Determinants of diastolic myocardial tissue Doppler velocities: influences of relaxation and preload

Myocardial tissueDoppler echocardiography (TDE) has been proposed as a tool for theassessment of diastolic function. Controversy exists regarding whetherTDE measurements are influenced by preload. In this study, leftventricular volume and high-fidelity pressures were obtained ineight closed-chest dogs during intermittent caval occlusion. The timeconstant of isovolumic ventricular relaxation () was alteredwith varying doses of dobutamine and esmolol. Peak early diastolicmyocardial (E_m) and transmitral (E)velocities were measured before and after preload reduction. Therelative effects of changes in preload and relaxation were determinedfor E_m and compared with their effects onE. The following results were observed: caval occlusionsignificantly decreased E (E = 16.4 ± 3.3 cm/s, 36.6 ± 13.7%, P < 0.01) andE_m (E_m = 1.3 ± 0.4 cm/s, 32.5 ± 26.1%, P < 0.01) underbaseline conditions. However, preload reduction was similar forE under all lusitropic conditions (P = notsignificant), but these effects on E_m decreasedwith worsening relaxation. At  < 50 ms, changes inE_m with preload reduction were significantlygreater (E_m = 2.8 ± 0.6 cm/s) than at  = 50-65 ms (E_m = 1.2 ± 0.2 cm/s) and at  >65 ms(E_m = 0.5 ± 0.1 cm/s,P < 0.05). We concluded that TDEE_m is preload dependent. However, this effectdecreases with worsening relaxation.

     

Intratracheal instillation of a novel NO/nucleophile adduct selectively reduces pulmonary hypertension

Brilli, Richard J., Brian Krafte-Jacobs, Daniel J. Smith,Dominick Roselle, Daniel Passerini, Amos Vromen, Lori Moore, CsabaSzabó, and Andrew L. Salzman. Intratracheal instillation ofa novel NO/nucleophile adduct selectively reduces pulmonary hypertension. J. Appl. Physiol. 83(6):1968-1975, 1997.We examined the pulmonary and systemichemodynamic effects of administering soluble nitric oxide (NO) donorcompounds (NO/nucleophile adducts, i.e., NONOates) directly into thetrachea of animals with experimentally induced pulmonary hypertension.Steady-state pulmonary hypertension was created by using thethromboxane agonist U-46619. Yorkshire pigs were randomly assigned toone of four groups: group 1,intratracheal saline (control; n = 8);group 2, intratracheal sodiumnitroprusside (n = 6);group 3, intratracheal ethylputreanineNONOate (n = 6); andgroup 4, intratracheal2-(dimethylamino)-ethylputreanine NONOate (DMAEP/NO;n = 6). Pulmonary and systemichemodynamics were monitored after drug instillation.Group 4 had significant reductions in pulmonary vascular resistance index (PVRI) at all time points comparedwith steady state and compared with group1 (P < 0.05), whereas systemic vascular resistance index did not change. The meanchange in mean pulmonary arterial pressure in group4 was 33.1 ± 1.2% compared with +6.4 ± 1.3% in group 1 (P < 0.001), and the mean change inmean arterial pressure was 9.3 ± 0.7% compared with acontrol value of 0.9 ± 0.5%(P < 0.05). Groups 2 and 3 hadsignificant decreases in both PVRI and systemic vascular resistanceindex compared with steady state and with group1. In conclusion, intratracheal instillation of apolar-charged tertiary amine NONOate DMAEP/NO results in the selectivereduction of PVRI. Intermittent intratracheal instillation of selectiveNONOates may be an alternative to continuously inhaled NO in thetreatment of pulmonary hypertension.

     

Scaling of submaximal oxygen uptake with body mass and combined mass during uphill treadmill bicycling

This study examined the scaling relationships ofnet O₂ uptake [O_2(net) = O₂  restingO₂] to body mass(M_B) andcombined mass (M_C = M_B + bicycle)during uphill treadmill bicycling. It was hypothesized thatO_2(net)(l/min) would scale proportionally withM_C [i.e.,O_2(net)  M^1.0_C] and less than proportionally withM_B [i.e.,O_2(net)  M_B].Twenty-five competitive cyclists [73.9 ± 8.8 and 85.0 ± 9.0 (SD) kg forM_B andM_C,respectively] rode their bicycles on a treadmill at 3.46 m/s andgrades of 1.7, 3.5, 5.2, and 7.0% whileO₂ was measured. Multiplelog-linear regression procedures were applied to the pooledO_2(net)data to determine the exponents forM_C andM_B afterstatistically controlling for differences in treadmill grade anddynamic friction. The regression models were highly significant (R² = 0.95, P < 0.001). Exponents forM_C (0.99, 95%confidence interval = 0.80-1.18) andM_B (0.89, 95%confidence interval = 0.72-1.07) did not differ significantly fromeach other or 1.0. It was concluded that the 0.99 M_C exponent wasdue to gravitational resistance, whereas theM_B exponent was<1.0 because the bicycles were relatively lighter for heaviercyclists.

