Min mmHg Research Articles

Evaluation of Hemodynamic Autonomic Control in an Animal Model of Acute Heart Failure Induced by High Dose of Halothane

Acute animal models of cardiac failure are necessary to study new therapeutic options and should be thoroughly characterized from the hemodynamic point of view, including the response of the autonomic nervous system. Thus, the aim of this work was to characterize the pathophysiological adaptation of the autonomic nervous system to acute cardiac failure induced by high doses of halothane (4%). In six sheep, electrocardiogram, aortic pressure and flow were obtained and calculation of systemic vascular resistances was done. Variability analyses in the time and frequency domains were also performed. In the time domain, after heart failure induction using halothane 4%, a significant decrease of both aortic blood flow variability (from 0.13 ± 0.05 to 0.09 ± 0.02 L min−1, p < 0.05) and the broad band spectra (from 1.80 ± 0.66 to 1.25 ± 0.57 L2 min−2, p < 0.005) was observed. Both mean RR (472 ± 44 to 567 ± 68 ms, p < 0.01), and low frequency band of RR intervals (from 6.2 ± 0.9 to 7.7 ± 1.5 ms2, p < 0.05), showed a significant increase, and no change in systemic vascular resistance (from 54.9 ± 29.5 to 50.3 ± 38.4 mmHg min L−1), all of them after heart failure induction. We conclude that in this model of heart failure the autonomic nervous system activity is still functioning, the combination of increased mean and RR low frequency band, with no change in systemic vascular resistance suggest an increase in the sympathetic control (due to maintained SVR), in an attempt to compensate the depression in the cardiac activity and hemodynamic alterations after severe myocardial depression induced by halothane.

Exercise Intensity and Limb Specificity Alter the Mechanisms of the Muscle Metaboreflex

PURPOSE: Previous studies in dogs have demonstrated a dichotomous response to muscle metaboreflex activation; at low and moderate intensity treadmill exercise, the pressor response was mediated primarily by increased cardiac output (CO), whereas peripheral vasoconstriction played a major role during high intensity exercise. We sought to extend these findings to humans by examining the relative contribution of central and peripheral factors to the pressor response elicited by the muscle metaboreflex following progressive arm and leg exercise. METHODS: In 7 healthy subjects (30 ± 2 yrs), small muscle mass arm and leg exercise was performed at three intensities, followed by 2-min of post-exercise circulatory occlusion (PECO). Dynamic handgrip exercise (1.5 min, 1 Hz) was performed at 20% 50%, and 70% of maximal voluntary contraction (MVC), and dynamic knee extensor exercise (3-min, 1 Hz) was performed at 20%, 60%, and 80% of peak work rate (WRmax). Heart rate (HR) and mean arterial pressure (MAP) were measured noninvasively (Finometer), from which stroke volume (SV), CO, and peripheral vascular conductance (PVC) were calculated. RESULTS: MAP increased from rest during all levels of PECO following exercise in the arm (20%MVC: +7 ± 2mmHg; 50%MVC: +11 ± 2mmHg; 70%MVC: +32 ± 2mmHg) and leg (20%WRmax: +22 ± 5mmHg; 60% WRmax: +14 ± 4mmHg; 80% WRmax: +40 ± 1mmHg) In the arm, the pressor response after exercise was achieved through an increase in CO at 20%MVC (+0.4 ± 0.2 L/min), while pressor responses at 50%MVC and 70%MVC were achieved through a reduction in PVC (-5.6 ± 2.1 ml min-1 mmHg-1and -18.5 ± 4.4 ml min-1 mmHg-1) with no change in CO. In contrast, following leg exercise the pressor responses was driven primarily by an increase in CO at 20%WRmax (+0.6 ± 0.3 L/min) and 50%WRmax (+1.0 ± 0.3 L/min), while the pressor response after high intensity KE exercise was achieved through a concomitant increase in CO (+0.9 ± 0.3 L/min) and a reduction in PVC (-9.6 ± 4.6 ml min-1 mmHg-1) CONCLUSION: These data suggest that during small muscle mass exercise in the arm and leg, changes in both CO and PVC contribute importantly to metaboreflex-induced pressor response in humans. Responses in both the arm and leg exhibited an intensity-dependent effect, with changes in PVC playing an increasingly important role during high exercise intensities.

