Subclinical regional left ventricular dysfunction in obese patients with and without hypertension or hypertrophy

We investigated the impact of obesity on the abnormalities of systolic and diastolic regional left ventricular (LV) function in patients with or without hypertension or hypertrophy, and without heart failure. We studied 120 individuals divided into 6 groups of 20 patients (42 ± 6 years, 60 females) using standard and pulsed-wave tissue Doppler imaging (TDI) echocardiography, and heterogeneity index (HI): nonobese (I: no hypertension, no hypertrophy, control group; II: hypertension, no hypertrophy; III: hypertension and hypertrophy) and obese (IV: no hypertension, no hypertrophy; V: hypertension, no hypertrophy; VI: hypertension and hypertrophy). The criterion for obesity was BMI ≥30 kg/m2, for hypertension was blood pressure ≥ 140/90 mm Hg, for hypertrophy in nonobese was LV mass/body surface area (BSA) >134 g/m(2) (men) and >110 mg/m2 (women), and in obese was LV mass/height(2.7) >50 (men) and >40 (women). Obese groups had normal LV ejection fraction compared with nonobese groups, but decreased longitudinal and radial systolic myocardial peak velocities (S'), and early diastolic myocardial peak velocity (E'). Also, a great variability of E' and late diastolic myocardial peak velocity (A') from the longitudinal basal region was observed in obese groups (E'basal nonobese: 11 ± 7 vs. obese 19 ± 11, P < 0.001, A'basal nonobese: 7 ± 4 vs. obese 11 ± 7, P < 0.001). Our findings were more evident when comparing groups IV with V and VI, with the latter having concentric hypertrophy and obvious segmental systolic and diastolic dysfunctions. Subclinical myocardial alterations and increased variability of the velocities were observed in obese groups, especially with hypertension and hypertrophy, reflecting impaired regional LV relaxation, segmental atrial, and systolic dysfunctions.     

Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats

A recent report indicated that hyperhomocysteinemia (Hhe), in addition to its atherothrombotic effects, exacerbates the adverse cardiac remodeling seen in response to hypertension, a powerful stimulus for pathological ventricular hypertrophy. The present study was undertaken to determine whether Hhe has a direct effect on ventricular remodeling and function in the absence of other hypertrophic stimuli. Male Wistar-Kyoto rats were fed either an amino acid-defined control diet or an intermediate Hhe-inducing diet. After 10 wk of dietary treatment, rats were subjected to echocardiographic assessment of left ventricular (LV) dimensions and systolic function. Subsequently, blood was collected for plasma homocysteine measurements, and the rats were killed for histomorphometric and biochemical assessment of cardiac remodeling and for in vitro cardiac function studies. Significant LV hypertrophy was detected by echocardiographic measurements, and in vitro results showed hypertrophy with significantly increased myocyte size in the LV and right ventricle (RV). LV and RV remodeling was characterized by a disproportionate increase in perivascular and interstitial collagen, coronary arteriolar wall thickening, and myocardial mast cell infiltration. In vitro study of LV function demonstrated abnormal diastolic function secondary to decreased compliance because the rate of relaxation did not differ between groups. LV systolic function did not vary between groups in vitro. In summary, in the absence of other hypertrophic stimuli short-term intermediate Hhe caused pathological hypertrophy and remodeling of both ventricles with diastolic dysfunction of the LV. These results demonstrate that Hhe has direct adverse effects on cardiac structure and function, which may represent a novel direct link between Hhe and cardiovascular morbidity and mortality, independent of other risk factors.     

Contribution of laminar myofiber architecture to load-dependent changes in mechanics of LV myocardium

The ventricular myocardium consists of a syncytium of myocytes organized into branching, transmurally oriented laminar sheets approximately four cells thick. When systolic deformation is expressed in an axis system determined by the anatomy of the laminar architecture, laminar sheets of myocytes shear and laterally extend in an approximately radial direction. These deformations account for ~90% of normal systolic wall thickening in the left ventricular free wall. In the present study, we investigated whether the changes in systolic and diastolic function of the sheets were sensitive to alterations in systolic and diastolic load. Our results indicate that there is substantial reorientation of the laminar architecture during systole and diastole. Moreover, this reorientation is both site and load dependent. Thus as end-diastolic pressure is increased and the left ventricular wall thins, sheets shorten and rotate away from the radial direction due to transverse shearing, opposite of what occurs in systole. Both mechanisms of thickening contribute substantially to normal left ventricular wall function. Whereas the relative contributions of shear and extension are comparable at the base, sheet shear is the predominant factor at the apex. The magnitude of shortening/extension and shear increases with preload and decreases with afterload. These findings underscore the essential contribution of the laminar myocardial architecture for normal ventricular function throughout the cardiac cycle.     

