Discovering the role of the adrenal gland in the control of body function

This essay looks at the historical significance of three APS classic papers that are freely available online: Cannon WB and de la Paz D. Emotional stimulation of adrenal secretion. Am J Physiol 28: 64-70, 1911 (http://ajplegacy.physiology.org/cgi/reprint/28/1/64). Cannon WB. The emergency function of the adrenal medulla in pain and the major emotions. Am J Physiol 33: 356-372, 1914 (http://ajplegacy.physiology.org/cgi/reprint/33/2/356). Cannon WB. Studies on the conditions of activity in endocrine glands. V. The isolated heart as an indicator of adrenal secretion induced by pain, asphyxia and excitement. Am J Physiol 50: 399-432, 1919 (http://ajplegacy.physiology.org/cgi/reprint/50/3/399).     

Understanding pulmonary gas exchange: ventilation-perfusion relationships

This essay looks at the historical significance of four APS classic papers that are freely available online: Fenn WO, Rahn H, and OTIS AB. A theoretical study of the composition of the alveolar air at altitude. Am J Physiol 146: 637-653. 1946 (http://ajplegacy.physiology.org/cgi/reprint/146/5/637). Rahn H. A concept of mean alveolar air and the ventilation-bloodflow relationships during pulmonary gas exchange. Am J Physiol 158: 21-30, 1949 (http://ajplegacy.physiology.org/cgi/reprint/158/1/21)). Riley RL. And Cournand A. "Ideal" Alveolar air and the analysis of ventilation-perfusion relationships in the lungs. J Appl Physiol 1: 825-847. 1949 (http://jap.physiology.org/cgi/reprint/1/12/825). Riley RL. And Cournand A. Analysis of factors affecting partial pressures of oxygen and carbon dioxide in gas and blood of lungs: theory. J Appl Physiol 4: 77-101. 1951 (http://jap.physiology.org/cgi/reprint/4/2/77).     

The pioneering use of systems analysis to study cardiac output regulation

This essay examines the historical significance of an APS classic paper that is freely available online: Guyton AC, Lindsey AW, and Kaufmann BN. Effect of mean circulatory filling pressure and other peripheral circulatory factors on cardiac output. Am J Physiol 180: 463-468, 1955 (http://ajplegacy.physiology.org/cgi/reprint/180/3/463).     

PLD pathway involved in carbachol-induced Cl- secretion: possible role of TNF-alpha

In a previous study, it was found thatexposure to tumor necrosis factor- (TNF-) potentiated theelectrophysiological response to carbachol in a time-dependent andcycloheximide-sensitive manner. It was deduced that the potentiationcould be due to protein kinase C activity because of increased1,2-diacylglycerol. It was also observed that propranolol coulddecrease the electrophysiological response to carbachol (Oprins JC,Meijer HP, and Groot JA. Am J Physiol Cell Physiol 278:C463-C472, 2000). The aim of the present study was to investigatewhether the phospholipase D (PLD) pathway plays a role in the carbacholresponse and the potentiating effect of TNF-. Thetransphosphatidylation reaction in the presence of the primary alcohol1-butanol [leading to stable phosphatidylbutanol (Pbut) formation]was used to measure activity of PLD. The phosphatidic acid (PA) levelswere also measured. Muscarinic stimulation resulted in an increasedformation of Pbut and PA. TNF- decreased levels of PA.

     

An immunologically distinct beta -adaptin on tubulovesicles of gastric oxyntic cells

