Airway constrictor effects of leukotriene D4 in dogs with hyperreactive airways

Leukotriene D₄ (5 μg/ml) aerosol constricts airways of dogs with nonspecific airway hyperreactivity but not of mongrel dogs which lack nonspecific airway hyperreactivity. R_L increased 200 + 25% and C_dyn decreased to 77 ± 5% of the pre-challenge value. LTD₄ (10 μg/ml) produced no further increase. Atropine (0.2 mg/kg) prevented the increase in R_L and decrease in C_dyn, suggesting that part of the effect of LTD₄ on airways is neurally mediated.     

Effect of inhibition of thromboxane production on the leukotriene D4-mediated bronchoconstriction in the guinea pig

Leukotriene D₄ (LTD₄) administered intravenously to anesthetized, spontaneously breathing guinea pigs elicited decreases in dynamic lung compliance (C_dyn) and airway conductance (G_AW) with a maximal response achieved at 0.5 min. Simultaneously, plasma levels of thromboxane metabolite, TxB₂, and the prostacyclin metabolite, 6-keto-PGF_1α, increased 10-fold over pre-LTD₄ levels. Pretreatment of the guinea pigs with meclofenamic acid delayed the onset of the LTD₄-induced bronchoconstriction, antagonized the magnitude of the decreases in C_dyn and G_AW, and blocked the increase in plasma TxB₂ and 6-keto-PGF_1α levels. The thromboxane synthetase inhibitor, UK 37,248, suppressed the LTD₄-induced bronchoconstriction, while it completely blocked TxB₂ production without significantly affecting 6-keto-PGF_1α. The SRS-A end organ antagonist, FPL 55712, blocked both the LTD₄-induced bronchoconstriction and the production of the arachidonic acid metabolites. These results suggest that thromboxane A₂ plays an important role in mediating part of the bronchoconstriction elicited by intravenously administered LTD₄ in the guinea pig.     

Vasoconstrictor effects of leukotrienes C4 and D4 in the feline mesenteric vascular bed

The effects of leukotriene C₄ (LTC₄) and leukotriene D₄ (LTD₄) in the feline mesenteric vascular bed were investigated under conditions of controlled blood flow so that changes in perfusion pressure directly reflect changes in vascular resistance. Intra-arterial injections of LTC₄ and LTD₄ (0.3–3.0 μg) increased perfusion pressure in a dose-related fashion. Vasoconstrictor responses to LTC₄ and LTD₄ were similar to norepinephrine (NE) whereas mesenteric vasoconstrictor response to the thromboxane analog, U46619, was markedly greater than were responses to LTC₄ and LTD₄. Meclofenamate in a dose that greatly attenuated the systemic depressor response to arachidonic acid was without effect on vasoconstrictor responses to LTC₄ and LTD₄, NE and U46619 in the mesenteric vascular bed. The present data show that LTC₄ and LTD₄ possess significant vasoconstrictor activity in the feline mesenteric vascular bed. In addition, the present data suggest that products of the cyclooxygenase pathway do not mediate vasoconstrictor responses to LTC₄ and LTD₄ in the intestinal circulation of the cat.     

Differing mechanisms for leukotriene D4-induced bronchoconstriction in guinea pigs following intravenous and aerosol administration

Leukotriene D₄ (LTD₄) when administered intravenously or by aerosol to guinea pigs produced changes in pulmonary mechanics including a decrease in dynamic compliance and an increase in pulmonary resistance. The effects of intravenous LTD₄ (0.5 μg kg⁻¹) were short lived and abolished by pretreatment of the animal with either cyclooxygenase inhibitors, a thromboxane synthetase inhibitor (OKY 1555) or an SRS-A antagonist (FPL 55712). These findings suggest that bronchoconstriction produced by the intravenous infusion of LTD₄ at 0.5 μg kg⁻¹ is due to the release of thromboxane A₂. However, in animals treated with indomethacin, LTD₄ at higher doses (>0.8 μg kg⁻¹) still elicited a bronchoconstriction which could be blocked by FPL 557112. Nebulization of 0.1 – 1.0 μg of LTD₄ into the lung produced prolonged changes in pulmonary mechanics which were inhibited by FPL 55712 and were potentiated indomethacin. LTD₄, therefore, when administered by aerosol produced effects on the lung which were not mediated by cyclooxygenase products. Responses to nebulized rather than intravenous LTD₄ in the guinea pig may more closely resemble those seen in human tissues.     