     

Pharmacological modulation of ion transport across wild-type and DeltaF508 CFTR-expressing human bronchial epithelia

Forskolin,UTP, 1-ethyl-2-benzimidazolinone (1-EBIO), NS004, 8-methoxypsoralen(Methoxsalen; 8-MOP), and genistein were evaluated for theireffects on ion transport across primary cultures of human bronchialepithelium (HBE) expressing wild-type (wt HBE) and F508(F-HBE) cystic fibrosis transmembrane conductance regulator. In wtHBE, the baseline short-circuit current (I_sc)averaged 27.0 ± 0.6 µA/cm² (n = 350). Amiloride reduced this I_sc by 13.5 ± 0.5 µA/cm² (n = 317). In F-HBE,baseline I_sc was 33.8 ± 1.2 µA/cm² (n = 200), and amiloride reducedthis by 29.6 ± 1.5 µA/cm² (n = 116), demonstrating the characteristic hyperabsorption of Na⁺ associated with cystic fibrosis (CF). In wt HBE,subsequent to amiloride, forskolin induced a sustained,bumetanide-sensitive I_sc(I_sc = 8.4 ± 0.8 µA/cm²; n = 119). Addition ofacetazolamide, 5-(N-ethyl-N-isopropyl)-amiloride, and serosal 4,4'-dinitrostilben-2,2'-disulfonic acid further reduced I_sc, suggesting forskolin also stimulatesHCO₃ secretion. This was confirmed by ionsubstitution studies. The forskolin-induced I_scwas inhibited by 293B, Ba²⁺, clofilium, and quinine,whereas charybdotoxin was without effect. In F-HBE the forskolinI_sc response was reduced to 1.2 ± 0.3 µA/cm² (n = 30). In wt HBE, mucosal UTPinduced a transient increase in I_sc ( I_sc = 15.5 ± 1.1 µA/cm²;n = 44) followed by a sustained plateau, whereas inF-HBE the increase in I_sc was reduced to5.8 ± 0.7 µA/cm² (n = 13). In wtHBE, 1-EBIO, NS004, 8-MOP, and genistein increased I_sc by 11.6 ± 0.9 (n = 20), 10.8 ± 1.7 (n = 18), 10.0 ± 1.6 (n = 5), and 7.9 ± 0.8 µA/cm²(n = 17), respectively. In F-HBE, 1-EBIO, NS004, and8-MOP failed to stimulate Cl secretion. However, additionof NS004 subsequent to forskolin induced a sustained Clsecretory response (2.1 ± 0.3 µA/cm²,n = 21). In F-HBE, genistein alone stimulatedCl secretion (2.5 ± 0.5 µA/cm²,n = 11). After incubation of F-HBE at 26°C for24 h, the responses to 1-EBIO, NS004, and genistein were allpotentiated. 1-EBIO and genistein increased Na⁺ absorptionacross F-HBE, whereas NS004 and 8-MOP had no effect. Finally,Ca²⁺-, but not cAMP-mediated agonists, stimulatedK⁺ secretion across both wt HBE and F-HBE in aglibenclamide-dependent fashion. Our results demonstrate thatpharmacological agents directed at both basolateral K⁺ andapical Cl conductances directly modulate Clsecretion across HBE, indicating they may be useful in ameliorating theion transport defect associated with CF.

     

A model for phosphocreatine resynthesis

Nevill, Alan M., David A. Jones, David McIntyre, Gregory C. Bogdanis, and Mary E. Nevill. A model forphosphocreatine resynthesis. J. Appl.Physiol. 82(1): 329-335, 1997.A model for phosphocreatine (PCr) resynthesis is proposed based on a simple electric circuit, where the PCr store in muscle is likened to thestored charge on the capacitor. The solution to the second-order differential equation that describes the potential around the circuitsuggests the model for PCr resynthesis is given byPCr(t) = R  [d₁ ^· exp(k₁ ^· t) ± d₂ ^· exp(k₂ ^· t)],where R is PCr concentration at rest,d₁,d₂, k₁, andk₂ are constants, andt is time. By using nonlinear leastsquares regression, this double-exponential model was shown to fit thePCr recovery data taken from two studies involving maximal exerciseaccurately. In study 1, when themuscle was electrically stimulated while occluded, PCr concentrations rose during the recovery phase to a level above that observed at rest.In study 2, after intensive dynamicexercise, PCr recovered monotonically to resting concentrations. Thesecond exponential term in the double-exponential model was found tomake a significant additional contribution to the quality of fit inboth study 1 (P < 0.05) andstudy 2 (P < 0.01).