Clathrin and the -adaptin subunit of the AP-1 clathrinadaptor have been previously identified on H-K-ATPase-richtubulovesicles from gastric acid secretory (oxyntic) cells [C. T. Okamoto, S. M. Karam, Y. Y. Jeng, J. G. Forte, and J. Goldenring.Am. J. Physiol. 274 (Cell Physiol. 43):C1017-C1029]. We further characterized this AP-1 adaptorfrom rabbit and hog tubulovesicles biochemically and immunologically.Clathrin coat proteins were stripped from purified tubulovesicularmembranes and fractionated by hydroxyapatite chromatography. The AP-1adaptor appears to elute at 200 mM sodium phosphate, based on thepresence of proteins in this fraction that are immunoreactive withantibodies against three of the four subunits of this heterotetramericcomplex: the -, µ₁-, and₁-adaptin subunits. Althoughthe putative -adaptin subunit in this fraction is not immunoreactivewith the anti--adaptin monoclonal antibody (MAb), this -adaptinis immunoreactive with polyclonal antibodies (PAbs) directed againstthe peptide sequenceGly⁶²⁵-Asp-Leu-Leu-Gly-Asp-Leu-Leu-Asn-Leu-Asp-Leu-Gly-Pro-Pro-Val⁶⁴⁰,a region conserved between ₁-and ₂-adaptins that is thought to be involved in the binding of clathrin heavy chain.Immunoprecipitation of the AP-1 adaptor complex from this fraction withanti--adaptin MAb 100/3 resulted in the coimmunoprecipitation of the-adaptin that did not react with the anti--adaptin MAb but didreact with the anti--adaptin PAbs. In contrast, immunoprecipitationof the AP-1 adaptor complex from crude clathrin-coated vesicles from brain resulted in the coimmunoprecipitation of a -adaptin that wasrecognized by both the anti--adaptin MAb and PAbs. These resultssuggest that the tubulovesicular AP-1 adaptor complex may be distinctfrom that found in the trans-Golgi network and may contain animmunologically distinct -adaptin. This immunologically distinct-adaptin may be diagnostic of apical tubulovesicular endosomes ofepithelial cells.

     

Interferon-gamma induces a decrease in the intracellular calcium pump in a human salivary gland cell line

Interferon- (IFN-) ± tumor necrosis factor-(TNF-) induces antiproliferation and intracellularCa²⁺ store depletion in a humansubmandibular ductal cell line (HSG), which can be reversed on cytokineremoval [A. J. Wu, G. C. Chen, B. J. Baum, and I. S. Ambudkar. Am. J. Physiol. 270 (Cell Physiol. 39): C514-C521,1996]. Here we have examined a possible mechanism for theIFN--induced intracellular Ca²⁺store depletion. There was a time-dependent decrease inthapsigargin-dependent internalCa²⁺ release after exposure of thecells to the cytokines. The intracellular Ca²⁺ pump[sarco(endo)plasmic reticulumCa²⁺-ATPase(SERCA)] protein in lysates and membranes of cellstreated with IFN- ± TNF-, but not with TNF- alone, showeda similar time-dependent decrease (examined using a SERCA2antibody). Removal of the cytokines, which resulted inrecovery of cell growth and refill of internalCa²⁺ stores, also increased thelevel of SERCA protein. The decrease in SERCA is not a result ofdecreased cell proliferation, since thapsigargin,2,5-di-(t-butyl)-1,4-hydroquinone, orserum-free growth conditions induced antiproliferative effects on HSGcells without any corresponding decrease in SERCA. We suggest that the IFN--induced decrease in the level of SERCA accounts for the depleted state of internal Ca²⁺stores in cytokine-treated HSG cells. These data suggest a novel mechanism for the inhibition of HSG cell growth by IFN-.

     

Role of laminin-1, collagen IV, and an autocrine factor(s) in regulated secretion by lacrimal acinar cells

Adhesion to novel basement membrane component BM180 in thepresence of laminin-1 promotes stimulus-secretion coupling in lacrimal acinar cells [G. W. Laurie, J. D. Glass, R. A. Ogle, C. M. Stone, J. R. Sluss, and L. Chen. Am. J. Physiol. 270 (CellPhysiol. 39): C1743-C1750,1996]. The identity of the active laminin-1 site andthe possibility that other promoters of coupling are present in theacinar cell microenvironment were probed by use of different substrates, media, neutralizing antibodies and cell numbers. Regulated peroxidase secretion was unaffected by basement membrane coat concentration and was detectable at reduced levels in serum-free medium. Anti-laminin-1 antibodies, particularly against sites in the1 and 1 chains, but not 1 chains, partially suppressed regulated secretion, as did an anti-collagen IV antibody. Without effect were RGD peptide and antibodies against entactin, the₁-integrin subunit, and severalgrowth factors. Increasing cell number in serum-free medium revealed anunknown, serum-maskable, secretion-enhancing activity with a remarkablespecificity for regulated secretion. Stimulus-secretion coupling,therefore, appears to be modulated by several extracellular factorswhose relative contributions remain to be determined.

