Similar Increases In Heart Rate Research Articles

Cortisol response under low intensity exercise during cognitive-behavioral therapy is associated with therapeutic outcome in panic disorder-an exploratory study.

Patients with Panic Disorder (PD) show an abnormal stress-induced functioning of the Hypothalamic-Pituitary-adrenal (HPA)-axis. Different protocols for stress induction are of rather low relevance for the psychotherapeutic treatment. In practice, interoceptive exposure is often realized as Low Intensity Exercise (LIE), as compared to an incremental cycle exercise test to exhaustion. Currently, it is not known, whether LIE displays an effective interoceptive stressor 1.) leading to a significant anxiety induction; 2.) a comparable HPA- and Sympathetic-Adreno-Medullar (SAM)-axis response in both patients and healthy controls; 3.) stress responses under LIE are associated with treatment outcomes. N = 20 patients with PD and n = 20 healthy controls were exposed to ten minutes of LIE on an exercise bike. LIE was applied as part of the interoceptive exposure, during an intensive Cognitive-Behavioral Therapy (CBT) in a day clinic. Heart rate was monitored and salivary cortisol samples collected. Before and after the LIE, state anxiety/ arousal were assessed. In order to evaluate psychopathology, the Panic and Agoraphobia Scale, Mobility Inventory, Agoraphobic Cognitions Questionnaire and Body Sensations Questionnaire were applied, before (T1) and after five weeks (T2) of an intensive CBT. LIE led to a significant and similar heart rate increase in both groups. Cortisol decreased over time in both groups, especially in male patients. A higher psychopathology before, and after CBT, was associated with a significantly lower cortisol response under LIE. In the present study, LIE led to a divergent stress response: while there was a significant heart rate increase, cortisol decreased over time, particularly in male patients. A lower reactivity of the HPA-axis seems to be associated with a lower treatment outcome, which may affect extinction based learning. The findings suggest, that interoceptive stimuli should be designed carefully in order to be potent stressors.

Regulation of heart rate following genetic deletion of the ß1 adrenergic receptor in larval zebrafish.

AimAlthough zebrafish are gaining popularity as biomedical models of cardiovascular disease, our understanding of their cardiac control mechanisms is fragmentary. Our goal was to clarify the controversial role of the ß1‐adrenergic receptor (AR) in the regulation of heart rate in zebrafish.MethodsCRISPR‐Cas9 was used to delete the adrb1 gene in zebrafish allowing us to generate a stable adrb1 −/− line. Larval heart rates were measured during pharmacological protocols and with exposure to hypercapnia. Expression of the five zebrafish adrb genes were measured in larval zebrafish hearts using qPCR.ResultsCompared with genetically matched wild‐types (adrb1 +/+ ), adrb1 −/− larvae exhibited ~20 beats min−1 lower heart rate, measured from 2 to 21 days post‐fertilization (dpf). Nevertheless, adrb1 −/− larvae exhibited preserved positive chronotropic responses to pharmacological treatment with AR agonists (adrenaline, noradrenaline, isoproterenol), which were blocked by propranolol (general ß‐AR antagonist). Regardless of genotype, larvae exhibited similar increases in heart rate in response to hypercapnia (1% CO2) at 5 dpf, but tachycardia was blunted in adrb1 −/− larvae at 6 dpf. adrb1 gene expression was abolished in the hearts of adrb1 −/− larvae, confirming successful knockout. While gene expression of adrb2a and adrb3a was unchanged, adrb2b and adrb3b mRNA levels increased in adrb1 −/− larval hearts.ConclusionDespite adrb1 contributing to the setting of resting heart rate in larvae, it is not strictly essential for zebrafish, as we generated a viable and breeding adrb1 −/− line. The chronotropic effects of adrenergic stimulation persist in adrb1 −/− zebrafish, likely due to the upregulation of other ß‐AR subtypes.

Cuff-Method Thigh Arterial Occlusion Counteracts Cerebral Hypoperfusion Against the Push-Pull Effect in Humans.