Regulation of middle cerebral artery blood velocity during recovery from dynamic exercise in humans.

We sought to examine the regulation of cerebral blood flow during 10 min of recovery from mild, moderate, and heavy cycling exercise by measuring middle cerebral artery blood velocity (MCA V). Transfer function analyses between changes in arterial blood pressure and MCA V were used to assess the frequency components of dynamic cerebral autoregulation (CA). After mild and moderate exercise, the decreases in mean arterial pressure (MAP) and mean MCA V (MCA Vm) were small. However, following heavy exercise, MAP was rapidly and markedly reduced, whereas MCA Vm decreased slowly (-23 +/- 4 mmHg and -4 +/- 1 cm/s after 1 min for MAP and MCA Vm, respectively; means +/- SE). Importantly, for each workload, the normalized low-frequency transfer function gain between MAP and MCA Vm remained unchanged from rest to exercise and during recovery, indicating a maintained dynamic CA. Similar results were found for the systolic blood pressure and systolic MCA V relationship. In contrast, the normalized low-frequency transfer function gain between diastolic blood pressure and diastolic MCA V (MCA Vd) increased from rest to exercise and remained elevated in the recovery period (P < 0.05). However, MCA Vd was quite stable on the cessation of exercise. These findings suggest that MCA V is well maintained following mild to heavy dynamic exercise. However, the increased transfer function gain between diastolic blood pressure and MCA Vd suggests that dynamic CA becomes less effective in response to rapid decreases in blood pressure during the initial 10 min of recovery from dynamic exercise.     

Effects of moderate physical training on blood pressure variability and hemodynamic pattern in mildly hypertensive subjects.

The objective of our study was to compare the cardiovascular effects of moderate exercise training in healthy young (NTS, n=18, 22.9+/-0.44 years) and in hypertensive human subjects (HTS, n=30, 23+/-1.1). The VO(2max) did not significantly differ between groups. HTS of systolic blood pressure (SBP) 148+/-3.6 mmHg and diastolic blood pressure(DBP) 88+/-2.2 mmHg, and NTS of SBP: 128.8 +/- 4 mmHg and DBP: 72 +/- 2.9 mmHg were submitted to moderate dynamic exercise training, at about 50% VO(2max) 3 times per week for one hour, over 3 months. VO(2max) was measured by Astrand's test. Arterial blood pressure was measured with Finapres technique, the stroke volume, cardiac output and arm blood flow were assessed by impedance reography. Variability of SBP and pulse interval values (PI) were estimated by computing the variance and power spectra according to FFT algorithm. After training period significant improvements in VO(2max) were observed in NTS- by 1.92 +/-0.76 and in HTS by 3+/-0.68 ml/kg/min). In HTS significantly decreased: SBP by 19 +/-2.9 mmHg, in DBP by 10.7+/-2 mmHg total peripheral resistance (TPR) by 0.28 +/-0.05 TPR units. The pretraining value of low frequency component power spectra SBP (LF(SPB)) was significantly greater in HTS, compared to NTS. PI variance was lower in HTS, compared to NTS. After physical training, in HTS PI variance increased suggesting a decrease in frequency modulated sympathetic activity and increase in vagal modulation of heart rate in mild hypertension. A major finding of the study is the significant decrease of resting low frequency component SBP power spectrum after training in HTS. The value of LF(SPB) in trained hypertensive subjects normalized to the resting level of LF(SPB) in NTS. Our findings suggest that antihypertensive hemodynamic effects of moderate dynamic physical training are associated with readjustment of the autonomic cardiovascular control system.     

