Marko Gujic

Acute Effects of Passive Smoking on Peripheral Vascular Function

Environmental tobacco smoke (ETS) acutely affects peripheral and coronary vascular tone. Whether ETS exerts specific deleterious effects on aortic wave reflection through nicotine exposure, whether they persist after ETS cessation, and whether the smoke environment impairs microvascular function and increases asymmetrical dimethyl-arginine levels are not known. We tested these hypotheses in a randomized, crossover study design in 11 healthy male nonsmokers. The effects of 1 hour of exposure to ETS, as compared with a nontobacco smoke and normal air, on augmentation index corrected for heart rate and skin microvascular hyperemia to local heating were examined. Augmentation index increased both during (P=0.01) and after (P<0.01) the ETS session but remained unchanged in the nontobacco smoke session when compared with normal air. Nicotine levels after the exposure were related to the peak rise in augmentation index (r=0.84; P<0.01), denoting a predominant role of nicotine in ETS vascular effects. This was confirmed in a second set of experiments (n=14), where the sublingual administration of nicotine was associated with an acute impairment in wave reflection as compared with placebo (P=0.001). Both ETS and nontobacco smokes increased plasma asymmetrical dimethyl-arginine levels (P<0.001), but only ETS reduced the late rise in skin blood flow in response to heating (P=0.03). In conclusion, passive smoking specifically increases aortic wave reflection through a nicotine-dependent pathway and impairs microvascular function, even after the end of the exposure. However, both tobacco and nontobacco passive smoking inhalation increase plasma asymmetrical dimethyl-arginine levels.

Beta-adrenergic blockade and metabo-chemoreflex contributions to exercise capacity.

PURPOSE Exercise-induced dyspnea in patients with cardiopulmonary diseases may be related to sympathetic nervous system activation, with increased metabo- and/or chemosensitivities. Whether this mechanism plays a role in exercising normal subjects remains unclear. METHODS Muscle sympathetic nerve activity (MSNA), HR, ventilation (V(E)), O2 saturation (SpO2), and end-tidal PCO2 (PetCO2) were measured in 14 healthy young adults after 1 wk of beta1-receptor blockade with bisoprolol 5 mg x d(-1) versus placebo after a double-blind, placebo-controlled, randomized crossover design. The MSNA and the ventilatory responses to hyperoxic hypercapnia (7% CO2 in O2), DeltaV(E)/DeltaPetCO2, and isocapnic hypoxia (10% O2 in N2), DeltaV(E)/DeltaSpO2, and to an isometric muscle contraction followed by a local circulatory arrest (metaboreflex) were determined at rest followed by an incremental cardiopulmonary exercise test. RESULTS Bisoprolol did not change the V(E) and MSNA responses to hypercapnia, hyperoxia, or isometric muscle contraction or ischemia. Bisoprolol decreased maximum O2 uptake (P < 0.05), workload (P < 0.05), and HR (P < 0.0001) and both V(E)/VO2 and V(E)/VCO2 slopes (P < 0.05). CONCLUSIONS These results suggest that decreased aerobic exercise capacity after intake of beta-blockers is accompanied by decreased ventilation at any metabolic rate. However, this occurs without detectable change in the sympathetic nervous system tone or in metabo- or chemosensitivity and is therefore probably of hemodynamic origin.

Differential effects of metaboreceptor and chemoreceptor activation on sympathetic and cardiac baroreflex control following exercise in hypoxia in human.

Muscle metaboreceptors and peripheral chemoreceptors exert differential effects on the cardiorespiratory and autonomic responses following hypoxic exercise. Whether these effects are accompanied by specific changes in sympathetic and cardiac baroreflex control is not known. Sympathetic and cardiac baroreflex functions were assessed by intravenous nitroprusside and phenylephrine boluses in 15 young male subjects. Recordings were performed in random order, under locally circulatory arrested conditions, during: (1) rest and normoxia (no metaboreflex and no chemoreflex activation); (2) normoxic post‐handgrip exercise at 30% of maximum voluntary contraction (metaboreflex activation without chemoreflex activation); (3) hypoxia without handgrip (10% O2 in N2, chemoreflex activation without metaboreflex activation); and (4) post‐handgrip exercise in hypoxia (chemoreflex and metaboreflex activation). When compared with normoxic rest (−42 ± 7% muscle sympathetic nerve activity (MSNA) mmHg−1), sympathetic baroreflex sensitivity did not change during normoxic post‐exercise ischaemia (PEI; −53 ± 9% MSNA mmHg−1, P= 0.5) and increased during resting hypoxia (−68 ± 5% MSNA mmHg−1, P < 0.01). Sympathetic baroreflex sensitivity decreased during PEI in hypoxia (−35 ± 6% MSNA mmHg−1, P < 0.001 versus hypoxia without exercise; P= 0.16 versus normoxic PEI). Conversely, when compared with normoxic rest (11.1 ± 1.7 ms mmHg−1), cardiac baroreflex sensitivity did not change during normoxic PEI (8.3 ± 1.3 ms mmHg−1, P= 0.09), but decreased during resting hypoxia (7.3 ± 0.8 ms mmHg−1, P < 0.05). Cardiac baroreflex sensitivity was lowest during PEI in hypoxia (4.3 ± 1 ms mmHg−1, P < 0.01 versus hypoxia without exercise; P < 0.001 versus normoxic exercise). The metaboreceptors and chemoreceptors exert differential effects on sympathetic and cardiac baroreflex function. Metaboreceptor activation is the major determinant of sympathetic baroreflex sensitivity, when these receptors are stimulated in the presence of hypoxia.

