetized dogs before and after blockade of prostaglandin synthesis with indomethacin (5 mg/kg). Also, to eliminate the effects of reflex tachycardia on the responses to NG and NP, these experiments were repeated in 6 dogs with heart rate held constant by pacing. NG infusion into dogs without pacing resulted in a maximal increase in coronary blood flow of 55% and after 8 minutes of infusion an increase of 20%, from a baseline of 57 ml/min. NP infusion resulted in a maximal increase in blood flow of 89% and after 8 minutes an increase of 71%, from a baseline of 64 ml/min. In dogs with heart rate held constant, NG infusion caused a maximal increase in coronary artery blood flow of 132% and after 8 minutes of infusion an increase of 18%, from a baseline of 48 ml/min; NP infusion resulted in increase from 51 ml/min of 132% and 62%, respectively. In neither group of dogs did indomethacin significantly change the increases in coronary blood flow or decreases in coronary resistance to NG or NP. Thus, both NG and NP, when infused into the coronary artery of dogs, cause increases in coronary blood flow and decreases in coronary resistance by a mechanism which is independent of prostaglandin release.

Leukotriene D4 reduces coronary blood flow in the anesthetized dog.

We studied the effects of intracoronary administration of leukotriene (LT)D4 on coronary blood flow and myocardial function in chloralose anesthetized dogs. For comparison, the effects of injections of U-46619 were examined in the same dogs. Both LTD4 and U-46619 decreased coronary blood flow, left ventricular dP/dt and cardiac output. LTD4 was ten times more potent than U-46619 in decreasing coronary blood flow. The effects of neither drug were different after indomethacin administration.