Effects of nifedipine on responses to exercise in normal subjects

The responses to sublingual nifedipine (20 mg) and placebo were compared in normal subjects during two studies on cycle ergometer [progressive exercise and constant work-load exercise at approximately 60% of maximal O2 consumption (VO2max)]. The use of nifedipine did not modify maximal power, ventilation (VE), VO2, and heart rate (HR) at the end of the multistage progressive exercise (30-W increments every 3 min). Over the 45 min of the constant-load exercise and the ensuing 30-min recovery we observed with nifedipine compared with placebo 1) no differences in VO2, VE, respiratory exchange ratio, and systolic arterial blood pressure; 2) a higher HR (P less than 0.001) and lower diastolic arterial blood pressure (P less than 0.01); 3) a greater and more prolonged rise in norepinephrine (P less than 0.01) and growth hormone (P less than 0.001); 4) no significant differences in epinephrine and insulin and a lesser increase in glucagon during recovery (P less than 0.01); and 5) a lesser fall in blood glucose (P less than 0.01) and greater increase in acetoacetate (P less than 0.001), beta-hydroxybutyrate (P less than 0.05), and blood lactate (P less than 0.001). Our data do not support the hypothesis that nifedipine reduces hormonal secretions in vivo and are best explained by an enhanced secretion of catecholamines compensating for the primary vasodilator effect of nifedipine.     

Time-dependent systolic and diastolic function in mice overexpressing calcineurin

Echocardiograms have been assessed only at 56 days in mice overexpressing calcineurin (CN mice). Age-dependent echocardiographic changes were evaluated because the development of sudden death is time dependent. Because cyclosporin A (CsA) reverses hypertrophy in CN mice, its effects on the time course of the development of sudden death and cardiac dysfunction were assessed. In wild-type (WT) mice, the left ventricular (LV) internal end-diastolic dimension (LVIDd) increased and the LV mass index (LVMI) decreased with age. In CN mice, two distinct phases of pathophysiology were found. After 14 days, in CN mice, the LVIDd and LVMI were significantly increased, but sudden death had not occurred. After 28 days, in CN mice, relative dilation of the left ventricle occurred, whereas the LVMI decreased. Sudden death developed during progressive dilation associated with systolic and diastolic dysfunction. CsA treatment reversed hypertrophy in CN mice but did not reverse systolic and diastolic dysfunction and exaggerated sudden death. Sudden cardiac death was associated with systolic and diastolic dysfunction but was not related to isolated cardiac hypertrophy in CN mice.     

Maximal oxygen uptake is not limited by a central nervous system governor.

We tested the hypothesis that the work of the heart was not a limiting factor in the attainment of maximal oxygen uptake (VO2 max). We measured cardiac output (Q) and blood pressures (BP) during exercise at two different rates of maximal work to estimate the work of the heart through calculation of the rate-pressure product, as a part of the ongoing discussion regarding factors limiting VO2 max. Eight well-trained men (age 24.4 +/- 2.8 yr, weight 81.3 +/- 7.8 kg, and VO2 max 59.1 +/- 2.0 ml x min(-1) x kg(-1)) performed two maximal combined arm and leg exercises, differing 10% in watts, with average duration of time to exhaustion of 4 min 50 s and 3 min 40 s, respectively. There were no differences between work rates in measured VO2 max, maximal Q, and peak heart rate between work rates (0.02 l/min, 0.3 l/min, and 0.8 beats/min, respectively), but the systolic, diastolic, and calculated mean BP were significantly higher (19, 5, and 10 mmHg, respectively) in the higher than in the lower maximal work rate. The products of heart rate times systolic or mean BP and Q times systolic or mean BP were significantly higher (3,715, 1,780, 569, and 1,780, respectively) during the higher than the lower work rate. Differences in these four products indicate a higher mechanical work of the heart on higher than lower maximal work rate. Therefore, this study does not support the theory, which states that the work of the heart, and consequently VO2 max, during maximal exercise is hindered by a command from the central nervous system aiming at protecting the heart from being ischemic.     

Cardiovascular effects of the combination of levosimendan and valsartan in hypertensive Dahl/Rapp rats

Hypertension is the main risk factor for left ventricular hypertrophy and development of diastolic heart failure. There is no yet treatment, which can effectively reduce mortality in patients suffering from heart failure with preserved systolic function. We tested whether the calcium sensitizer levosimendan and the AT1-receptor antagonist valsartan could protect from salt-induced hypertension, cardiovascular mortality and heart failure in Dahl/Rapp salt-sensitive rats fed for 7 weeks with a high salt diet (8% NaCl). Levosimendan (1 mg/kg/day via drinking water) and valsartan (30 mg/kg in the food) monotherapies and their combination prevented mortality in Dahl/Rapp rats. The drug combination evoked an additive effect on blood pressure, cardiac hypertrophy, cardiomyocyte cross-sectional area, target organ damage and myocardial ANP mRNA expression. There was a close correlation between systolic blood pressure and cardiac hypertrophy, cardiac and renal damage. As compared to Dahl/Rapp controls kept on low-salt diet (NaCl 0.3%). The high salt rats exhibited impaired diastolic relaxation as assessed by isovolumic relaxation time. Levosimendan alone and in combination with valsartan, improved diastolic relaxation without significantly improving systolic function. Our findings are evidence for an additive effect between levosimendan and valsartan on blood pressure and a blood pressure-dependent protection against the development of salt-induced target organ damage. The present study also demonstrates that levosimendan, alone or in combination with valsartan, can correct diastolic dysfunction induced by salt-dependent hypertension.     