Exposure to acute transition from negative (−Gz) to positive (+ Gz) gravity significantly impairs cerebral perfusion in pilots of high-performance aircraft during push—pull maneuver. This push—pull effect may raise the risk for loss of vision or consciousness. The aim of the present study was to explore effective countermeasures against cerebral hypoperfusion induced by the push—pull effect. Twenty healthy young volunteers (male, 21 ± 1 year old) were tested during the simulated push–pull maneuver by tilting. A thigh cuff (TC) pressure of 200 mmHg was applied before and during simulated push—pull maneuver (−0.87 to + 1.00 Gz). Beat-to-beat cerebral and systemic hemodynamics were measured continuously. During rapid −Gz to + Gz transition, mean cerebral blood flow velocity (CBFV) was decreased, but to a lesser extent, in the TC bout compared with the control bout (−3.1 ± 4.9 vs. −7.8 ± 4.4 cm/s, P < 0.001). Similarly, brain-level mean blood pressure showed smaller reduction in the TC bout than in the control bout (−46 ± 12 vs. −61 ± 13 mmHg, P < 0.001). The systolic CBFV was lower but diastolic CBFV was higher in the TC bout. The systemic blood pressure response was blunted in the TC bout, along with similar heart rate increase, smaller decrease, and earlier recovery of total peripheral resistance index than control during the gravitational transition. These data demonstrated that restricting thigh blood flow can effectively mitigate the transient cerebral hypoperfusion induced by rapid shift from −Gz to + Gz, characterized by remarkable improvement of cerebral diastolic flow.

Renal Sympathetic Nerve Activity and Heart Rate Responses to Renal Pelvic Infusion of Bradykinin and Capsaicin in Rats Exposed to Intermittent Hypoxia

Renal oxidative stress and inflammation are evident in individuals with obstructive sleep apnea and in animals exposed to intermittent hypoxia (IH). It is known that kidney injury alters renal afferent nerve activity disrupting reno-renal reflex mechanisms. This study investigated reno-renal reflex changes in response to intra-renal pelvic infusion of bradykinin and capsaicin in rats exposed to IH. Wistar rats were exposed to 96 cycles of IH (6% O2, n=10) or to normoxia (sham, 21% O2, n=11) daily for 14 days. On day 15, rats were anesthetized (induction: urethane, α-chloralose and sodium pentobarbitone mixture i.p. (416, 27 and 33mg/kg), maintenance: urethane and α-chloralose mixture i.v. (62 and 4mg/kg)) to record cardiovascular parameters, renal sympathetic nerve activity (RSNA), and urine flow (UF). Intra-renal pelvic infusion of three doses of bradykinin (53µg/kg, 141µg/kg, 247µg/kg, for 5 min at 20µl/min in random order) was performed, and was repeated following the blockade of bradykinin receptors 1 (BK1R) and 2 (BK2R). Finally, an intra-renal pelvic infusion of capsaicin (0.133µg/kg) was performed. During infusions, changes in blood pressure, heart rate (HR) and contralateral RSNA were recorded. Urine samples were collected from the contralateral kidney. Data are expressed as mean±SD and were analyzed using t-test or ANOVA, where appropriate. IH rats were hypertensive (128±17 vs. 112±22mmHg) with elevated HR (440±37 vs. 403±42bpm), and increased basal UF (56±18 vs. 26±12µl/min/kg); all p<0.05. IH rats had increased resting RSNA, but this was not statistically significant (% of max: 19.6±6.4 vs. 14.8±7.2, p=0.105). All intra-renal pelvic doses of bradykinin augmented RSNA in IH and sham rats (all p<0.05), without changes in blood pressure during infusions. However, UF during bradykinin infusion was unchanged in IH and sham rats. Increases in RSNA and HR in response to 247µg/kg bradykinin were blunted in IH rats compared with shams (RSNA p=0.005; HR p=0.021), with diminished increase in RSNA most evident during the last three mins of infusion (% of baseline: 126±20 vs. 108±5%, p=0.016) and attenuated increase in HR during the last 30s of infusion (∆HR: +7±7 vs. +18±15bpm, p=0.05). This was also evident by a decrease in the area under RSNA curves (AUC) in IH rats compared with shams (1884±970 vs. 5437±3950%.s, p=0.046). AUC analysis revealed that increases in RSNA in response to bradykinin were attenuated during BK1R blockade (p=0.012), and greater suppression of bradykinin-induced increase in RSNA was observed following concurrent BK2R blockade (p=0.005). Intra-pelvic infusion of capsaicin induced a similar increase in HR, RSNA and UF in IH and sham rats. Protein expression of bradykinin and TRPV1 receptors in kidney tissue was equivalent between groups. However, in isolated renal pelvic wall, BK2R expression was 53% less in IH (n=4) compared with sham (n=4), but not statistically significant (p=0.120), which might be related to the small sample size. Our results indicate a blunted reflex increase in RSNA and HR in response to intra-pelvic bradykinin in IH rats, which could be due to down-regulation of the BK2R pathway.

