Venous responses during exercise in rainbow trout, Oncorhynchus mykiss: alpha-adrenergic control and the antihypotensive function of the renin-angiotensin system

The role of the alpha-adrenergic system in the control of cardiac preload (central venous blood pressure; P(ven)) and venous capacitance during exercise was investigated in rainbow trout (Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin-angiotesin system (RAS) was investigated during exercise after alpha-adrenoceptor blockade. Fish were subjected to a 20-min exercise challenge at 0.66 body lengths s(-1) (BL s(-1)) while P(ven), dorsal aortic blood pressure (P(da)) and relative cardiac output (Q) was recorded continuously. Heart rate (f(H)), cardiac stroke volume (SV) and total systemic resistance (R(sys)) were derived from these variables. The mean circulatory filling pressure (MCFP) was measured at rest and at the end of the exercise challenge, to investigate potential exercise-mediated changes in venous capacitance. The protocol was repeated after alpha-adrenoceptor blockade with prazosin (1 mg kg(-1)M(b)) and again after additional blockade of angiotensin converting enzyme (ACE) with enalapril (1 mg kg(-1)M(b)). In untreated fish, exercise was associated with a rapid (within approx. 1-2 min) and sustained increase in Q and P(ven) associated with a significant increase in MCFP (0.17+/-0.02 kPa at rest to 0.27+/-0.02 kPa at the end of exercise). Prazosin treatment did not block the exercise-mediated increase in MCFP (0.25+/-0.04 kPa to 0.33+/-0.04 kPa at the end of exercise), but delayed the other cardiovascular responses to swimming such that Q and P(ven) did not increase significantly until around 10-13 min of exercise, suggesting that an endogenous humoral control mechanism had been activated. Subsequent enalapril treatment revealed that these delayed responses were in fact due to activation of the RAS, because resting P(da) and R(sys) were decreased further and essentially all cardiovascular changes during exercise were abolished. This study shows that the alpha-adrenergic system normally plays an important role in the control of venous function during exercise in rainbow trout. It is also the first study to suggest that the RAS may be an important modulator of venous pressure and capacitance in fish.     

Adrenergic control of venous capacitance during moderate hypoxia in the rainbow trout (Oncorhynchus mykiss): role of neural and circulating catecholamines

Central venous blood pressure (P(ven)) increases in response to hypoxia in rainbow trout (Oncorhynchus mykiss), but details on the control mechanisms of the venous vasculature during hypoxia have not been studied in fish. Basic cardiovascular variables including P(ven), dorsal aortic blood pressure, cardiac output, and heart rate were monitored in vivo during normoxia and moderate hypoxia (P(W)O(2) = approximately 9 kPa), where P(W)O(2) is water oxygen partial pressure. Venous capacitance curves for normoxia and hypoxia were constructed at 80-100, 90-110, and 100-120% of total blood volume by transiently (8 s) occluding the ventral aorta and measure P(ven) during circulatory arrest to estimate the mean circulatory filling pressure (MCFP). This allowed for estimates of hypoxia-induced changes in unstressed blood volume (USBV) and venous compliance. MCFP increased due to a decreased USBV at all blood volumes during hypoxia. These venous responses were blocked by alpha-adrenoceptor blockade with prazosin (1 mg/kg body mass). MCFP still increased during hypoxia after pretreatment with the adrenergic nerve-blocking agent bretylium (10 mg/kg body mass), but the decrease in USBV only persisted at 80-100% blood volume, whereas vascular capacitance decreased significantly at 90-110% blood volume. In all treatments, hypoxia typically reduced heart rate while cardiac output was maintained through a compensatory increase in stroke volume. Despite the markedly reduced response in venous capacitance after adrenergic blockade, P(ven) always increased in response to hypoxia. This study reveals that venous capacitance in rainbow trout is actively modulated in response to hypoxia by an alpha-adrenergic mechanism with both humoral and neural components.     

Cod (Gadus morhua) cardiorespiratory physiology and hypoxia tolerance following acclimation to low-oxygen conditions

