Diaphragm fatigue during exercise at high altitude: the role of hypoxia and workload.

The effect of high altitude (HA) on exercise-induced diaphragm fatigue in normal subjects was examined. Eight normal subjects completed an incremental exercise test at sea level (SL) and at 3,325 m. Before (baseline), during, and after exercise (recovery), maximal transdiaphragm pressure (Pdi,sniff), breathing pattern, and diaphragmatic effort (PTPdi) were measured. Arterialized blood lactate was measured at baseline and during recovery. At maximal exercise (WRmax) Pdi,sniff fell to 72% and 61% of baseline at SL and HA respectively, recovering to baseline in 60 min at SL, and >60 min at HA. At the 5th min of recovery, circulating lactate was six-fold and seven-fold baseline at SL and HA, respectively. The time course of circulating lactate recovery was as for Pdi,sniff. At WRmax PTPdi was 80.74+/-9.87 kPa.s(-1) at SL and 64.13+/-8.21 kPa.s(-1) at HA. HA WRmax compared to isowork rate, SL data showed a lower Pdi,sniff (8.90+/-0.68 versus 11.24+/-0.59 kPa) and higher minute ventilation (117+/-11 versus 91+/-13 L.min(-1)), PTPdi being equal. To conclude, in normal subjects hypoxia-related effects, and not an increase in diaphragm work, hastens exercise-induced diaphragm fatigue and delays its recovery at high altitude compared to sea level.

Cardiovascular risk factors and relatedness in an Icelandic subpopulation.

Theoretical and empirical studies suggest adverse effects of inbreeding on general vigour. The genetic architecture of physiological and biochemical cardiovascular risk factors is, furthermore, an unsolved issue. Our aim with this study is to investigate potential effects of inbreeding on stated risk factors in a relatively well demarcated Icelandic subpopulation. We used genealogical records to calculate coefficient of inbreeding and estimated the potential association of the coefficient with stated risk factors with known statistical methods. The results suggest absence of inbreeding depression with exception of HDL cholesterol.

Delayed rectifier K+ current of dog bronchial myocytes: effect of pollen sensitization and PKC activation.

The properties of delayed rectifier K+ current [IK(dr)] of canine airway smooth muscle cells isolated from small bronchi and its modulation by protein kinase C (PKC) were studied by whole cell patch clamp. IK(dr) activated positive to -40 mV, with half-maximal activation at -16 +/- 1.2 mV (n = 15) and average current density of 31 +/- 2.6 pA/pF (n = 15) at +30 mV. The capacitive surface area, current density, and voltage dependence of activation of IK(dr) of myocytes of ragweed pollen-sensitized dogs were not different from age-matched control dogs. However, the sensitization reduced the availability of IK(dr) between -40 and -20 mV due to a hyperpolarizing shift in the voltage dependence of steady-state inactivation (-29.9 +/- 1.2 in sensitized versus -26.0 +/- 0.7 mV in control dogs, n = 9 and 11, respectively; P < 0.05). PKC activation with diacylglycerol analog or phorbol ester depressed IK(dr) amplitude, whereas an inactive diacylglycerol analog had no effect. The hyperpolarizing shift in voltage dependence of inactivation and/or modulation of IK(dr) by PKC may be two mechanisms that contribute to the enhanced reactivity of bronchial tissues from ragweed pollen-sensitized dogs.

Effect of lobaric acid on cysteinyl-leukotriene formation and contractile activity of guinea pig taenia coli.

Lobaric acid, a constituent of the lichen Stereocaulon alpinum, was investigated for effects on the smooth muscle taenia coli from guinea pigs. Inhibitory effects of lobaric acid on spontaneous contractile activity and on contractile activity stimulated by ionophore A23187 were studied. In addition, the activity of lobaric acid on ionophore-induced generation of cysteinyl-leukotrienes in taenia coli was determined by enzyme immunoassay. Lobaric acid significantly reduced spontaneous contractile activity of the muscle and inhibited contractions caused by ionophore A23187 with an effective dose of 5.8 microM. Increased contractility caused by leukotriene D4 was not influenced by lobaric acid. Lobaric acid inhibited the formation of cysteinyl-leukotrienes as determined by enzyme immunoassay with an effective dose of 5.5 microM.