Sex differences in heart rate responses to postural provocations

Sex differences are known in several facets of cardiac electrophysiology, mostly concerning myocardial repolarisation. In this study, heart rate and heart rate variability (HRV) responses to postural provocations were compared in 175 and 176 healthy females and males, respectively (aged 33.1 ± 9.1 years). Two different postural provocative tests with position changes supine→sitting→standing→supine and supine→standing→sitting→supine (15-min standing, 10-min other positions) were performed up to 4 times in each subject. Heart rate and heart rate variability spectral indices were measured in 5-min windows before positional changes. At supine position, females had averaged heart rate approximately 5 beats per minute (bpm) faster than males and this sex difference was practically constant during the postural changes. In both sexes, change supine→sitting and supine→standing increased heart rate by approximately 10 and 30 bpm, respectively, with no statistical differences between the sex groups. At supine baseline, females had normalised high frequency components (nHF) of HRV approximately 7% larger compared to males (p < 0.001). While the same difference in nHF was found at sitting, the change to standing position lead to significantly larger nHF reduction in females compared to males (mean changes 22.5 vs 17.2%, p < 0.001). This shows that despite similar heart rate increase, females respond to standing by more substantial shifts in cardiac sympatho-vagal modulations. This makes it plausible to speculate that the differences in autonomic reactions to stress contribute to the known sex-differences in psychosocial responses to stressful situations and to the known difference in susceptibility to ventricular fibrillation between females and males.

GABAergic Contribution to the Muscle Mechanoreflex‐Mediated Heart Rate Responses at the Onset of Exercise in Humans

It is well stablished that the cardiovascular response to exercise is governed by both central and peripheral mechanisms. However the possible neurotransmitters involved in the autonomic responses during exercise are not fully understood. During exercise, Potts et al. (Neuroscience 2003;119:201–14) showed that electrically evoked muscular contraction inhibits arterial baroreceptors signaling within the nucleus of the tractus solitaries (NTS) via activation of GABAergic receptors in rats, suggesting that skeletal muscle afferents are a potential source synaptic drive to GABAergic neurons within the NTS. However, the extent to which these findings can be extrapolated to humans remains unclear. We reasoned that the GABAergic mechanisms involved in the heart rate (HR) responses at the onset of dynamic exercise is primarily mediated by muscle mechanoreceptors afferents. Therefore, in this study we sought to determine if 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) aged between 18 to 35 years randomly performed three bouts of 5‐s of passive and active cycling under placebo and following oral administration of diazepam (10 mg), a benzodiazepine that produces an enhancement in GABAA activity. Beat‐to‐beat HR (electrocardiography) and arterial blood pressure (BP ‐ finger photopletysmography) were continuously measured. Electromyography of vastus lateralis was obtained to confirm no electrical activity during passive trials. HR increased from rest under placebo and further increased following administration of diazepam in both passive (Δ12 ± 1 beats min−1 vs. Δ17 ± 1 beats min−1, P &lt; 0.01) and active (Δ14 ± 1 beats min−1 vs. Δ18 ± 1 beats min−1, P &lt; 0.01) cycling. Arterial BP increased from rest similarly during all conditions. Importantly, no sex‐related differences were found in any variables during all experiments. These findings demonstrate for the first time that the central GABAergic mechanisms significantly contribute to the muscle mechanoreflex‐mediated cardiac vagal withdrawal at the onset of exercise in humans.Support or Funding InformationBrazilian National Council of Scientific and Technological Development (CNPq)Foundation for Research Support of Federal District (FAPDF)Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

OP 30 Maternal hemodynamics in hypertensive disorders and different feto-placental growth patterns, in pregnancy and post-partum