Evolution of volume sensitivity during hemodialysis and ultrafiltration

This study aimed at assessing the evolution of cardiovascular characteristics during hemodialysis and ultrafiltration by a perturbation accurately defined in its magnitude and directly relevant to the problem of volume adjustment in stable hemodialysis patients. Excess fluid volume was removed by constant ultrafiltration-rate as prescribed. Hemodynamic variables were continuously measured throughout treatments using non-invasive finger plethysmography. In addition to ongoing volume reduction by ultrafiltration (long-term perturbation), well-defined magnitudes of intravascular volume were transiently and reversibly sequestered (short-term perturbation) into the extracorporeal circulation at hourly intervals. Sensitivities of hemodynamic variables and of the baroreflex to the acute change in intravascular volume (volume sensitivities) were analyzed. Eight stable patients were assessed during two subsequent treatments. Treatments were accompanied by a decrease in cardiac output (p<0.05) and stroke volume (p<0.01), and by an increase in peripheral resistance (p<0.05) and diastolic pressure (p<0.05). Mean arterial pressure remained unchanged for the whole group but correlated with the change in total peripheral resistance in individual treatments (p<0.01). The average volume sensitivity of mean arterial pressure was 11.9±9.9 mmHg/L and increased (p<0.01) during treatments, while the average volume sensitivity of heart rate remained unchanged at -7.9±8.58 1/(min L). The corresponding volume sensitivity of the baroreflex was -0.81±1.5 1/(min mmHg) and remained unchanged for the whole group, but the change correlated with the change in mean arterial pressure in individual treatments (p<0.05). The changes in arterial pressures during hemodialysis appear to relate to an unbalanced response of barocontrol mechanisms characterized by a compromised chronotropy and vascular over-reactivity.

Progesterone enhances adrenergic control of skin blood flow in women with high but not low orthostatic tolerance

Women are more susceptible to orthostatic intolerance. Peripheral α-adrenergic responsiveness is important in orthostasis and is lower in women compared to men, and is modulated by female sex hormones. We tested the hypothesis that oestradiol attenuates peripheral cutaneous adrenergic responses in women with low orthostatic tolerance (LT), whereas progesterone enhances adrenergic responses in women with high orthostatic tolerance (HT). After completing a maximal lower body negative pressure test to determine level of orthostatic tolerance (cumulative stress index, CSI), women self administered a gonadotropin releasing hormone (GnRH) antagonist for 16 days to suppress endogenous sex hormone production. Oestradiol (E2, 0.2 mg day−1, patch; days 4–16), and progesterone (P4, 200 mg day−1, oral; days 12–16) were administered. Skin blood flow responses to graded intradermal microdialysis infusions of noradrenaline (NA) were measured during GnRH antagonist, E2, and E2+P4, in eight HT (s.e.m. = 22 ± 1 years, CSI −871 ± 86 mmHg min) and eight LT (21 ± 1 years, CSI −397 ± 65 mmHg min) women. In separate probes, NA was infused alone, and co-infused with the nitric oxide synthase inhibitor NG-monomethyl-l-arginine (l-NMMA, 10 mm), the non-selective cyclooxygenase inhibitor ketorolac tromethamine (Keto, 10 mm), and combined l-NMMA + Keto (10 mm each). Progesterone administration enhanced adrenergic responses in HT women (logEC50 GnRH −4.02 ± 0.39, E2+P4 −5.18 ± 0.31, P < 0.05); this response was reversed with Keto (E2+P4 logEC50 NA+Keto −3.82 ± 0.35, P < 0.05). In contrast, no change in adrenergic responsiveness occurred in LT women during any hormone condition. These data indicate differential regulation of cutaneous adrenergic responses by progesterone via the cyclooxygenase pathway in women with high and low orthostatic tolerance.

Estimation of cerebral vascular tone during exercise; evaluation by critical closing pressure in humans

The aim of the present study was to calculate critical closing pressure (CCP) of the cerebral vasculature at rest and during exercise to estimate cerebral vascular tone. Five men and two women were seated upright for 15 min and then performed 15 min of right-legged knee extension exercise at 40, 60 and 75% of their maximal workload (WL(max)). Middle cerebral artery blood velocity (MCA V) and blood pressure in the radial artery were recorded. The CCP was calculated by linear extrapolation from 1 min recordings of pairs of systolic and diastolic pressure and MCA V waveforms from both the right and the left MCA. In both arteries, the CCP increased (right MCA, +6.6 +/- 8.5 mmHg, P = 0.023; left MCA, +7.3 +/- 9.1 mmHg, P = 0.016) during 75% WL(max) without changes in resistance-area product, while femoral vascular resistance of the non-exercising leg decreased (from 0.32 +/- 0.07 to 0.18 +/- 0.05 mmHg min ml(1); P < 0.001). There was no significant difference in CCP between the right and left MCA (P = 0.31). These findings suggest an increase in cerebral vascular tone in both the right and the left MCA from rest to exercise despite a decrease in vascular resistance of the systemic vasculature. In addition, the increases in CCP were related to the increases in plasma noradrenaline concentrations (right, P = 0.001; left, P = 0.025) and decreases in the partial pressure of arterial carbon dioxide (right, P = 0.008; left, P = 0.086), but not to changes in mean arterial pressure (right, P = 0.282; left, P = 0.564) or adrenaline concentrations (right, P = 0.138; left, P = 0.108). We consider that an exercise-induced increase in cerebral vascular tone serves to protect the blood-brain barrier from the exercise-induced hypertension.

