Hemodynamic changes induced by liposomes and liposome-encapsulated hemoglobin in pigs: a model for pseudoallergic cardiopulmonary reactions to liposomes. Role of complement and inhibition by soluble CR1 and anti-C5a antibody.

BACKGROUND: Intravenous administration of some liposomal drugs can trigger immediate hypersensitivity reactions that include symptoms of cardiopulmonary distress. The mechanism underlying the cardiovascular changes has not been clarified. METHODS AND RESULTS: Anesthetized pigs (n=18) were injected intravenously with 5-mg boluses of large multilamellar liposomes, and the ensuing hemodynamic, hematologic, and laboratory changes were recorded. The significant (P<0.01) alterations included 79+/-9% (mean+/-SEM) rise in pulmonary arterial pressure, 30+/-7% decline in cardiac output, 11+/-2% increase in heart rate, 236+/-54% increase in pulmonary vascular resistance, 71+/-27% increase in systemic vascular resistance, and up to a 100-fold increase in plasma thromboxane B2. These changes peaked between 1 and 5 minutes after injection, subsided within 10 to 20 minutes, were lipid dose-dependent (ED50=4. 5+/-1.4 mg), and were quantitatively reproducible in the same animal several times over 7 hours. The liposome-induced rises of pulmonary arterial pressure showed close quantitative and temporal correlation with elevations of plasma thromboxane B2 and were inhibited by an anti-C5a monoclonal antibody (GS1), by sCR1, or by indomethacin. Liposomes caused C5a production in pig serum in vitro through classic pathway activation and bound IgG and IgM natural antibodies. Zymosan- and hemoglobin-containing liposomes and empty liposomes caused essentially identical pulmonary changes. CONCLUSIONS: The intense, nontachyphylactic, highly reproducible, complement-mediated pulmonary hypertensive effect of minute amounts of intravenous liposomes in pigs represents a unique, unexplored phenomenon in circulation physiology. The model provides highly sensitive detection and study of cardiopulmonary side effects of liposomal drugs and many other pharmaceutical products due to "complement activation-related pseudoallergy" (CARPA).

Endothelin-mediated constriction of prenodal lymphatic vessels in the canine forelimb.

Endothelin is a 21 amino acid peptide which is produced by the vascular endothelium and is believed to be the mediator of endothelium-dependent vasoconstriction. In the current study we assessed the ability of synthetic human endothelin-1 to affect prenodal lymphatic vessel contractility in the canine forelimb. Intralymphatic infusion of endothelin at 1.09 x 10(-9), 1.09 x 10(-8) and 1.09 x 10(-7) M significantly constricted lymphatic vessels as evidenced by dose-dependent increases in lymphatic perfusion pressure. The increase in lymphatic perfusion pressure seen during intralymphatic infusion of endothelin at 1.09 x 10(-8) M during the intra-arterial infusion of phentolamine was not significantly different from that seen prior to phentolamine, indicating that endothelin-mediated lymphatic constriction is not alpha-receptor mediated. Intra-arterial infusion of endothelin at three infusion rates significantly increased forelimb arterial, systemic and lymphatic perfusion pressures. The constriction seen when endothelin (1.09 x 10(-8) M) was infused intralymphatically in the intact lymphatic system was not significantly different from that observed when only the prenodal lymph vessel was perfused. This indicated that the lymph nodes and efferent lymph vessels do not contribute significantly to the lymphatic constriction produced by endothelin. These data are consistent with the hypothesis that endothelin may modulate lymphatic function under either normal or pathophysiological conditions.

Receptor mechanisms of bradykinin-mediated activation of prenodal lymphatic smooth muscle.