Maternal hemodynamics varies in different clinical phenotypes of preeclampsia: early placental damage associated with fetal growth restriction; maternal cardiovascular risk factors most frequently associated with appropriate feto-placental growth. We compared maternal hemodynamic profile during pregnancy and at 6–12 months postpartum in women affected by Hypertensive Disorder of Pregnancy (HDP), associated with two different feto-placental growth patterns. 89 patients from 24 weeks to term were enrolled in this prospective observational study: 24 HDP with appropriate for gestational age fetus (HDP-AGAf), 27 HDP with intrauterine growth restriction (HDP-IUGR), 16 normotensive women with severe IUGR (s-IUGR), 22 controls. Diagnosis of HDP was made according to the ISSHP criteria, with the exclusion of chronic hypertension. s-IUGR was defined as abdominal circumference 2SD. Maternal echocardiography was performed by a cardiologist blinded to clinical diagnosis, at recruitment and at 6–12 months postpartum. During pregnancy, HDP-IUGR showed significantly lower heart rate (HR), lower cardiac output (CO) and increased total vascular resistances (TVR), compared to controls. s-IUGR presented significantly lower CO and increased TVR, compared to controls. These profiles remained relatively unchanged at 6–12 months postpartum. HDP-AGAf showed increased CO as in control pregnancies, but significantly higher TVR; this group also presented significantly increased left ventricular mass (LVM) and relative wall thickness (RWT), and a reduced E/A ratio, indicating an impaired myocardial relaxation. In post-partum we observed persistently increased MAP values, due to high TVR, in spite of a return to normal HR and CO values. Our hypothesis, that prioritizes the feto-placental phenotype, allowed us to observe a significantly poor cardiovascular adaptation to pregnancy metabolic demands in HDP-IUGR and s-IUGR. This was profoundly different from uneventful pregnancies, characterized by increased HR and CO and low TVR. HDP-AGAf presented similar increase in HR and CO as in controls, but at the cost of diastolic function impairment and of left ventricle remodeling. In postpartum, HR and CO returned to normal, but TVR and MAP remained higher.

Cardiac remodeling and increased central venous pressure underlie elevated stroke volume and cardiac output of seawater-acclimated rainbow trout.

Substantial increases in cardiac output (CO), stroke volume (SV), and gastrointestinal blood flow are essential for euryhaline rainbow trout (Oncorhyncus mykiss) osmoregulation in seawater. However, the underlying hemodynamic mechanisms responsible for these changes are unknown. By examining a range of circulatory and cardiac morphological variables of seawater- and freshwater-acclimated rainbow trout, the present study revealed a significantly higher central venous pressure (CVP) in seawater-acclimated trout (~0.09 vs. -0.02 kPa). This serves to increase cardiac end-diastolic volume in seawater and explains the elevations in SV (~0.41 vs. 0.27 ml/kg) and CO (~21.5 vs. 14.2 ml·min-1·kg-1) when compared with trout in freshwater. Furthermore, these hemodynamic modifications coincided with a significant increase in the proportion of compact myocardium, which may be necessary to compensate for the increased wall tension associated with a larger stroke volume. Following a temperature increase from 10 to 16.5°C, both acclimation groups exhibited similar increases in heart rate (Q10 of ~2), but SV tended to decrease in seawater-acclimated trout despite the fact that CVP was maintained in both groups. This resulted in CO of seawater- and freshwater-acclimated trout stabilizing at a similar level after warming (~26 ml·min-1·kg-1). The consistently higher CVP of seawater-acclimated trout suggests that factors other than compromised cardiac filling constrained the SV and CO of these individuals at high temperatures. The present study highlights, for the first time, the complex interacting effects of temperature and water salinity on cardiovascular responses in a euryhaline fish species.

Altered autonomic nervous system reactivity to pain in trigeminal neuralgia.

In the past two decades, there has been increasing evidence to suggest that trigeminal neuralgia (TN) may be linked to a dysfunction of the autonomic nervous system (ANS). The aim of the present study was to formally test this hypothesis by comparing the reactivity of the ANS to experimental pain in a population of TN patients and healthy controls. Twelve patients diagnosed with classical TN and 12 healthy controls participated in the study. Cardiac activity was assessed while participants were instructed to rest and again during a cold pressor test (CPT). Heart rate variability analyses were performed off-line to obtain parasympathetic (high-frequency) and sympathetic (low-frequency) indices. At baseline, ANS measures did not differ between healthy controls and TN patients, and both groups showed a similar increase in heart rate during the CPT (all p values >0.05). However, TN patients showed a greater increase in cardiac sympathetic activity and a greater decrease in cardiac parasympathetic activity during CPT compared with healthy controls (all p values <0.05). Importantly, changes in sympathetic reactivity, from baseline to CPT, were negatively associated with the number of pain paroxysms experienced each day by TN patients in the preceding week (r=-.58, p<0.05). These results suggest that TN, like many other short-lasting, unilateral facial pain conditions, is linked to ANS alterations. Future studies are required to determine if the altered ANS response observed in TN patients is a cause or a consequence of TN pain.