Previous research has shown that hypoxia-acclimated Atlantic cod (Gadus morhua) have significantly reduced cardiac function but can consume more oxygen for a given cardiac output (Q). However, it is not known (1) which physiological changes permit a greater "oxygen pulse" (oxygen consumed per mL of blood pumped) in hypoxia-acclimated individuals or (2) whether chronic exposure to low-oxygen conditions improves the hypoxia tolerance of cod. Thus, we exposed normoxia- and hypoxia-acclimated (> 6 wk at a water oxygen partial pressure [P(w)O(2)] ~8-9 kPa) cod to a graded normoxia challenge until loss of equilibrium occurred while recording the following cardiorespiratory variables: oxygen consumption (MO(2)), ventilatory rate, cardiac function (Q, heart rate f(H), and stroke volume S(V)), ventral aortic blood pressure (P(VA)), venous oxygen partial pressure (P(v)O(2)) and oxygen content (C(v)O(2)), plasma catecholamines, and blood hemoglobin ([Hb]) and hematocrit (Hct). In addition, we performed in vitro hemoglobin oxygen binding curves to examine whether hypoxia acclimation influences hemoglobin functional properties. Numerous physiological adjustments occurred in vivo during the > 6 wk of hypoxia acclimation: that is, increased f(H), decreased S(V) and Q, elevated [Hb], enhanced tissue oxygen extraction (by 10% at a P(w)O(2) of 20 kPa), and a more robust stress response as evidenced by circulating catecholamine levels that were two to eight times higher when fish were acutely exposed to severe hypoxia. In contrast, chronic hypoxia had no significant effect on the affinity of hemoglobin for oxygen, on in vitro hemoglobin oxygen carrying capacity, or on the cod's hypoxia tolerance (H(crit); the P(w)O(2) at which the fish lost equilibrium, which was 4.3 ± 0.2 and 4.8 ± 0.3 kPa in normoxia- and hypoxia-acclimated fish, respectively). These data suggest that while chronic hypoxia results in numerous physiological adjustments, these changes do not improve the cod's capacity to tolerate low-oxygen conditions.     

Evidence that neurotensin mediates postprandial intestinal hyperemia in the python, Python regius

Digestion of large meals in pythons produces substantial increases in heart rate and cardiac output, as well as a dilation of the mesenteric vascular bed leading to intestinal hyperemia, but the mediators of these effects are unknown. Bolus intra-arterial injections of python neurotensin ([His(3), Val(4), Ala(7)]NT) (1 - 1,000 pmol/kg) into the anesthetized ball python Python regius (n = 7) produced a dose-dependent vasodilation that was associated with a decrease in systemic pressure (P(sys)) and increase in systemic blood flow (Q(sys)). There was no effect on pulmonary pressure and conductance. A significant (P < 0.05) increase in heart rate (f(H)) and total cardiac output (Q(tot)) was seen only at high doses (>30 pmol/kg). The systemic vasodilation and increase in Q(tot) persisted after beta-adrenergic blockade with propranolol, but the rise in f(H) was abolished. Also, the systemic vasodilation persisted after histamine H(2)-receptor blockade. In unanesthetized pythons (n = 4), bolus injection of python NT in a dose as low as 1 pmol/kg produced a significant increase in blood flow to the mesenteric artery (177% +/- 54%; mean +/- SE) and mesenteric conductance (219% +/- 74%) without any increase in Q(sys), systemic conductance, P(sys), and f(H). The data provide evidence that NT is an important hormonal mediator of postprandial intestinal hyperemia in the python, but its involvement in mediating the cardiac responses to digestion may be relatively minor.     

Peripheral chemoreceptor contributions to sympathetic and cardiovascular responses during hypercapnia

We tested the hypothesis that integrated sympathetic and cardiovascular reflexes are modulated by systemic CO2 differently in hypoxia than in hyperoxia (n = 7). Subjects performed a CO2 rebreathe protocol that equilibrates CO2 partial pressures between arterial and venous blood and that elevates end tidal CO2 (PET(CO2)) from approximately 40 to approximately 58 mmHg. This test was repeated under conditions where end tidal oxygen levels were clamped at 50 (hypoxia) or 200 (hyperoxia) mmHg. Heart rate (HR; EKG), stroke volume (SV; Doppler ultrasound), blood pressure (MAP; finger plethysmograph), and muscle sympathetic nerve activity (MSNA) were measured continuously during the two protocols. MAP at 40 mmHg PET(CO2) (i.e., the first minute of the rebreathe) was greater during hypoxia versus hyperoxia (P < 0.05). However, the increase in MAP during the rebreathe (P < 0.05) was similar in hypoxia (16 +/- 3 mmHg) and hyperoxia (17 +/- 2 mmHg PET(CO2)). The increase in cardiac output (Q) at 55 mmHg PET(CO2) was greater in hypoxia (2.61 +/- 0.7 L/min) versus hyperoxia (1.09 +/- 0.44 L/min) (P < 0.05). In both conditions the increase in Q was due to elevations in both HR and SV (P < 0.05). Systemic vascular conductance (SVC) increased to similar absolute levels in both conditions but rose earlier during hypoxia (> 50 mmHg PET(CO2)) than hyperoxia (> 55 mmHg). MSNA increased earlier during hypoxic hypercapnia (> 45 mmHg) compared with hyperoxic hypercapnia (> 55 mmHg). Thus, in these conscious humans, the dose-response effect of PET(CO2) on the integrated cardiovascular responses was shifted to the left during hypoxic hypercapnia. The combined data indicate that peripheral chemoreceptors exert important influence over cardiovascular reflex responses to hypercapnia.     