We have previously shown that several endogenous vasoactive agents constrict prenodal lymph vessels in the canine forelimb. In this study, we assessed the receptor mechanisms by which bradykinin activates lymphatic smooth muscle. Intralymphatic (i.l.) infusion of bradykinin at concentrations of 3.82 x 10(-6), 3.82 x 10(-5) and 3.82 x 10(-4) molar significantly increased lymphatic perfusion pressure. To determine the potential role of lymphatic alpha-receptors in this response, we infused bradykinin at a concentration of 3.82 x 10(-4) molar i.l. before and during intra-arterial (i.a.) phentolamine administration. Prior to phentolamine, bradykinin resulted in a doubling of the lymphatic perfusion pressure. Phentolamine alone had no effect on the resting lymphatic pressure, but significantly reduced forelimb arterial pressures. When the infusion of bradykinin was repeated during phentolamine administration, there was no significant change in the lymphatic perfusion pressure. To determine the subclass of alpha-adrenergic receptors involved in this response, we infused bradykinin and the alpha1-receptor agonist phenylephrine i.l. before and during administration of i.a. prazosin, a specific alpha1-receptor antagonist, i.a. Prior to prazosin, both phenylephrine and bradykinin significantly increased lymphatic perfusion pressure. During prazosin administration, neither phenylephrine nor bradykinin significantly altered the lymphatic perfusion pressure. These data indicate that bradykinin-mediated increases in prenodal lymphatic smooth muscle tone are mediated by lymphatic alpha1-adrenergic receptors.

Relationship between substance P, intestinal wall compliance and vascular resistance in the canine ileum.

Substance P (SP) is one of many vasoactive peptides found within the gastrointestinal tract with actions on intestinal smooth muscle. Thus, its vasodilatory action could be attenuated through its stimulatory effect on intestinal smooth muscle producing subsequent elevations in extravascular pressure and thus, passively opposing the vasodilation. The aim of this study was to examine for such a possibility for SP by simultaneously assessing ileal perfusion pressure and intestinal wall compliance in the canine ileum during intra-arterial infusion of SP. Infusion of SP at either 0.74 or 7.4 pmol/min significantly decreased ileal perfusion pressure by 8 and 30%, respectively, without affecting wall compliance. During SP infusion at 74 pmol/min, perfusion pressure fell by 49% while wall compliance decreased by 43%, reflecting a significant increase in ileal wall tension. During SP infusion at 7.4 and 74 pmol/min, a 'two-phase' reduction in perfusion pressure was observed. These data suggest that although SP markedly increases ileal wall tension, the elevation in extravascular pressure produced is not strong enough to overcome its potent vasodilatory action in the canine ileum. The potential of a physiologic role for blood-borne SP is discussed.

Neuropeptide modulation of lymphatic smooth muscle tone in the canine forelimb.

Neurokinin A and B are putative inflammatory mediators. We assessed their ability to alter prenodal lymphatic resistance. Intralymphatic neurokinin A (3.0 x 10(-6), 3.0 x 10(-5) and 3.0 x 10(-4) mol l(-1)) significantly constricted lymphatics at the two highest doses. Preliminary experiments suggested that neurokinin B might dilate lymphatics. To test this, lymphatic pressure was increased by norepinephrine (3.1 x 10(-6) mol l(-1)). Neurokinin B (2.7 x 10(-4) mol l(-1)) was then infused intralymphatically during norepinephrine infusion. Norepinephrine increased perfusion pressure from 5.6 +/- 0.6 mmHg to 12.1 +/- 1.4 mmHg. Subsequent infusion of neurokinin B significantly decreased lymphatic perfusion pressure from 11.9 +/- 1.3 mmHg to 9.9 +/- 1.1 mmHg. These data indicate that neurokinin A and B can alter lymphatic resistance and are consistent with the hypothesis that lymph vessel function may be subject to modulation by neurokinins.

Receptor mechanisms of PAF mediated lymphatic constriction in the canine forelimb.