In vivo creatine kinase reaction kinetics at rest and stress in type II diabetic rat heart

The effects of type II diabetes on cardiac creatine kinase (CK) enzyme activity and/or flux are unknown. We therefore measured steady‐state phosphocreatine (PCr) and adenosine triphosphate (ATP) content and forward CK reaction kinetic parameters in Zucker Diabetic Fatty (ZDF) rat hearts, a type II diabetes research model. At baseline the PCr to ATP ratio (PCr/ATP) was significantly lower in diabetic heart when compared with matched controls (1.71 ± 0.21 vs. 2.26 ± 0.24, P < 0.01). Furthermore, the forward CK reaction rate constant (kf) was higher in diabetic animals (0.52 ± 0.09 s−1 vs. 0.35 ± 0.06 s−1, P < 0.01) and CK flux calculated as a product of PCr concentration ([PCr]) and kf was similar between two groups (4.32 ± 1.05 μmol/g/s vs. 4.94 ± 1.23 μmol/g/s, P = 0.20). Dobutamine administration resulted in similar increases in heart rate (~38%) and kf (~0.12 s−1) in both groups. No significant change in PCr and ATP content was observed with dobutamine. In summary, our data showed reduced PCr/ATP in diabetic myocardium as an indicator of cardiac energy deficit. The forward CK reaction rate constant is elevated at baseline which might reflect a compensatory mechanics to support energy flux through the CK shuttle and maintain constant ATP supply. When hearts were stimulated similar increase in kf was observed in both groups thus it seems that CK shuttle does not limit ATP supply for the range of workload studied.

Is there any difference in pelvic floor muscles performance between continent and incontinent women?

To compare pelvic floor muscles (PFMs) performance in women with and without stress urinary incontinence (SUI) during endurance test. It is a prospective case-control clinical trial. After determining PFM maximal voluntary contraction (MVC) by electromyography (EMG), women underwent endurance test, which consisted of consecutively PFM 1-sec fast contractions reaching MVC amplitude followed by 1-sec rest. Training time guided by Borg perceived exertion scale was noted. Heart rate (HR) behavior and EMG variables were assessed before and after training making a physiological analysis in both groups. A total of 56 women, mean age 52.19 years old, were evaluated (26 continent and 30 incontinent women). The time that SUI and continent women took to reach fatigue (Borg 10) was 9.1 ± 4.7 and 14.19 ± 8.32 min, respectively (P = 0.006). Confirming that all women performed similar effort during the test, analysis of variance with repeated measures showed that during the endurance test both groups presented similar increase in HR, showing detectable and significant increase from resting time to Borg 10 (P < 0.001). Besides, there was similar behavior in EMG for continent and SUI women, with a decrease from the baseline resting amplitude (P = 0.003 for SUI women and P = 0.006 for continent women). Women with SUI showed worse performance during an endurance test than continent women. It suggests that women have different capacity to perform PFM training. An initial evaluation based on PFM performance would help to define the best individualized PFM training.

Abstract 528: Response of Muscle Sympathetic Nerve Activity to Heat Stress is Attenuated in Chronic Heart Failure

Cutaneous vascular conductance (CVC) rises during heat stress in normal humans. Recently, we showed that this response is attenuated in chronic heart failure (CHF), even though the skin sympathetic nerve activity response to heat stress was not attenuated. Of note, heat stress evokes significant increases in muscle sympathetic nerve activity (MSNA) in healthy individuals. This effect may allow flow to be distributed to other tissues. The MSNA response to heat stress in CHF has not been reported. We postulated that in CHF the MSNA response to heat stress is attenuated. Passive whole body heating was applied with water-perfused suits on 9 male (60 ± 3 yrs) patients with stable class II-III CHF and 9 age-matched male healthy subjects. Whole body heating induced similar increases in skin temperature (~4 °C), internal temperature (~0.6 °C), similar reduction in blood pressure, and similar increase in heart rate. The elevation in forearm CVC in CHF patients was significantly lower than that in healthy control subjects (102 ± 29 vs. 312 ± 54 units, P &lt; 0.001). While baseline MSNA in CHF was higher than in controls ( P &lt; 0.05); heat stress increased MSNA in the controls (33.2 ± 3.8 to 47.3 ± 4.4 bursts/min; 618 ± 74 to 934 ± 93 units/min, both P &lt; 0.001, N = 9), but not in CHF (43.4 ± 5.7 to 49.6 ± 7.0 bursts/min; 996 ± 104 to 1039 ± 108 units/min, both P &gt; 0.15, N = 6; two-factor ANOVA with repeated measure on one factor). Moreover, the MSNA change by heating in CHF was significantly lower than that in the controls (6.2 ± 2.6 to 14.1 ± 1.5 bursts/min; 43 ± 45 to 316 ± 34 units/min; both P &lt; 0.01, unpaired t-test). The attenuated MSNA response to heating was not due to a ceiling effect as that static fatiguing handgrip in CHF in a control trial evoked significant increases in MSNA. These data show that the MSNA response to heat stress is attenuated in CHF patients. We postulate that the attenuated MSNA response contributes to an impaired re-distribution of blood low to the skin during heat stress in CHF.

