Antiarrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction.

BACKGROUND: Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction. METHODS: Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (Smax) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation. RESULTS: TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and Smax was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity. CONCLUSIONS: TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in Smax, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.

Interaction of simultaneous hypoxia and baroreflex loading on control of sympathetic action potential subpopulations.

Efferent muscle sympathetic nerve activity (MSNA) is under tonic baroreflex control. The arterial baroreflex exerts the strongest influence over medium-sized sympathetic action potential (AP) subpopulations in efferent MSNA recordings. Prior work from multiunit MSNA recordings has shown baroreflex loading selectively abolishes the sympathetic response to hypoxia. The purpose of the study was to examine baroreflex control over different-sized AP clusters and characterize the neural recruitment strategies of sympathetic AP subpopulations with baroreflex and combined baroreflex/chemoreflex (i.e., hypoxia) activation. We loaded the arterial baroreceptors [intravenous phenylephrine (PE)] alone and in combination with systemic hypoxia ([Formula: see text] 80%) in nine healthy young men. We extracted sympathetic APs using the wavelet-based methodology and quantified baroreflex gain for individual AP clusters. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability versus diastolic blood pressure for 10 normalized clusters. Baroreflex loading with phenylephrine decreased MSNA and AP firing compared with baseline (all P < 0.05). However, the phenylephrine-mediated decrease in AP firing was lost with concurrent hypoxia (P = 0.384). Compared with baseline, baroreflex loading reduced medium-sized AP cluster baroreflex threshold slope (condition P = 0.005) and discharge probability (condition P < 0.0001); these reductions from baseline were maintained during simultaneous hypoxia (both P < 0.05). Present findings indicate a key modulatory role of the baroreceptors on medium-sized APs in blood pressure regulation that withstands competing signals from peripheral chemoreflex activation.NEW & NOTEWORTHY This study provides a novel understanding on baroreflex control of efferent sympathetic nervous system activity during competing stressors: baroreflex loading and peripheral chemoreflex activation. We show chemoreflex activation buffers baroreflex-mediated reductions in sympathetic nervous system activity. More importantly, baroreflex loading reduced baroreflex threshold gain of sympathetic action potential clusters and this reduction withstood chemoreflex activation. These data suggest the arterial baroreflex holds a primary regulatory role over medium-sized sympathetic neurons despite competing chemoreflex signals.

Does a single oral administration of amiloride affect spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults?

Preclinical models indicate that amiloride (AMD) reduces baroreflex sensitivity and perturbs homeostatic blood pressure (BP) regulation. However, it remains unclear whether these findings translate to humans. This study investigated whether oral administration of AMD reduces spontaneous cardiac and sympathetic baroreflex sensitivity and perturbs BP regulation in healthy young humans. Heart rate (HR; electrocardiography), beat-to-beat BP (photoplethysmography), and muscle sympathetic activity (MSNA, microneurography) were continuously measured in 10 young subjects (4 females) during rest across two randomized experimental visits: 1) after 3 h of oral administration of placebo (PLA, 10 mg of methylcellulose within a gelatin capsule) and 2) after 3 h of oral administration of AMD (10 mg). Visits were separated for at least 48 h. We calculated the standard deviation and other indices of BP variability. Spontaneous cardiac baroreflex was assessed via the sequence technique and cardiac autonomic modulation through time- and frequency-domain HR variability. The sensitivity (gain) of the sympathetic baroreflex was determined via weighted linear regression analysis between MSNA and diastolic BP. AMD did not affect HR, BP, and MSNA compared with PLA. Indexes of cardiac autonomic modulation (time- and frequency-domain HR variability) and BP variability were also unchanged after AMD ingestion. Likewise, AMD did not modify the gain of both spontaneous cardiac and sympathetic arterial baroreflex. A single oral dose of AMD does not affect spontaneous arterial baroreflex sensitivity and BP variability in healthy young adults.NEW & NOTEWORTHY Preclinical models indicate that amiloride (AMD), a nonselective antagonist of the acid-sensing ion channels (ASICs), impairs baroreflex sensitivity and perturbs blood pressure regulation. We translated these findings into humans, investigating the impact of acute oral ingestion of AMD on blood pressure variability and spontaneous cardiac and sympathetic baroreflex sensitivity in healthy young humans. In contrast to preclinical evidence, AMD does not impair spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults.

Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults.

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.

Complete autonomic blockade reveals nitric oxide contribution to blood pressure regulation in obese Black women.

PURPOSE: Hypertension is one of the major causes of cardiovascular morbidity and mortality in the USA and disproportionately affects Black women. Endothelial-derived nitric oxide (eNO) substantially regulates blood pressure in humans, and impaired NO-mediated vasodilation has been reported in the Black population. Previous studies using an NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA) did not fully determine the NO contribution to blood pressure because of baroreflex buffering. Therefore, in the present study we used trimethaphan, a ganglionic blocker, to inhibit baroreflex buffering and study NO modulation of blood pressure in Black women during L-NMMA infusion. METHODS: L-NMMA at doses of 250 µg/kg per minute was infused in combination with trimethaphan at doses of 4 mg/min to eliminate baroreflex mechanisms. Heart rate (HR) was obtained with continuous electrocardiogram monitoring, and continuous blood pressure was measured with the volume clamp method. The increase in systolic blood pressure (SBP) during both infusions was used to estimate the contribution of NO to blood pressure. RESULTS: Ten Black (age range 30-50 years, body mass index [BMI] 30-45 kg/m2), and nine White women (age range 30-50 years, body mass index 30-45 kg/m2) were enrolled in this study. During autonomic blockade, there was no difference in the decrease in SBP between Black and White women (- 20 ± 16.45 vs. - 24 ± 15.49 mm Hg, respectively; P = 0.659). When autonomic blockade was combined with L-NMMA, Black women had a significant increase in SBP compared to White women (54 ± 13.62 vs. 39 ± 09.64 mm Hg, respectively; P = 0.022, respectively). CONCLUSION: Autonomic blood pressure regulation was similar between Black and White women. However, NO contribution to blood pressure was significantly greater in Black women compared to White women. REGISTRATION: ClinicalTrials.gov: NCT01122407.

Intranasal orexin A modulates sympathetic vascular tone: a pilot study in healthy male humans.

Previous research suggests that the neuropeptide orexin A contributes to sympathetic blood pressure (BP) control inasmuch as hypothalamic injection of orexin A increases sympathetic vasomotor tone and arterial BP in rodents. In humans with narcolepsy, a disorder associated with loss of orexin-producing neurons, vasoconstrictive muscle sympathetic nerve activity (MSNA) is reduced. Since intranasally administered oligopeptides like orexin are known to modulate brain function, we investigated the effect of intranasal orexin A on vascular sympathetic baroreflex function in healthy humans. In a balanced, double-blind crossover study, orexin A (500 nmol) and placebo, respectively, were intranasally administered to 10 lean healthy males (age 25.8 ± 4.6 yr). MSNA was assessed microneurographically before and 30-45 min after either substance administration. Additionally, baroreflex was challenged via graded infusions of vasoactive drugs before and after substance administration. Baroreflex function was defined as the correlation of BP with MSNA and heart rate. Intranasal orexin A compared with placebo induced a significant increase in resting MSNA from pre-to postadministration [Δburst rate, orexin A vs. placebo: +5.8 ± 0.8 vs. +2.1 ± 0.6 bursts/min, P = 0.007; total activity 169 ± 11.5% vs. 115 ± 5.0%; P = 0.002]. BP, heart rate, and sympathovagal balance to the heart, as represented by heart rate variability (HRV), as well as baroreflex sensitivity during the vasoactive challenge were not altered. Intranasally administered orexin A acutely induced vasoconstrictory sympathoactivation in healthy male humans. This result suggests that orexin A mediates upward resetting of the vascular baroreflex set point at centers superordinate to the mere baroreflex feedback loop.NEW & NOTEWORTHY Our pilot study adds another important part to the complex network of neuroendocrine-sympathetic interaction. Our results demonstrate that intranasal orexin A elicits an excitatory effect on sympathetic vascular tone superordinate to mere baroreflex feedback regulation. This resetting of the baroreflex set point suggests an activation of hypothalamic core centers such as the paraventricular nucleus (PVN). The role of the orexinergic system in the development of neurogenic arterial hypertension warrants further investigations.