Platelet activating factor (PAF) is a potent inflammatory lipid. In this study we assessed the ability of PAF to impact lymphatic vessel function by altering prenodal lymphatic resistance. Intralymphatic PAF (7.47 x 10(-6), 7.47 x 10(-5) and 7.47 x 10(-4) M) increased lymphatic perfusion pressure at the two highest infusion rates. PAF mediated lymphatic constriction was not altered by the intra-arterial infusion of phentolamine but was blocked by the intra-arterial infusion of the PAF receptor antagonist WEB 2170. These data indicate that in addition to PAF's effects on microvascular permeability, this agent may also impact the ability of the lymphatics to transport fluid through alterations in lymphatic smooth muscle tone. PAF mediated lymphatic constriction is not mediated by alpha-receptors but rather through PAF receptor mediated mechanism.

Catecholamine-mediated lymphatic constriction: involvement of both alpha 1- and alpha 2-adrenoreceptors.

It has been proposed that catecholamines may regulate lymphatic function by altering lymphatic resistance. In this study we perfused lymphatics in the paw of the anesthetized dog, administering catecholamines intralymphatically before and during intra-arterial administration of adrenoreceptor antagonists. Epinephrine and norepinephrine both increased lymphatic perfusion pressure. When the infusions were repeated during intra-arterial phentolamine, neither catecholamine significantly altered lymphatic perfusion pressure, thus implicating lymphatic adrenoreceptors. Intralymphatic infusion of these catecholamines during the intra-arterial infusion of prazosin significantly increased lymphatic perfusion pressure, but the increase was markedly less than that seen prior to prazosin. In these same animals, the lymphatic constriction produced by intralymphatic phenylephrine was completely blocked, indicating an effective blockade of the alpha 1-receptors. The intralymphatic infusion of phenylephrine or alpha-methylnorepinephrine both significantly increased lymphatic perfusion pressure, confirming the presence of both alpha 1- and alpha 2-receptors. These data demonstrate that the prenodal lymph vessels of the canine forelimb contain both alpha 1- and alpha 2-receptors and that epinephrine and norepinephrine interact with both classes of receptors to produce lymphatic constriction.

Receptor mechanisms of serotonin-induced prenodal lymphatic constriction in the canine forelimb.

Numerous endogenous vasoactive agents have been shown to cause lymphatic smooth muscle contraction. In this study, we assessed the ability of serotonin (5-HT) to alter lymphatic smooth muscle activity and elucidated the receptor mechanisms of 5-HT's actions. Both intralymphatic and intra-arterial administration of 5-HT significantly increased lymphatic smooth muscle activity in lymphatics perfused at constant flow, as indicated by an increase in lymphatic perfusion pressure. The 5-HT-induced increase in lymphatic perfusion pressure is attenuated but not blocked by the intra-arterial infusion of phentolamine, suggesting the involvement of alpha-adrenoreceptors and 5-HT receptors. Intralymphatic infusion of the 5-HT2-receptor-agonist alpha-methylserotonin significantly increased lymphatic perfusion pressure, either alone or when administered into an alpha-receptor blocked preparation, whereas the 5-HT1-receptor-agonist carboxyami-dotryptamine maleate did not effect the prenodal lymphatics. These data indicate that the lymphatic smooth muscle contraction produced by 5-HT is mediated both by lymphatic alpha-adrenoreceptors and 5-HT2 receptors.

CGRP-mediated changes in segmental resistances in the canine forelimb.

Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide which is found in high concentrations in the perivascular nerves innervating the resistance vessels of the peripheral circulation. In the current study we have infused CGRP at three infusion rates (.01, .1 and 1.0 micrograms/min into the brachial artery for thirty minutes at each infusion rate) in the isolated, innervated canine forelimb perfused at natural flow. We measured large artery and vein pressures, small artery and vein pressures and blood flows in both the skin and skeletal muscle circulations for the calculation of total and segmental (large artery, small vessel and large vein) vascular resistances. Infusion of the lowest dosage of CGRP produced slight vasodilation in some animals but did not significantly alter the mean resistances of all the animals as a group. The middle dosage resulted in a 55% decrease in total forelimb resistance and a small but significant decrease in systemic arterial pressure. The highest dosage of CGRP resulted in a 65% decrease in total forelimb resistance and a 34% decrease in systemic arterial pressure. The decreases in forelimb resistances were equally distributed between skin and muscle and were manifested in both large artery and small vessel resistances. The potent vasodilatory effects of CGRP and its concentration in perivascular nerves innervating the resistance vessels of the peripheral circulation suggests a potential role for CGRP in control of circulatory function under normal and/or pathophysiological conditions.