     

Isolated mouse pancreatic beta-cells show cell-specific temporal response pattern

The length of the silent lag time beforeelevation of the cytosolic free Ca²⁺ concentration([Ca²⁺]_i) differs between individualpancreatic -cells. One important question is whether thesedifferences reflect a random phenomenon or whether the length of lagtime is inherent in the individual -cell. We compared the lag times,initial dips, and initial peak heights for[Ca²⁺]_i from two consecutive glucosestimulations (with either 10 or 20 mM glucose) in individualob/ob mouse -cells with the fura 2 technique in amicrofluorimetric system. There was a strong correlation between thelengths of the lag times in each -cell (10 mM glucose:r = 0.94, P < 0.001; 20 mM glucose:r = 0.96, P < 0.001) as well as between theinitial dips in [Ca²⁺]_i (10 mM glucose:r = 0.93, P < 0.001; 20 mM glucose:r = 0.79, P < 0.001) and between theinitial peak heights (10 mM glucose: r = 0.51, P < 0.01; 20 mM glucose: r = 0.77, P < 0.001). These data provide evidence that theresponse pattern, including both the length of the lag time and thedynamics of the subsequent [Ca²⁺]_i, isspecific for the individual -cell.

     

Cardiovascular adaptations to 10days of cycle exercise

Mier, Constance M., Michael J. Turner, Ali A. Ehsani, andRobert J. Spina. Cardiovascular adaptations to 10 days of cycleexercise. J. Appl. Physiol. 83(6):1900-1906, 1997.We hypothesized that 10 days of training wouldenhance cardiac output (CO) and stroke volume (SV) during peak exerciseand increase the inotropic response to -adrenergic stimulation. Tensubjects [age 26 ± 2 (SE) yr] trained on a cycleergometer for 10 days. At peak exercise, training increasedO₂ uptake, CO, and SV(P < 0.001). Left ventricular (LV)size and function at rest were assessed with two-dimensional echocardiography before (baseline) and after atropine injection (1.0 mg) and during four graded doses of dobutamine. LV end-diastolic diameter increased with training (P < 0.02), whereas LV wall thickness was unchanged. LV contractileperformance was assessed by relating fractional shortening (FS) to theestimated end-systolic wall stress(_ES). Training increased theslope of the FS-_ES relationship (P < 0.05), indicating enhancedsystolic function. The increase in slope correlated with increases inCO (r = 0.71,P < 0.05) and SV(r = 0.70,P < 0.05). The increase in bloodvolume also correlated with increases in CO(r = 0.80, P < 0.01) and SV (r = 0.85, P < 0.004). These datashow that 10 days of training enhance the inotropic response to-adrenergic stimulation, associated with increases in CO and SVduring peak exercise.

     

Effect of ventilation on vascular permeability and cyclic nucleotide concentrations in ischemic sheep lungs

Ventilation during ischemia attenuatesischemia-reperfusion lung injury, but the mechanism is unknown.Increasing tissue cyclic nucleotide levels has been shown to attenuatelung ischemia-reperfusion injury. We hypothesized thatventilation prevented increased pulmonary vascular permeability duringischemia by increasing lung cyclic nucleotide concentrations.To test this hypothesis, we measured vascular permeability and cGMP andcAMP concentrations in ischemic (75 min) sheep lungs that wereventilated (12 ml/kg tidal volume) or statically inflated with the samepositive end-expiratory pressure (5 Torr). The reflection coefficientfor albumin (_alb) was 0.54 ± 0.07 and 0.74 ± 0.02 (SE) in nonventilated and ventilatedlungs, respectively (n = 5, P < 0.05). Filtration coefficientsand capillary blood gas tensions were not different. The effect ofventilation was not mediated by cyclic compression of alveolarcapillaries, because negative-pressure ventilation(n = 4) also was protective (_alb = 0.78 ± 0.09). Thefinal cGMP concentration was less in nonventilated than in ventilatedlungs (0.02 ± 0.02 and 0.49 ± 0.18 nmol/g blood-free dry wt,respectively, n = 5, P < 0.05). cAMP concentrations werenot different between groups or over time. Sodium nitroprussideincreased cGMP (1.97 ± 0.35 nmol/g blood-free dry wt) and_alb (0.81 ± 0.09) innonventilated lungs (n = 5, P < 0.05). Isoproterenol increasedcAMP in nonventilated lungs (n = 4, P < 0.05) but had no effect on_alb. The nitric oxide synthaseinhibitor N^G-nitro-L-arginine methylester had no effect on lung cGMP (n = 9) or _alb(n = 16) in ventilated lungs but didincrease pulmonary vascular resistance threefold(P < 0.05) in perfused sheep lungs (n = 3). These results suggest thatventilation during ischemia prevented an increase in pulmonaryvascular protein permeability, possibly through maintenance of lungcGMP by a nitric oxide-independent mechanism.