Interactions between Verapamil and Digoxin in Langendorff‐Perfused Rat Hearts: The Role of Inhibition of P‐glycoprotein in the Heart

P-glycoprotein (P-gp) is expressed in tumour cells as well as normal tissues including heart. Modulation of P-gp transport in vivo may lead to increased drug penetrance to tissues with resulting increases in toxicity. We aimed to investigate the effects of P-gp on the isolated heart by digoxin infusion in the absence and presence of verapamil. The study was performed in Langendorff isolated perfused rat hearts. After a 20 min. stabilisation period with Tyrode Buffer, digoxin (125 μg/5 mL) was infused for 10 min. in the control group (n = 7). The same dose of digoxin was infused during perfusion with verapamil (1 nm) containing Tyrode Buffer (n = 8) in the study group. Outflow concentration and cardiac parameters of digoxin were measured at frequent intervals for 40 min. AUEC((0-40 min)) for left ventricular developed pressure was significantly increased in the presence of verapamil (4260 ± 39.37 mmHg min versus 4607 ± 98.09 mmHg min; 95% CI -587.7 to -105.8; p = 0.0083). The significant increases in left ventricular developed pressure were at 20, 25, 30, 35 and 40 min. AUC((0-40 min)) value for outflow digoxin concentration-time curve was significantly lower in the presence of verapamil. Verapamil increased the positive inotropic effect of digoxin, probably through the inhibition of P-gp, which effluxes digoxin out of cardiac cells.

Pulmonary NO and C18O2 uptake during pressure-induced lung expansion in rabbits

In artificially ventilated animals we investigated the dependence of the pulmonary diffusing capacities of nitric oxide (NO) and doubly 18O-labeled carbon dioxide (D L NO, D L C 18 O 2) on lung expansion with respect to ventilator-driven increases in intrapulmonary pressure. For this purpose we applied computerized single-breath experiments to 11 anesthetized paralyzed rabbits (weight 2.8–3.8 kg) at various alveolar volumes (45–72 ml) by studying the almost entire inspiratory limb of the respective pressure/volume curves (intrapulmonary pressure: 6–27 cmH 2O). The animals were ventilated with room air, employing a computerized ventilatory servo-system that we designed to maintain mechanical ventilation and to execute the particular lung function tests automatically. Each single-breath maneuver was started from residual volume (13.5 ± 2 ml, mean ± SD) by inflating the rabbit lungs with 35–55 ml indicator gas mixture containing 0.05% NO in N 2 or 0.9% C 18 O 2 in N 2. Alveolar partial pressures of NO and C 18 O 2 were measured by respiratory mass spectrometry. Values of D L NO and D L C 18 O 2 ranged between 1.55 and 2.49 ml/(mmHg min) and 11.7 and 16.6 ml/(mmHg min), respectively. Linear regression analyses yielded a significant increase in D L NO with simultaneous increase in alveolar volume ( P < 0.005) and intrapulmonary pressure ( P < 0.023) whereas D L C 18 O 2 was not improved. Our results suggest that the ventilator-driven lung expansion impaired the C 18 O 2 blood uptake conductance, finally compensating for the beneficial effect of the increase in alveolar volume on D L C 18 O 2 values.