     

Determination of production of nitric oxide by lower airways of humans---theory

Hyde, Richard W., Edgar J. Geigel, Albert J. Olszowka, JohnA. Krasney, Robert E. Forster II, Mark J. Utell, and Mark W. Frampton.Determination of production of nitric oxide by the lower airwaysof humanstheory. J. Appl. Physiol.82(4): 1290-1296, 1997.Exercise and inflammatory lung disorderssuch as asthma and acute lung injury increase exhaled nitric oxide(NO). This finding is interpreted as a rise in production of NO by thelungs (NO)but fails to take into account the diffusing capacity for NO(DNO) that carries NO into thepulmonary capillary blood. We have derived equations to measureNO from thefollowing rates, which determine NO tension in the lungs(PL) at any moment from 1) production(NO);2) diffusion, whereDNO(PL) = rate of removal by lung capillary blood; and3) ventilation, whereA(PL)/(PB  47) = the rate of NO removal by alveolar ventilation(A) and PB is barometric pressure. During open-circuit breathingwhen PL is not in equilibrium,d/dtPL[V_L/(PB  47)] (where V_L is volumeof NO in the lower airways) = NO  DNO(PL)  A(PL)/(PB  47). When PL reaches asteady state so that d/dt = 0 andA iseliminated by rebreathing or breath holding, then PL = NO/DNO.PL can be interpreted as NOproduction per unit of DNO. Thisequation predicts that diseases that diminishDNO but do not alterNO willincrease expired NO levels. These equations permit precise measurementsof NO thatcan be applied to determining factors controlling NO production by thelungs.

     

nPKC{varepsilon}, a P2Y2-R downstream effector in regulated mucin secretion from airway goblet cells

Airway goblet cell mucin secretion is controlled by agonist activation of P2Y₂ purinoceptors, acting through Gq/PLC, inositol-1,4,5-trisphosphate (IP₃), diacylglycerol, Ca²⁺ and protein kinase C (PKC). Previously, we showed that SPOC1 cells express cPKC, nPKC, nPKC, and nPKC; of these, only nPKC translocated to the membrane in correlation with mucin secretion (Abdullah LH, Bundy JT, Ehre C, Davis CW. Am J Physiol Lung Physiol 285: L149–L160, 2003). We have verified these results and pursued the identity of the PKC effector isoform by testing the effects of altered PKC expression on regulated mucin release using SPOC1 cell and mouse models. SPOC1 cells overexpressing cPKC, nPKC, and nPKC had the same levels of ATPS- and phorbol-1,2-myristate-13-acetate (PMA)-stimulated mucin secretion as the levels in empty retroviral vector expressing cells. Secretagogue-induced mucin secretion was elevated only in cells overexpressing nPKC (14.6 and 23.5%, for ATPS and PMA). Similarly, only SPOC1 cells infected with a kinase-deficient nPKC exhibited the expected diminution of stimulated mucin secretion, relative to wild-type (WT) isoform overexpression. ATPS-stimulated mucin secretion from isolated, perfused mouse tracheas was diminished in P2Y₂-R null mice by 82% relative to WT mice, demonstrating the utility of mouse models in studies of regulated mucin secretion. Littermate WT and nPKC knockout (KO) mice had nearly identical levels of stimulated mucin secretion, whereas mucin release was nearly abolished in nPKC KO mice relative to its WT littermates. We conclude that nPKC is the effector isoform downstream of P2Y₂-R activation in the goblet cell secretory response. The translocation of nPKC observed in activated cells is likely not related to mucin secretion but to some other aspect of goblet cell biology. protein kinase C; mucins; goblet cells; exocytosis; airways; epithelium; lung     

Distinct kinases are involved in contraction of cat esophageal and lower esophageal sphincter smooth muscles