Effects of amino acid isomers on canine renal hemodynamics.

The major objective of this study was to ascertain whether the renal hemodynamic response to amino acid infusion in dogs is stereospecific. To test this hypothesis, we examined the renal hemodynamic effects of two isomers (L and D) of an amino acid mixture of serine, alanine, and proline (SAP; 0.051 mmol.kg-1.min-1) in anesthetized dogs. Intravenous infusion of L-SAP (n = 6) significantly elevated renal blood flow (RBF) and glomerular filtration rate (GFR) by 33 +/- 3 and 30 +/- 5%, respectively, over 1 h. DL-SAP (n = 6) elevated RBF and GFR by only 14 +/- 3 and 13 +/- 3%, respectively. Yet D-SAP (n = 6) failed to elevate either RBF or GFR over 1 h. Intravenous mannitol (940 mos-mol/kg; osmotic control; n = 6) also failed to elevate renal hemodynamics. In six other dogs, intrarenal infusion of L-, but not D-, SAP marginally elevated RBF and GFR by 13 +/- 2 and 12 +/- 2%, respectively, over 1 h. Infusion of alpha-aminoisobutyric acid (0.051 mmol.kg-1.min-1; n = 6), an amino acid analogue that is cotransported with sodium but not metabolized by renal cells, elevated RBF and GFR by 22 +/- 5 and 18 +/- 6%, respectively, over 1 h. These data indicate that vascular infusion of L, but not D, isomers of amino acids elevate RBF and GFR. We therefore suggest the importance of amino acid stereospecificity in the renal vascular response to amino acid infusion in dogs.

Perfused prenodal lymphatics are constricted by prostaglandins.

Prostaglandins may contribute to the control of lymph flow by affecting lymphatic vessel contractility. We measured the pressure in perfused prenodal lymphatic vessel in the paw of the anesthetized dog as affected by administration of prostaglandins E1, E2, F2 alpha or arachidonic acid. The forelimb was perfused at constant flow with blood obtained from a femoral artery. Systemic arterial, central venous, and forelimb vascular pressures were measured. When added to the lymphatic perfusate, all of the prostaglandins and arachidonic acid caused constriction of lymphatic vessels. Perfusion of prenodal lymphatics separated from downstream nodes and vessels showed that this constriction occurred primarily in prenodal vessels. However, only prostaglandin F2 alpha caused lymphatic constriction when infused into the blood to the forelimb. Because prostaglandins are a common component of the lymph leaving an area of tissue damage, these results are compatible with the possibility that prostaglandins, by directly affecting lymphatics, help modulate lymph flow following local injury.

Bradykinin-mediated edema formation is blocked by levorotatory but not dextrorotatory terbutaline.