An evaluation of capnography monitoring during the apnoea test in brain-dead patients

Diagnosis of brain death usually requires the absence of spontaneous respiratory movements during the apnoea test and an arterial carbon dioxide partial pressure above 60 mmHg. On the other hand, although capnography (end-tidal CO(2)) is currently monitored in intensive care unit patients, it has not been evaluated during the apnoea test in brain-dead patients. Therefore, the aim of this prospective study was first to investigate the usefulness of capnography monitoring, and secondly to evaluate the variation of the carbon dioxide partial pressure-end-tidal CO(2) gradient during the apnoea test in clinically brain-dead patients. After local Ethics Committee approval, 60 clinically brain-dead patients were investigated. End-tidal CO(2) was continuously recorded before, during and after the apnoea test. Arterial blood gases were sampled immediately before and after the apnoea test for calculation of the carbon dioxide partial pressure-end-tidal CO(2) gradient. The apnoea test was clinically positive in 58 patients, whereas end-tidal CO(2) was equal to 0 during the apnoea. During the 20-min apnoea test, carbon dioxide partial pressure increased from 40 +/- 7 to 97 +/- 19 mmHg (P < 0.001) with a rate of 2.8 +/- 0.9 mmHg min(-1), end-tidal CO(2) increased from 31 +/- 6 to 68 +/- 17 mmHg (P < 0.001) and carbon dioxide partial pressure-end-tidal CO(2) gradient increased from 9 +/- 4 to 29 +/- 10 mmHg (P < 0.001). In two patients, the apnoea test was clinically negative because of the occurrence of spontaneous respiratory movements, whereas capnography showed contemporaneously significant increases in end-tidal CO(2). End-tidal CO(2) should be systematically monitored and recorded, at least for medico-legal considerations, during the apnoea test in brain-dead patients. The high variability in the carbon dioxide partial pressure-end-tidal CO(2) gradient increase precludes any extrapolation of the carbon dioxide partial pressure from the end-tidal CO(2) at the end of the apnoea test.

Modulation of the Spontaneous Beat-to-beat Fluctuations in Peripheral Vascular Resistance during Activation of Muscle Metaboreflex

Continuous measurement of leg blood flow (LBF) using Doppler ultrasound with simultaneous noninvasive arterial blood pressure measurement permits beat-to-beat estimates of leg vascular resistance (LVR) in humans. PURPOSE: We tested the hypothesis that the beat-to-beat fluctuations in LVR and the dynamic relationship between mean arterial blood pressure (MAP) and LVR are modulated during activation of the muscle metaboreflex. METHODS: Twelve healthy subjects performed a 1-min isometric handgrip exercise at 50% maximal voluntary contraction, which was followed by a period of imposed post-exercise muscle ischemia (PEMI). We then employed transfer function analysis to examine the dynamic relationships between MAP and LBF, and MAP and LVR, both at rest (control) and during PEMI. RESULTS: (a) The spectral power for LBF and LVR in low-frequency (LF: 0.03 ∼ 0.15 Hz) range significantly increased from control during PEMI without a significant change in the high-frequency (HF: 0.15 ∼0.35 Hz) power. The spectral power for MAP within both the LF and HF ranges did not differ during control and PEMI periods, (b) The transfer function gains for MAP and LBF and MAP and LVR in the LF range (0.05 ∼ 0.15 Hz) were significantly increased during PEMI (vs. control), (MAP and LBF: 10 ± 1.2 vs. 15 ± 1.9 ml min-1 mmHg-1, P < 0.05; MAP and LVR: 0.009 ± 0.002 vs. 0.015 ± 0.003 LVRu mmHg-1, P < 0.05) but were unchanged in the HF range (0.2 ∼0.3 Hz). (c) The phase relationships between MAP and LBF, and MAP and LVR did not different during the control and PEMI periods (MAP and LBF in LF: 74.5 ± 11.0 vs. 91.6 ± 6.3 degrees, HF: 9.1 ± 5.6 vs. 1.2 ± 7.8 degrees; MAP and LVR in LF: −47.5 ± 7.0 vs. −44.3 ± 6.5 degrees, HF: −38.5 ± 23.9 vs. −2.1 ± 20.1 degrees). The phase relationship between MAP and LVR revealed that changes in MAP were followed by directionally similar changes in LVR, which is consistent with the characteristics of intrinsic vascular regulatory mechanisms such as the myogenic response of the resistance arteries. CONCLUSION: We suggest that, in humans, modulation of the dynamic relationship between MAP and LVR during activation of the muscle metaboreflex reflects complex interactions between intrinsic vascular regulatory mechanisms and sympathetic vascular regulation.