     

Calcium dependence of C-type natriuretic peptide-formed fast K+ channel

The lipid bilayertechnique was used to characterize theCa²⁺ dependence of a fastK⁺ channel formed by a synthetic17-amino acid segment [OaCNP-39-(1-17)] ofa 39-amino acid C-type natriuretic peptide (OaCNP-39) found in platypus (Ornithorhynchusanatinus) venom (OaV). TheOaCNP-39-(1-17)-formed K⁺ channel was reversiblydependent on1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-buffered cis (cytoplasmic)Ca²⁺ concentration([Ca²⁺]_cis).The channel was fully active when[Ca²⁺]_ciswas >10⁴ M andtrans (luminal)Ca²⁺ concentration was 1.0 mM, butnot at low[Ca²⁺]_cis.The open probability of single channels increased from zero at1 × 10⁶ McisCa²⁺ to 0.73 ± 0.17 (n = 22) at10³ McisCa²⁺. Channel openings to themaximum conductance of 38 pS were rapidly and reversibly activated when[Ca²⁺]_cis,but not transCa²⁺ concentration(n = 5), was increased to >5 × 10⁴ M(n = 14). Channel openings to thesubmaximal conductance of 10.5 pS were dominant at5 × 10⁴ MCa²⁺.K⁺ channels did not open whencisMg²⁺ orSr²⁺ concentrations were increasedfrom zero to 10³ M or when[Ca²⁺]_ciswas maintained at 10⁶ M(n = 3 and 2). The Hill coefficientand the inhibition constant were 1 and 0.8 × 10⁴ McisCa²⁺, respectively. Thisdependence of the channel on high[Ca²⁺]_cissuggests that it may become active under1) physiological conditions whereCa²⁺ levels are high, e.g., duringcardiac and skeletal muscle contractions, and2) pathological conditions that leadto a Ca²⁺ overload, e.g., ischemicheart and muscle fatigue. The channel could modify a cascade ofphysiological functions that are dependent on theCa²⁺-activatedK⁺ channels, e.g., vasodilationand salt secretion.

     

Letters to the Editor

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

Venegas, José G., R. Scott Harris, and BrettA. Simon. A comprehensive equation for the pulmonarypressure-volume curve. J. Appl. Physiol. 84(1): 389-395, 1998.Quantification of pulmonary pressure-volume (P-V) curves isoften limited to calculation of specific compliance at a given pressureor the recoil pressure (P) at a given volume (V). These parameters can be substantially different depending on the arbitrary pressure orvolume used in the comparison and may lead to erroneous conclusions. Weevaluated a sigmoidal equation of the form, V = a + b[1 + e^(Pc)/d]¹, for its ability to characterize lung and respiratory system P-V curves obtained under a variety of conditions including normal andhypocapnic pneumoconstricted dog lungs (n = 9), oleicacid-induced acute respiratory distress syndrome (n = 2), andmechanically ventilated patients with acute respiratory distresssyndrome (n = 10). In this equation, a corresponds tothe V of a lower asymptote, b to the V difference between upperand lower asymptotes, c to the P at the true inflection pointof the curve, and d to a width parameter proportional to the Prange within which most of the V change occurs. The equation fittedequally well inflation and deflation limbs of P-V curves with a meangoodness-of-fit coefficient (R²) of 0.997 ± 0.02 (SD). When the data from all analyzed P-V curves were normalized by thebest-fit parameters and plotted as (V  a)/b vs.(P  c)/d, they collapsed into a single and tightrelationship (R² = 0.997). These resultsdemonstrate that this sigmoidal equation can fit with excellentprecision inflation and deflation P-V curves of normal lungs and oflungs with alveolar derecruitment and/or a region of gastrapping while yielding robust and physiologically useful parameters.