The ability of the purified stereoisomers of the beta 2-receptor agonist terbutaline to block bradykinin-mediated increases in lymph flow and protein concentration was assessed in the canine forelimb perfused at constant arterial flow. Intra-arterial infusion of bradykinin (2 micrograms/min, n = 8) decreased forelimb arterial pressures but did not affect skin small vein pressure or systemic pressure. Lymph flow, protein concentration and protein transport were significantly increased. Intra-arterial infusion of 1-terbutaline (1 microgram/min, n = 9) decreased forelimb arterial pressures and systemic pressure but did not affect lymph parameters. Subsequent infusion of bradykinin during the continued infusion of 1-terbutaline failed to alter forelimb lymph parameters. Intra-arterial infusion of d-terbutaline (1 microgram/min, n = 11) did not alter vascular pressures or lymph parameters. Subsequent infusion of bradykinin during the continued infusion of d-terbutaline decreased forelimb arterial pressures and significantly increased lymph flow, protein concentration and protein transport. Intra-arterial infusion of a high dose (100 micrograms/min, n = 9) of d-terbutaline significantly decreased forelimb arterial pressure but was likewise ineffective in blocking the increases in lymph parameters produced by subsequent bradykinin infusion. These data indicate that the beta 2-receptor agonistic and anti-permeability actions of terbutaline are found solely in the levorotatory enantiomer.

Physiological and pharmacological evidence for the regulation of permeability.

Local intraarterial infusions of histamine-type mediators produce increases in microvascular pressure (Pmv), protein efflux, and net fluid filtration that promote edema formation. The rise in Pmv is not the primary determinant of edema formation inasmuch as mediator-stimulated edema formation develops without an increase in Pmv. The inflammatory mediators increase the hydraulic conductivity of the microvascular membrane as evidenced by a large increase in the capillary filtration coefficient (CFC) subsequent to an increase in permeability. The development of inflammatory edema is primarily attributable to the increase in protein efflux, which decreases the lymph-to-plasma total-protein ratio (L/P ratio), virtually eliminating the transmural colloid osmotic pressure gradient. Hence, fluid filtration is increased at almost any level of Pmv. Noninflammatory vasodilators and venous occlusion produce increases in Pmv and protein clearance, but fail to increase the L/P ratio. The increase in protein efflux and L/P ratio is attributable to a nonhemodynamic action of the inflammatory mediators, an increase in microvascular permeability to macromolecules. The increase in protein efflux, CFC, and net fluid filtration produced by various inflammatory mediators is largely inhibited by cooling, treatment with endothelial cell stabilizers, or perfusion with blood from hemorrhaged animals. This inhibition is independent of changes in hemodynamics and must be ascribed to a direct effect on the microvascular membrane, providing evidence for a variable macromolecular transport pathway. In contrast, increases in protein clearance produced by increasing Pmv are not inhibited by these maneuvers, which provides evidence for a static macromolecular transport pathway. These findings correlate well with those from microscopic studies supporting the concept that macromolecular permeability may be directly regulated at the level of the venular endothelial cell subsequent to the modulation of interendothelial cell junction gap size.

Effects of bolus injections of leukotrienes and norepinephrine on forelimb vascular and lymphatic pressures.

Leukotrienes, lypoxygenase metabolites of arachadonic acid, have been reported to be potent vasoconstrictors in some organs. This study was undertaken to delineate the actions of leukotrienes on both vascular and lymphatic vessels in the canine forelimb. Bolus intra-arterial injections of 1 microgram and 10 micrograms of leukotriene B4, C4, and D4 and 1 microgram of norepinephrine were made into forelimbs perfused at constant flow. Norepinephrine significantly increased systemic, forelimb perfusion and small artery pressures. Lymphatic pressure was significantly increased from a control of 6.6 mmHg to a peak of 14.4 mmHg. Leukotriene B4 in either dosage, did not significantly affect vascular or lymphatic pressures. Leukotriene C4 (1 microgram or 10 micrograms) significantly increased systemic and forelimb arterial pressures but did not alter lymphatic pressure. Leukotriene D4 (1 microgram) significantly increased small artery pressure. Leukotriene D4 (10 micrograms) increased systemic and forelimb arterial pressures. Neither dosage of leukotriene D4 significantly affected lymphatic pressure. Repeat injection of norepinephrine after completion of all leukotriene injections again markedly increased systemic, forelimb arterial and lymphatic pressures. These data indicate that leukotrienes exhibit only mild constrictor effects on forelimb blood vessels and do not significantly affect forelimb prenodal lymphatic vessels.