Patterns of cardio-respiratory motor outputs during acute and subacute exposure to chlorpyrifos in an ex-vivo in situ preparation in rats.

While a considerable body of literature has characterized the clinical features induced by organophosphate pesticides, the field lacks scrutiny into cardio-respiratory changes in different phases of poisoning. Herein, we evaluated the impact of chlorpyrifos (CPF) and its active metabolite chlorpyrifos-oxon (CPO) on the cardiorespiratory system during acute and subacute phases of poisoning using an in situ experimental rodent model. CPF (30 mg/kg) was injected intraperitoneally to rats beforehand (24 h) whereas CPO (15 mg/kg) was added into the perfusate reservoir to evaluate the effects on the motor outputs throughout the three phases of the respiratory cycle: inspiration, post-inspiration and late expiration. Phrenic, recurrent laryngeal (RLN) and thoracic sympathetic nerve activity (tSNA) were recorded. Heart rate was derived from the electrocardiogram (ECG) and the baro- and chemo-reflexes tested. CPF and CPO led to a time-dependent change in cardiorespiratory motor outputs. In the acute phase, the CPO induced bradypnea, transiently reduced the inspiratory time (TI), and increased the amplitude of phrenic. Post-inspiratory (PI) discharge recorded from the RLN was progressively reduced while tSNA was increased. CPO significantly depressed the chemoreflex but had no effect on baroreflex. During subacute phase, CPF prolongated TI with no effect on respiratory rate. Both the RLN PI discharge, the chemoreflex and the baroreflex sympathetic gain were reduced. In addition, both CPF and CPO shifted the cardiac sympatho-vagal balance towards sympathetic dominance. Our data show that different phases of poisoning are associated with specific changes in the cardio-respiratory system and might therefore demand distinct approaches by health care providers.

Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Neurotoxicity is one of its major adverse effects that often demands dose limitation. However, the effects of chronic oxaliplatin on the toxicity of the autonomic nervous system regulating cardiorespiratory function and adaptive reflexes are unknown. Male Sprague Dawley rats were treated with intraperitoneal oxaliplatin (3 mg kg-1 per dose) 3 times a week for 14 days. The effects of chronic oxaliplatin treatment on baseline mean arterial pressure (MAP); heart rate (HR); splanchnic sympathetic nerve activity (sSNA); phrenic nerve activity (PNA) and its amplitude (PNamp) and frequency (PNf); and sympathetic reflexes were investigated in anaesthetised, vagotomised and artificially ventilated rats. The same parameters were evaluated after acute oxaliplatin injection, and in the chronic treatment group following a single dose of oxaliplatin. The amount of platinum in the brain was determined with atomic absorption spectrophotometry. Chronic oxaliplatin treatment significantly increased MAP, sSNA and PNf and decreased HR and PNamp, while acute oxaliplatin had no effects. Platinum was accumulated in the brain after chronic oxaliplatin treatment. In the chronic oxaliplatin treatment group, further administration of a single dose of oxaliplatin increased MAP and sSNA. The baroreceptor sensitivity and somatosympathetic reflex were attenuated at rest while the sympathoexcitatory response to hypercapnia was increased in the chronic treatment group. This is the first study to reveal oxaliplatin-induced alterations in the central regulation of cardiovascular and respiratory functions as well as reflexes that may lead to hypertension and breathing disorders which may be mediated via accumulated platinum in the brain.

Bed nucleus of the stria terminalis modulates baroreflex cardiac activity: an interaction between alpha-1 receptors and NMDA/nitric oxide pathway.

