Changes In Plasma Norepinephrine Research Articles

Effects of Acute and Chronic Gabapentin Treatment on Cardiovascular Function of Rats

Gabapentin (GBP), a GABA analogue, is primarily used as an anticonvulsant to treat partial seizures and neuropathic pain. While a majority of the side effects are associated with the nervous system, emerging evidence suggests a high risk for heart disease in the patients taking GBP. Given GBP can bind with high affnity to the α2δ subunits of voltage-gated Ca2+ channels (VGCCs) to block Ca2+ influx of cardiomyocytes, we hypothesize GBP suppresses cardiac function by evoking calcium signaling dysfunction. By using a preclinical rat model treated with GBP, we investigated (1) the acute cardiovascular responses to GBP (bolus i.v. injection; 50 mg/kg, 100 mg/ml x 0.1 ml in 3 min) and (2) the effects of chronic GBP treatment (i.p. 100 mg/kg/day x 7 days) on cardiovascular function and the myocardial proteome. Under isoflurane-anesthesia, blood pressure (BP), heart rate (HR), and left ventricular (LV) hemodynamics of the rats were measured using two Millar pressure transducers; one was implanted in abdominal aorta via right femoral artery, and the another was implanted in the LV chamber via right carotid artery. The LV myocardium was analyzed by proteomics, bioinformatics, and western blot to explore the molecular mechanisms underlying GBP-induced cardiac dysfunction, with the brain cortex used as a control tissue. In experiment (1), we found that i.v. GBP treatment significantly decreased BP, HR, maximal LV pressure, and maximal and minimal dP/dt, whereas it increased IRP-AdP/dt, Tau, systolic, diastolic, and cycle durations (*p < 0.05 and **p < 0.01 vs baseline; n = 4/group). This cardiovascular inhibition started at the injection time point and lasted at least 60 min, with a maximal effect appearing at 30 min post injection. In experiment (2), we found that chronic GBP treatment resulted in hypotension, bradycardia, and LV systolic dysfunction, with no change in plasma norepinephrine. In the myocardium of these rats, we used mass spectra to identify 109 differentially expressed proteins involved in calcium pathways, cholesterol metabolism, and galactose metabolism. Particularly, we found that calmodulin, a key protein of intracellular calcium signaling, was significantly upregulated by GBP in the heart but not in the brain, suggesting a myocardium-specific dysregulation of calcium signaling pathway, which may play a critical role in GBP-induced cardiac inhibition. Subsequent bioinformatics assays revealed a reduced Ca2+ release of sarcoplasmic reticulum (SR) and increased electrophoretic Ca2+ uptake into the matrix of mitochondria in the hearts of GBP-treated rats. In summary, we found that acute and chronic GBP treatments suppressed cardiovascular function in rats, which is attributed to abnormal calcium signaling in cardiomyocytes where GBP binds to VGCCs to reduce extracellular Ca2+ influx and cytosolic Ca2+ release from SR, resulting in blockage of excitation-contraction coupling. These data reveal a novel side effect of GBP independent of the nervous system, providing important translational evidence to suggest that GBP can evoke adverse cardiovascular events by depression of myocardial function. This project is funded by NIH R01 HL 160820. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Acute and Chronic Gabapentin Treatment on Cardiovascular Function of Rats.