Cardiac structure and exercise blood pressure in urban and rural Canadian men of Icelandic descent.

The objective of the study was to determine the relationship between exercise systolic blood pressure (ESBP), during bicycle ergometry, and echocardiographically determined left ventricular structure in rural and urban Canadian men of Icelandic descent. The study was cross-sectional in design. The settings were urban Winnipeg and the rural Interlake District in the province of Manitoba, Canada. Subjects were adult male volunteers from families of wholly Icelandic descent. The subjects were 30 to 60 years of age and had supine blood pressure < 160/95 mm Hg. Anthropomorphic measurements, echocardiography and sphygmomanometry, at rest and during bicycle ergometry, were performed on all subjects. Prevalence of exaggerated ESBP (> or = 200 mm Hg) and left ventricular hypertrophy (LVH) was not significantly different in the two groups. In all but one individual LVH was classified as eccentric hypertrophy. In both urban and rural subjects with exaggerated ESBP, left ventricular mass index (LVMI) was greater than in those subjects without exaggerated ESBP. The LVMI correlated with ESBP at the highest workloads (> or = 150 W). Multivariate analysis of all subjects showed that cardiac index, ESBP, body mass index, and low exercise heart rate were predictive of LVMI. There was no significant difference in prevalence of ESBP or LVH between urban and rural Manitobans of Icelandic descent. However, LVMI levels were lower, and values for ESBP greater, in the rural group compared with the urban group. Within each of the two groups there was a positive association between ESBP and LVMI; hence, the study supports findings of our previous investigation showing evidence of early target organ effects in normotensive men with an exaggerated ESBP.

Increased response to antigen and histamine release in smaller sensitized canine bronchi.

We studied the Schultz-Dale response in vitro in large and small size branches from 3rd to 6th generation bronchi from ragweed-sensitized dogs. The response to electric field stimulation (EFS) increased after antigen from 65.56 +/- 8.11 to 78.6 +/- 9.0 mN/mm2 of smooth muscle (P < 0.01), but no topographical difference was observed. The response to ragweed (% of the response to EFS) was 158.3 +/- 12 and 67.1 +/- 11.7 in strips from small and large branches respectively (P < 0.01), while no difference was observed between generations; when clustering bronchi according to dimension, it was 129.9 +/- 13.4 in small and 71.9 +/- 19.8 in large bronchi (P < 0.01). Histamine released from small and large branches was 2.90 +/- 1.01 and 0.76 +/- 0.20 (ng/mg of tissue) respectively (P < 0.05); no difference was found between generations. In conclusion, in sensitized dogs a greater response to antigen, which involves a higher histamine release, occurs in small compared to large bronchi. We suggest that control of distribution of ventilation occurs mainly at small bronchi level, which becomes the elective tissue to study the Schultz-Dale response. Finally, the classification of bronchi into generations is inadequate to study allergic bronchospasm.

The Schultz-Dale response of sensitized canine bronchial smooth muscle.

We wished to determine why in vitro agonist dose-response curves show reduced leftward shift (1/2-1 log dose units) in sensitized canine airway smooth muscle compared to curves elicited in vivo (2-3 log dose unit). The Schultz-Dale response was studied in sensitized dog tracheal (TSM) and bronchial (BSM) smooth muscle. Sensitized TSM challenged with specific antigen showed greater mechanical response, but only on exposure to 300 micrograms/ml; BSM responded to concentrations of ragweed as low as 0.001 microgram/ml. This result resolved the problem cited at the outset. Control TSM and BSM showed no response. The response in BSM is mediated through histamine release, and to a smaller extent by acetylcholine. With challenge release of histamine and acetylcholine increased significantly in sensitized airway smooth muscle. Integrated contractile responses obtained with high and low concentrations of antigen showed a dose-response relationship. Increased sensitivity of BSM to antigen compared to TSM indicates the former is the preparation of choice for study of allergic bronchoconstriction.