Mechanism of A23187-induced airway obstruction in the guinea pig

Exposure of conscious guinea pigs to A23187 aerosol produced a concentration-related increase of excised lung gas volume (ELGV), . ., postmortem pulmonary gas trapping. Measurements of ELGV were highly correlated with measurements of dynamic compliance (C_dyn) and total pulmonary resistance (R_L) and were used as an indication of airway obstruction. We pretreated guinea pigs intravenously with the following drugs: atropine; LY163443, a selective LTD₄/E₄ antagonist; indomethacin; propranolol; and pyrilamine. The guinea pigs were exposed for 8 minutes to the A23187 aerosol, and ELGV measurements were then made. Atropine or pyrilamine prevented the A23187-induced gas trapping. Indomethacin or propranolol tended to potentiate the response and when combined, they potentiated the gas trapping by 80%. LY163443 had no effect alone, but when combined with indomethacin, propranolol, and pyrilamine, inhibited A23187-induced gas trapping by 67%. We conclude that cholinergic and histaminergic mechanisms play major roles in the ionophore-induced pulmonary gas trapping of the guinea pig. With appropriate pretreatment, sulfidopeptide leukotrienes may produce a substantial effect.     

Propranolol potentiates leukotriene D4-induced bronchoconstriction and enhances antagonism by FPL 55712

Aerosol LTD₄-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs was potentiated by either pretreatment with propranolol or bilateral adrenalectomy, whereas bilateral vagotomy did not affect the LTD₄ response. The dose-response curve describing LTD₄-induced changes in dynamic lung compliance (C_{D Y N}) and pulmonary resistance (R_L) [as reflective indices of bronchochonstriction] was shifted to the left by approximately 20-fold by propranolol. Against an equal degree of LTD₄-induced bronchoconstriction, the leukotriene antagonist, FPL 55712, had an apparent 20-fold greater potency in propranolol-pretreated animals vis a vis saline-treated controls. The duration of action of aerosol FPL 55712 was similar in both propranolol-treated and saline-treated animals. These results demonstrate that aerosol LTD₄-induced bronchoconstriction is modulated by an adrenergic compensatory bronchodilator mechanism that is apparently dependent upon the adrenals and independent of vagal influences. Inhibition of the effect of this reflex with propranolol also enhances the apparent potency of an aerosol leukotriene antagonist, FPL 55712, presumably reflecting a constant LTD₄ to antagonist ratio in the saline-treated and propranolol-pretreated guinea pigs.     

Pulmonary microcirculatory responses to leukotrienes B4, C4 and D4 in sheep

The pulmonary microvascular responses to leukotrienes B₄, C₄ and D₄ (total dosage of 4 μg/kg i.v.) were examined in acutely-prepared halothane anesthetized and awake sheep prepared with lung lymp fistulas. In anesthetized as well as unanesthetized sheep, LTB₄ caused a marked and transient decrease in the circulating leukocyte count. Pulmonary transvascular protein clearance (pulmonary lymph flow x lymph-to-plasma protein concentration ratio) increased transiently in awake sheep, suggesting a small increase in pulmonary vascular permeability. The mean pulmonary artery pressure (P ) also increased. In the acutely-prepared sheep, the LTB₄-induced pulmonary hemodynamic and lymph flow responses were damped. Leukotriene C₄ increased P to a greater extent in awake sheep than in anesthetized sheep, but did not significantly affect the pulmonary lymph flow rate (Q̇_lym) and lmph-to-plasma protein concentration (L/P) ration in either group. LTD₄ increased P and Q̇_lymp in both acute and awake sheep; Q̇_lym increased without a significant change in the L/P ratio. The LTD₄-induced rise in P occurred in association with an increase in plasma thromboxane B₂ (Txb₂) cocentration. The relativity small increase in Q̇_lym with LTD₄ suggests that the increase in the transvascular fluid filtration rate is the result of a rise in the pulmonary capillary hydrostatic pressure. In conclusion, LTB₄ induces a marked neutropenia, pulmonary hypertension, and may transiently increase lung vascular permeability. Both LTC₄ and LTD₄ cause a similar degree of pulmonary hypertension in awake sheep, but had different lymph flow responses which may be due to pulmonary vasoconstriction at different sites, i.e. greather pre-capillary constriction with LTC₄ because Q̇_lym did not change and greater post-capillary constriction with LTD₄ because Q̇ increased with the same rise in P .     