Enforced exercise, but not acute temperature elevation, decreases venous capacitance in the stenothermal Antarctic fish Pagothenia borchgrevinki

The venous haemodynamic response to enforced exercise and acute temperature increase was examined in the Antarctic fish Pagothenia borchgrevinki (borch) to enable comparisons with the existing literature for temperate species, and investigate if the unusual cardiovascular response to temperature changes previously observed in the borch can be linked to an inability to regulate the venous vasculature. Routine central venous blood pressure (P (cv)) was 0.08 kPa and the mean circulatory filling pressure (P (mcf); an index of venous capacitance) was 0.14 kPa. Acute warming from 0 to 2.5 and 5 degrees C increased heart rate (f (H)), while dorsal aortic blood pressure (P (da)) decreased. P (mcf) did not change, while P (cv) decreased significantly at 5 degrees C. This contrasts with the venoconstriction previously observed in rainbow trout in response to increased temperature. Exercise resulted in small increases in P (mcf) and P (cv), a response that was abolished by alpha-adrenoceptor blockade. This study demonstrates that the heart of P. borchgrevinki normally operates at positive filling pressures (i.e. P (cv)) and that venous capacitance can be actively regulated by an alpha-adrenergic mechanism. The lack of decrease in venous capacitance during warming may suggest that a small increase in venous tone is offset by a passive temperature-mediated increase in compliance.     

Deciphering the metabolic and mechanical contributions to the exercise-induced circulatory response: insights from eccentric cycling

Metabolic demand and muscle mechanical tension are closely coupled during exercise, making their respective drives to the circulatory response difficult to establish. This coupling being altered in eccentric cycling, we implemented an experimental design featuring eccentric vs. concentric constant-load cycling bouts to gain insights into the control of the exercise-induced circulatory response in humans. Heart rate (HR), stroke volume (SV), cardiac output (Q), oxygen uptake (V(.-)(O(2))), and electromyographic (EMG) activity of quadriceps muscles were measured in 11 subjects during heavy concentric (heavy CON: 270 +/- 13 W; V(.-)(O(2)) = 3.59 +/- 0.20 l/min), heavy eccentric (heavy ECC: 270 +/- 13 W, V(.-)(O(2)) = 1.17 +/- 0.15 l/min), and light concentric (light CON: 70 +/- 9 W, V(.-)(O(2)) = 1.14 +/- 0.12 l/min) cycle bouts. Using a reductionist approach, the circulatory responses observed between heavy CON vs. light CON (difference in V(.-)(O(2)) and power output) was ascribed either to metabolic demand, as estimated from heavy CON vs. heavy ECC (similar power output, different V(.-)(O(2))), or to muscle mechanical tension, as estimated from heavy ECC vs. light CON (similar V(.-)(O(2)), different power output). 74% of the Q response was determined by the metabolic demand, also accounting for 65% and 84% of HR and SV responses, respectively. Consequently, muscle mechanical tension determined 26%, 35%, and 16% of the Q, HR, and SV responses, respectively. Q was significantly related to V(.-)(O(2)) (r(2) = 0.83) and EMG activity (r(2) = 0.82; both P < 0.001). These results suggest that the exercise-induced circulatory response is mainly under metabolic control and support the idea that the level of muscle activation plays a role in the cardiovascular regulation during cycle exercise in humans.     

Myocardial function defined by strain rate and strain during alterations in inotropic states and heart rate