     

Comparisons of two-, three-, and four-compartment models of body composition analysis in men and women

This study compared the traditionaltwo-compartment (fat mass or FM; fat free mass or FFM)hydrodensitometric method of body composition measurement, which isbased on body density, with three (FM, total body water or TBW, fatfree dry mass)- and four (FM, TBW, bone mineral mass or BMM,residual)-compartment models in highly trained men(n = 12), sedentary men(n = 12), highly trained women(n = 12), and sedentary women(n = 12). The means andvariances for the relative body fat (%BF) differences between the two-and three-compartment models [2.2 ± 1.6 (SD) % BF;n = 48] were significantlygreater (P  0.02) than those between the three- and four-compartment models (0.2 ± 0.3% BF;n = 48) for all four groups. Thethree-compartment model is more valid than the two-compartmenthydrodensitometric model because it controls for biological variabilityin TBW, but additional control for interindividual variability in BMMvia the four-compartment model achieves little extra accuracy. Thecombined group (n = 48) exhibited greater (P < 0.001) FFM densities(1.1075 ± 0.0049 g/cm³) thanthe hydrodensitometric assumption of 1.1000 g/cm³, which is based on analysesof three male cadavers aged 25, 35, and 46 yr. This was primarilybecause their FFM hydration (72.4 ± 1.1%;n = 48) was lower(P  0.001) than thehydrodensitometric assumption of 73.72%.

     

Immunocompetence of macrophages in rats exposed to Candida albicans infection and stress

The integration of innate andadaptive immune responses is required for efficient control ofCandida albicans. The present work aimed to assess, at thelocal site of the infection, the immunocompetence of macrophages inrats infected intraperitoneally with C. albicans and exposedsimultaneously to stress during 3 days (CaS group). We studied the1) ability to remove and kill C. albicans,2) tumor necrosis factor- (TNF-) release,3) balance of the inducible enzymes NO synthase (iNOS) andarginase, and 4) expression of interleukin (IL)-1 andIL-1 receptor antagonist (ra) mRNA. Compared with only infected animals(Ca group), the number of colony-forming units was significantly higherin CaS rats (P < 0.01), and the macrophagecandidicidal activity was ~2.5-fold lower (P < 0.01). Release of TNF- was diminished in both unstimulated andheat-killed C. albicans restimulated macrophages of the CaSgroup (Ca vs. CaS, P < 0.03 and P < 0.05, respectively). In Ca- and CaS-group rats, the rates for both thearginase activity and the NO synthesis were significantly enhanced.However, the stress exposure downregulated the activity of both enzymes(CaS vs. Ca, P < 0.05). After in vitro restimulation,the IL-1ra/IL-1 ratio was significantly diminished in CaS-group rats(P < 0.05). Our results indicate that a correlationexists between early impairment of macrophage function and stress exposure.

     

Mechanical and metabolic determination of VO2 and fatigue during repetitive isometric contractions in situ

Repetitiveisometric tetanic contractions (1/s) of the caninegastrocnemius-plantaris muscle were studied either at optimal length(L_o) or shortlength (L_s;~0.9 · L_o),to determine the effects of initial length on mechanical and metabolicperformance in situ. Respective averages of mechanical and metabolicvariables were(L_o vs.L_s, allP < 0.05) passive tension (preload) = 55 vs. 6 g/g, maximal active tetanic tension(P_o) = 544 vs. 174 (0.38 · P_o)g/g, maximal blood flow () = 2.0 vs. 1.4 ml · min¹ · g¹,and maximal oxygen uptake(O₂) = 12 vs. 9 µmol · min¹ · g¹.Tension at L_odecreased to0.64 · P_o over20 min of repetitive contractions, demonstrating fatigue; there were nosignificant changes in tension atL_s. In separatemuscles contracting atL_o, was set to that measured atL_s (1.1 ml · min¹ · g¹),resulting in decreased O₂(7 µmol · min¹ · g¹),and rapid fatigue, to0.44 · P_o. Thesedata demonstrate that 1)muscles at L_ohave higher andO₂ values than those at L_s;2) fatigue occurs atL_o with highO₂, adjusting metabolic demand (tension output) to match supply; and3) the lack of fatigue atL_s with lowertension, , andO₂ suggestsadequate matching of metabolic demand, set low by shortmuscle length, with supply optimized by low preload. Thesedifferences in tension andO₂ betweenL_o andL_s groupsindicate that muscles contracting isometrically at initial lengthsshorter than L_oare working under submaximal conditions.