The bed nucleus of the stria terminalis (BNST) is a forebrain structure, involved in the modulation of neuroendocrine, cardiovascular and autonomic responses. One of the responses is baroreflex activity, which consists in a neural mechanism responsible for keeping the blood pressure within a narrow range of variation. It has been reported that blockade of BNST α1-adrenoceptors increased the bradycardic component of baroreflex. In addition, such receptors are able to modulate glutamate release in this structure. Interestingly, BNST NMDA receptor antagonism and neuronal nitric oxide synthase (nNOS) inhibition led to the same effect of the α1-adrenoceptors blockade on baroreflex bradycardic response. Therefore, the hypothesis of the present study is that BNST noradrenergic transmission interacts with NMDA/NO pathway through α1 adrenoceptors to modulate the baroreflex activity. Male Wistar rats had stainless steel guide cannulas bilaterally implanted in the BNST. Subsequently, a catheter was inserted into the femoral artery for cardiovascular recordings, and into the femoral vein for assessing baroreflex activation. Injection of the noradrenaline reuptake inhibitor reboxetine in the BNST did not modify the tachycardic, but significantly decreased the bradycardic component of baroreflex. Administration of an α1, but not an α2 antagonist into the BNST prior to reboxetine prevented this effect. Likewise, previous injection of NMDA/NO pathway blockers inhibited the effect of reboxetine on bradycardic response. In conclusion, it was demonstrated for the first time the existence of an interaction between BNST noradrenergic, glutamatergic and nitrergic neurotransmissions in the modulation of bradycardic baroreflex response.

Chronic intermittent hypoxia impairs diuretic and natriuretic responses to volume expansion in rats with preserved low-pressure baroreflex control of the kidney.

We examined the effects of exposure to chronic intermittent hypoxia (CIH) on baroreflex control of renal sympathetic nerve activity (RSNA) and renal excretory responses to volume expansion (VE) before and after intrarenal transient receptor potential vanilloid 1 (TRPV1) blockade by capsaizepine (CPZ). Male Wistar rats were exposed to 96 cycles of hypoxia per day for 14 days (CIH) or normoxia. Urine flow and absolute Na+ excretion during VE were less in CIH-exposed rats, but the progressive decrease in RSNA during VE was preserved. Assessment of the high-pressure baroreflex revealed an increase in the operating and response range of RSNA and decreased slope in CIH-exposed rats with substantial hypertension [+19 mmHg basal mean arterial pressure (MAP)] but not in a second cohort with modest hypertension (+12 mmHg). Intrarenal CPZ caused diuresis, natriuresis, and a reduction in MAP in sham-exposed (sham) and CIH-exposed rats. After intrarenal CPZ, diuretic and natriuretic responses to VE in CIH-exposed rats were equivalent to those of sham rats. TRPV1 expression in the renal pelvic wall was similar in both experimental groups. Exposure to CIH did not elicit glomerular hypertrophy, renal inflammation, or oxidative stress. We conclude that exposure to CIH 1) does not impair the low-pressure baroreflex control of RSNA; 2) has modest effects on the high-pressure baroreflex control of RSNA, most likely indirectly due to hypertension; 3) can elicit hypertension in the absence of kidney injury; and 4) impairs diuretic and natriuretic responses to fluid overload. Our results suggest that exposure to CIH causes renal dysfunction, which may be relevant to obstructive sleep apnea.

Acute effects of electronic cigarettes on arterial pressure and peripheral sympathetic activity in young nonsmokers.