For porcine myocardium, ultrasonic regional deformation parameters, systolic strain (epsilon(sys)) and peak systolic strain rate (SR(sys)), were compared with stroke volume (SV) and contractility [contractility index (CI)] measured as the ratio of end-systolic strain to end-systolic wall stress. Heart rate (HR) and contractility were varied by atrial pacing (AP = 120-180 beats/min, n = 7), incremental dobutamine infusion (DI = 2.5-20 microg. kg(-1). min(-1), n = 7), or continuous esmolol infusion (0.5 mg. kg(-1). min(-1)) + subsequent pacing (120-180 beats/min) (EI group, n = 6). Baseline SR(sys) and epsilon(sys) averaged 5.0 +/- 0.4 s(-1) and 60 +/- 4%. SR(sys) and CI increased linearly with DI (20 microg. kg(-1). min(-1); SR(sys) = 9.9 +/- 0.7 s(-1), P < 0.0001) and decreased with EI (SR(sys) = 3.4 +/- 0.1 s(-1), P < 0.01). During pacing, SR(sys) and CI remained unchanged in the AP and EI groups. During DI, epsilon(sys) and SV initially increased (5 microg. kg(-1). min(-1); epsilon(sys) = 77 +/- 6%, P < 0.01) and then progressively returned to baseline. During EI, SV and epsilon(sys) decreased (epsilon(sys) = 38 +/- 2%, P < 0.001). Pacing also decreased SV and epsilon(sys) in the AP (180 beats/min; epsilon(sys) = 36 +/- 2%, P < 0.001) and EI groups (180 beats/min; epsilon(sys) = 25 +/- 3%, P < 0.001). Thus, for normal myocardium, SR(sys) reflects regional contractile function (being relatively independent of HR), whereas epsilon(sys) reflects changes in SV.     

Inspiratory muscle work in acute hypoxia influences locomotor muscle fatigue and exercise performance of healthy humans

Our aim was to isolate the independent effects of 1) inspiratory muscle work (W(b)) and 2) arterial hypoxemia during heavy-intensity exercise in acute hypoxia on locomotor muscle fatigue. Eight cyclists exercised to exhaustion in hypoxia [inspired O(2) fraction (Fi(O(2))) = 0.15, arterial hemoglobin saturation (Sa(O(2))) = 81 +/- 1%; 8.6 +/- 0.5 min, 273 +/- 6 W; Hypoxia-control (Ctrl)] and at the same work rate and duration in normoxia (Sa(O(2)) = 95 +/- 1%; Normoxia-Ctrl). These trials were repeated, but with a 35-80% reduction in W(b) achieved via proportional assist ventilation (PAV). Quadriceps twitch force was assessed via magnetic femoral nerve stimulation before and 2 min after exercise. The isolated effects of W(b) in hypoxia on quadriceps fatigue, independent of reductions in Sa(O(2)), were revealed by comparing Hypoxia-Ctrl and Hypoxia-PAV at equal levels of Sa(O(2)) (P = 0.10). Immediately after hypoxic exercise potentiated twitch force of the quadriceps (Q(tw,pot)) decreased by 30 +/- 3% below preexercise baseline, and this reduction was attenuated by about one-third after PAV exercise (21 +/- 4%; P = 0.0007). This effect of W(b) on quadriceps fatigue occurred at exercise work rates during which, in normoxia, reducing W(b) had no significant effect on fatigue. The isolated effects of reduced Sa(O(2)) on quadriceps fatigue, independent of changes in W(b), were revealed by comparing Hypoxia-PAV and Normoxia-PAV at equal levels of W(b). Q(tw,pot) decreased by 15 +/- 2% below preexercise baseline after Normoxia-PAV, and this reduction was exacerbated by about one-third after Hypoxia-PAV (-22 +/- 3%; P = 0.034). We conclude that both arterial hypoxemia and W(b) contribute significantly to the rate of development of locomotor muscle fatigue during exercise in acute hypoxia; this occurs at work rates during which, in normoxia, W(b) has no effect on peripheral fatigue.     

Chronic hypertension in ANP knockout mice: contribution of peripheral resistance

Atrial Natriuretic Peptide (ANP) exerts a chronic hypotensive effect which is mediated by a reduction in total peripheral resistance (TPR). Mice with a homozygous disruption of the pro-ANP gene (-/-) fail to synthesize ANP and develop chronic hypertension in comparison to their normotensive wild-type (+/+) siblings. In order to determine whether alterations in basal hemodynamics underlie the hypertension associated with lack of endogenous ANP activity, we used anesthetized mice to measure arterial blood pressure (ABP) and heart rate (HR), as well as cardiac output (CO) by thermodilution technique. -/- (n = 7) and +/+ (n = 10) mice of comparable weight and age were used. Stroke volume (SV) and TPR were derived from CO, HR, and ABP by a standard formula. ABP (mm Hg) was significantly higher in -/- (132+/-4) (P < 0.0001) than in +/+ mice (95+/-2). CO (ml min(-1)), HR(beats min(-1))and SV (microl beat(-1)) did not differ significantly between -/- and +/+ mice (CO -/- = 7.3+/-0.5, +/+ = 8.3+/-0.6; HR -/- = 407+/-22, +/+ = 462+/-21; SV -/- = 17.6+/-1.1, +/+ = 17.6+/-1.7). However, TPR (mm Hg ml(-1) min(-1)) was significantly elevated in -/- mice (18.4+/-0.7) compared to +/+ mice (12.3+/-1) (P = 0.0003). Autonomic ganglion blockade with a mixture of hexamethonium and pentolinium was followed by comparable percent reductions in CO (-/- = 28+/-4, +/+ = 29+/-3), HR (-/- = 9+/-4, +/+ = 16+/-4) and SV(-/- = 21+/-4, +/+ = 15+/-6) in both genotypes. However, the concomitant decrease in ABP (%) in -/- (41+/-2) was significantly greater than in +/+ (23+/-4) mice (P = 0.0009) and was accompanied by a significant reduction in TPR. We conclude that the hypertension associated with lack of endogenous ANP is due to elevated TPR, which is determined by an increase in cardiovascular autonomic tone.     