Plasma fatty acids and lipids in two separate, but genetically comparable, Icelandic populations.

Levels of serum lipids and lipoproteins, and the fatty acid composition of plasma phospholipids, were measured in two genetically comparable, but widely separated, populations. The 1975 mortality rates for ischemic heart disease were significantly higher in one of these populations, the Manitoban residents of pure Icelandic descent, than in the other, a rural population from Northeastern Iceland. Two study populations, Icelanders and Icelandic-Canadians, were drawn from these larger populations. The study populations were matched for age and sex and divided into three age groups, 20-39, 40-59, and 60-69 years. In comparison to the Icelandic-Canadians, the Icelanders exhibited significantly higher levels of total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, but lower triglyceride levels. Their plasma phospholipids contained significantly lower levels of saturated fatty acids (SFA), monounsaturated fatty acids, and n-6 polyunsaturated fatty acids (PUFA); but their n-3 PUFA levels were three times as high. It was additionally found that fatty acid composition of plasma phospholipids differed among Icelanders of different ages. SFA levels were significantly lower, and n-6 PUFA levels significantly higher, in the 20-39 year group than in the 60-69 year group, possibly due to different dietary fat consumption patterns between generations. No corresponding age-related difference in the fatty acid composition of plasma phospholipids was found in the Icelandic-Canadian study population. As the Icelandic and Icelandic-Canadian groups are assumed to be genetically similar, the biochemical differences between them are evidently due to environmental, probably dietary, differences. The findings indicate that n-3 PUFA may be cardioprotective in the context of an otherwise atherogenic diet.

The relationship of serum ferritin with sex and exercise in Canadians of Icelandic descent: implications for prevention of coronary artery disease.

OBJECTIVE: To investigate the relationship of serum ferritin with sex and exercise. DESIGN AND SETTING: A cross-sectional design study carried out in Winnipeg, Manitoba. SUBJECTS: Urban Canadians of Icelandic descent, aged 21 to 60 years, took part in this investigation. Subjects were stratified by age, sex and menstrual status. INTERVENTIONS: Venous blood samples from fasting subjects were drawn for serum ferritin, hemoglobin and hematocrit analyses. Various anthropomorphic measurements were taken, and subjects underwent submaximal cycle ergometry testing. A health and lifestyles questionnaire and a four-day prospective food record were administered. MAIN RESULTS: Mean serum ferritin levels obtained were 187.93 and 47.84 micrograms/L for males and females, respectively. Mean serum ferritin levels were 33.06 micrograms/L and 71.14 micrograms/L for premenopausal and postmenopausal females, respectively. The mean weekly consumption of alcohol was 190 mL/week and 80 mL/week for males and females, respectively. The mean dietary intake of iron was 27.3 and 18.9 mg/day for males and females, respectively. Males, but not females, who exercised 45 mins or more per week had significantly lower levels of serum ferritin than their sedentary counterparts. In males, hemoglobin, hematocrit and the consumption of alcohol were positively correlated with serum ferritin, while exercise time was negatively correlated with serum ferritin. A trend towards lower serum ferritin levels at higher workloads was observed in males, but did not reach statistical significance. In females, age and dietary intake of iron were found to be positively correlated with serum ferritin, while history of anemia, menstrual status and workload were negatively correlated with serum ferritin. CONCLUSIONS: These findings suggest that regular aerobic exercise may decrease iron stores in the body. This may be clinically significant since high serum ferritin has been cited as a risk factor for coronary artery disease.

Relevance of classification by size to topographical differences in bronchial smooth muscle response.