Electromyogram power spectrum during dynamic contractions at different intensities of exercise

During dynamic contractions performed on a cycle ergometer, we studied the influence of motor unit (MU) recruitment on the electromyographic (EMG) spectral content by exerting mechanical power of different intensities, which was chosen to remain below the maximal aerobic power (VO2max). The spectral parameters: EMG total power (PEMG), mean (MPF) and median (MED) power frequencies, which are the most representative of the EMG spectral content, were calculated according to the EMG activity of the vastus medialis muscle (VM) and soleus muscle (SOL) of the right leg. For VM and SOL, PEMG increased linearly with exerted power demonstrating an enhancement of MU recruitment. Moreover these relationships were less scattered when exerted power was expressed as a percentage of VO2max. Changes in MPF and MED with varying exercise intensities were different from one subject to another. For a set of subjects, MPF and MED were found to be independent of exerted power. Although VM and SOL muscles are different in fibre type composition, similar results were obtained for both EMG activities. We have concluded that for dynamic contractions performed at different intensities below VO2max, the recruitment of the MU has a poor effect on the EMG spectral content whatever the predominant type of fibre.     

Cardiovascular effects of melanin-concentrating hormone

Melanin-concentrating hormone (MCH) is a cyclic 19-amino acid neuropeptide exclusively synthesized in the lateral hypothalamic area (LHA) and the zona incerta (ZI) that has been implicated in the regulation of energy balance. Despite what is known about the orexigenic effect of MCH, whether MCH has distinct cardiovascular and metabolic effects has yet to be determined. Thus, our goal here was to characterize the concurrent cardiovascular, metabolic, and behavioral responses of male rats to chronic intracerebroventricular (icv) infusion of MCH. Male Long-Evans rats were instrumented with telemetry transmitters for measurement of heart rate (HR) and housed in room calorimeters for assessment of food intake and oxygen consumption (VO(2)) at standard lab ambient temperature (23 degrees C) in order to examine physiological responses to chronic infusion of MCH (8 microg/d and 16 microg/d). Our findings provide the first evidence that chronic administration of MCH induces bradycardia and reduced mean arterial pressure, while it did not affect VO(2). A second experiment was performed in which the physiological responses to an acute icv infusion of MCH were observed. The results of experiment 2 indicate that MCH leads to a low HR that is maintained during the first 2 h post-infusion, the time period during which MCH acutely stimulated feeding. Collectively, these findings confirm that MCH may be an important modulator of sympathetic nervous system activity and thus may play a critical role in coordinating normal responses to negative energy balance.     

Control of blood pressure and risk of first acute myocardial infarction: Skaraborg hypertension project.

OBJECTIVE--To analyse the relation between treated blood pressure and concomitant risk factor and morbidity from acute myocardial infarction. DESIGN--Prospective longitudinal study. Treated blood pressures and other variables were used to predict acute myocardial infarction. SETTING--Primary health care in Skaraborg, Sweden. SUBJECTS--1121 men and 1453 women aged 40-69 years at registration at outpatient clinics, 1977-81, with no evidence of previous myocardial infarction were followed up for an average of 7.4 years. Subjects were undergoing treatment with drugs to lower blood pressure or had blood pressure that exceeded the systolic or diastolic limits, or both, for diagnosis (> 170/> 105 mm Hg (patients aged 40-60 years) and > 180/> 110 mm Hg (older than 60 years)) on three different occasions, or both. MAIN OUTCOME MEASURES--First validated event of fatal or non-fatal acute myocardial infarction. RESULTS--In men but not in women there was a negative relation between treated diastolic blood pressure and risk of acute myocardial infarction. Left ventricular hypertrophy and smoking were contributory risk factors in both sexes, as was serum cholesterol concentration in men. In men with normal electrocardiograms (n = 345) risk increased with increasing diastolic blood pressure (P = 0.047), whereas the opposite was found in men with electrocardiograms suggesting ischaemia or hypertrophy, or both (n = 499, P = 0.009). In those with a reading of 95-99 mm Hg the relative risk was 0.30 (P = 0.034); at > or = 100 mm Hg it was 0.37 (P = 0.027). No similar relations were seen in women or for systolic blood pressure. CONCLUSION--It may be hazardous to lower diastolic blood pressure below 95 mm Hg in hypertensive men with possible ischaemia or hypertrophy, or both. Electrocardiographic findings should be considered when treatment goals are decided for men with hypertension.     