The effects of inspiratory intrathoracic pressure production on the cardiovascular response to submaximal exercise in health and chronic heart failure

We sought to determine whether the normal inspiratory intrathoracic pressures (P(ITP)) produced during exercise contribute to the blunted cardiac output and locomotor limb blood flow responses observed in chronic heart failure (CHF). Five chronically instrumented dogs exercised on a treadmill at 2.5 mile/h at 5% grade while healthy or after the induction of tachycardia-induced CHF. We observed several key differences in the cardiovascular responses to changes in the inspiratory P(ITP) excursion between health and CHF; namely, 1) removing approximately 70% of the normally produced inspiratory P(ITP) excursion during exercise (with 15 cmH(2)O inspiratory positive pressure ventilation) significantly reduced stroke volume (SV) in healthy animals by 5 +/- 2% (P < 0.05) but significantly increased SV and cardiac output (Q(TOT)) in animals with CHF by 5 +/- 1% (P < 0.05); 2) doubling the magnitude of the inspiratory P(ITP) excursion had no effect on SV or Q(TOT) in healthy animals but significantly reduced steady-state Q(TOT) and SV in animals with CHF by -4 +/- 3% and -10 +/- 3%, respectively; 3) removing the majority of the normally produced inspiratory P(ITP) excursion had no effect on blood flow distribution in healthy animals but increased hindlimb blood flow (9 +/- 3%, P < 0.05) out of proportion to the increases in Q(TOT); and 4) the only similarity between healthy and CHF animals was that increasing the inspiratory P(ITP) excursion significantly reduced steady-state locomotor limb blood flow by 5 +/- 2% and 6 +/- 3%, respectively (P < 0.05 for both). We conclude that 1) the normally produced inspiratory P(ITP) excursions are required for a maximal SV response to submaximal exercise in healthy animals but detrimental to the SV and Q(TOT) responses to submaximal exercise in CHF, 2) the respiratory muscle ergoreflex tonically restrains locomotor limb blood flow during submaximal exercise in CHF, and 3) excessive inspiratory muscle work further compromises cardiac function and blood flow distribution in both health and CHF.     

Impaired pulmonary oxygen uptake kinetics and reduced peak aerobic power during small muscle mass exercise in heart transplant recipients.

We examined peak and reserve cardiovascular function and skeletal muscle oxygenation during unilateral knee extension (ULKE) exercise in five heart transplant recipients (HTR, mean +/- SE; age: 53 +/- 3 years; years posttransplant: 6 +/- 4) and five age- and body mass-matched healthy controls (CON). Pulmonary oxygen uptake (Vo(2)(p)), heart rate (HR), stroke volume (SV), cardiac output (Q), and skeletal muscle deoxygenation (HHb) kinetics were assessed during moderate-intensity ULKE exercise. Peak exercise and reserve Vo(2)(p), Q, and systemic arterial-venous oxygen difference (a-vO(2diff)) were 23-52% lower (P < 0.05) in HTR. The reduced Q and a-vO(2diff) reserves were associated with lower HR and HHb reserves, respectively. The phase II Vo(2)(p) time delay was greater (HTR: 38 +/- 2 vs. CON: 25 +/- 1 s, P < 0.05), while time constants for phase II Vo(2)(p) (HTR: 54 +/- 8 vs. CON: 31 +/- 3 s), Q (HTR: 66 +/- 8 vs. CON: 28 +/- 4 s), and HHb (HTR: 27 +/- 5 vs. CON: 13 +/- 3 s) were significantly slower in HTR. The HR half-time was slower in HTR (113 +/- 21 s) vs. CON (21 +/- 2 s, P < 0.05); however, no significant difference was found between groups for SV kinetics (HTR: 39 +/- 8 s vs. CON 31 +/- 6 s). The lower peak Vo(2)(p) and prolonged Vo(2)(p) kinetics in HTR were secondary to impairments in both cardiovascular and skeletal muscle function that result in reduced oxygen delivery and utilization by the active muscles.     