To investigate heterogeneity of airway smooth muscle response, we studied strips of large and small branches from third- to sixth-generation bronchi obtained from ragweed antigen-sensitized and control dogs. The response to electrical field stimulation and carbamylcholine chloride was greater in strips from larger branches of the same generation when expressed as "tissue stress" (force per unit cross-sectional area of the whole tissue), whereas no difference emerged with use of the more appropriate "smooth muscle stress" (force per unit cross-sectional area of the muscle tissue). The response to histamine was significantly higher in small branches than in large ones, and histamine sensitivity [mean effective concentration (EC50)] was 7.79 x 10(-6) [geometric standard error of the mean (GSEM) 1.20] and 1.49 x 10(-5) M (GSEM 1.14), respectively (P < 0.01). Strips from control and sensitized animals at each site and strips from different generations did not show any significant difference. When we clustered our preparations according to dimensions, the response to histamine was significantly higher in small bronchi than in large ones and histamine EC50 was 8.95 x 10(-6) (GSEM 1.17) and 1.57 x 10(-5) M (GSEM 1.18), respectively (P < 0.05). We conclude that evaluation of muscle response in different tissues requires appropriate normalization. Furthermore, classification into generations is inadequate to study bronchial responsiveness, inasmuch as major differences originate from airway size.

Exercise blood pressure and echocardiographic abnormalities in genetically comparable populations.

OBJECTIVE: To determine the relationship between the systolic blood pressure response to exercise and the echocardiographic dimensions of the left atrium and ventricle in two geographically separate, but genetically comparable, populations. DESIGN AND SETTING: The study was cross-sectional. The settings were two semirural communities, one in Iceland and one in Manitoba. SUBJECTS: Individuals from families where there had been no intermarriage with non-Icelandic individuals were eligible. Of the 200 eligible men in Manitoba and the 150 men in Iceland, 157 and 121 men, respectively, agreed to participate. In the majority of cases, those who chose not to participate stated that work commitments prevented them from taking part. The subjects were aged 25 to 63 years and had blood pressure less than 160/95 mmHg at rest. INTERVENTIONS: Blood pressure was taken at rest and during standardized bicycle ergometry. Left ventricular and atrial echocardiography was performed on a selected number of subjects. MAIN RESULTS: The Canadians of 'pure' Icelandic descent had a higher prevalence of exaggerated exercise systolic blood pressure (ESBP), left atrial enlargement (LAE) and left ventricular hypertrophy (LVH) than native Icelanders. Given their genetic similarity, it is suggested that the difference between the two groups is due to environmental factors. Within each group, subjects with exaggerated ESBP had a significantly greater left atrial dimension index and left ventricular mass index than subjects without an exaggerated ESBP. The relationship of ESBP with left atrial dimension index and left ventricular mass index was independent of age, body mass index and resting blood pressure. LVH was of the eccentric type and was absent in the majority of cases with LAE; however, LAE was present in nearly all LVH cases. CONCLUSIONS: This study demonstrates that an exaggerated ESBP in individuals with resting blood pressure less than 160/95 mmHg is not an innocuous finding it is associated with demonstrable cardiac abnormalities (LAE and LVH). Furthermore, it is proposed that the presence of LAE, with or without LVH, may add to the value of an exaggerated ESBP in identifying individuals at increased risk of developing sustained resting essential hypertension.

Echocardiographic indices and their relationship to the blood pressure response to ergometric exercise in apparently healthy men.

The relationship between atrial and ventricular echocardiographic abnormalities and ergometric exercise systolic blood pressure was studied in 77 apparently healthy men, of whom the majority (77%) were normotensive (resting blood pressure less than 140/90 mmHg), and the remainder (23%) borderline hypertensive (resting systolic blood pressure 140 to 159 mmHg and/or diastolic blood pressure 90 to 95 mmHg). Four categories of exercise systolic blood pressure were defined (less than 190, 190 to 199, 200 to 209 and greater than or equal to 210 mmHg). Left ventricular mass and left atrial dimension were measured by M-mode echocardiography and divided by body surface area to derive the left ventricular mass index and the left atrial dimension index. The prevalence of left ventricular hypertrophy, defined as a left ventricular mass index greater than or equal to 125 g/m2, was 11%. Two key findings were the much higher prevalence of left atrial enlargement, defined as left atrial dimension index greater than or equal to 2 cm/m2 at 23%, and the fact that left atrial enlargement occurred in the absence of left ventricular hypertrophy in the majority of subjects, whereas occurrence of left ventricular hypertrophy in the absence of left atrial enlargement was rare. This is consistent with the view that left atrial enlargement is a common precursor of left ventricular hypertrophy. Multivariate analysis showed exercise systolic blood pressure and cardiac index to be independent predictors of left atrial dimension index and left ventricular mass index (R2 for statistical models was 0.38 [P less than 0.0001] and 0.47 [P less than 0.0001], respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Membrane potential in smooth muscle cells from hypertrophic rat portal vein.