Specificity of receptors for leukotrienes A4, B4, C4, D4, E4 and histamine on the guinea-pig lung parenchyma. Effect of FPL-55712 and desensitization of the myotropic activity

The novel metabolites of arachidonic acid, leukotriene (LT) A₄, B₄, C₄, D₄ and E₄ have potent myotropic activity on guinea-pig lung parenchymal strip . The receptors responsible for their action were characterized using desensitization experiments and the selective SRS-A antagonist, FPL-55712. During the continuous infusion of LTB₄, the tissues became desensitized to LTB₄ but were still responsive to histamine, LTA₄, LTC₄, LTD₄ and LTE₄. When LTD₄ was infused continuously, the lung strips contracted to LTB₄ and histamine but were no longer responsive to LTA₄, LTC₄, LTD₄ and LTE₄. Furthermore, FPL-55712 (10 ng ml⁻¹− 10 ug ml⁻¹) produced dose-dependent inhibitions of LTA₄, LTC₄, LTD₄ and LTE₄ without inhibiting the contraction to LTB₄ and histamine. On the basis of these results, it appears that the guinea-pig lung parenchyma may have one type of receptor for LTB₄ and another for LTD₄; LTA₄, LTC₄ and LTE₄ probably act on the LTD₄ receptor.     

Cyclooxygenase mediated airway response to leukotriene D4 in the cat

The effects of leukotriene D4 (LTD4) on pulmonary mechanics were investigated in anesthetized, paralyzed cats under conditions of controlled ventilation. Intravenous injections of LTD4 in doses of 3, 10, and 30 micrograms caused significant increases in transpulmonary pressure (PTP) and lung resistance (RL) while decreasing dynamic compliance (Cdyn). LTD4 also increased systemic arterial pressure (PAo). The changes in PTP, RL, and Cdyn in response to LTD4 were blocked by sodium meclofenamate, a cyclooxygenase inhibitor. However, there was no significant change in the increase in PAo following cyclooxygenase blockade. U 46619, a thromboxane mimic, was 30 to 100 times more potent than LTD4 in increasing PTP, RL and decreasing Cdyn in the cat. These data show that LTD4 has significant smooth muscle constrictor activity in central airways as well as peripheral portions of the feline lung. In addition, these data suggest that in the cat the actions of intravenously administered LTD4 on lung mechanics are mediated by release of cyclooxygenase products while the systemic pressor effects are not dependent upon the integrity of the cyclooxygenase pathway.     

Neutralisation of Interleukin-13 in Mice Prevents Airway Pathology Caused by Chronic Exposure to House Dust Mite

Background

Repeated exposure to inhaled allergen can cause airway inflammation, remodeling and dysfunction that manifests as the symptoms of allergic asthma. We have investigated the role of the cytokine interleukin-13 (IL-13) in the generation and persistence of airway cellular inflammation, bronchial remodeling and deterioration in airway function in a model of allergic asthma caused by chronic exposure to the aeroallergen House Dust Mite (HDM).

Methodology/Principal Findings

Mice were exposed to HDM via the intranasal route for 4 consecutive days per week for up to 8 consecutive weeks. Mice were treated either prophylactically or therapeutically with a potent neutralising anti-IL-13 monoclonal antibody (mAb) administered subcutaneously (s.c.). Airway cellular inflammation was assessed by flow cytometry, peribronchial collagen deposition by histocytochemistry and airway hyperreactivity (AHR) by invasive measurement of lung resistance (R_L) and dynamic compliance (C_dyn). Both prophylactic and therapeutic treatment with an anti-IL-13 mAb significantly inhibited (P<0.05) the generation and maintenance of chronic HDM-induced airway cellular inflammation, peribronchial collagen deposition, epithelial goblet cell upregulation. AHR to inhaled methacholine was reversed by prophylactic but not therapeutic treatment with anti-IL-13 mAb. Both prophylactic and therapeutic treatment with anti-IL-13 mAb significantly reversed (P<0.05) the increase in baseline R_L and the decrease in baseline C_dyn caused by chronic exposure to inhaled HDM.

Conclusions/Significance

These data demonstrate that in a model of allergic lung disease driven by chronic exposure to a clinically relevant aeroallergen, IL-13 plays a significant role in the generation and persistence of airway inflammation, remodeling and dysfunction.     