Gabapentin (GBP), a GABA analogue, is primarily used as an anticonvulsant for the treatment of partial seizures and neuropathic pain. Whereas a majority of the side effects are associated with the nervous system, emerging evidence suggests there is a high risk of heart diseases in patients taking GBP. In the present study, we first used a preclinical model of rats to investigate, firstly, the acute cardiovascular responses to GBP (bolus i.v. injection, 50 mg/kg) and secondly the effects of chronic GBP treatment (i.p. 100 mg/kg/day × 7 days) on cardiovascular function and the myocardial proteome. Under isoflurane anesthesia, rat blood pressure (BP), heart rate (HR), and left ventricular (LV) hemodynamics were measured using Millar pressure transducers. The LV myocardium and brain cortex were analyzed by proteomics, bioinformatics, and western blot to explore the molecular mechanisms underlying GBP-induced cardiac dysfunction. In the first experiment, we found that i.v. GBP significantly decreased BP, HR, maximal LV pressure, and maximal and minimal dP/dt, whereas it increased IRP-AdP/dt, Tau, systolic, diastolic, and cycle durations (* p < 0.05 and ** p < 0.01 vs. baseline; n = 4). In the second experiment, we found that chronic GBP treatment resulted in hypotension, bradycardia, and LV systolic dysfunction, with no change in plasma norepinephrine. In the myocardium, we identified 109 differentially expressed proteins involved in calcium pathways, cholesterol metabolism, and galactose metabolism. Notably, we found that calmodulin, a key protein of intracellular calcium signaling, was significantly upregulated by GBP in the heart but not in the brain. In summary, we found that acute and chronic GBP treatments suppressed cardiovascular function in rats, which is attributed to abnormal calcium signaling in cardiomyocytes. These data reveal a novel side effect of GBP independent of the nervous system, providing important translational evidence to suggest that GBP can evoke adverse cardiovascular events by depression of myocardial function.

Effects of catheter-based renal denervation on renin-aldosterone system, catecholamines, and electrolytes: A systematic review and meta-analysis.

In recent years, catheter-based renal denervation (RDN) has emerged as a promising instrumental therapy for hypertension. The interruption of sympathetic nervous system was regarded as a possible mechanism for RDN regulating blood pressure. While the results reflected by renin-angiotensin-aldosterone system (RAAS), catecholamines and electrolytes remained inconsistent and was never systematically assessed. Pubmed, Embase, and Web of Science were comprehensively searched from inception to September 5, 2021. Studies that evaluated the effects of RDN on RAAS, catecholamines, and electrolytes were identified. Primary outcomes were changes in RAAS hormones after RDN, and secondary outcomes involved changes in plasma norepinephrine, serum, and urinary sodium and potassium. Out of 6391 retrieved studies, 20 studies (two randomized controlled studies and 18 observational studies) involving 771 persons were eventually included. Plasma renin activity had a statistically significant reduction after RDN (0.24ng/mL/h, 95% CI 0.04 to 0.44, P=.02). While no significant change was found regarding plasma aldosterone (1.53ng/dL, 95% CI -0.61 to 3.67, P=.16), norepinephrine (0.42nmol/L, 95% -0.51 to 1.35, P=0.38), serum sodium and potassium (0.16mmol/L, 95% CI -0.17 to 0.49, P=.34; -0.02mmol/L, 95% CI -0.09 to 0.04, P=.48, respectively), and urinary sodium and potassium (3.95mmol/24h, 95% CI -29.36 to 37.26, P=.82; 10.22mmol/24h, 95% CI -12.11 to 32.54, P=.37, respectively). In conclusion, plasma renin activity significantly decreased after RDN, while no significant change was observed in plasma aldosterone, plasma norepinephrine, and serum and urinary electrolytes.

Liposome-encapsulated hemoglobin (HbV) transfusion rescues rats undergoing progressive lethal 85% hemorrhage as a result of an anti-arrhythmogenic effect on the myocardium.

Liposome-encapsulated hemoglobin vesicles (HbV) can serve as a blood substitute with oxygen-carrying capacity comparable to that of human blood and lethal hemorrhage is associated with lethal arrhythmias. To investigate the resuscitation effect of HbV on lethal hemorrhage and anti-arrhythmogenesis, we performed optical mapping analysis (OMP) and electrophysiological study (EPS) in graded blood exchange (85% blood loss) in the rat model. We also measured cardiac autonomic activity, as assessed by heart rate variability (HRV), and changes in plasma norepinephrine and left ventricle ejection fraction (LVEF) by echocardiography. Pathological study on Connexin43 was performed. A 5% albumin (ALB group), washed rat erythrocytes (wRBC group), and HbV (HbV group) were used as a resuscitation fluid. The survival effects over 24hours were examined. All rats died in the ALB group, whereas almost all survived for 24-hours period in wRBC and HbV groups. OMP showed impaired action potential duration dispersion (APDd) in the ALB group, whereas normal APDs in HbV and wRBC groups. Lethal arrhythmias were induced by EPS in the ALB group, but not in wRBC and HbV groups. HRV indices, LVEF, Connexin43 were preserved in HbV and wRBC groups. Lethal hemorrhage causes lethal arrhythmias in the presence of impaired APDd. HbV acutely rescues lethal hemorrhage by preventing lethal arrhythmias and preserving arrhythmogenic factors.