Contraction of smooth muscle depends on the balance of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activities. Because MLCK activation depends on the activation of calmodulin, which requires a high Ca²⁺ concentration, phosphatase inhibition has been invoked to explain contraction at low cytosolic Ca²⁺ levels. The link between activation of the Ca²⁺-independent protein kinase C (PKC) and MLC phosphorylation observed in the esophagus (ESO) (Sohn UD, Cao W, Tang DC, Stull JT, Haeberle JR, Wang CLA, Harnett KM, Behar J, and Biancani P. Am J Physiol Gastrointest Liver Physiol 281: G467–G478, 2001), however, has not been elucidated. We used phosphatase and kinase inhibitors and antibodies to signaling enzymes in combination with intact and saponin-permeabilized isolated smooth muscle cells from ESO and lower esophageal sphincter (LES) to examine PKC-dependent, Ca²⁺-independent signaling in ESO. The phosphatase inhibitors okadaic acid and microcystin-LR, as well as an antibody to the catalytic subunit of type 1 protein serine/threonine phosphatase, elicited similar contractions in ESO and LES. MLCK inhibitors (ML-7, ML-9, and SM-1) and antibodies to MLCK inhibited contraction induced by phosphatase inhibition in LES but not in ESO. The PKC inhibitor chelerythrine and antibodies to PKC, but not antibodies to PKCII, inhibited contraction of ESO but not of LES. In ESO, okadaic acid triggered translocation of PKC from cytosolic to particulate fraction and increased activity of integrin-linked kinase (ILK). Antibodies to the mitogen-activated protein (MAP) kinases ERK1/ERK2 and to ILK, and the MAP kinase kinase (MEK) inhibitor PD-98059, inhibited okadaic acid-induced ILK activity and contraction of ESO. We conclude that phosphatase inhibition potentiates the effects of MLCK in LES but not in ESO. Contraction of ESO is mediated by activation of PKC, MEK, ERK1/2, and ILK. protein kinase C; myosin light chain kinase; phosphatase; integrin-linked kinase     

Combined myofibrillar and mitochondrial creatine kinase deficiency impairs mouse diaphragm isotonic function

Watchko, Jon F., Monica J. Daood, Gary C. Sieck, John J. LaBella, Bill T. Ameredes, Alan P. Koretsky, and BeWieringa. Combined myofibrillar and mitochondrialcreatine kinase deficiency impairs mouse diaphragm isotonic function.J. Appl. Physiol. 82(5): 1416-1423, 1997.Creatine kinase (CK) is an enzyme central to cellular high-energy phosphate metabolism in muscle. To characterize the physiological role of CK in respiratory muscle during dynamic contractions, we compared the force-velocity relationships, power, andwork output characteristics of the diaphragm (Dia) from mice withcombined myofibrillar and sarcomeric mitochondrial CK deficiency (CK[/]) with CK-sufficient controls (Ctl).Maximum velocity of shortening was significantly lower inCK[/] Dia (14.1 ± 0.9 L_o/s,where L_o isoptimal fiber length) compared with Ctl Dia (17.5 ± 1.1 L_o/s)(P < 0.01). Maximum power wasobtained at 0.4-0.5 tetanic force in both groups; absolute maximumpower (2,293 ± 138 W/m²) andwork (201 ± 9 J/m²) werelower in CK[/] Dia compared with Ctl Dia(2,744 ± 146 W/m² and 284 ± 26 J/m², respectively)(P < 0.05). The ability ofCK[/] Dia to sustain shortening duringrepetitive isotonic activation (75 Hz, 330-ms duration repeated eachsecond at 0.4 tetanic force load) was markedly impaired, withCK[/] Dia power and work declining to zero by 37 ± 4 s, compared with 61 ± 5 s in Ctl Dia. We conclude that combined myofibrillar and sarcomeric mitochondrial CK deficiency profoundly impairs Dia power and work output, underscoring the functional importance of CK during dynamic contractions in skeletal muscle.

     

Letters to the Editor

The following is the abstract of the article discussed in thesubsequent letter:

Mitchell, Claire H., Jin Jun Zhang, Liwei Wang, andTim J. C. Jacob. Volume-sensitive chloride current in pigmented ciliary epithelial cells: role of phospholipases. Am. J. Physiol. 272 (Cell Physiol. 41): C212-C222, 1997.Thewhole cell recording technique was used to examine an outwardlyrectifying chloride current activated by hypotonic shock in bovinepigmented ciliary epithelial (PCE) cells. Removal of internal andexternal Ca²⁺ did not affect the activation of thesecurrents, but they were abolished by the phospholipase C inhibitorneomycin. The current was blocked by5-nitro-2-(3-phenylpropylamino)benzoic acid,4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid, and4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) in avoltage-dependent manner, but tamoxifen, dideoxyforskolin, andquinidine did not affect it. This blocking profile differs from that ofthe volume-sensitive chloride channel in neighboring nonpigmentedciliary epithelial cells (Wu, J., J. J. Zhang, H. Koppel, and T. J. C. Jacob. J. Physiol. Lond. 491: 743-755, 1996), and thisdifference implies that the volume responses of the two cell types aremediated by different chloride channels (Jacob, T. J. C., and J. J. Zhang. J. Physiol. Lond. In press). Intracellular administration of guanosine 5'-O-(3-thiotriphosphate) (GTPS) to PCE cells induced a transient, time-independent, outwardly rectifying chloride current that closely resembled the current activated by hypotonic shock. DIDS produced a voltage-dependent blockof the GTPS-activated current similar to the block of the hypotonically activated current. Intracellular neomycin completely prevented activation of this current as did incubation of the cells incalphostin C, an inhibitor of protein kinase C (PKC). Removal ofCa²⁺ did not affect activation of the current by GTPSbut extended the duration of the response. Inhibition of phospholipaseA₂ (PLA₂) with p-bromophenacyl bromideprevented the activation of the hypotonically induced current and alsoinhibited the current once activated by hypotonic solution. Thefindings imply that the hypotonic response in PCE cells is mediated byboth phospholipase C (PLC) and PLA₂. Both phospholipasesgenerate arachidonic acid, and, in addition, the PLC pathway regulatesthe PLA₂ pathway via a PKC-dependent phosphorylation ofPLA₂.