     

Role of inhibition of nitric oxide production in monocrotaline-induced pulmonary hypertension

Mathew, Rajamma, Elizabeth S. Gloster, T. Sundararajan, Carl I. Thompson, Guillermo A. Zeballos, andMichael H. Gewitz. Role of inhibition of nitric oxide productionin monocrotaline-induced pulmonary hypertension. J. Appl. Physiol. 82(5): 1493-1498, 1997.Monocrotaline (MCT)-induced pulmonary hypertension (PH) isassociated with impaired endothelium-dependent nitric oxide(NO)-mediated relaxation. To examine the role of NO in PH,Sprague-Dawley rats were given a single subcutaneous injection ofnormal saline [control (C)], 80 mg/kg MCT, or the same doseof MCT and a continuous subcutaneous infusion of 2 mg · kg¹ · day¹of molsidomine, a NO prodrug (MCT+MD). Two weeks later, plasma NO₃ levels, pulmonary arterialpressure (Ppa), ratio of right-to-left ventricular weights (RV/LV) toassess right ventricular hypertrophy, and pulmonary histology wereevaluated. The plasma NO₃ level inthe MCT group was reduced to 9.2 ± 1.5 µM(n = 12) vs. C level of 17.7 ± 1.8 µM (n = 8; P < 0.02). In the MCT+MD group,plasma NO₃ level was 12.3 ± 2.0 µM (n = 8). Ppa and RV/LV in theMCT group were increased compared with C [Ppa, 34 ± 3.4 mmHg(n = 6) vs. 19 ± 0.8 mmHg(n = 8) and 0.41 ± 0.01 (n = 9) vs. 0.25 ± 0.008 (n = 8), respectively;P < 0.001]. In the MCT+MDgroup, Ppa and RV/LV were not different when compared with C [19 ± 0.5 mmHg (n = 5) and 0.27 ± 0.01 (n = 9), respectively;P < 0.001 vs. MCT]. Medial wall thickness of lung vessels in the MCT group was increased comparedwith C [31 ± 1.5% (n = 9)vs. 13 ± 0.66% (n = 9);P < 0.001], and MDpartially prevented MCT-induced pulmonary vascular remodeling [22 ± 1.2% (n = 11);P < 0.001 vs. MCT and C].These results indicate that a defect in the availability of bioactive NO may play an important role in the pathogenesis of MCT-induced PH.

     

Age and gender dependency of baroreflex sensitivity in healthy subjects

Laitinen, Tomi, Juha Hartikainen, Esko Vanninen, LeoNiskanen, Ghislaine Geelen, and Esko Länsimies. Age andgender dependency of baroreflex sensitivity in healthy subjects.J. Appl. Physiol. 84(2): 576-583, 1998.We evaluated the correlates of baroreflex sensitivity (BRS) inhealthy subjects. The study consisted of 117 healthy, normal-weight,nonsmoking male and female subjects aged 23-77 yr. Baroreflexcontrol of heart rate was measured by using the phenylephrinebolus-injection technique. Frequency- and time-domain analysis of heartrate variability and an exercise test were performed. Plasmanorepinephrine, epinephrine, insulin, and arginine vasopressinconcentrations and plasma renin activity were measured. In theunivariate analysis, BRS correlated with age(r = 0.65,P < 0.001), diastolic blood pressure(r = 0.47, P < 0.001), exercise capacity(r = 0.60, P < 0.001), and the high-frequency component of heart rate variability (r = 0.64, P < 0.001). There was also asignificant correlation between BRS and plasma norepinephrine concentration (r = 0.22,P < 0.05) and plasma renin activity (r = 0.32, P < 0.001). According to themultivariate analysis, age and gender were the most importantphysiological correlates of BRS. They accounted for 52% ofinterindividual BRS variation. In addition, diastolic blood pressureand high-frequency component of heart rate variability were significantindependent correlates of BRS. BRS was significantly higher in men thanin women (15.0 ± 1.2 vs. 10.2 ± 1.1 ms/mmHg, respectively;P < 0.01). Twenty-four percent ofwomen >40 yr old and 18% of men >60 yr old had markedly depressedBRS (<3 ms/mmHg). We conclude that physiological factors, particularly age and gender, have significant impact on BRS in healthysubjects. In addition, we demonstrate that BRS values that have beenproposed to be useful in identifying postinfarction patients at highrisk of sudden death are frequently found in healthy subjects.