β3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure.

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. We have previously shown that in HF at rest stimulation of β3-adrenergic receptors by endogenous catecholamine depresses LV contraction and relaxation. β3-Adrenergic receptors are activated at higher concentrations of catecholamine. Thus exercise may cause increased stimulation of cardiac β3-adrenergic receptors and contribute to this abnormal response. We assessed the effect of L-748,337 (50 μg/kg iv), a selective β3-adrenergic receptor antagonist (β3-ANT), on LV dynamics during exercise in 12 chronically instrumented dogs with pacing-induced HF. Compared with HF at rest, exercise increased LV end-systolic pressure (PES), minimum LV pressure (LVPmin), and the time constant of LV relaxation (τ) with an upward shift of early diastolic portion of LV pressure-volume loop. LV contractility decreased and arterial elastance (EA) increased. LV arterial coupling (EES/EA) (0.40 vs. 0.51) was impaired. Compared with exercise in HF preparation, exercise after β3-ANT caused similar increases in heart rate and PES but significantly decreased τ (34.9 vs. 38.3 ms) and LVPmin with a downward shift of the early diastolic portion of LV pressure-volume loop and further augmented dV/dtmax. Both EES and EES/EA (0.68 vs. 0.40) were increased. LV mechanical efficiency improved from 0.39 to 0.53. In conclusion, after HF, β3-ANT improves LV diastolic filling; increases LV contractility, LV arterial coupling, and mechanical efficiency; and improves exercise performance.

A Comparison of the Subjective and Cardiovascular Effects Produced by Exposure to Intravenous versus Smoked Methamphetamine in the Laboratory

Previous research has demonstrated that intravenous (IV) and smoked cocaine administration produced similar increases in heart rate (HR) and blood pressure (BP), whereas comparable doses of smoked cocaine resulted in higher subjective ratings of stimulated and high. To our knowledge, there have not been any studies conducted directly comparing the subjective and cardiovascular responses produced by IV methamphetamine (METH) versus smoked METH. Thirteen non‐treatment seeking METH‐dependent individuals, participated in separate protocols in which they were administered IV METH and smoked METH. In the first study, participants were administered METH (0 and 30 mg, IV) and subjective effects, as well as cardiovascular effects, were assessed prior to and 5, 15, 30, 45, and 60 min after METH administration. In the second study, smoked METH (0 and 30 mg) was administered and subjective and cardiovascular effects were obtained on the same time course as above. While not reaching statistical significance, METH administered via the IV route resulted in higher BP and HR across the time course assessed. Interestingly, subjective reports of desire METH and likely to use METH was higher when the route of administration was smoked. These findings demonstrate that the administration of IV versus smoked METH have differential cardiovascular and subjective effects in METH‐dependent participants.

Nitric oxide and passive limb movement: a new approach to assess vascular function

Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC), but the peripheral vascular mechanisms associated with this increase in LBF and LVC are unknown. This study sought to determine the contribution of nitric oxide (NO) to movement-induced LBF and LVC and document the potential for passive-limb movement to assess NO-mediated vasodilatation and therefore NO bioavailability. Six subjects underwent passive knee extension with and without nitric oxide synthase (NOS) inhibition via intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA). LBF was determined second-by-second by Doppler ultrasound, and central haemodynamics were measured by finger photoplethysmography. Although L-NMMA did not alter the immediate increase (initial ∼9 s) in LBF and LVC, NOS blockade attenuated the peak increase in LBF (control: 653 ± 81; L-NMMA: 399 ± 112 ml(−1) min(−1), P = 0.03) and LVC (control: 7.5 ± 0.8; L-NMMA: 4.1 ± 1.1 ml min(−1) mmHg(−1), P = 0.02) and dramatically reduced the overall vasodilatory and hyperaemic response (area under the curve) by nearly 80% (LBF: control: 270 ± 51; L-NMMA: 75 ± 32 ml, P = 0.001; LVC: control: 2.9 ± 0.5; L-NMMA: 0.8 ± 0.3 ml mmHg(−1), P < 0.001). Passive movement in control and L-NMMA trials evoked similar increases in heart rate, stroke volume, cardiac output and a reduction in mean arterial pressure. As movement-induced increases in LBF and LVC are predominantly NO dependent, passive limb movement appears to have significant promise as a new approach to assess NO-mediated vascular function, an important predictor of cardiovascular disease risk.