Expiratory threshold loading impairs cardiovascular function in health and chronic heart failure during submaximal exercise.

We determined the effects of augmented expiratory intrathoracic pressure (P(ITP)) production on cardiac output (Q(TOT)) and blood flow distribution in healthy dogs and dogs with chronic heart failure (CHF). From a control expiratory P(ITP) excursion of 7 +/- 2 cmH2O, the application of 5, 10, or 15 cmH2O expiratory threshold loads increased the expiratory P(ITP) excursion by 47 +/- 23, 67 +/- 32, and 118 +/- 18% (P < 0.05 for all). Stroke volume (SV) rapidly decreased (onset <10 s) with increases in the expiratory P(ITP) excursion (-2.1 +/- 0.5%, -2.4 +/- 0.9%, and -3.6 +/- 0.7%, P < 0.05), with slightly smaller reductions in Q(TOT) (0.8 +/- 0.6, 1.0 +/- 1.1, and 1.8 +/- 0.8%, P < 0.05) owing to small increases in heart rate. Both Q(TOT) and SV were restored to control levels when the inspiratory P(ITP) excursion was augmented by the addition of an inspiratory resistive load during 15 cmH2O expiratory threshold loading. The highest level of expiratory loading significantly reduced hindlimb blood flow by -5 +/- 2% owing to significant reductions in vascular conductance (-7 +/- 2%). After the induction of CHF by 6 wk of rapid cardiac pacing at 210 beats/min, the expiratory P(ITP) excursions during nonloaded breathing were not significantly changed (8 +/- 2 cmH2O), and the application of 5, 10, and 15 cmH2O expiratory threshold loads increased the expiratory P(ITP) excursion by 15 +/- 7, 23 +/- 7, and 31 +/- 7%, respectively (P < 0.05 for all). Both 10 and 15 cmH2O expiratory threshold loads significantly reduced SV (-3.5 +/- 0.7 and -4.2 +/- 0.7%, respectively) and Q(TOT) (-1.7 +/- 0.4 and -2.5 +/- 0.4%, P < 0.05) after the induction of CHF, with the reductions in SV predominantly occurring during inspiration. However, the augmentation of the inspiratory P(ITP) excursion now elicited further decreases in SV and Q(TOT). Only the highest level of expiratory loading significantly reduced hindlimb blood flow (-4 +/- 2%) as a result of significant reductions in vascular conductance (-5 +/- 2%). We conclude that increases in expiratory P(ITP) production-similar to those observed during severe expiratory flow limitation-reduce cardiac output and hindlimb blood flow during submaximal exercise in health and CHF.     

Cellular PO2 as a determinant of maximal mitochondrial O(2) consumption in trained human skeletal muscle.

Previously, by measuring myoglobin-associated PO(2) (P(Mb)O(2)) during maximal exercise, we have demonstrated that 1) intracellular PO(2) is 10-fold less than calculated mean capillary PO(2) and 2) intracellular PO(2) and maximum O(2) uptake (VO(2 max)) fall proportionately in hypoxia. To further elucidate this relationship, five trained subjects performed maximum knee-extensor exercise under conditions of normoxia (21% O(2)), hypoxia (12% O(2)), and hyperoxia (100% O(2)) in balanced order. Quadriceps O(2) uptake (VO(2)) was calculated from arterial and venous blood O(2) concentrations and thermodilution blood flow measurements. Magnetic resonance spectroscopy was used to determine myoglobin desaturation, and an O(2) half-saturation pressure of 3.2 Torr was used to calculate P(Mb)O(2) from saturation. Skeletal muscle VO(2 max) at 12, 21, and 100% O(2) was 0.86 +/- 0.1, 1.08 +/- 0.2, and 1.28 +/- 0.2 ml. min(-1). ml(-1), respectively. The 100% O(2) values approached twice that previously reported in human skeletal muscle. P(Mb)O(2) values were 2.3 +/- 0.5, 3.0 +/- 0.7, and 4.1 +/- 0.7 Torr while the subjects breathed 12, 21, and 100% O(2), respectively. From 12 to 21% O(2), VO(2) and P(Mb)O(2) were again proportionately related. However, 100% O(2) increased VO(2 max) relatively less than P(Mb)O(2), suggesting an approach to maximal mitochondrial capacity with 100% O(2). These data 1) again demonstrate very low cytoplasmic PO(2) at VO(2 max), 2) are consistent with supply limitation of VO(2 max) of trained skeletal muscle, even in hyperoxia, and 3) reveal a disproportionate increase in intracellular PO(2) in hyperoxia, which may be interpreted as evidence that, in trained skeletal muscle, very high mitochondrial metabolic limits to muscle VO(2) are being approached.     