     

Effect of leucine metabolite beta -hydroxy-beta -methylbutyrate on muscle metabolism during resistance-exercise training

Nissen, S., R. Sharp, M. Ray, J. A. Rathmacher, D. Rice, J. C. Fuller, Jr., A. S. Connelly, and N. Abumrad. Effect of leucinemetabolite -hydroxy--methylbutyrate on muscle metabolism duringresistance-exercise training. J. Appl.Physiol. 81(5): 2095-2104, 1996.The effects ofdietary supplementation with the leucine metabolite-hydroxy--methylbutyrate (HMB) were studied in two experiments.In study 1, subjects(n = 41) were randomized among threelevels of HMB supplementation (0, 1.5 or 3.0 g HMB/day) and two proteinlevels (normal, 117 g/day, or high, 175 g/day) and weight lifted for1.5 h 3 days/wk for 3 wk. In study 2,subjects (n = 28) were fed either 0 or3.0 g HMB/day and weight lifted for 2-3 h 6 days/wk for 7 wk. Instudy 1, HMB significantly decreased the exercise-induced rise in muscle proteolysis as measured by urine3-methylhistidine during the first 2 wk of exercise (linear decrease,P < 0.04). Plasma creatinephosphokinase was also decreased with HMB supplementation(week 3, linear decrease,P < 0.05). Weight lifted wasincreased by HMB supplementation when compared with the unsupplementedsubjects during each week of the study (linear increase,P < 0.02). In study2, fat-free mass was significantly increased inHMB-supplemented subjects compared with the unsupplemented group at 2 and 4-6 wk of the study (P < 0.05). In conclusion, supplementation with either 1.5 or 3 g HMB/daycan partly prevent exercise-induced proteolysis and/or muscledamage and result in larger gains in muscle function associated withresistance training.

     

Pseudomonas aeruginosa induces changes in fluid transport across airway surface epithelia

Fluid transport across cultures of bovine tracheal epitheliumwas measured with a capacitance probe technique. Baseline fluid absorption (J_v)across bovine cells of 3.2 µl · cm² · h¹was inhibited by ~78% after 1 h of exposure to suspensions of Pseudomonas aeruginosa, with aconcomitant decrease in transepithelial potential (TEP) and increase intransepithelial resistance(R_t). Effectsof P. aeruginosa were blocked byamiloride, which decreased J_v by 112% frombaseline of 2.35 ± 1.25 µl · cm² · h¹,increased R_t by101% from baseline of 610 ± 257  · cm², anddecreased TEP by 91% from baseline of 55 ± 18.5 mV.Microelectrode studies suggested that effects of P. aeruginosa on amiloride-sensitive Na absorption weredue in part to a block of basolateral membrane K channels. In thepresence of Cl transport inhibitors[5-nitro-2-(3-phenylpropylamino)-benzoic acid,H₂-DIDS, and bumetanide],P. aeruginosa induced a fluid secretion of ~2.5 ± 0.4 µl · cm² · h¹and decreased R_twithout changing TEP. However, these changes were abolished when thetransport inhibitors were used in a medium in which Cl was replaced byan impermeant organic anion. Filtrates of P. aeruginosa suspensions had no effect onJ_v, TEP, orR_t. Mutantslacking exotoxin A or rhamnolipids or with defective lipopolysaccharide still inhibited fluid absorption and altered bioelectrical properties. By contrast, mutations in the rpoN gene encodinga  factor of RNA polymerase abolished actions of P. aeruginosa. In vivo, changes in transepithelial saltand water transport induced by P. aeruginosa may alter viscosity and ionic composition ofairway secretions so as to foster further bacterial colonization.

     

Protective effects of intravascular pressure and nitric oxide in ischemic lung injury