Naturally occurring motoneuron cell death in rat upper respiratory tract motor nuclei: A histological,fast dil and immunocytochemical study in the nucleus ambiguus

The mammalian upper respiratory tract (URT) serves as the common modality for aspects of respiration, deglutition, and vocalization. Although these actions are dependent on coordinated and specific neuromuscular control, little is known about the development of URT control centers. As such, this study investigated the occurrence of naturally occurring motoneuron cell death (MCD) in the nucleus ambiguus (NA) of a developmental series of rats. Standard histological techniques were used to count motoneurons in the ventrolateral brainstem where the mature NA is found. In addition, the neural tracer, fast Dil, was used to determine whether motoneurons were still migrating into the region of the NA during the period that cell counts were first taken. Furthermore, to elucidate the potential effect of inadvertently counting large interneurons on the assessment of motoneuron numbers, an antibody to γ-aminobutyric acid (GABA) was used. The results of this study have, for the first time, demonstrated that MCD occurs in a URT-related motor nucleus. Approximately a 50% cell death was observed during the prenatal development of NA, with no further loss seen postnatally. The fast DiI studies showed that by embryonic day 17, NA was fully formed, suggesting that motoneuron migration from the basal plate was complete. In addition, use of the GABA antibody showed a lack of inhibitory interneurons within the NA. The finding of MCD in the NA helps define a critical period in the formation of URT neuromuscular control. As the course of MCD is modifiable by epigenetic signals, insult to the organism during this prenatal period may compromise future URT control. © 1995 John Wiley & Sons, Inc.     

Correlation of average muscle fiber conduction velocity measured during cycling exercise with myosin heavy chain composition, lactate threshold, and VO2max.

The aim of the study was to investigate the correlation between myosin heavy chain (MHC) composition, lactate threshold (LT), maximal oxygen uptake VO2max, and average muscle fiber conduction velocity (MFCV) measured from surface electromyographic (EMG) signals during cycling exercise. Ten healthy male subjects participated in the study. MHC isoforms were identified from a sample of the vastus lateralis muscle and characterized as type I, IIA, and IIX. At least three days after a measure of LT and VO2max, the subjects performed a 2-min cycling exercise at 90 revolutions per minute and power output corresponding to LT, during which surface EMG signals were recorded from the vastus lateralis muscle with an adhesive electrode array. MFCV and instantaneous mean power spectral frequency of the surface EMG were estimated at the maximal instantaneous knee angular speed. Output power corresponding to LT and VO2max were correlated with percentage of MHC I (R2=0.77; and 0.42, respectively; P<0.05). MFCV was positively correlated with percentage of MHC I, power corresponding to LT and to VO2max (R2=0.84; 0.74; 0.53, respectively; P<0.05). Instantaneous mean power spectral frequency was not correlated with any of these variables or with MFCV, thus questioning the use of surface EMG spectral analysis for indirect estimation of MFCV in dynamic contractions.     

Synthesis and characterization of mononuclear oxovanadium(IV) complexes and their enzyme inhibition studies with a carbohydrate metabolic enzyme phosphodiesterase I

The increasing interest in vanadium coordination chemistry is based on its well-established chemical and biological functions. A beta-diketonato complex of oxovanadium(IV) is known to be having numerous catalytic applications and also exhibits promising insulin mimetic properties. In continuation of our structure activity relationship studies of metal complexes, we report herein the synthesis and characterization of the vanadium complexes of beta-diketonato ligand system with systematic variations of electronic and steric factors. Two complexes, VO(tmh)(2) (tmh = 2,2,6,6,-tetramethyl-3,5-heptanedione), and VO(hd)(2) (hd = 3,5-heptanedione) were synthesized and characterized by using different spectroscopic techniques. Elemental and mass spectral analysis supports the presence of two beta-diketonato ligands per VO(2+) unit. UV-Vis spectra in different solvents indicate coordination of coordinating solvent molecules at sixth position resulting in red shift of the band I transition. NMR and IR spectra reveal binding of coordinating solvent molecule at vacant sixth position trans to oxo group without releasing beta-diketonato ligands. Enzyme inhibition studies of these and other related oxovanadium(IV) complexes with beta-diketonato ligand system are conducted with snake venom phosphodiesterase I (SPVDE). All of these complexes showed significant inhibitory potential and were found to be non-competitive inhibitors against this enzyme.     