The cerebellar fastigial nucleus contributes to CO2-H+ ventilatory sensitivity in awake goats

The purpose of this study was to test the hypothesis that an intact cerebellar fastigial nucleus (CFN) is an important determinant of CO(2)-H(+) sensitivity during wakefulness. Bilateral, stainless steel microtubules were implanted into the CFN (N=9) for injection (0.5-10 microl) of the neurotoxin ibotenic acid. Two or more weeks after implantation of the microtubules, eupneic breathing and CO(2)-H(+) sensitivity did not differ significantly (P>0.10) from pre-implantation conditions. Injection of ibotenic acid (50 mM) did not significantly alter eupneic Pa(CO2) (P>0.10). The coefficient of variation of eupneic Pa(CO2) was 4.0+/-0.6 and 3.7+/-0.4% over the 2 weeks before and after the lesion, respectively. CO(2)-H(+) sensitivity expressed as inspired ventilation/Pa(CO2) decreased from 2.15+/-0.17 pre-lesion to 1.58+/-0.26 l/(min mmHg) 3-6 days post-lesion (P<0.02, -27%). There was no significant (P>0.10) recovery of sensitivity between 7 and 10 days post-lesion. The lesion also increased (P<0.05) the day-to-day variability of this index by nearly 100%. When CO(2) sensitivity was expressed as elevated inspired CO(2)/room air V (I), values at 7%, but not 3 and 5% inspired CO(2), were reduced and more variable (P<0.05) after the ibotenic acid injections. We conclude that during wakefulness, the CFN contributes relatively more to overall ventilatory drive at high relative to low levels of hypercapnia.

Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction

We previously observed that pulmonary hypertension secondary to myocardial infarction (MI) in swine is characterized by elevated plasma endothelin (ET) levels and pulmonary vascular resistance (PVR). Consequently, we tested the hypothesis that an increased ET-mediated vasoconstrictor influence contributes to secondary pulmonary hypertension after MI and investigated the involvement of ET(A) and ET(B) receptor subtypes. Chronically instrumented swine with (MI swine; n = 25) or without (normal swine; n = 19) MI were studied at rest and during treadmill exercise (up to 4 km h(-1)), in the absence and presence of the ET(A) antagonist EMD 122946 or the mixed ET(A)/ET(B) antagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ET(A) blockade had no effect on PVR at rest or during exercise. Conversely, ET(A)/ET(B) blockade decreased PVR but only during exercise (at 4 km h(-1), from 3.0 +/- 0.1 to 2.3 +/- 0.1 mmHg min l(-1); P <or= 0.05). MI increased pulmonary arterial pressure and PVR both at rest and during exercise (both P <or= 0.05). The increased pulmonary arterial pressure correlated with the increased plasma ET levels in resting MI swine (r = 0.71; P <or= 0.01). Furthermore, the pulmonary vasoconstrictor response to ET-1 infusion was enhanced after MI (P <or= 0.05). ET(A)/ET(B) blockade decreased PVR in MI swine from 3.6 +/- 0.3 to 3.1 +/- 0.5 mmHg min l(-1) at rest and from 3.4 +/- 0.3 to 2.4 +/- 0.2 mmHg min l(-1) during exercise at 4 km h(-1) (both P <or= 0.05). This increased response to mixed ET(A)/ET(B) blockade in MI compared to normal swine appeared to be the result of an increased ET(A)-mediated vasoconstriction, as ET(A) blockade decreased PVR in MI swine from 3.4 +/- 0.4 to 2.8 +/- 0.2 mmHg min l(-1) at rest and from 3.1 +/- 0.3 to 2.6 +/- 0.2 mmHg min l(-1) at 4 km h(-1) (both P <or= 0.05). In conclusion, increased plasma ET levels together with increased pulmonary resistance vessel responsiveness to ET result in an exaggerated pulmonary vasoconstrictor influence of ET in swine with a recent MI. This vasoconstrictor influence is the result of an emergent tonic ET(A)-mediated vasoconstriction in addition to the exercise-induced ET(B)-mediated vasoconstriction that is already present in normal swine.

Supplementation with omega-3 polyunsaturated fatty acids augments brachial artery dilation and blood flow during forearm contraction

Omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have beneficial effects on the heart and vasculature. We tested the hypothesis that 6 weeks of dietary supplementation with DHA (2.0 g/day) and EPA (3.0 g/day) enhances exercise-induced increases in brachial artery diameter and blood flow during rhythmic exercise. In seven healthy subjects, blood pressure, heart rate and brachial artery diameter, blood flow, and conductance were assessed before and during the last 30 s of 90 s of rhythmic handgrip exercise (30% of maximal handgrip tension). Blood pressure (MAP), heart rate (HR), and brachial artery vascular conductance were also determined. This paradigm was also performed in six other healthy subjects who received 6 weeks of placebo (safflower oil). Placebo treatment had no effect on any variable. DHA and EPA supplementation enhanced contraction-induced increases in brachial artery diameter (0.28+/-0.04 vs. 0.14+/-0.03 mm), blood flow (367+/-65 vs. 293+/-55 ml min-1) and conductance (3.86+/-0.71 vs. 2.89+/-0.61 ml min-1 mmHg-1) (P<0.05). MAP and HR were unchanged. Results indicate that treatment with DHA and EPA enhances brachial artery blood flow and conductance during exercise. These findings may have implications for individuals with cardiovascular disease and exercise intolerance (e.g., heart failure).