Acute effects of nicotine on arterial stiffness and wave reflection in healthy young non-smokers.

1 Recently, we have demonstrated that cigarette smoke exposure proportionally increases plasma nicotine levels and arterial wave reflection to the aorta. However, the exact contribution of nicotine to the smoke‐induced enhancement of wave reflection and the potential underlying mechanisms have not been fully investigated. 2 The present study was a prospective study in 15 healthy male non‐smokers. All received a placebo and a 2 mg nicotine tablet, according to a randomized double‐blind cross‐over study design. Each subject underwent repeated measurements at baseline and for 1 h after nicotine or placebo intake, using carotid–femoral pulse wave velocity (PWV) to assess arterial compliance. Concurrently, aortic pressures and the augmentation index were evaluated using applanation tonometry. 3 Plasma nicotine concentrations achieved 1 h after intake of the nicotine tablet reached comparable levels to those achieved after 1 h exposure to passive smoke (3.6 ± 0.4 vs 3.2 ± 0.4 ng/mL, respectively; P = 0.4). 4 Nicotine enhanced arterial wave reflection to the aorta, as assessed by the augmentation index corrected for heart rate (4.2 ± 1.3 vs–0.7 ± 0.8% with placebo; P = 0.001). In addition, a progressive increase in carotid–femoral PWV was noted after nicotine administration (0.3 ± 0.1 vs–0.02 ± 0.1 m/s with placebo; P = 0.04). This remained significant even after adjustment for changes in mean blood pressure and heart rate (P = 0.01). 5 Plasma nicotine concentrations comparable to those achieved after exposure to passive smoke enhance arterial wave reflection to the aorta. This is accompanied by an increase in carotid–femoral PWV, denoting a deterioration of arterial compliance by nicotine.

Nicotine increases chemoreflex sensitivity to hypoxia in non-smokers.

Background The peripheral chemoreflex contributes to cardiovascular regulation and represents the first line of defence against hypoxia. The effects of nicotine on chemoreflex regulation in non-smoking humans are unknown. Method We conducted a prospective, randomized, crossover, and placebo-controlled study in 20 male non-smokers to test the hypothesis that nicotine increases chemoreflex sensitivity. The effects of two intakes of 2 mg nicotine tabs and placebo on sympathetic nerve activity to muscle circulation (muscle sympathetic nerve activity; MSNA), minute ventilation (Ve), blood pressure and heart rate were assessed during normoxia, moderate isocapnic hypoxia, hyperoxic hypercapnia and an isometric handgrip in 10 subjects. Maximal end-expiratory apnoeas were performed at baseline and at the end of the fifth minute of hypoxia. In a second experimental setting, we studied the ventilatory response to a more marked isocapnic hypoxia in 10 other volunteers. Results Mean MSNA and Ve were not modified by nicotine during the 5 min of normoxia or moderate hypoxia. In the presence of nicotine MSNA was related to oxygen desaturation (P < 0.01). The sympathoexcitatory effects of nicotine became especially evident when apnoeas achieved oxygen saturations less than 85% (511 ± 44% increase in MSNA after the first intake, and 436 ± 43% increase after the second intake versus 387 ± 56% and 338 ± 31% with placebo, respectively, P < 0.05). Nicotine also increased the ventilatory response compared with placebo when oxygen saturation decreased to less than 85% (P < 0.05). Conclusion This is the first study to demonstrate that nicotine increases peripheral chemoreflex sensitivity to large reductions in arterial oxygen content in healthy non-smokers.

Sympathoexcitation Increases the QT/RR Slope in Healthy Men: Differential Effects of Hypoxia, Dobutamine, and Phenylephrine

Introduction: Dynamic ventricular repolarization assessed by QT/RR slopes studies the effects of modifications in cardiac repolarization independently of variations in RR interval (RR). The effects of changes in sympathetic and vagal activity on the QT/RR slope are controversial. We tested the hypothesis that sympathoexcitation is an important determinant of the QT/RR slope.