     

Reduction of allergic airway responses in P-selectin-deficient mice

De Sanctis, George T., Walter W. Wolyniec, Francis H. Y. Green, Shixin Qin, Aiping Jiao, Patricia W. Finn, Thomas Noonan, Anthony A. Joetham, Erwin Gelfand, Claire M. Doerschuk, and Jeffrey M. Drazen. Reduction of allergic airway responses inP-selectin-deficient mice. J. Appl.Physiol. 83(3): 681-687, 1997.P-selectin is an adhesion receptor that has been shown to be important in therecruitment of eosinophils and lymphocytes in a variety of inflammatoryconditions. Because cellular recruitment is thought to be a criticalevent in allergen-induced changes in airway responsiveness, we reasoned that P-selectin-deficient mice would exhibit reduced airwayresponsiveness and cellular trafficking noted in wild-type (+/+) mice.Both (+/+) and P-selectin-deficient (/) micesensitized and challenged with ovalbumin (OVA/OVA) exhibited thesame capacity to produce increased titers of total and OVA-specificimmunoglobulin E. Airway responsiveness to methacholine wassignificantly greater in the (+/+) (OVA/OVA) animals than it was in therespective (/) (OVA/OVA) group or control groups(P = 0.0016). Bronchoalveolarlavage fluid from (/) (OVA/OVA) mice contained significantlyfewer eosinophils and lymphocytes compared with the (+/+) (OVA/OVA)mice (P < 0.05). These resultssuggest that the predominant role of P-selectin in OVA-inducedairway hyperresponsiveness is to promote the airway inflammatoryresponse to allergen inhalation.

     

Superoxide dismutase restores endothelium-dependent arteriolar dilatation during acute infusion of nicotine

We previouslyshowed [Am. J. Physiol. 272 (Heart Circ. Physiol. 41):H2337-H2342, 1997] that nicotine impairsendothelium-dependent arteriolar dilatation. However, mechanisms thataccounted for the effect of nicotine on endothelium-dependentvasodilatation were not examined. Thus the goal of this study was toexamine the role of oxygen radicals in nicotine-induced impairment of arteriolar reactivity. We measured diameter of cheek pouch resistance arterioles (~50 µm diameter) in response to endothelium-dependent (ACh and ADP) and -independent (nitroglycerin) agonists before andafter infusion of vehicle or nicotine in the absence or presence ofsuperoxide dismutase. ACh, ADP, and nitroglycerin produced dose-relateddilatation of cheek pouch arterioles before infusion of vehicle ornicotine. Infusion of vehicle, in the absence or presence of superoxidedismutase (150 U/ml), did not alter endothelium-dependent or-independent arteriolar dilatation. In contrast, infusion of nicotine(2 µg · kg¹ · min¹)impaired endothelium-dependent, but not -independent, arteriolar dilatation. In addition, the effect of nicotine onendothelium-dependent vasodilatation was reversed by topicalapplication of superoxide dismutase. We suggest that nicotine impairsendothelium-dependent arteriolar dilatation via an increase in thesynthesis/release of oxygen-derived free radicals.

