Potentiation of GABAergic synaptic transmission by diazepam acutely increases resting beat-to-beat blood pressure variability in young adults.

Resting beat-to-beat blood pressure variability is a powerful predictor of cardiovascular events and end-organ damage. However, its underlying mechanisms remain unknown. Herein, we tested the hypothesis that a potentiation of GABAergic synaptic transmission by diazepam would acutely increase resting beat-to-beat blood pressure variability. In 40 (17 females) young, normotensive subjects, resting beat-to-beat blood pressure (finger photoplethysmography) was continuously measured for 5-10 min, 60 min after the oral administration of either diazepam (10 mg) or placebo. The experiments were conducted in a randomized, double-blinded, and placebo-controlled design. Stroke volume was estimated from the blood pressure waveform (ModelFlow) permitting the calculation of cardiac output and total peripheral resistance. Direct recordings of muscle sympathetic nerve activity (MSNA, microneurography) were obtained in a subset of subjects (n = 13), and spontaneous cardiac and sympathetic baroreflex sensitivity were calculated. Compared with placebo, diazepam significantly increased the standard deviation of systolic blood pressure (4.7 ± 1.4 vs. 5.7 ± 1.5 mmHg, P = 0.001), diastolic blood pressure (3.8 ± 1.2 vs. 4.5 ± 1.2 mmHg, P = 0.007), and mean blood pressure (3.8 ± 1.1 vs. 4.5 ± 1.1 mmHg, P = 0.002), as well as cardiac output (469 ± 149 vs. 626 ± 259 mL/min, P < 0.001) and total peripheral resistance (1.0 ± 0.3 vs. 1.4 ± 0.6 mmHg/L/min, P < 0.001). Similar results were found using different indices of variability. Furthermore, diazepam reduced MSNA (placebo: 22 ± 6 vs. diazepam: 18 ± 8 bursts/min, P = 0.025) without affecting the arterial baroreflex control of heart rate (placebo: 18.6 ± 6.7 vs. diazepam: 18.8 ± 7.0 ms/mmHg, P = 0.87) and MSNA (placebo: -3.6 ± 1.2 vs. diazepam: -3.4 ± 1.5 bursts/100 Hb/mmHg, P = 0.55). Importantly, these findings were not impacted by biological sex. We conclude that GABAA receptors modulate resting beat-to-beat blood pressure variability in young adults.

GABAergic contribution to the muscle mechanoreflex-mediated heart rate responses at the onset of exercise in humans.

Previous studies have indicated that central GABAergic mechanisms are involved in the heart rate (HR) responses at the onset of exercise. On the basis of previous research that showed similar increases in HR during passive and active cycling, we reasoned that the GABAergic mechanisms involved in the HR responses at the exercise onset are primarily mediated by muscle mechanoreceptor afferents. Therefore, in this study, we sought to determine whether central GABA mechanisms are involved in the muscle mechanoreflex-mediated HR responses at the onset of exercise in humans. Twenty-eight healthy subjects (14 men and 14 women) aged between 18 and 35 yr randomly performed three bouts of 5-s passive and active cycling under placebo and after oral administration of diazepam (10 mg), a benzodiazepine that produces an enhancement in GABAA activity. Beat-to-beat HR (electrocardiography) and arterial blood pressure (finger photopletysmography) were continuously measured. Electromyography of the vastus lateralis was obtained to confirm no electrical activity during passive trials. HR increased from rest under placebo and further increased after administration of diazepam in both passive (change: 12 ± 1 vs. 17 ± 1 beats/min, P < 0.01) and active (change: 14 ± 1 vs. 18 ± 1 beats/min, P < 0.01) cycling. Arterial blood pressure increased from rest similarly during all conditions ( P > 0.05). Importantly, no sex-related differences were found in any variables during experiments. These findings demonstrate, for the first time, that the GABAergic mechanisms significantly contribute to the muscle mechanoreflex-mediated HR responses at the onset of exercise in humans. NEW & NOTEWORTHY We found that passive and voluntary cycling evokes similar increases in heart rate and that these responses were enhanced after diazepam administration, a benzodiazepine that enhances GABAA activity. These findings suggest that the GABAergic system may contribute to the muscle mechanoreflex-mediated vagal withdrawal at the onset of exercise in humans.

Heart rate variability across the menstrual cycle in young women taking oral contraceptives.