The influence of hepatic lipase C-480T polymorphism on coronary flow reserve in young men is independent of the plasma cholesterol level

Background The hepatic lipase (HL) gene C-480T promoter polymorphism affects gene transcription and enzyme activity and leads to CC, CT, and TT genotypes. Recently, HL expression was detected in macrophages. It has been postulated that HL might have a direct role in the pathogenesis of atherosclerosis without changes in the plasma profile. We hypothesized that the difference of plasma cholesterol level may not influence the effect of HL genotype on coronary reactivity. Methods A total of 108 young men (aged 34 ± 5 years) were genotyped and divided into three groups. These groups contained 45, 49 and 14 men having either normal (4.9 ± 1.2 mmol/L), mildly (5.5 ± 0.8 mmol/L) or severely (7.8 ± 1.9 mmol/L, subjects with familial hypercholesterolemia) elevated mean plasma cholesterol level, respectively. Myocardial blood flow (MBF) was measured at rest and during adenosine or dipyridamole-induced hyperemia with positron emission tomography using [ 15O] H 2O. Results The effect of HL genotype on the indices of MBF was parallel within all cholesterol groups and therefore they were combined. In all subjects, basal flow did not differ between the genotypes. However, men with CC genotype had a significantly higher hyperemic blood flow (3.86 ± 1.26 mL g −1 min −1 versus 3.20 ± 1.38 mL g −1 min −1, p = 0.007), higher coronary flow reserve (CFR, 4.80 ± 1.77 versus 3.77 ± 1.43, p = 0.001) and lower coronary resistance during hyperemia (25.63 ± 9.98 mmHg min g mL −1 versus 35.00 ± 23.95 mmHg min g mL −1, p = 0.003) than T allele carriers. In multivariate regression analysis, after adjustment for age, body mass index, serum lipids, blood pressure, adenosine or dipyridamole administration, and study group, HL polymorphism was an independent predictor of blood flow during hyperemia ( p = 0.016), coronary resistance ( p = 0.014), and CFR ( p = 0.005), respectively. Conclusions The HL C-480T polymorphism is associated with CFR, which is an early indicator of atherosclerosis, independently of the level of plasma cholesterol in young men.

Short-term changes in inflammatory response protein (hsCRP) do not parallel with changes in coronary vasoreactivity in obese men

Obese subjects are characterized by increased high-sensitivity C-reactive protein (hsCRP) and coronary vascular resistance. Clucocorticoids suppress inflammation, a possible cardioprotective effect. We tested the short-term anti-inflammatory effect of dexamethasone (dx) on these parameters in obese subjects. Coronary vascular resistance was quantitated basally and during adenosine infusion with or without simultaneous euglycemic hyperinsulinemic clamp (insulin infusion rate of 1 mU/kg/min) in 11 obese and 19 age-matched nonobese males using positron emission tomography and (15)O-water. Each subject was studied both with and without previous dx treatment for 2 days (2 mg/day). Before dx treatment, hsCRP concentration was significantly higher in obese than in nonobese subjects (1.55+/-1.73 vs 0.32+/-0.32 mg/l, P = 0.005). In addition, coronary vascular resistances were higher (P < 0.05) in obese than in nonobese subjects at baseline (139+/-36 vs 117+/-22) and during adenosine infusion without (32+/-7 vs 26+/-7) or with simultaneous clamp (26+/-8 vs 21+/-5 mmHg min g/ ml). Dx treatment decreased significantly hsCRP concentration in obese but not in nonobese subjects, leading to similar hsCRP concentrations between the groups (0.45+/-0.43 vs 0.26+/-0.42 mg/l, respectively, P = 0.3). Dx had no effect on coronary vascular resistances (NS). Obese subjects are characterized by high hsCRP, which can be normalized by dx. However, despite this, coronary vascular resistances did not decrease in obese subjects. Short-term changes in inflammatory response protein appear not to parallel with changes in coronary vasoreactivity in obese men.