     

Chronic beta -blockade increases skeletal muscle beta -adrenergicreceptor density and enhances contractile force

Murphy, René J. L., Phillip F. Gardiner, Guy Rousseau,Michel Bouvier, and Louise Béliveau. Chronic -blockadeincreases skeletal muscle -adrenergic-receptor density and enhancescontractile force. J. Appl. Physiol.83(2): 459-465, 1997.The effects of a chronic 14-dayadministration of a selective₂-adrenergic-receptor antagonist (ICI-118551) on skeletal muscle were evaluated in female Sprague-Dawley rats. Chronic ICI-118551 treatment did not modify musclemass, oxidative potential, or protein concentration of the medialgastrocnemius muscle, suggesting that maintenance of these skeletalmuscle characteristics is not dependent on₂-adrenergic-receptor stimulation. However, the drug treatment increased-adrenergic-receptor density of the lateral gastrocnemius (42%) andcaused an increase in specific (g/g) isometric in situ contractileforces of the medial gastrocnemius [twitch, 56%; tetanic (200 Hz), 28%]. The elevated contractile forces observed after achronic treatment with ICI-118551 were completely abolished when the₂-adrenergic antagonist wasalso administered acutely before measurement of contractile forces,suggesting that this response is₂-adrenergic-receptor dependent. Possible mechanisms for the increased forces were studied. Caffeine administration potentiated twitch forces but had little effecton tetanic force in control animals. Administration of dibutyryladenosine 3,5-cyclic monophosphate in control animals also resulted in small increases of twitch force but did not modify tetanic forces. We conclude that increases in -adrenergic-receptor density and the stimulation of the receptors by endogenouscatecholamines appear to be responsible for increased contractileforces but that the mechanism remains to be demonstrated.

     

Windchill and the risk of tissue freezing

Danielsson, Ulf. Windchill and the risk of tissuefreezing. J. Appl. Physiol. 81(6): 2666-2673, 1996.Low air temperatures and high wind speeds are associated with anincreased risk of freezing of the exposed skin. P. A. Siple and C. F. Passel (Proc. Am. Phil. Soc. 89: 177-199, 1945) derivedtheir windchill index from cooling experiments on a water-filledcylinder to quantify the risk of frostbite. Their results arereexamined here. It is found that their windchill index does notcorrectly describe the convective heat transfer coefficient(h_c) for such a cylinder; theeffect of the airspeed (v) isunderestimated. New risk curves have been developed, based on theconvection equations valid for cylinders in a cross flow,h_c  v^0.62, and tissuefreezing data from the literature. An analysis of the data reveals alinear relationship between the frequency of finger frostbite and thesurface temperature. This relation closely follows a normaldistribution of finger-freezing temperatures, with an SD of 1°C. Asthe skin surface temperature falls from 4.8 to 7.8°C,the risk of frostbite increases from 5 to 95%. These data indicatethat the risk of finger frostbite is minor above an air temperature of10°C, irrespective of v,but below 25°C there is a pronounced risk, even at lowv.

     

Wave-speed-determined flow limitation at peak flow in normal and asthmatic subjects

Pedersen, O. F., H. J. L. Brackel, J. M. Bogaard, and K. F. Kerrebijn. Wave-speed-determined flow limitation at peak flow innormal and asthmatic subjects. J. Appl.Physiol. 83(5): 1721-1732, 1997.The purpose ofthis study was to examine whether peak expiratory flow is determined bythe wave-speed flow-limiting mechanism. We examined 17 healthy subjectsand 11 subjects with stable asthma, the latter treated with inhaledbronchodilators and corticosteroids. We used an esophageal balloon anda Pitot-static probe positioned at five locations between the rightlower lobe and midtrachea to obtain dynamic area-transmural pressure(A-Ptm) curves as described (O. F. Pedersen, B. Thiessen, and S. Lyager. J. Appl.Physiol. 52: 357-369, 1982). From these curves weobtained cross-sectional area (A)and airway compliance (Caw = dA/dPtm) at PEF, calculated flow at wave speed {ws = A[A/(Caw*)^0.5],where  is density} and speed index is (SI = /ws). In 13 of 15 healthy andin 4 of 10 asthmatic subjects, who could produce satisfactory curves,SI at PEF was >0.9 at one or more measured positions. Alveolarpressure continued to increase after PEF was achieved, suggesting flowlimitation somewhere in the airway in all of these subjects. Weconclude that wave speed is reached in central airways at PEF in mostsubjects, but it cannot be excluded that wave speed is also reached inmore peripheral airways.