Elucidation of spatially distinct compensatory mechanisms in diastole: radial compensation for impaired longitudinal filling in left ventricular hypertrophy.

Cardiac output maintenance is so fundamental that, when regional systolic function is impaired, as during ischemia, nonischemic segments compensate by becoming hypercontractile. By analogy, diastolic compensatory mechanisms that maintain filling volume must exist but remain to be fully elucidated. Viewing filling in spatially distinct (longitudinal, radial) mechanistic terms facilitates elucidation of diastolic compensatory mechanisms. Because impairment of longitudinal (long axis) diastolic function (DF) in left ventricular hypertrophy (LVH) is established, we hypothesized that to maintain filling volume, radial (short-axis) filling function would compensate. In 20 normal left ventricular ejection fraction (LVEF) subjects (10 with LVH, 10 without LVH), we analyzed longitudinal function via Doppler tissue imaging of mitral annular motion and radial function as change in short-axis endocardial dimension via M-mode. The spatial (long axis, short axis) endocardial LV dimensions and their changes allowed assignment of E-wave filling volume into (cylindrical geometry-based) longitudinal and radial components. Despite indistinguishable (P = 0.70) E-wave velocity-time integrals (E-wave filling volume surrogate), systolic stroke volumes, and end-diastolic volumes in the LVH and control groups, longitudinal volume in absolute terms and the percent of E-wave volume accommodated longitudinally were reduced in the LVH group (P < 0.05 and P < 0.01, respectively), whereas the percent of E-wave volume accommodated radially was enhanced (P < 0.01). We conclude that, in normal LVEF (decreased longitudinal volume accommodation) LVH subjects vs. controls, spatially distinct compensatory mechanisms in diastole manifest as increased radial volume accommodation per unit of E-wave filling volume. Assessment of spatially distinct diastolic compensatory mechanisms in other pathophysiological subsets is warranted.     

An influence of exercise of increasing intensity on aminotransferase activity and electrolyte level in red blood cells and blood serum in men with average and very high physical working capacity.

Healthy subjects with average and very high physical working capacity were submitted to two 6-min periods of work on a cycloergometer at the work loads 70 and 90 percent VO2max. Changes in the activity of Asp AT and Al AT as well as in the concentrations of NA, K and lactates in erythrocytes and serum were determined. In the subjects with average physical working capacity the serum concentrations of lactate and sodium, as well as the activity of Asp AT were much more increased than in the highly efficient subjects. In both groups similar changes of electrolyte concentrations in erythrocytes occured. The activity of Al AT was increased only in the group of subjects with high physical working capacity after the first period of work and showed a tendency to return to the resting values after the second period.     

Metabolic effects of exposure to hypoxia plus cold at rest and during exercise in humans

To determine effects on metabolic responses, subjects were exposed to four environmental conditions for 90 min at rest followed by 30 min of exercise: breathing room air with an ambient temperature of 25 degrees C (NN); breathing room air with an ambient temperature of 8 degrees C (NC); hypoxia (induced by breathing 12% O2 in N2) with a neutral temperature (HN); and hypoxia in the cold (HC). Hypoxia increased heart rate (HR), systolic blood pressure (SBP), pulmonary ventilation (VE), respiratory exchange ratio (R), blood lactate, and perceived exertion during exercise while depressing rectal temperature (Tre) and O2 uptake (VO2). Cold exposure elevated SBP, diastolic blood pressure (DBP), VE, VO2, blood glucose, and blood glycerol but decreased HR, Tre, and R. Shivering and DBP were higher and Tre was lower in HC compared with NC. HR, SBP, VE, R, and lactate tended to be higher in HC compared with NC, whereas VO2 and blood glycerol tended to be depressed. These results suggest that cold exposure during hypoxia results in an increased reliance on shivering for thermogenesis at rest whereas, during exercise, heat loss is accelerated.