Electronic cigarettes (e-cigarettes) are marketed as an alternative to smoking for those who want to decrease the health risks of tobacco. Tobacco cigarettes increase heart rate (HR) and arterial pressure, while reducing muscle sympathetic nerve activity (MSNA) through sympathetic baroreflex inhibition. The acute effects of e-cigarettes on arterial pressure and MSNA have not been reported: our purpose was to clarify this issue. Using a randomized crossover design, participants inhaled on a JUUL e-cigarette containing nicotine (59 mg/mL) and a similar placebo e-cigarette (0 mg/mL). Experiments were separated by ∼1 mo. We recorded baseline ECG, finger arterial pressure (n = 15), and MSNA (n = 10). Subjects rested for 10 min (BASE) and then inhaled once every 30 s on an e-cigarette that contained nicotine or placebo (VAPE) for 10 min followed by a 10-min recovery (REC). Data were expressed as Δ means ± SE from BASE. Heart rate increased in the nicotine condition during VAPE and returned to BASE values in REC (5.0 ± 1.3 beats/min nicotine vs. 0.1 ± 0.8 beats/min placebo, during VAPE; P < 0.01). Mean arterial pressure increased in the nicotine condition during VAPE and remained elevated during REC (6.5 ± 1.6 mmHg nicotine vs. 2.6 ± 1 mmHg placebo, during VAPE and 4.6.0 ± 1.7 mmHg nicotine vs. 1.4 ± 1.4 mmHg placebo, during REC; P < 0.05). MSNA decreased from BASE to VAPE and did not restore during REC (-7.1 ± 1.6 bursts/min nicotine vs. 2.6 ± 2 bursts/min placebo, during VAPE and -5.8 ± 1.7 bursts/min nicotine vs. 0.5 ± 1.4 bursts/min placebo, during REC; P < 0.05). Our results show that acute e-cigarette usage increases mean arterial pressure leading to a baroreflex-mediated inhibition of MSNA.NEW & NOTEWORTHY The JUUL e-cigarette is the most popular e-cigarette in the market. In the present study, inhaling on a JUUL e-cigarette increased mean arterial pressure and heart rate, and decreased muscle sympathetic nerve activity (MSNA). In contrast, inhaling on a placebo e-cigarette without nicotine elicited no sympathomimetic effects. Although previous tobacco cigarette studies have demonstrated increased mean arterial pressure and MSNA inhibition, ours is the first study to report similar responses while inhaling on an e-cigarette. Listen to this article's corresponding podcast at @ https://ajpheart.podbean.com/e/aerosolized-nicotine-and-cardiovascular-control/.

Morning sympathetic activity after evening binge alcohol consumption.

Binge alcohol consumption elicits acute and robust increases of muscle sympathetic nerve activity (MSNA), yet the impact of evening binge drinking on morning-after MSNA is unknown. The present study examined the effects of evening binge alcohol consumption on polysomnographic sleep and morning-after MSNA. We hypothesized that evening binge drinking (i.e. 4-5 drink equivalent in <2 h) would reduce sleep quality and increase morning-after blood pressure (BP) and MSNA. Following a familiarization night within the sleep laboratory, 22 participants (12 men, 10 women; 25 ± 1 yr) were examined after simulated binge drinking or fluid control (randomized, crossover design). Morning MSNA was successfully recorded across both conditions in 16 participants (8 men, 8 women) during a 10-min baseline and three Valsalva's maneuvers (VM). Binge drinking reduced rapid eye movement (REM) sleep (15 ± 1 vs. 20 ± 1%, P = 0.003), increased stage II sleep (54 ± 1 vs. 51 ± 1%, P = 0.002), and increased total urine output (2.9 ± 0.2 vs. 2.1 ± 0.1 liters, P < 0.001) but did not alter morning-after urine specific gravity. Binge drinking increased morning-after heart rate [65 (54-72) vs. 58 (51-67) beats/min, P = 0.013] but not resting BP or MSNA. Binge drinking elicited greater sympathoexcitation during VM (38 ± 3 vs. 43 ± 3 bursts/min, P = 0.036). Binge drinking augmented heart rate (P = 0.002), systolic BP (P = 0.022), and diastolic BP (P = 0.037) reactivity to VM phase IV and blunted cardiovagal baroreflex sensitivity during VM phases II (P = 0.028) and IV (P = 0.043). In conclusion, evening binge alcohol consumption disrupted REM sleep and morning-after autonomic function. These findings provide new mechanistic insight into the potential role of binge drinking on cardiovascular risk.NEW & NOTEWORTHY Chronic binge alcohol consumption is associated with future cardiovascular disease (CVD) risk in both men and women. In addition, binge alcohol consumption is known to disrupt normal sleep quality during the early morning hours, coinciding with the morning sympathetic surge. In the present study, an evening of binge alcohol consumption increased baseline morning heart rate and cardiovascular reactivity during the Valsalva maneuver (VM) strain. Specifically, muscle sympathetic nerve activity and phase IV hemodynamic responses increased during VM the morning after binge alcohol consumption. The autonomic dysfunction and increased cardiovascular reactivity during VM suggests a contributing mechanism to CVD risk present in individuals who binge drink.

Acute effects of sublingual nitroglycerin on cardiovagal and sympathetic baroreflex sensitivity.