     

Human ventilatory response to 8h of euoxic hypercapnia

Tansley, John G., Michala E. F. Pedersen, Christine Clar,and Peter A. Robbins. Human ventilatory response to 8 h of euoxic hypercapnia. J. Appl.Physiol. 84(2): 431-434, 1998.Ventilation (E) risesthroughout 40 min of constant elevated end-tidalPCO₂ without reaching steady state(S. Khamnei and P. A. Robbins. Respir. Physiol. 81: 117-134, 1990). The present studyinvestigates 8 h of euoxic hypercapnia to determine whetherE reachessteady state within this time. Two protocols were employed:1) 8-h euoxic hypercapnia (end-tidalPCO₂ = 6.5 Torr above prestudy value,end-tidal PO₂ = 100 Torr) followed by 8-h poikilocapnic euoxia; and2) control, where the inspired gaswas air. Ewas measured over a 5-min period before the experiment and then hourly over a 16-h period. In the hypercapnia protocol,E had notreached a steady state by the first hour(P < 0.001, analysis of variance), but there were no further significant differences inEover hours 2-8 (analysis ofvariance). Efell promptly on return to eucapnic conditions. We conclude that,whereas there is a component of theE responseto hypercapnia that is slow, there is no progressive rise inE throughoutthe 8-h period.

     

Selective endothelial dysfunction in conscious dogs after cardiopulmonary bypass

Zanaboni, Paul, Paul A. Murray, Brett A. Simon, Kenton Zehr,Kirk Fleischer, Elaine Tseng, and Daniel P. Nyhan. Selective endothelial dysfunction in conscious dogs after cardiopulmonary bypass.J. Appl. Physiol. 82(6):1776-1784, 1997.It has previously been demonstrated thatcardiopulmonary bypass (CPB) causes prolonged pulmonary vascularhyperreactivity (D. P. Nyhan, J. M. Redmond, A. M. Gillinov, K. Nishiwaki, and P. A. Murray. J. Appl.Physiol. 77: 1584-1590, 1994). Thisstudy investigated the effects of CPB on endothelium-dependent(acetylcholine and bradykinin) and endothelium-independent (sodiumnitroprusside) pulmonary vasodilation in conscious dogs. Continuousleft pulmonary vascular pressure-flow (LP-) plots were generated in conscious dogs before CPB and again in the same animals 3-4 days post-CPB. The dose of U-46619 used to acutely preconstrict the pulmonary circulation to similar levels pre- andpost-CPB was decreased (0.13 ± 0.01 vs. 0.10 ± 0.01 mg · kg¹ · min¹,P < 0.01) after CPB. Acetylcholine,bradykinin, and sodium nitroprusside all caused dose-dependentpulmonary vasodilation pre-CPB. The pulmonary vasodilator response toacetylcholine was completely abolished post-CPB. For example, at leftpulmonary blood flow of 80 ml · kg¹ · min¹acetylcholine (10 µg · kg¹ · min¹)resulted in 72 ± 15% reversal (P < 0.01) of U-46619 preconstriction pre-CPB but caused no changepost-CPB. However, the responses to bradykinin and sodium nitroprussidewere unchanged post-CPB. The impaired pulmonary vasodilator response toacetylcholine, but not to bradykinin, suggests a selective endothelialdefect post-CPB. The normal response to sodium nitroprusside indicates that cGMP-mediated vasodilation is unchanged post-CPB.

     

Bronchial vasodilatory response to ionic and nonionic contrast media

Baile, Elisabeth M., Lu Wang, Lorraine Verburgt, and PeterD. Paré. Bronchial vasodilatory response to ionic andnonionic contrast media. J. Appl.Physiol. 82(3): 841-845, 1997.It has recentlybeen shown that bronchial arterial injection of conventional contrastmedium causes a significant increase in bronchial blood flow(br) and that this response is partially attenuatedafter infusion ofN-nitro-L-arginine(L-NNA). However, the precisemechanism for this increase in br is unknown. Inthis study we examined the effect of bronchial arterial injection ofconventional ionic as well as nonionic contrast media. We measuredbr in nine anesthetized, ventilated, open-chestsheep. br was recorded before (baseline) and at thepeak response to injection of 0.5 ml of either 0.9% saline (control;isosmolar with plasma), Omnipaque 300 (iohexol; nonionic), Conray 66 (sodium iothalamate; ionic), or 50% dextrose (viscouscontrol).