Modulation of leukotriene synthesis and actions by synthetic derivatives of arachidonic acid

Seven analogs of arachidonic acid were tested for their coronary vasoactivity and their ability to inhibit LTC₄ and LTD₄ synthesis by lung tissue and to antagonize LTD₄ induced coronary constriction. None of the seven arachidonic acid analogs significantly altered peptide leukotriene production by minced cat lung. Two of the analogs (i.e., 7, 13-diethanoarachidonic acid and 7, 10, 13-triethanoarachidonic acid) exerted modest but significant coronary vasodilation in isolated cat coronary arteries, and significantly antagonized the coronary vasoconstrictor response to LTD₄. These analogs may be of interest in modulating leukotriene actions.     

Contraction of guinea pig gail bladder strips by leukotrienes and other agonists

In the presence of indomethacin, Leukotriene C₄ (LTC₄), LTD₄ and LTE₄ were shown to be contractile agents on guinea pig gall bladder strips. The respective pD₂ values for LTC₄, LTD₄ ad LTE₄ were 9.1, 9.1 and 7.7. The contractile effects of LTD₄ were not mediated through the generation of cyclooxygenase products and were antagonized by the SRS-A antagonist FPL-55712. The effects of PGE₁, PGF_2α, the endoperoxide analogue U44069 and histamine on gall bladder strips were also examined. All these agents caused dose-related contractions but were considerably less potent than the leukotrienes. Leukotrienes are therefore potent contractile agents on the guinea pig gall bladder and may contribute to gall bladder contractions or spasms .     

The mechanism of action of leukotrienes C4 and D4 in guinea-pig isolated perfused lung and parenchymal strips of guinea pig, rabbit and rat

The biological actions of pure slow-reacting substance of anaphylaxis (SRS-A) from guinea-pig lung, pure slow-reacting substances (SRS) from rat basophilic leukaemia cells (RBL-1) and synthetic leukotrienes C₄ (LTC₄) and D₄ (LTD₄) have been investigated on lung tissue from guinea pig, rabbit and rat. In the guinea pig, the leukotrienes released cyclo-oxygenase products from the perfused lung and contracted strips of parenchyma. The effects of SRS-A, SRS and LTD₄ were indistinguishable. LTC₄ and LTD₄ had similar actions although LTD₄ was more potent than LTC₄. Indo-methacin (1 μg/ml) inhibited the release of cyclo-oxygenase products from perfused guinea-pig lung and caused a marked reduction in contractions of guinea-pig parenchymal strips (GPP) due to LTC₄ and LTD₄. The residual contraction on the GPP was abolished by FPL 55712 (0.5 – 1.0 μg/ml). It appears, therefore, that a major part of the constrictor actions of LTC₄ and LTD₄ in guinea-pig lung are mediated by myotropic cyclo-oxygenase products, i.e. thromboxane A₂ (TxA₂) and prostaglandins (PGs).In rabbit and rat lung, however, SRS-A, SRS and the leukotrienes were much less potent in contracting parenchymal strips and there was little evidence of the release of cyclo-oxygenase products. FPL 55712 at a concentration of 1 μg/ml failed to antagonise leukotriene-induced contractions.     

Differences in airway responsiveness to leukotriene D4 in allergic sheep with and without late bronchial responses

Allergic sheep respond to inhaled antigen with either acute and late bronchial obstructions (dual responders) or only acute bronchoconstriction (acute responders). In this study we tested the hypothesis that one factor which may distinguish between these two populations is the difference in sensitivity to a specific mediator of airway anaphylaxis, leukotriene (LT) D₄ (a major component of slow reacting substance of anaphylaxis). We postulated that if the hypothesis was correct than dual responders should demonstrate increased airway responses to inhaled LTD₄ and that this increased responsiveness should also be reflected by a more severe response to inhaled antigen. To test this we used animals from both groups with the same degree of non-specific airway responsiveness to carbachol and determined their airway responses to controlled inhlation challenges with synthetic LTD₄ and antigen. Airway responsiveness to carbachol was determined by measuring the change in specific lung resistance (SR_L) to increasing concentrations of carbachol aerosol, and then identifying, by linear interpolation, the provocative carbachol concentration which produced a 150% increase (PC₁₅₀) in SR_L. Airway responses to LTD₄, and antigen were determined by measuring the percentage change in SR_L after a controlled inhlation challenge with either aerosol. Airway responsiveness to carbachol was not different between the two groups. There was, however, a difference (p<0.05) in the airway response to the same dose of LTD₄ in the two groups. Dual responders showed a 297±72% increase in SR_L as compared to a 90±13% increase in SR_L in the acute responders. Dual responders also showed a greater immediate and more prolonged response to antigen than did acute responders. These results suggest that increased responsiveness to LTD₄ may be one factor which may distinguish dual responders from acute responders.     