Cessation of bloodflow during ischemia will decrease both distending and shearforces exerted on endothelium and may worsen ischemic lung injury bydecreasing production of nitric oxide (NO), which influences vascularbarrier function. We hypothesized that increased intravascular pressure(Piv) during ventilated ischemia might maintain NO productionby increasing endothelial stretch or shear forces, thereby attenuatingischemic lung injury. Injury was assessed by measuring the filtrationcoefficient(K_f) and theosmotic reflection coefficient for albumin(_alb) after 3 h of ventilated(95% O₂-5%CO₂; expiratory pressure 3 mmHg) ischemia. Lungs were flushed with physiological salt solution, and then Piv was adjusted to achieve High Piv (mean 6.7 ± 0.4 mmHg, n = 15) or Low Piv (mean0.83 ± 0.4 mmHg, n = 10).N^G-nitro-L-arginine methyl ester(L-NAME;10⁵ M,n = 10),N^G-nitro-D-argininemethyl ester (D-NAME;10⁵ M,n = 11), orL-NAME(10⁵M)+L-arginine (5 × 10⁴ M,n = 6) was added at the start ofischemia in three additional groups of lungs with High Piv.High Piv attenuated ischemic injury compared with Low Piv(_alb 0.67 ± 0.04 vs. 0.35 ± 0.04, P < 0.05). Theprotective effect of High Piv was abolished byL-NAME(_alb 0.37 ± 0.04, P < 0.05) but not byD-NAME(_alb 0.63 ± 0.07). The effects of L-NAME were overcomeby an excess of L-arginine(_alb 0.56 ± 0.05, P < 0.05).K_f did not differsignificantly among groups. These results suggest that Piv modulatesischemia-induced barrier dysfunction in the lung, and theseeffects may be mediated by NO.

     

Rabbit conjunctival epithelium transports fluid, and P2Y22 receptor agonists stimulate Cl{-} and fluid secretion

Rabbit conjunctival epithelium exhibits UTP-dependentCl secretion into the tears. We investigated whetherfluid secretion also takes place. Short-circuit current(I_sc) was 14.9 ± 1.4 µA/cm²(n = 16). Four P2Y₂ purinergic receptoragonists [UTP and the novel compounds INS365, INS306, and INS440(Inspire Pharmaceuticals)] added apically (10 µM) resulted intemporary (~30 min) I_sc increases (88%, 66%,57%, and 28%, respectively; n = 4 each). Importantly, the conjunctiva transported fluid from serosa to mucosa at a rate of6.5 ± 0.7 µl · h¹ · cm² (range2.1-15.3, n = 20). Fluid transport was stimulatedby mucosal additions of 10 µM: 1) UTP, from 7.4 ± 2.3 to 10.7 ± 3.3 µl · h¹ · cm²,n = 5; and 2) INS365, from 6.3 ± 1.0 to 9.8 ± 2.5 µl · h¹ · cm²,n = 5. Fluid transport was abolished by 1 mMouabain (n = 5) and was drastically inhibited by 300 µM quinidine (from 6.4 ± 1.2 to 3.6 ± 1.0 µl · h¹ · cm²,n = 4). We conclude that this epithelium secretes fluidactively and that P2Y₂ agonists stimulate bothCl and fluid secretions.

     

Mechanical overload and skeletal muscle fiber hyperplasia: a meta-analysis

Kelley, George. Mechanical overload and skeletal musclefiber hyperplasia: a meta-analysis. J. Appl.Physiol. 81(4): 1584-1588, 1996.With use of themeta-analytic approach, the purpose of this study was to examine theeffects of mechanical overload on skeletal muscle fiber number inanimals. A total of 17 studies yielding 37 data points and 360 subjectsmet the initial inclusion criteria:1) "basic" research studiespublished in journals, 2) animals(no humans) as subjects, 3) controlgroup included, 4) some type ofmechanical overload (stretch, exercise, or compensatory hypertrophy)used to induce changes in muscle fiber number, and 5) sufficient data to accuratelycalculate percent changes in muscle fiber number. Across all designsand categories, statistically significant increases were found formuscle fiber number [15.00 ± 19.60% (SD), 95% confidenceinterval = 8.65-21.53], muscle fiber area (31.60 ± 44.30%, 95% confidence interval = 16.83-46.37), and muscle mass(90.50 ± 86.50%, 95% confidence interval = 61.59-119.34). When partitioned according to the fiber-counting technique, larger increases in muscle fiber number were found by using the histological vs. nitric acid digestion method (histological = 20.70%, nitric aciddigestion = 11.10%; P = 0.14).Increases in fiber number partitioned according to species weregreatest among those groups that used an avian vs. mammalian model(avian = 20.95%, mammalian = 7.97%;P = 0.07). Stretch overload yieldedlarger increases in muscle fiber number than did exercise andcompensatory hypertrophy (stretch = 20.95%, exercise = 11.59%,compensatory hypertrophy = 5.44%; P = 0.06). No significant differences between changes in fiber number werefound when data were partitioned according to type of control(intra-animal = 15.20%, between animal = 13.90%; P = 0.82) or fiber arrangement ofmuscle (parallel = 15.80%, pennate = 11.60%;P = 0.61). The results of this studysuggest that in several animal species certain forms of mechanicaloverload increase muscle fiber number.