Previous studies have shown that resting heart rate variability (HRV) is modified by different phases of the menstrual cycle in nonusers of oral contraceptive pills (OCP); however, the effect of OCP on autonomic control of the heart remains unclear. The purpose of this study was to investigate HRV during the low hormone (LH-not taking OCP) and during the high hormone (HH-active OCP use) phases of the menstrual cycle in young women. Seventeen healthy women (19-31 years) taking OCP for at least 6 consecutive months were enrolled in this study. Plasma estradiol and progesterone were verified at each visit. HRV was assessed by using one-lead electrocardiography in time and frequency domains, in which participants rested in the supine position for a 20-min period with a breathing rate of 15 cycles/min. In addition, resting heart rate, and systolic and diastolic blood pressure were obtained. Both plasma estradiol (LH: 19.8 ± 4.2 pg/mL vs. HH: 12.4 ± 1.5 pg/mL; p > .05) and progesterone (LH: 0.247 ± 0.58 ng/mL vs. HH: 0.371 ± 0.08 ng/mL; p > .05) (mean ± SE) levels were similar in both phases. No significant difference was obtained for any component of HRV, heart rate, or blood pressure between the LH and HH phases (p > .05). These results provide preliminary evidence that use of OCP does not affect HRV during the menstrual cycle in healthy women.

Effects of ovarian hormones and oral contraceptive pills on cardiac vagal withdrawal at the onset of dynamic exercise.

The purpose of this study was to investigate the effects of the ovarian hormones and the use of oral contraceptive pills (OCP) on cardiac vagal withdrawal at the onset of dynamic exercise. Thirty physically active women aged 19-32 years were divided into two groups: OCP users (n = 17) and non-OCP users (n = 13). Participants were studied randomly at three different phases of the menstrual cycle: early follicular (day 3.6 ± 1.2; range 1-5), ovulatory (day 14.3 ± 0.8; range 13-16) and midluteal (day 21.3 ± 0.8; range 20-24), according to endogenous (in non-OCP users) or exogenous (in OCP users) estradiol and progesterone variations. The cardiac vagal withdrawal was represented by the cardiac vagal index (CVI), which was obtained by the 4-s exercise test. Additionally, resting heart rate, systolic (SBP) and diastolic blood pressure (DBP) were obtained. The CVI was not significantly different between the three phases of the menstrual cycle in either the non-OCP users (early follicular: 1.58 ± 0.1; ovulatory: 1.56 ± 0.1; midluteal: 1.58 ± 0.1, P > 0.05) or OCP users (early follicular: 1.47 ± 0.1; ovulatory: 1.49 ± 0.1; midluteal: 1.47 ± 0.1, P > 0.05) (mean ± SEM). Resting cardiovascular responses were not affected by hormonal phase or OCP use, except that the SBP was higher in the OCP users than non-OCP users in all phases of the cycle (P < 0.05). In summary, our results demonstrate that cardiac vagal withdrawal at the onset of dynamic exercise was not impacted by the menstrual cycle or OCP use in physically active women.

Cardiac vagal withdrawal and reactivation during repeated rest-exercise transitions.

It is not known whether subjects that have higher cardiac vagal reactivation (CVR) during repeated exercise transitions also have higher cardiac vagal withdrawal (CVW) at the onset of exercise, which would lead to better heart rate (HR) regulation during exercise transitions. Therefore, our aims were to investigate: (a) the influence of CVR on CVW during repeated rest-exercise transitions; and (b) the influence of the sympathetic activity on CVR and CVW. Fifty-eight healthy men (22 ± 4 years) performed 20 rest-exercise transitions interspaced by 30 s. In addition, nine healthy men (24 ± 3 years) ingested either 25 mg of atenolol or placebo, on a crossover, double-blind, randomized design, then performed 20 rest-exercise transitions interspaced by 30 s. Cardiac vagal reactivation was assessed by a HR variability index (RMSSD) and CVW by the HR increase at the onset of a valid and reliable cycling protocol. The CVR and CVW responses were associated (partial r ranged from 0.60 to 0.66; p < 0.05). Participants with higher CVR over transitions maintained their CVW over repeated transitions [first transition (mean ± SEM) = 1.59 ± 0.04 vs. 20th = 1.50 ± 0.03 (a.u.), p = 0.24], while participants with lower CVR had a CVW decrease over repeated transitions [first transition (mean ± SEM) = 1.38 ± 0.04 vs. 20th = 1.19 ± 0.03 (a.u.), p < 0.01). In addition, the CVR and CVW over the rest-exercise transitions were similar during atenolol and placebo (ANCOVA interaction p = 0.12 and p = 0.48, respectively). In conclusion, the CVR among repeated rest-exercise transitions influenced the CVW at the onset of exercise, which was not affected by a partial ß(1) cardioselective adrenoceptor blockade.