Portal hypertension was induced in rats by partial ligation of the hepatic branches of the portal vein. After 5 days the vein was removed and mounted in vitro. In contrast to control (C) veins, hypertensive (H) vessels were almost devoid of spontaneous contractions. Microelectrode recordings showed that the smooth muscle cells of H vessels were hyperpolarized. If [K+]o was increased, or if Ba2+ was added spontaneous activity could be initiated in H vessels. A relation in H cells between hyperpolarization and increased aerobic glycolysis (suggesting an increased electrogenic Na+-K+-pumping) is proposed.

Comparison of portal vein responsiveness in Tris, HEPES or bicarbonate-phosphate buffered media.

The effects of using Tris or HEPES buffered solutions instead of bicarbonate-phosphate buffered solution on the spontaneous activity of the rat portal vein were studied. The effect of the solution buffered with Tris on the spontaneous contractile activity was a minor change in amplitude and frequency, increasing the integrated isometric force by about 20%. A small increase in the mechanical response to variations in [Ca2+]0 (1.0-2.5 mM) was also observed. The response to field stimulation of intramural nerves was significantly lowered in Tris but the response to exogenous noradrenaline was not affected. HEPES buffer does not significantly affect the spontaneous activity, the concentration-effect curve for Ca2+, the response to field stimulation or to exogenous noradrenaline. Transient changes in the spontaneous activity and the resting membrane potential were observed when the solution was changed from Krebs to Tris (or HEPES) solution or vice versa. These changes disappear if the Tris or HEPES solutions were aerated with 4% CO2 in O2 (at pH 7.4) instead of pure O2. A small change in extracellular pH (+/- 0.2 pH units) significantly affects the spontaneous activity. A change in pH may be the reason for the observed effects in the different buffer media.

Stimulatory effects of Ba2+ on contractile activity in the smooth muscle of the rat portal vein.

The effects on mechanical activity in rat portal vein of adding Ba2+, Sr2+ or Mg2+ (0.3--10 mM) to a tris-buffered solution (Na-tris) with 2.5 mM Ca2+ was investigated and compared to the effects of addition of Ca2+. Ba2+ induced a continuous tetanical activity and increased integrated force from threshold (0.3 mM) to sevenfold (10 mM). Addition of Sr2+ and Ca2+ had only minor effects on mechanical activity, whereas Mg2+ in increasing concentrations exerted an inhibitory effect. Contractures were elicited in K+-high tris solution with 2.5 mM Ca2+. The amplitudes of the contractures were not affected by added Mg2+, whereas Ca2+, Sr2+, and Ba2+ increased contracture force to some extent, the increase being highest for Ba2+ (twofold in 10 mM). Sucrose gap recordings of electrical and mechanical activity showed that added Ba2+ (0.3 mM) to Na-tris with 2.5 mM Ca2+ increased spike discharge and force/spike, the latter almost twofold. A corresponding addition of 0.3 mM Ca2+ had no effect. The effects of adding Sr2+ are very similar to that of added Ca2+, Mg2+ decreased spontaneous mechanical activity. Relaxation rates after K-contractures with 2.5 mM Ca2+, Ba2+, or Sr2+ were determined. No difference was found after K-tris with Ca2+ or Ba2+, whereas the veins relaxed faster after K-tris with Sr2+. We conclude tht Ba2+ acts as a constrictor of the smooth muscle in rat portal vein partly by initiating an increased spike discharge, and partly by increasing the entry or release of Ca2+ per spike, whereas the removal of Ca2+ is unaffected.