Constriction of lymphatics by catecholamines, carotid occlusion, or hemorrhage.

Regulation of lymphatics by sympathetic nerves or hormones seems probable. To elucidate this, we perfused a lymphatic vessel in the paw of the anesthetized dog while measuring lymphatic perfusion pressure. We studied the effects of norepinephrine, epinephrine, hemorrhage, and carotid occlusion on lymphatic pressure. Blood was pumped to the forelimb via the brachial artery. Cannulas were placed to measure systemic, central venous, and forelimb vascular pressures. Catecholamines, whether added to the lymphatic perfusate or infused into the forelimb arterial blood, and bilateral carotid occlusion significantly increased lymphatic perfusion pressure. Perfusion of prenodal lymphatics disconnected from downstream vessels and nodes indicated that this increase occurred primarily in prenodal lymph vessels. Hemorrhagic hypotension to 55 mmHg did not affect lymphatic pressure but reduction to 35 mmHg did. The increase in lymphatic pressure produced by epinephrine and norepinephrine was blocked by phentolamine. Increased lymphatic perfusion pressure subsequent to exogenous catecholamines, severe hemorrhagic hypotension, or bilateral carotid occlusion supports the possibility that lymphatic function is modulated by adrenergic mechanisms in physiological and/or pathophysiological states.

O-(beta-hydroxyethyl)-rutoside (Venoruton) fails to block histamine or bradykinin-induced edema formation in the canine forelimb perfused at constant arterial inflow.

O-(beta-hydroxyethyl)-rutoside (Venoruton) has been reported to alleviate edema formation in chronic venous insufficiency. In an attempt to elucidate Venoruton's potential as an antiinflammatory agent, we infused Venoruton (20 mg/minute) intraarterially into the canine forelimb perfused at constant flow during the simultaneous intraarterial infusion of histamine (4 micrograms base/minute) or bradykinin (2 micrograms/minute). The infusion of Venoruton alone for forty minutes resulted in a small but significant increase in forelimb arterial pressures but no change in systemic pressure or forelimb skin lymph flow, protein concentration or protein transport. Subsequent infusion of either histamine or bradykinin resulted in a significant decrease in forelimb arterial pressures and a marked increase in skin lymph flow, lymph total protein concentration and lymph total protein transport. The changes in forelimb vascular pressures and skin lymph parameters were similar to those seen during the infusion of either histamine or bradykinin alone. These data indicate that the intraarterial infusion of Venoruton at this dosage does not inhibit the ability of simultaneously infused histamine or bradykinin to increase transvascular fluid and macromolecular efflux in the canine forelimb perfused at constant arterial inflow.

Stereospecificity of the anti-inflammatory actions of terbutaline.

Intra-arterial infusion of a racemic mixture of the beta 2-agonist terbutaline blocks histamine-mediated increases in lymph flow and protein concentration in the canine forelimb. In the current study we have assessed the relative anti-inflammatory potencies of the purified stereoisomers of terbutaline. Infusion of histamine (4 micrograms base/min) increased lymph flow, protein concentration and protein transport. The intra-arterial infusion of 1-terbutaline (1 microgram/min) significantly decreased forelimb arterial pressures and prevented any changes in lymph parameters due to subsequent histamine infusion. Intra-arterial infusion of d-terbutaline (1 microgram/min) did not significantly affect forelimb vascular pressures but subsequent to histamine administration, lymph parameters increased similar to that seen with histamine alone. Infusion of a high dose of d-terbutaline (100 micrograms/min) slightly decreased forelimb arterial pressures but failed to inhibit histamine-mediated increases in lymph parameters. Infusion of 1-terbutaline alone (1 microgram/min) significantly decreased forelimb arterial pressures, lymph flow and protein transport and slightly but significantly increased lymph protein concentration. These data indicate that the beta 2-agonistic and anti-inflammatory properties of terbutaline are confined solely to the levorotatory enantiomer.