The effects of nitroglycerin (glyceryl trinitrate, GTN) on baroreflex sensitivity (BRS) are incompletely understood. Moreover, there are no reports evaluating the acute responses in both the sympathetic BRS (SBRS) and the cardiovagal BRS (CBRS) to the administration of sublingual GTN. We hypothesized that sublingual GTN modulates both CBRS and SBRS. In 10 healthy subjects, beat-to-beat heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were recorded before and for 10 min after sublingual administration of GTN 0.4 mg. SBRS was evaluated from the relationship between spontaneous variations in diastolic BP and MSNA. CBRS was assessed with the sequence technique. These variables were assessed during baseline, during 3rd-6th min (post A), and 7th-10th min (post B) after GTN administration. Two min after GTN administration, MSNA increased significantly and remained significantly elevated during recording. Compared with baseline, CBRS decreased significantly (post A: 12.9 ± 1.6 to 7.1 ± 1.0 ms/mmHg, P < 0.05), whereas SBRS increased significantly (post A: 0.8 ± 0.2 to 1.5 ± 0.2 units·beat-1·mmHg-1, P < 0.05) with an upward shift of the operating point. There were no differences in these variables between posts A and B. A clinical dose of GTN increased MSNA rapidly through effects on both CBRS and SBRS. These effects should be kept in mind when nitrates are used to clinically treat chest pain and acute coronary syndromes and used as vasodilators in experimental settings.

Nicotinamide attenuates streptozotocin-induced diabetes complications and increases survival rate in rats: role of autonomic nervous system.

BACKGROUND: To evaluate the effect of nicotinamide prior to streptozotocin-induced (STZ) diabetes in baroreflex sensitivity and cardiovascular autonomic modulation, and its association with hemodynamics and metabolic parameters. METHODS: Methods: Male Wistar rats were divided into control (Cont) and STZ-induced diabetes (Diab). Half of the rats from each group received a single dose of nicotinamide (100 mg/Kg) before STZ injection (Cont+NicA and Diab+NicA). All groups were followed-up for 5 weeks. RESULTS: Body weight loss of more than 40% was observed in Diab throughout the period (Diab: 271.00 ± 12.74 g; Diab+NicA: 344.62 ± 17.82). Increased glycemia was seen in Diab rats (541.28 ± 18.68 mg/dl) while Diab+NicA group had a slight decrease (440.87 ± 20.96 mg/dl). However, insulin resistance was observed only in Diab. In relation to Cont, heart rate, mean blood pressure and diastolic function were reduced when compared to Diab, together with parasympathetic modulation and baroreflex sensitivity. All of these parameters were improved in Diab+NicA when compared to Diab. Improved baroreflex sensitivity and parasympathetic modulation were correlated with glycemia, insulin resistance, and body weight mass. Additionally, Diab+NicA group increased survival rate. CONCLUSIONS: Results suggest that the association of nicotinamide in STZ-induced diabetic rats prevents most of the expected derangements mainly by preserving parasympathetic and baroreflex parameters.

Pharmacological characterization of MT-1207, a novel multitarget antihypertensive agent.