Use of the Frank-Starling mechanism during exercise is linked to exercise-induced changes in arterial load

Effective arterial elastance(E(A)) is a measure of the net arterial load imposed on the heart that integrates the effects of heart rate(HR), peripheral vascular resistance(PVR), and total arterial compliance(TAC) and is a modulator of cardiac performance. To what extent the change in E(A) during exercise impacts on cardiac performance and aerobic capacity is unknown. We examined E(A) and its relationship with cardiovascular performance in 352 healthy subjects. Subjects underwent rest and exercise gated scans to measure cardiac volumes and to derive E(A)[end-systolic pressure/stroke volume index(SV)], PVR[MAP/(SV*HR)], and TAC(SV/pulse pressure). E(A) varied with exercise intensity: the ΔE(A) between rest and peak exercise along with its determinants, differed among individuals and ranged from -44% to +149%, and was independent of age and sex. Individuals were separated into 3 groups based on their ΔE(A)I. Individuals with the largest increase in ΔE(A)(group 3;ΔE(A)≥0.98 mmHg.m(2)/ml) had the smallest reduction in PVR, the greatest reduction in TAC and a similar increase in HR vs. group 1(ΔE(A)<0.22 mmHg.m(2)/ml). Furthermore, group 3 had a reduction in end-diastolic volume, and a blunted increase in SV(80%), and cardiac output(27%), during exercise vs. group 1. Despite limitations in the Frank-Starling mechanism and cardiac function, peak aerobic capacity did not differ by group because arterial-venous oxygen difference was greater in group 3 vs. 1. Thus the change in arterial load during exercise has important effects on the Frank-Starling mechanism and cardiac performance but not on exercise capacity. These findings provide interesting insights into the dynamic cardiovascular alterations during exercise.

Developmental changes in adolescents’ neural response to challenge

Adolescents often fail to adaptively regulate their emotions and behaviors. This is most clearly demonstrated by the marked increase during this period in fatalities that are attributable to preventable causes. Using functional magnetic resonance methodology, this study explored whether adolescents and adults differed in their engagement of prefrontal circuitry in response to a cognitive and emotional challenge. Twenty-four adolescents and twenty-three adults were scanned while they solved difficult math problems with induced failure and negative social evaluation. Data is reported from 23 adolescents and 23 adults. Adult and adolescent participants showed similar increases in heart rate when responding to the experimental challenge. Despite the similarity of the autonomic response, adolescents recruited a more restricted network of prefrontal regions as compared to adults. Both adolescents and adults recruited the dorsal anterior cingulate cortex and the dorsolateral prefrontal cortex, however adults additionally recruited the anterior insula. Functional connectivity between the anterior insula and other prefrontal regions was stronger in adults as compared to adolescents. Further, for adults, the magnitude of activity in the insula predicted lower autonomic activity in response to the challenge. Differences between adolescents and adults engagement of prefrontal networks may relate to adolescents’ poor behavioral and emotional regulation.

Interactive effects of development and hypoxia on catecholamine synthesis and cardiac function in zebrafish (Danio rerio)