Quantitation of luekotrienes C4, D4 amd E4 released by pathophysiological stimuli

In order to examine the modulation of leukotriene (LT) release, the PAF-acether-mediated stimulation of these compounds in rat lung was studied. Release of LTC₄, LTD₄ and LTE₄ in both perfused and chopped lung preparations was measured using HPLC and radioimmunoassay. Pre-incubation or pre-infusion of the tissue with indomethacin and PGE₂ was conducted to investigate the effect of cyclooxygenase inhibitors and products on the lipoxygenase pathway. In addition, the effects of LT levels of pre-incubation with vasoactive intenstinal polypeptide (VIP) in chopped lung were observed.In perfused rat lung, indomethacin reduced the levels of LTC₄ relative to LTD₄ as measured in the first 2 min after stimulation of the lung by PAF-acether. Chopped lung preparations, incubated for 15 min. exhibited higher levels of LTC₄ and LTD₄ in indomethacin-treated samples, this increases being effectively reversed by PGE₂.In the VIP pre-incubation experiments clear inhibition of peptido -leukotriene synthesis was observed, with no LTC₄ and only low levels of LTD₄ and LTE₄ observed in VIP-incubated samples. In preliminary experiments using rabbit C5a des arg and PAF-acether on rabbit lung parenchyma strips to stimulaet LT release, disodium cromoglycate pre-incubation was observed to inhibit this release.Inhibition of the 5-lipoxygenase pathway of PGE₂ is supported by these experiments. VIP appears to act as an inhibitor of LTC₄ and LTD₄ biosynthesis or release in this model. Too little is known that peptidergic actions to postulate a mechanism by which a neuroendocrine peptide exerts control of release of arachidonate metabolites; however, VIP is associated with muscarinic stimulation (1) and has been found in mast cells (2).     

Spasmogenic activity of C5adesArg anaphylatoxin on guinea pig lung parenchymal strips: Sensitivity of the leukotriene-mediated component to cyclooxygenase inhibitors

The leukotriene-dependent component of C5a_desArg-induced contractile activity on guinea pig lung parenchymal strips is inhibited by cyclooxygenase inhibitors. Indomethacin simultaneously increased leukotriene release while inhibiting both cyclooxygenase-dependent mediator release and the contractile force generated. Tissue responses to LTC₄ and LTD₄ are also inhibited by cyclooxygenase blockade, while contractions induced by the thromboxane A₂ analog, U-46619, histamine or acetylcholine are not affected. These data indicate a functional role for cyclooxygenase metabolites in leukotriene-induced contractile responses in lung.     

The effect of an orally active leukotriene D4/E4 antagonist, LY171883, on antigen-induced airway responses in allergic sheep

Leukotriene (LT) D₄ is a putative mediator of allergic asthma: inhaled LTD₄ produces early and late increases in specific lung resistance (SR_L) and slows tracheal mucus velocity (TMV) similat to inhaled antigen. In this study we examined the effects of an orally active LTD₄/LTE₄ antagonist, LY171883 [1-<2-Hydroxy-3-propyl-4-<4-(1H-Tetra-zol-5-yl) Butoxy>Phenyl>Ethanonel], on early and late changes in SR_L and TMV following airway challenge with antigen in conscious allergic sheep. SR_L and TMV were measured before and up to 8 h and 24 h after antigen challenge after either LY171883 (30 mg/kg, p.o. 2 h before challenge) or placebo pretreatment. After placebo pretreatment antigen challenge resulted in significant early (483% over baseline) and late (221% over baseline) increases in SR_L (n=9). LY171883 pretreatment, however, significantly reduced the early increase in SR_L (163% over baseline) and blocked the late response. LY171883 did not prevent the antigen-induced fall in TMV from 5–8 h post challenge (n=6), but TMV recovered more rapidly in the drug trial returning to baseline values by 24 h. These results suggest that the generation of LTD₄, and its metabolite LTE₄, during airway anaphylaxis contributes to the early increase in SR_L and is important for eliciting the late increase in SR_L as well as contributing to the fall in TMV.     