Hypertension is a serious public health problem worldwide. MT-1207, chemically named 3-(4-(4-(1H-benzotriazole-1-yl)butyl)piperazine-1-yl) benzisothiazole hydrochloride, is a new chemical entity that has entered into clinical trial as antihypertensive agent in China. In this paper we report the pharmacological profile of MT-1207 regarding its acute, subacute, and long-term effects on hypertensive animal models, and its actions on isolated organs in vitro as well as its molecular targets. Blood pressure (BP) was measured in conscious animals; amlodipine was taken as a positive control drug. We showed that both single dose of MT-1207 (1.25-20 mg/kg, ig) in spontaneously hypertensive rats (SHR) and MT-1207 (0.25-6 mg/kg, ig) in two-kidney one-clip (2K1C) dogs dose-dependently decreased BP. MT-1207 quickly decreased BP within 5 min after administration; the hypotensive effect lasted for 8 and 12 h, respectively, in SHR and 2K1C dogs without reflex increase in heart rate. Multiple doses of MT-1207 (5 mg · kg-1 · d-1 in SHR; 2 mg · kg-1 · d-1 in 2K1C dogs, for 7 days) significantly decreased BP, slightly reduced heart rate, and both of them recovered after withdrawal. Long-term administration of MT-1207 (10 mg · kg-1 · d-1 for 4 months or more time) produced a stable BP reduction, improved baroreflex sensitivity, reduced renal and cardiovascular damage in SHR, and delayed stroke occurrence and death in stroke-prone SHR. In isolated rat aortic rings precontracted by adrenaline, KCl, noradrenaline or 5-hydroxytryptamine (5-HT), MT-1207 (10-9-10-4 M) caused concentration-dependent relaxation. In a panel of enzyme activity or radioligand binding assays of 87 molecular targets, MT-1207 potently inhibited adrenergic α1A, α1B, α1D, and 5-HT2A receptors with Ki < 1 nM. The antagonism of MT-1207 against these receptors was confirmed in isolated rabbit arteries. We conclude that MT-1207 is a novel and promising single-molecule multitarget agent for hypertension treatment to reduce hypertensive organ damage and stroke mortality.

The baroreflex afferent pathway plays a critical role in H2S-mediated autonomic control of blood pressure regulation under physiological and hypertensive conditions.

Hydrogen sulfide (H2S), which is closely related to various cardiovascular disorders, lowers blood pressure (BP), but whether this action is mediated via the modification of baroreflex afferent function has not been elucidated. Therefore, the current study aimed to investigate the role of the baroreflex afferent pathway in H2S-mediated autonomic control of BP regulation. The results showed that baroreflex sensitivity (BRS) was increased by acute intravenous NaHS (a H2S donor) administration to renovascular hypertensive (RVH) and control rats. Molecular expression data also showed that the expression levels of critical enzymes related to H2S were aberrantly downregulated in the nodose ganglion (NG) and nucleus tractus solitarius (NTS) in RVH rats. A clear reduction in BP by the microinjection of NaHS or L-cysteine into the NG was confirmed in both RVH and control rats, and a less dramatic effect was observed in model rats. Furthermore, the beneficial effects of NaHS administered by chronic intraperitoneal infusion on dysregulated systolic blood pressure (SBP), cardiac parameters, and BRS were verified in RVH rats. Moreover, the increase in BRS was attributed to activation and upregulation of the ATP-sensitive potassium (KATP) channels Kir6.2 and SUR1, which are functionally expressed in the NG and NTS. In summary, H2S plays a crucial role in the autonomic control of BP regulation by improving baroreflex afferent function due at least in part to increased KATP channel expression in the baroreflex afferent pathway under physiological and hypertensive conditions.

Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension.

The renin-angiotensin-aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed.

Empagliflozin modulates renal sympathetic and heart rate baroreflexes in a rabbit model of diabetes.

AIMS/HYPOTHESIS: We determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits. METHODS: Diabetes was induced by alloxan, and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1 week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits. RESULTS: Four weeks after alloxan administration, blood glucose was threefold and MAP 9% higher than non-diabetic controls (p < 0.05). One week of treatment with empagliflozin produced a stable fall in blood glucose (-43%) and increased water intake (+49%) but did not change RSNA, MAP or heart rate compared with untreated diabetic rabbits. The maximum RSNA to hypotension was augmented by 75% (p < 0.01) in diabetic rabbits but the heart rate baroreflex was unaltered. Empagliflozin and acetazolamide reduced the augmentation of the RSNA baroreflex (p < 0.05) to be similar to the non-diabetic group. Noradrenaline (norepinephrine) spillover was similar in untreated diabetic and non-diabetic rabbits but twofold greater in empagliflozin- and acetazolamide-treated rabbits (p < 0.05). CONCLUSIONS/INTERPRETATION: As empagliflozin can restore diabetes-induced augmented sympathetic reflexes, this may be beneficial in diabetic patients. A similar action of the diuretic acetazolamide suggests that the mechanism may involve increased sodium and water excretion. Graphical abstract.

Worsening baroreflex sensitivity on progression to type 2 diabetes: localized vs. systemic inflammation and role of antidiabetic therapy.