Regulation of Transplacental Water Transfer: the Role of Fetoplacental Venous Tone

We used the in vitro dually perfused human placental lobule to test the hypothesis that known vasoconstrictors of the fetal placental circulation, angiotensin II and the thromboxane mimetic U46619 could induce fetomaternal water transfer. Secondly, we used a combination of vasoconstrictor and mechanically induced increases in fetal placental circulatory pressure to examine the role of the venous system in this context. Fetal-side administration of angiotensin II (A-II) and U46619 (n=6 and n=9, for A-II and U46619, respectively) induced dose dependent, recoverable elevations in fetal inflow hydrostatic pressure (HP; A-II: maximum contractility=83 mmHg, EC50=22.0 nM; U46619: maximum contractility was not achieved, but exceeded the A-II effect) and loss of perfusate from the fetal side (A-II: EC50=70.2 nM, maximum fetal-side solvent loss=1906 microl/min; U46619: maximum fetal-side solvent loss was not achieved, but exceeded the A-II effect). Fetal-side solvent loss, for both agonists, was correlated linearly with fetomaternal inflow HP (FMIHP) in a biphasic manner (between 0 and 30 mmHg the slopes (+/-S.E.) were 6.4+/-2.2 and 17.1+/-5.8 microl/(min mmHg) for A-II and U46619, respectively; between 30 and 70 mmHg the slopes (+/-S.E.) were 35.6+/-6.5 and 43.7+/-15.9 microl/(min mmHg) for A-II and U46619, respectively). Increasing fetal-side lumenal pressure (n=3) by raising the fetal outflow catheter caused a loss of perfusate from the fetal side which was reduced in the presence of U46619 (fetal solvent loss per unit increase in fetal-side inflow HP: slopes were 1.198+/-0.123 and 0.783+/-0.085 microl/(min mmHg mmHg), respectively). Notwithstanding the possibility of fetoplacental arterial constriction, we conclude that vasoconstrictive agonists in the fetoplacental circulation affect venous resistance, causing fetomaternal fluid loss. These observations could be relevant to the oligohydramnios associated with intrauterine growth restriction, a condition associated with increased resistance in the umbilical circulation.

Separating the direct effect of hypoxia from the indirect effect of changes in cardiac output on the maximum pressure difference across the tricuspid valve in healthy humans

In healthy humans, changes in cardiac output are commonly accommodated with minimal change in pulmonary artery pressure. Conversely, exposure to hypoxia is associated with substantial increases in pulmonary artery pressure. In this study we used non-invasive measurement of an index of pulmonary artery pressure, the maximum systolic pressure difference across the tricuspid valve (DeltaPmax), to examine the pulmonary vascular response to changes in blood flow during both air breathing and hypoxia. We used Doppler echocardiography in 33 resting healthy humans breathing air over 6-24 h to measure spontaneous diurnal variations in DeltaPmax and cardiac output. Cardiac output varied by up to approximately 2.5 l/min; DeltaPmax varied little with cardiac output [0.61+/-0.74 (SD) mmHg min l(-1)]. Eight of the volunteers were also exposed to eucapnic hypoxia (end-tidal PO2 = 50 mmHg) for 8 h. In this group DeltaPmax rose progressively from 21 mmHg to 37 mmHg over 8 h. By comparing diurnal variations in DeltaPmax during air breathing with changes in DeltaPmax during hypoxia in the same eight individuals, we concluded that only approximately 5% of the changes in DeltaPmax during hypoxia could be attributed to concurrent changes in cardiac output. The low sensitivity of DeltaPmax to changes in cardiac output makes it a useful index of hypoxic pulmonary vasoconstriction in healthy humans.

Autonomic nervous system influence on arterial baroreflex control of heart rate during exercise in humans

A combination of sympathoexcitation and vagal withdrawal increases heart rate (HR) during exercise, however, their specific contribution to arterial baroreflex sensitivity remains unclear. Eight subjects performed 25 min bouts of exercise at a HR of 90, 120, and 150 beats min-1, respectively, with and without metoprolol (0.16 +/- 0.01 mg kg(-1); mean +/- S.E.M.) or glycopyrrolate (12.6 +/- 1.6 microg kg-1). Carotid baroreflex (CBR) function was determined using 5 s pulses of neck pressure (NP) and neck suction (NS) from +40 to -80 Torr, while transfer function gain (GTF) was calculated to assess the linear dynamic relationship between mean arterial pressure and HR. Spontaneous baroreflex sensitivity (SBR) was evaluated as the slope of sequences of three consecutive beats in which systolic blood pressure and the R-R interval of the ECG either increased or decreased, in a linear fashion. The beta-1 adrenergic blockade decreased and vagal cardiac blockade increased HR both at rest and during exercise (P < 0.05). The gain at the operating point of the modelled reflex function curve (GOP) obtained using NP and NS decreased with workload independent of beta-1 adrenergic blockade. In contrast, vagal blockade decreased GOP from -0.40 +/- 0.04 to -0.06 +/- 0.01 beats min-1 mmHg-1 at rest (P < 0.05). Furthermore, as workload increased both GOP and SBR, and GOP and GTF were correlated (P < 0.001), suggesting that the two dynamic methods applied to evaluate arterial baroreflex (ABR) function provide the same information as the modelled GOP. These findings suggest that during exercise the reduction of arterial baroreceptor reflex sensitivity at the operating point was a result of vagal withdrawal rather than an increase in sympathetic activity.