Constriction of perfused lymphatics by acetylcholine, bradykinin and histamine.

We have previously reported that perfused lymphatic vessels in the canine forelimb constrict in response to increased sympathetic nerve activity or local infusions of endogenous vasoconstrictor substances. In the present study we have assessed the effects of three endogenous vasodilators; acetylcholine, bradykinin and histamine on lymphatic vessel contractility. Each one of these agents, when infused intralymphatically, produced lymphatic constriction as evidenced by significant increases in lymphatic perfusion pressure. The threshold concentrations which produced lymphatic constriction were between 10(-6) and 10(-5) molar for acetylcholine and bradykinin and between 10(-5) and 10(-4) molar for histamine. Surgical exclusion of the lymph nodes and efferent lymph vessels from the perfused tissue did not significantly affect the observed response, indicating that the response occurs predominately in the prenodal segments of the lymphatic system. Infusion of acetylcholine and bradykinin into the arterial supply to the forelimb did not significantly alter lymphatic perfusion pressure, unlike the response seen when catecholamines are infused intra-arterially. Histamine displayed an unusual property in that it constricts lymph vessels upon initial administration but was thereafter completely ineffective. Constriction of lymphatic vessels by substances which are potent vasodilators clearly indicates that significant functional differences exist in endothelial cell/smooth muscle relationships between blood vessels and lymph vessels.

Neurokinin A and B: potent vasodilators in the canine forelimb.

Neurokinin A and neurokinin B may play a role in control of the peripheral circulation in either physiological or pathophysiological conditions. We have infused these peptides intra-arterially at three infusion rates each to assess their actions on vascular pressures, blood flows and total and segmental resistances in skin and skeletal muscle in the canine forelimb. Neurokinin A infusions (.01, .1, and 1 micrograms/min) decreased total forelimb resistance; transiently, 26% and 57%, respectively. The decrease in resistance was equally distributed between the skin and skeletal muscle circulations and was manifest in both large artery and small vessel resistances. Systemic and forelimb arterial pressures were decreased in a dose-dependent manner. Neurokinin B infusions (.5, 1 and 5 micrograms/min) decreased total forelimb resistance 29%, 31%, and 52%, respectively. The decrease in resistance was equally distributed between the skin and skeletal muscle circulations and was the result of decreases in both large artery and small vessel resistances. Systemic and forelimb arterial pressures were decreased in a dose-dependent manner. The potent effect of neurokinins on vascular resistance and their concentration in perivascular nerves innervating the resistance vessels of the circulation suggests a potential role for these neuropeptides in circulatory control.

The inflammatory actions of platelet activating factor are blocked by levorotatory terbutaline.

Platelet activating factor (PAF), a potent vasoactive lipid, may play an important role in the inflammatory process. In this study, we infused PAF intra-arterially to characterize its edematogenic potency in the canine forelimb. We have also assessed the ability of the beta 2-receptor agonist l-terbutaline to block PAF-mediated edema formation. The infusion of PAF at .25 micrograms/min, .5 micrograms/min and 1 micrograms/min increased forelimb arterial pressures and, at the two higher dosages, significantly decreased systemic arterial pressure. PAF infusions increased transvascular fluid and macromolecular flux as indicated by significant increases in skin lymph flow, protein concentration and protein transport. The intra-arterial infusion of l-terbutaline at 1 micrograms/min significantly decreased forelimb arterial pressures but did not affect small vein pressure, systemic pressure or forelimb lymph parameters. The subsequent infusion of PAF at .5 micrograms/min, during the continued infusion of l-terbutaline, failed to significantly affect forelimb lymph parameters. These data indicate that PAF is significantly more potent as an edematogenic agent in the forelimb than histamine or bradykinin. Furthermore, the blockade of PAF-mediated edema formation by l-terbutaline suggests that beta 2-receptor agonists may be capable of antagonizing the inflammatory actions of a wide variety of putative inflammatory mediators.