Effect of muscle mass on muscle mechanoreflex-mediated heart rate increase at the onset of dynamic exercise.

This study was conducted to determine whether the heart rate increase at the onset of passive dynamic exercise is related to the amount of skeletal muscle mass engaged in movement. Fifteen healthy male subjects, 18-30 years old, performed, from the 4th to the 8th second of a 12-s apnea, four different 4-s bouts of passive cycling assigned in a counterbalanced order, each one different from the others by the number of limbs engaged in the movement (i.e., 1 arm, 2 arms, 2 arms + 1 leg and 2 arms + 2 legs), while respiratory movements and limb muscle electromyography were recorded. A repeated-measures ANOVA showed that the RR interval at the end of 4-s passive cycling was reduced in all the four different bouts (P < 0.05); the variations (delta values from pre-exercise to the end of 4 s of passive cycling) were directly related, in a non-linear trend, to the amount of muscle mass engaged in movement. These variations were more expressive when extremes were compared (110 +/- 16 vs. 184 +/- 24 ms, respectively, 1 limb vs. 4 limbs, P < 0.05), with differences observed from the first cardiac cycle after the onset of exercise. It was concluded that in healthy subjects, heart rate increase at the onset of passive cycling is directly related to the number of limbs and consequently the amount of muscle mass engaged, which is possibly related to a greater afferent input from stretch-sensitive muscle mechanoreceptors.

Similar cardiac vagal withdrawal at the onset of arm and leg dynamic exercise.

Electrocardiogram RR intervals duration reduce rapidly in the first seconds of dynamic exercise mainly due to a cardiac vagal withdrawal. However, it remains unclear if this response varies between exercises performed with different body segments (i.e. arm vs. leg). Our aim was to compare the vagal withdrawal at the onset of arm and leg dynamic exercise. Cardiac vagal withdrawal was assessed by the 4-s exercise test (4sET), a pharmacologically validated and highly reliable procedure. Initially, 60 healthy subjects performed the 4sET using arms (ARM 4sET) and legs (LEG 4sET), in a random order. Later, 20 of them repeated the testing, controlling for cycling rate and time of exercise onset within a RR interval, potential intervenient variables. Similar results were found for ARM and LEG 4sET considering the RR interval duration obtained immediately before the onset of exercise (RRB) (mean +/- SEM; 852 +/- 23 vs. 857 +/- 23 ms; P = 0.55), the shortest RR interval duration during exercise (RRC) (570 +/- 10 vs. 563 +/- 10 ms; P = 0.22) and the cardiac vagal index (CVI), which is the ratio between RRB and RRC (1.49 +/- 0.03 vs. 1.52 +/- 0.03; P = 0.10). Furthermore, high intraclass correlation coefficients were found (RRB r (i) = 0.94, P < 0.001; RRC r (i) = 0.85, P < 0.001; CVI r (i) = 0.81, P < 0.001). We conclude that similar cardiac vagal withdrawal was induced by 4-s fast unloaded cycling exercise performed with arms or legs.

Water intake accelerates post-exercise cardiac vagal reactivation in humans.

Post-exercise cardiac vagal reactivation is well-investigated; however, the effect of water intake during this period has not been well studied. Therefore, our aim was to assess the influence of water intake on the cardiac vagal reactivation after 30 min of a submaximal cycling exercise. Ten healthy subjects (eight men) aged 23-35 years were evaluated. A 3-day testing cycle duration, subjects were randomly chosen to drink either 500 ml (experimental visit) or 50 ml (control visit) of water immediately after the 30-min cycling exercise at a workload representing 80% of a previously measured anaerobic threshold. A cardiac vagal index (CVI) was obtained using the 4-s exercise test measured before and after (10 and 30 min) exercise at each testing day. Data analysis (2 x 3 ANOVA for repeated measures) showed higher cardiac vagal activity at the 30-min post-exercise period when 500 ml of water was ingested. CVI values for the 500 and 50 ml trials were 1.55 +/- 0.04 vs. 1.49 +/- 0.04, P = 0.003 (mean +/- SEM), respectively. Heart rate and blood pressure values were relatively the same. In conclusion, water intake of about 500 ml immediately after 30 min of cycling exercise accelerates post-exercise cardiac vagal reactivation. These results suggest that post-exercise hydration might be beneficial not only for thermoregulation, but also for vagal reactivation.