Effect of age on outflow resistance washout during anterior chamber perfusion in rhesus and cynomolgus monkeys

When aqueous humour outflow resistance is measured by two-level constant pressure perfusion in non-human primate eyes, a progressive decrease in outflow resistance, known as the ‘washout effect’ occurs with time. The effect of age on total outflow resistance washout (the reciprocal of outflow facility (OF)) was determined in rhesus and cynomolgus monkeys. In cynomolgus monkeys, the effect of time between exchange of the anterior chamber (AC) contents and post-exchange OF measurements on outflow resistance was also examined. Total OF was determined at baseline in one eye of 35 rhesus monkeys aged 4–29 yrs, and in 27 cynomolgus monkeys, aged 3–17 yrs, at baseline and after 10 min AC exchange with 1 or 2 ml Bárány's perfusand or in Bárány's containing 0.01–1% dimethyl sulfoxide (DMSO) or Tris base. Resistance washout did not differ with age at baseline in rhesus or cynomolgus monkeys. Similarly, no changes were found when comparing post-exchange resistance washout vs. age in cynomolgus monkeys that had undergone AC exchange with Bárány's perfusand only or Bárány's containing 0.01–1% DMSO or Tris base. Rate of resistance washout decreased with increased length of time between exchange of the AC contents and post-exchange outflow facility readings (−0.0004±0.0092 mmHg min −1 μl −1 yr −1; p=0.016). Several explanations for these findings are plausible.

Pulmonary 15NO uptake in interstitial lung disease

Because lung nitric oxide (NO) diffusing capacity ( D L) represents alveolar–capillary gas diffusion, we queried as to whether disturbances of pulmonary gas exchange in interstitial lung disease (ILD) are appropriately reflected by using NO. In this pilot study, we applied the 15N-labeled stable isotope 15NO (relative abundance 0.37% of total NO) in order to ignore the endogenous NO production. In 10 ILD-outpatients, we measured D L 15NO by performing the single-breath method. Lung function parameters as well as arterial oxygen partial pressure (PaO 2) were also tested. Values of D L 15NO ranged within 50–151 ml 15NO/(mmHg min). Ratios of D L 15NO/reference were between 43 and 108% of predicted data as taken from our previous work on healthy volunteers [Eur. J. Physiol. 446 (2003) 256]. We found a significant reduction of D L 15NO/reference in five patients. Additionally, values of PaO 2 were significantly correlated to ratios of D L 15NO/reference (adjusted R 2 ± SEE=0.407 ± 8.051). In conclusion, 15NO represents an appropriate indicator gas for reflecting an ILD-induced impairment of alveolar–capillary gas exchange.

Microcirculation and tolerability following i.v. infusion of PGE 1 and iloprost: a randomized cross-over study in patients with critical limb ischemia

In a randomized cross-over study, the effect of PGE 1 and iloprost on microcirculation as well as the tolerability was investigated in 36 patients with peripheral arterial occlusive disease stage III and IV according to Fontaine. Patients received PGE 1 and iloprost by single 3-h i.v. infusions on two different days at doses recommended by the manufacturers or in previous studies (PGE 1: first hour 20 μg, next 2 h 30 μg each. Iloprost: first hour 0.5 ng/kg/min, next 2 h 1.0 ng/kg/min). Transcutaneous oxygen pressure (tc PO 2) values increased much more with PGE 1. Median tc PO 2 increase over baseline 30 min after the end of infusion was 9 and 2 mmHg for PGE 1 and iloprost, respectively, corresponding to median AUC differences from baseline of 1050 and 210 min mmHg. Because of its exploratory character, the study was not powered to test for significance. Adverse effects occurred in 19.4% (PGE 1) and 30.6% (iloprost) of patients. Dose reduction was required in 3 patients receiving iloprost (hypotension, nausea, irritation of the infused vein), and in none receiving PGE 1.