Facial cooling and peripheral chemoreflex mechanisms in humans

Aim:  Reductions in arterial oxygen partial pressure activate the peripheral chemoreceptors which increase ventilation, and, after cessation of breathing, reduce heart rate. We tested the hypothesis that facial cooling facilitates these peripheral chemoreflex mechanisms.

BRS analysis from baroreflex sequences and baroreflex events compared using spontaneous and drug induced data

Spontaneous time domain BRS estimation is based on the SBP-RR slope, which can be computed from either baroreflex sequences (BS) or baroreflex events (BE). BRS analysis from BEs was recently shown be advantageous particularly in the cases of reduced BRS or when BS are not identified. Also, it offers a superior discrimination between lying and standing positions. In this work, the methods developed for spontaneous BRS analysis are further compared using spontaneous and drug induced data. The results corroborate that spontaneous and drug induced estimates are different although correlated. In particular, if BEs are used the differences and the correlation between the estimates is higher. No precision improvement is achieved if the BRS is estimated from drug induced data. In spontaneous, the higher number of beats in BEs in comparison with BSs (at the expense of a lower SBP-RR correlation) allows a higher BRS estimate precision using recordings of the same length.

Differential Effects of Oral β Blockade on Cardiovascular and Sympathetic Regulation

In patients with hypertension, β blockade decreases muscle sympathetic nerve activity (MSNA; micrographic technique) expressed in burst frequency (burst/min) but does not affect MSNA expressed in burst incidence (burst/100 heart beats), because reductions in blood pressure (BP) upon each diastole continue to deactivate the arterial baroreceptors, but at a slower heart rate (HR). We studied the effects of oral β blockade on MSNA and baroreflex sensitivity (BRS) in normal participants. Bisoprolol (5 mg, 1 week) was administered in 10 healthy young adults, using a double-blind, placebo-controlled, randomized cross-over study design. The beat-to-beat mean RR interval (RR) and systolic blood pressure (SBP) series were analyzed by power spectral analysis and power computation over the very low frequency (VLF), low frequency, and high frequency (HF) bands. Baroreflex sensitivity was computed from SBP and RR cross-analysis, using time and frequency domain methods. Bisoprolol increased RR (P < .0005), decreased mean SBP and diastolic blood pressure values (P < .01), did not change the SBP and RR powers, except for RR power in VLF (P < .02) and SBP power in HF (P < .03). The MSNA variability (P > .13) and respiratory pattern (P = .84) did not change from placebo to bisoprolol condition. The bisoprolol-induced bradycardia was associated with higher burst/100 heart beats (P < .05) and bisoprolol did not affect burst/min (P = .80). Time domain BRS estimates were increased after bisoprolol (P < .05), while frequency domain ones did not change (P > .1). Oral bisoprolol induces differential effects on sympathetic burst frequency and incidence in normal participants. Peripheral sympathetic outflow over time is preserved as a result of an increased burst incidence, in the presence of a slower HR. Unchanged BP and HR and MSNA variability suggests that the larger burst incidence is not due to sympathetic activation.

Nicotine does not compromise resting myocardial blood flow autoregulation in smokers at high cardiovascular risk.

Nicotine has been recognized for years as being pharmacologically responsible for the sympathoexcitatory effects of smoking. The effects of nicotine supplementation on myocardial blood flow as assessed by positron emission tomography are, however, unknown. We tested the hypothesis that nicotine substitution could interfere with myocardial blood flow autoregulation at rest in habitual smokers at risk of coronary artery disease. The short-term effect of a 4-mg nicotine tablet on myocardial blood flow was quantified with 13N ammonia positron emission tomography in 12 smokers with high cardiovascular risk (10 males and 2 females; mean age = 58+/-8 years; SCORE risk >5%). Nicotine increased systolic blood pressure from 129+/-7 to 134+/-7 mmHg (p = .03) and heart rate from 67+/-2 to 69+/-2 bpm (p = .04). As a result, nicotine raised the rate-pressure product from 8618+/-622 to 9285+/-627 bpm mmHg (p = .02). Nicotine tended to increase myocardial blood flow in the circumflex artery territory, but this effect failed to reach the level of statistical significance (from 0.56+/-0.06 to 0.63+/-0.03 ml/min/g; p>.15). This trend disappeared when myocardial blood flow was normalized for the rise in the rate-pressure product. Global myocardial perfusion, normalized for the changes in rate-pressure product, remained unchanged from 0.70+/-0.06 at baseline to 0.71+/-0.03 (ml/min/g)/(bpm mmHg) after nicotine. Nicotine supplementation in habitual smokers with high cardiovascular risk increased myocardial work without compromising resting myocardial blood flow autoregulation.