Cardiac autonomic neuropathy (CAN) is an early cardiovascular manifestation of type 2 diabetes (T2D) that constitutes an independent risk factor for cardiovascular mortality and morbidity. Nevertheless, its underlying pathophysiology remains poorly understood. We recently showed that localized perivascular adipose tissue (PVAT) inflammation underlies the incidence of parasympathetic CAN in prediabetes. Here, we extend our investigation to provide a mechanistic framework for the evolution of autonomic impairment as the metabolic insult worsens. Early metabolic dysfunction was induced in rats fed a mild hypercaloric diet. Two low-dose streptozotocin injections were used to evoke a state of late decompensated T2D. Cardiac autonomic function was assessed by invasive measurement of baroreflex sensitivity using the vasoactive method. Progression into T2D was associated with aggravation of CAN to include both sympathetic and parasympathetic arms. Unlike prediabetic rats, T2D rats showed markers of brainstem neuronal injury and inflammation as well as increased serum levels of IL-1ß. Experiments on PC12 cells differentiated into sympathetic-like neurons demonstrated that brainstem injury observed in T2D rats resulted from exposure to possible proinflammatory mediators in rat serum rather than a direct effect of the altered metabolic profile. CAN and the associated cardiovascular damage in T2D only responded to combined treatment with insulin to manage hyperglycemia in addition to a nonhypoglycemic dose of metformin or pioglitazone providing an anti-inflammatory effect, coincident with the effect of these combinations on serum IL-1ß. Our present results indicate that CAN worsening upon progression to T2D involves brainstem inflammatory changes likely triggered by systemic inflammation.

Sympathetic arterial baroreflex hysteresis in humans: different patterns during low- and high-pressure levels.

Fluctuations in diastolic pressure modulate muscle sympathetic nerve activity (MSNA) through the arterial baroreflex. A higher sympathetic baroreflex sensitivity (sBRS) to pressure falls compared with rises has been reported; however, the underlying mechanisms are unclear. We assessed whether beat-to-beat falling and rising diastolic pressures operate on two distinct baroreflex response curves. Twenty-two men (32 ± 8 yr) underwent sequential bolus injections of nitroprusside and phenylephrine (modified Oxford test) with continuous recording of heart rate, blood pressure, and MSNA. The weighted negative linear regression slope between falling or rising diastolic pressure and MSNA burst incidence quantified sBRSfall and sBRSrise, respectively. The diastolic pressure evoking a MSNA burst incidence of 50 (T50) was calculated. sBRSfall was greater than sBRSrise (-6.24 ± 2.80 vs. -4.34 ± 2.16 bursts·100 heartbeats-1·mmHg-1, P = 0.01) and had a narrower operating range (14 ± 8 vs. 20 ± 10 mmHg, P = 0.01) that was shifted rightward (T50, 75 ± 9 and 70 ± 11 mmHg, P < 0.001). At diastolic pressures below baseline, sBRSfall was less than sBRSrise (-1.81 ± 1.31 vs. -3.59 ± 1.70 bursts·100 heartbeats-1·mmHg-1, P = 0.003) as low absolute pressures operated closer to the saturation plateau on the falling, compared with the rising pressure curve. At pressures above baseline, sBRSfall was greater than sBRSrise (-5.23 ± 1.94 and -3.79 ± 1.67 bursts·100 heartbeats-1·mmHg-1, P = 0.03). These findings demonstrate that the sympathetic arterial baroreflex possesses two response curves for processing beat-to-beat diastolic pressure falls and rises. The falling pressure curve is rightward shifted, which reduces sensitivity to falling pressure at low absolute pressures. This demonstrates that the direction of the hysteresis is influenced by the prevailing pressure level relative to each baroreflex response curve.NEW & NOTEWORTHY The findings show that the arterial baroreflex processes diastolic pressure dependent on the direction of pressure change from the previous beat, yielding two distinct baroreflex response curves to falling and rising pressure. Overall, the falling pressure curve is rightward shifted and more sensitive. The rightward shift caused a hysteresis reversal at hypotensive pressures as the falling pressure saturation plateau of the sigmoid response curve occurred at higher pressures than the rising pressure curve.