The rate-limiting enzyme in the biosynthetic pathway of catecholamines is tyrosine hydroxylase (TH), the activity of which is dependent on molecular oxygen. Zebrafish (Danio rerio) possess two non-allelic TH coding genes, TH1 and TH2. A principal goal of the present study was to determine if the expression of these genes is sensitive to environmental hypoxia. Additionally, we sought to determine if catecholamine content of larvae was changed by environmental hypoxia, and whether the hearts of hypoxic larvae were equally responsive to exogenous catecholamine (norepinephrine) exposure. After 2 days of exposure to hypoxia [5-7 days post-fertilization (dpf); PO(2) = 30 Torr] TH2 mRNA expression was significantly lower and dopamine β hydroxylase (DβH) mRNA was significantly higher in whole larvae. Whole body catecholamine levels were unchanged until after 4 days of hypoxic exposure (5-9 dpf), at which time there was a significant increase in epinephrine and norepinephrine contents. Norepinephrine content was significantly elevated in the hearts of adult fish after 2 and 4 days of hypoxic exposure, and TH1 mRNA expression was increased in the kidney of both groups. After 2 or 4 days of exposure to hypoxia, larvae displayed significantly lower heart rates than normoxic fish. However, application of exogenous norepinephrine caused similar increases in heart rate in both groups. Overall, it is concluded that the mRNA expression of TH1 and TH2 is differentially affected by hypoxia exposure in larvae and adults. Also, catecholamine biosynthesis appears to be activated by 2 dpf and although whole body catecholamine levels increase during hypoxia (possibly promoting downregulation of cardiac β-adrenergic receptors), there is no accompanying decrease in the response of the heart to adrenergic stimulation.

Is the Standard Weight-Based Dosing of Dobutamine for Stress Testing Appropriate for Patients of Widely Varying Body Mass Index?

Although a gradual increase in heart rate (HR) during dobutamine stress testing (DST) is desired, few data exists regarding whether this is similarly achieved in patients of widely varying body mass index (BMI). Whether difference in BMI contributes to variation in the hemodynamic and symptomatic response to dobutamine is also unknown. From prospectively acquired data of 2776 consecutive patients who underwent DST according to standard weight-based clinical protocol, we classified patients into 4 groups of BMI (kg/m( 2)): <25 (normal), 25 to 29.9 (overweight), 30 to 39.9 (obese), and ≥ 40 (severely obese) and compared the rate of increase of HR, mean blood pressure, and development of symptoms for the groups. Age was 68 + 12 years, 52% were men, BMI was 29.8 + 6.6 kg/m(2) (range 14.5-81.4), 198 (7%) had BMI ≥ 40, and target HR was achieved in 2433 (88%). The rate of increase in HR was similar for each group of BMI after adjustment for age, gender, baseline HR, negative chronotropic use, and atropine administration. The percentage of patients in each group who achieved target HR was similar and the percentage of target HR achieved at each stage of dobutamine was essentially equivalent. Blood pressure responses and development of symptoms were similar in the 4 groups of BMI. Independent predictors of failure to achieve target HR included age, diabetes mellitus, treatment with negative chronotropic medications, and baseline HR; BMI was not a predictor (odds ratio [OR] 0.98, P = .086). The current weight-based protocol of dobutamine dosing for DST results in similar increases in HR and blood pressure for patients of widely varying BMI.

Effects of Simulation Versus Traditional Tutorial-Based Training on Physiologic Stress Levels Among Clinicians: A Pilot Study

Emotionality and heightened anxiety during medical simulation encounters have been hypothesized to contribute to improved cognition and learning, but the overall stress "dose response curve" of experiential learning remains unclear. We sought to (1) identify the degree and time course of physiologic stress induced in physicians by simulation-based training (SBT), when compared with a traditional tutorial-based interactive-education training (IET) and (2) compare differences in stress responses to simulation activities among pediatric provider groups. Twenty-seven gastroenterology physicians were randomized among six crisis resource management courses taught by SBT versus IET. Eleven RNs and four technicians participated in the SBT exercises. Heart rate (HR) and salivary cortisol (SC) levels were measured in all participants at four time points before, during, and after participation in the SBT sessions and at two time points before and after the IET sessions. Physicians who underwent SBT (n = 13) demonstrated increased tachycardia at the end of the session (+17 beats/min), when compared with those in the IET group (n = 14) who demonstrated an overall negative response (-4 beats/min, P = 0.001). Similarly, physicians in the SBT group demonstrated increased SC (+0.140 μg/dL, 70% over baseline), when compared with physicians in the IET group who had a median decrease in SC (-0.015 μg/dL, 20% under baseline, P = 0.001). There were similar increases in HR in all participants after SBT, but technicians experienced a relatively smaller increase in SC compared with physicians and nurses. After high-fidelity SBT within the gastroenterology suite, clinicians independent of their role demonstrated increased physiologic stress levels-as measured by HR and SC levels-compared with traditional IET sessions. The study provides novel calibration data compared with a traditional baseline for future investigations aimed at further understanding the dose-response curve of simulation-based experiences to optimize emotionality, cognition, and learning.