Two different mechanisms for modulation of bronchoconstriction in guinea-pigs by cyclooxygenase metabolites

Leukotriene D₄ (LTD₄)-induced bronchoconstriction in guinea-pig airways has a cyclooxygenase (COX)-dependent component. The main objective of this study was to establish if prostaglandin (PG) D₂-induced bronchoconstriction also was modulated by COX products. The effects of non-selective and selective COX-1 and COX-2 inhibitors on bronchoconstriction induced by LTD₄ and PGD₂ were investigated in the perfused and ventilated guinea-pig lung (IPL). Both LTD₄-induced bronchoconstriction and thromboxane (TX) A₂ release was suppressed by COX inhibitors or by TX synthesis inhibition. The release of additional COX products following CysLT₁ receptor activation by LTD₄ was established by measurements of immunoreactive 6-keto PGF_1α (a stable metabolite of PGI₂) and PGE₂. In contrast, TP receptor-mediated bronchoconstriction by PGD₂ was somewhat enhanced by COX inhibitors, and there was no measurable release of COX products after TP receptor activation with U-46619. PGE₂ was bronchoprotective in IPL as it inhibited the histamine-induced bronchoconstriction. In the isolated guinea-pig trachea, neither PGD₂ nor U-46619 actively released PGE₂, but continuous production of PGE₂ and PGI₂ was established, and the response to PGD₂ was enhanced also in the trachea by COX inhibition. The study documented that bronchoconstriction induced by LTD₄ and PGD₂ in IPL was modulated differently by COX products. Whereas bronchoconstriction induced by LTD₄ was amplified predominantly by secondarily released TXA₂, that induced by PGD₂ was attenuated by bronchoprotective PGE₂ and PGI₂, presumably tonically produced in the airways.     

Growth,energy and nitrogen budgets and efficiencies of the growing larvae of Megachile pacifica (Panzer) (Hymenoptera: Megachilidae)

Summary The larvae of Megachile pacifica, the leafcutter bee, develop within a cell constructed of pieces of leaf by the adult female which also provides a plug of nectar and pollen, the sole source of nutrient for the larvae. In this study, eggs (1 per cell) hatched in 2–3 days and larvae were fully grown after a further 9 days at 28° C.The mean larval dry weight (dw) when fully grown (P _L ) was 18.89 mg. Larvae ate 45.99 mg (dw) (C) of their food leaving 0.90 mg (dw) unconsumed. The faeces (FU) weighed an average of 5.62 mg (dw) and their cocoon weighed 2.68 mg (dw) (P _E ). The components of their energy budget (C=(P _L +P _E )+R+FU) were C=1079.4 J, P _L =569.1 J, P _E =62.25 J, R (metabolic energy measured with a Gilson respirometer)=218.3 J and FU=134.4 J. R calculated by difference was 313.6 J.Full grown larvae contained 1.17 mg of nitrogen (N). They egested 0.19 mg N and incorporated 0.16 mg N in the cocoons. They ingested 1.51 mg N (measured) — the calculated consumption of nitrogen (by difference) was 1.52 mg.The ecological efficiencies showed that these larvae are among the most efficient invertebrate converters of energy and nitrogen yet recorded. The assimilation efficiencies (A·C ^-1 ) were 87.5% (energy), 87.2% (N), the net ecological efficiencies (P·A ^-1 ) were 66.8% (energy) and 100% (N) and the gross ecological efficiencies (P·C ^-1 ) were 58.5% (energy) and 87.6% (N). the production to respiration ratio (x100) was 201.5% using calculated R.     

Basin-Wide Considerations for Water Quality Management: Importance of Phosphorus Retention by Reservoirs

The relationship between phosphorus retention (R_P) and water residence time (R_T) was assessed for selected U.S. Army Corps of Engineers reservoirs and found to be influenced by areal phosphorus loading rate (P_L). For reservoirs with high P_L (>15 gm/m²/yr), R_P increased markedly with modest increases in R_T. Reservoirs with lower values of P_L exhibited less dramatic responses in R_P to changes in R_T. The water quality management implications of this are great since reservoirs for which marked changes in R_P can occur with modest changes in R_T are potential management loci within a drainage basin.