Evaluating cardiac vagal activity on a conventional electrocardiogram.

OBJECTIVE: To determine the viability of using a conventional electrocardiogram (ECG) tracing for assessment of CVA. METHODS: We retrospectively analyzed 1395 individuals (995 males), aged 46 +/- 17.2 years (mean +/- standard deviation) with conventional ECG tracings to measure the delta RR (which represents the difference in milliseconds (ms) between the greatest and smallest RR interval) and results of a second autonomic parasympathetic evaluation, the 4-second exercise test (T4s), that quantifies CVA by the cardiac vagal index (CVI). ROC curves were obtained to determine the values of Delta RR for a closer correlation with sensitivity and specificity for 1.20 and 1.95 ms, the low and high CVA cutoff points, respectively. RESULTS: The delta RR levels correlated significantly with those of the CVI (r=0.40; p<0.001). We identified < or = 60 and > or = 120 ms as the best cutoff points for low and high CVA. Sensitivity was 75% and 57%, specificity was 62% and 79%, and the areas of the ROC curves were 0.76 and 0.74, respectively. CONCLUSION: The visual measurement of delta RR on an ECG tracing seems to be a valid quick preliminary clinical evaluation of CVA and can be useful in medical offices, emergency units, or situations in which the use of more sophisticated methods may not be feasible, appropriate, or convenient.

Avaliando a atividade vagal cardíaca na eletrocardiografia convencional / Evaluating cardiac vagal activity on a conventional electrocardiogram

OBJETIVO: Determinar a viabilidade da utilização de traçado convencional de eletrocardiografia (ECG) para avaliação da atividade vagal cardíaca (AVC). MÉTODOS: Foram analisados, retrospectivamente, 1.395 indivíduos (995 homens), na faixa de idade de 46 + 17,2 anos (média ± desvio padrão), com traçados de ECG convencional para medida do Delta RR, que representa a diferença, em ms, entre o maior e o menor intervalo RR, e com resultados da avaliação autonômica parassimpática, o teste de exercício de quatro segundos (T4s), que quantifica a AVC por meio do índice vagal cardíaco (IVC). Foram obtidas curvas ROC para determinar os valores de Delta RR com melhor relação entre sensibilidade e especificidade para os pontos de corte de baixa e alta AVC, respectivamente, de 1,20 e 1,95. RESULTADOS: Os valores de delta RR correlacionaram-se significativamente com os de IVC (r = 0,40; p < 0,001). Foram identificados < 60 ms e > 120 ms como os melhores pontos de corte para baixa e alta AVC, com sensibilidade de 75 por cento e 57 por cento, especificidade de 62 por cento e 79 por cento e áreas das curvas ROC de 0,76 e 0,74, respectivamente. CONCLUSÃO: A medida visual do delta RR em um traçado de ECG parece ser válida para a avaliação clínica preliminar e rápida da AVC, podendo ser útil em consultórios, emergências ou situações nas quais o uso de métodos mais sofisticados de avaliação autonômica não seja viável, oportuno ou conveniente.

OBJECTIVE: To determine the viability of using a conventional electrocardiogram (ECG) tracing for assessment of CVA. METHODS: We retrospectively analyzed 1395 individuals (995 males), aged 46 ± 17.2 years (mean ± standard deviation) with conventional ECG tracings to measure the delta RR (which represents the difference in milliseconds (ms) between the greatest and smallest RR interval) and results of a second autonomic parasympathetic evaluation, the 4-second exercise test (T4s), that quantifies CVA by the cardiac vagal index (CVI). ROC curves were obtained to determine the values of Delta RR for a closer correlation with sensitivity and specificity for 1.20 and 1.95 ms, the low and high CVA cutoff points, respectively. RESULTS: The delta RR levels correlated significantly with those of the CVI (r=0.40; p<0.001). We identified < 60 and > 120 ms as the best cutoff points for low and high CVA. Sensitivity was 75 percent and 57 percent, specificity was 62 percent and 79 percent, and the areas of the ROC curves were 0.76 and 0.74, respectively. CONCLUSION: The visual measurement of delta RR on an ECG tracing seems to be a valid quick preliminary clinical evaluation of CVA and can be useful in medical offices, emergency units, or situations in which the use of more sophisticated methods may not be feasible, appropriate, or convenient.