Heart rate deflection point as a strategy to defend stroke volume during incremental exercise.

The purpose of this study was to examine whether the heart rate (HR) deflection point (HRDP) in the HR-power relationship is concomitant with the maximal stroke volume (SV(max)) value achievement in endurance-trained subjects. Twenty-two international male cyclists (30.3 +/- 7.3 yr, 179.7 +/- 7.2 cm, 71.3 +/- 5.5 kg) undertook a graded cycling exercise (50 W every 3 min) in the upright position. Thoracic impedance was used to measure continuously the HR and stroke volume (SV) values. The HRDP was estimated by the third-order curvilinear regression method. As a result, 72.7% of the subjects (HRDP group, n = 16) presented a break point in their HR-work rate curve at 89.9 +/- 2.8% of their maximal HR value. The SV value increased until 78.0 +/- 9.3% of the power associated with maximal O(2) uptake (Vo(2 max)) in the HRDP group, whereas it increased until 94.4 +/- 8.6% of the power associated with Vo(2 max) in six other subjects (no-HRDP group, P = 0.004). Neither SV(max) (ml/beat or ml.beat(-1).m(-2)) nor Vo(2 max) (ml/min or ml.kg(-1).min(-1)) were different between both groups. However, SV significantly decreased before exhaustion in the HRDP group (153 +/- 44 vs. 144 +/- 40 ml/beat, P = 0.005). In the HRDP group, 62% of the variance in the power associated with the SV(max) could also be predicted by the power output at which HRDP appeared. In conclusion, in well-trained subjects, the power associated with the SV(max)-HRDP relationship supposed that the HR deflection coincided with the optimal cardiac work for which SV(max) was attained.     

Phase I dynamics of cardiac output, systemic O2 delivery, and lung O2 uptake at exercise onset in men in acute normobaric hypoxia

We tested the hypothesis that vagal withdrawal plays a role in the rapid (phase I) cardiopulmonary response to exercise. To this aim, in five men (24.6+/-3.4 yr, 82.1+/-13.7 kg, maximal aerobic power 330+/-67 W), we determined beat-by-beat cardiac output (Q), oxygen delivery (QaO2), and breath-by-breath lung oxygen uptake (VO2) at light exercise (50 and 100 W) in normoxia and acute hypoxia (fraction of inspired O2=0.11), because the latter reduces resting vagal activity. We computed Q from stroke volume (Qst, by model flow) and heart rate (fH, electrocardiography), and QaO2 from Q and arterial O2 concentration. Double exponentials were fitted to the data. In hypoxia compared with normoxia, steady-state fH and Q were higher, and Qst and VO2 were unchanged. QaO2 was unchanged at rest and lower at exercise. During transients, amplitude of phase I (A1) for VO2 was unchanged. For fH, Q and QaO2, A1 was lower. Phase I time constant (tau1) for QaO2 and VO2 was unchanged. The same was the case for Q at 100 W and for fH at 50 W. Qst kinetics were unaffected. In conclusion, the results do not fully support the hypothesis that vagal withdrawal determines phase I, because it was not completely suppressed. Although we can attribute the decrease in A1 of fH to a diminished degree of vagal withdrawal in hypoxia, this is not so for Qst. Thus the dual origin of the phase I of Q and QaO2, neural (vagal) and mechanical (venous return increase by muscle pump action), would rather be confirmed.     

Effects of lethal levels of environmental hypercapnia on cardiovascular and blood-gas status in yellowtail,Seriola quinqueradiata

The cardiorespiratory responses were examined in yellowtail, Seriola quinqueradiata exposed to two levels of hypercapnia (seawater equilibrated with a gas mixture containing 1% CO(2) (water PCO(2) = 7 mmHg) or 5% CO(2) (38 mmHg)) for 72 hr at 20 degrees C. Mortality was 100% within 8 hr at 5% CO(2), while no fish died at 1% CO(2). No cardiovascular variables (cardiac output, Q; heart rate, HR; stroke volume, SV and arterial blood pressure, BP) significantly changed from pre-exposure values during exposure to 1% CO(2). Arterial CO(2) partial pressure (PaCO(2)) significantly increased (P < 0.05), reaching a new steady-state level after 3 hr. Arterial blood pH (pHa) decreased initially (P < 0.05), but was subsequently restored by elevation of plasma bicarbonate ([HCO(3)(-)]). Arterial O(2) partial pressure (PaO(2)), oxygen content (CaO(2)), and hematocrit (Hct) were maintained throughout the exposure period. In contrast, exposure to 5% CO(2) dramatically reduced Q (P < 0.05) through decreasing SV (P < 0.05), although HR did not change. BP was transiently elevated (P < 0.05), followed by a precipitous fall before death. The pHa was restored incompletely despite a significant increase in [HCO(3)(-)]. PaO(2) decreased only shortly before death, whereas CaO(2) kept elevated due to a large increase in Hct (P < 0.05). We tentatively conclude that cardiac failure is a primary physiological disorder that would lead to death of fish subjected to high environmental CO(2) pressures.     

Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans

Recurrent and intermittent nocturnal hypoxia is characteristic of several diseases including chronic obstructive pulmonary disease, congestive heart failure, obesity-hypoventilation syndrome, and obstructive sleep apnea. The contribution of hypoxia to cardiovascular morbidity and mortality in these disease states is unclear, however. To investigate the impact of recurrent nocturnal hypoxia on hemodynamics, sympathetic activity, and vascular tone we evaluated 10 normal volunteers before and after 14 nights of nocturnal sustained hypoxia (mean oxygen saturation 84.2%, 9 h/night). Over the exposure, subjects exhibited ventilatory acclimatization to hypoxia as evidenced by an increase in resting ventilation (arterial Pco(2) 41.8 +/- 1.5 vs. 37.5 +/- 1.3 mmHg, mean +/- SD; P < 0.05) and in the isocapnic hypoxic ventilatory response (slope 0.49 +/- 0.1 vs. 1.32 +/- 0.2 l/min per 1% fall in saturation; P < 0.05). Subjects exhibited a significant increase in mean arterial pressure (86.7 +/- 6.1 vs. 90.5 +/- 7.6 mmHg; P < 0.001), muscle sympathetic nerve activity (20.8 +/- 2.8 vs. 28.2 +/- 3.3 bursts/min; P < 0.01), and forearm vascular resistance (39.6 +/- 3.5 vs. 47.5 +/- 4.8 mmHg.ml(-1).100 g tissue.min; P < 0.05). Forearm blood flow during acute isocapnic hypoxia was increased after exposure but during selective brachial intra-arterial vascular infusion of the alpha-blocker phentolamine it was unchanged after exposure. Finally, there was a decrease in reactive hyperemia to 15 min of forearm ischemia after the hypoxic exposure. Recurrent nocturnal hypoxia thus increases sympathetic activity and alters peripheral vascular tone. These changes may contribute to the increased cardiovascular and cerebrovascular risk associated with clinical diseases that are associated with chronic recurrent hypoxia.     

Repeated pregnancies (multiparity) increases venous tone and reduces compliance

In humans, multiparity (repeated pregnancy) is associated with increased risk of cardiovascular disease. In rats, multiparity increases the pressor response to phenylephrine and to acute stress, due in part to changes in tone of the splanchnic arterial vasculature. Given that the venous system also changes during pregnancy, we studied the effects of multiparity on venous tone and compliance. Cardiovascular responses to volume loading (2 ml/100 g body wt), and mean circulatory filling pressure (MCFP, an index of venomotor tone) were measured in conscious, repeatedly bred (RB), and age-matched virgin rats. In addition, passive compliance and venous reactivity of isolated mesenteric veins were measured by pressure myography. There was a greater increase in mean arterial pressure after volume loading in RB rats (+7.2 +/- 2.5 mmHg, n = 8) than virgin rats (-1.4 +/- 1.7 mmHg, n = 7) (P < 0.05). The increase in MCFP in response to norepinephrine (NE) was also greater in RB rats [half maximal effective dose (ED(50)) 3.1 +/- 0.5 nmol.kg(-1).min(-1), n = 6] than virgins (ED(50): 12.1 +/- 2.7 nmol.kg(-1).min(-1), n = 6) (P < 0.05). Pressure-induced changes in passive diameter were lower in isolated mesenteric veins from RB rats (29.3 +/- 1.8 microm/mmHg, n = 6) than from virgins (36.9 +/- 1.3 microm/mmHg, n = 6) (P < 0.05). Venous reactivity to NE in isolated veins was also greater in RB rats (EC(50): 2.68 +/- 0.37x10(-8) M, n = 5) than virgins (EC(50): 4.67 +/- 0.93 x 10(-8) M, n = 8). We conclude that repeated pregnancy induces a long-term reduction in splanchnic venous compliance and augments splanchnic venous reactivity and sympathetic tonic control of total body venous tone. This compromises the ability of the capacitance (venous) system to accommodate volume overloads and to buffer changes in cardiac preload.