Ivabradine reduces baseline and stress-induced increase of heart rate and blood pressure and modulates neuroendocrine stress response in rats depending on stressor intensity.

Ivabradine, a selective inhibitor of the sinoatrial pacemaker, is used in clinical practice to reduce heart rate. However, its potential effect on the neuroendocrine stress response has not been investigated. Therefore, we determined the effect of administering ivabradine to rats on cardiovascular parameters and plasma levels of epinephrine, norepinephrine, and corticosterone. Ivabradine was administered intraperitoneally 30 min before exposing animals to either handling, restraint, or immobilization stress. Heart rate and blood pressure were monitored telemetrically. Blood samples were collected before, during, and after stressor exposure to determine the extent of the neuroendocrine stress response as reflected by plasma epinephrine, norepinephrine, and corticosterone levels. In animals pretreated with ivabradine, significantly lower values of heart rate and blood pressure were found during both the baseline period and during exposure to stressors, as well as during the rest period following stressor exposure. Ivabradine also significantly reduced handling-induced epinephrine and norepinephrine release into the bloodstream. However, ivabradine significantly potentiated restraint- and immobilization-induced increases of plasma epinephrine levels, whereas stress-induced changes in plasma norepinephrine and corticosterone levels were ambiguous. Our data shows that ivabradine significantly reduces blood pressure in rats during both baseline and stressful conditions, and also affects the neuroendocrine stress response. These findings show that viscerosensory signaling from the cardiovascular system may significantly modulate the neuroendocrine stress response.

Muscle Weakness Is Associated With an Increase of Left Ventricular Mass Through Excessive Blood Pressure Elevation During Exercise in Patients With Hypertension

Autonomic imbalance in hypertension induces excessive blood pressure (BP) elevation during exercise, thereby increasing left ventricular mass (LVM). Although muscle weakness enhances autonomic imbalance by stimulating muscle sympathetic activity during exercise, it is unclear whether muscle weakness is associated with an increase of LVM in patients with hypertension. This study aimed to investigate the relationships between muscle weakness, BP elevation during exercise, and LVM in these patients. Eighty-six hypertensive patients aged 69 ± 8 years with controlled resting BP (ie, < 140/90 mmHg) were recruited. Plasma brain natriuretic peptide (BNP), left ventricular mass index (LVMI), and knee extension muscle strength were measured. Changes in plasma noradrenaline (NORA) and brachial-ankle pulse wave velocity (ba-PWV) were assessed before and after an ergometer exercise test performed at moderate intensity (ΔNORA and ΔPWV, respectively). A difference between baseline and peak systolic BP during the exercise test was defined as BP elevation during exercise (ΔSBP). Relationships between muscle strength, ΔNORA, ΔPWV, ΔSBP, BNP, and LVMI were analyzed, and significant factors increasing LVM were identified using univariate and multivariate regression analyses. Muscle strength was negatively correlated with ΔNORA (r = -0.202, P = 0.048), ΔPWV (r = -0.328, P = 0.002), ΔSBP (r = -0.230, P = 0.033), BNP (r = -0.265, P = 0.014), and LVMI (r = -0.233, P = 0.031). LVMI was positively correlated with ΔPWV (r = 0.246, P = 0.023) and ΔSBP (r = 0.307, P = 0.004). Muscle strength was a significant independent factor associated with LVMI (β = -0.331, P = 0.010). Our findings suggest that muscle weakness is associated with an increase of LVM through excessive BP elevation during exercise in patients with hypertension.

Acute arterial baroreflex-mediated changes in plasma catecholamine concentrations in a chronic rat model of myocardial infarction.

While it may be predictable that plasma norepinephrine (NE) concentration changes with efferent sympathetic nerve activity (SNA) in response to baroreceptor pressure inputs, an exact relationship between SNA and plasma NE concentration remains to be quantified in heart failure. We examined acute baroreflex‐mediated changes in plasma NE and epinephrine (Epi) concentrations in normal control (NC) rats and rats with myocardial infarction (MI) (n = 6 each). Plasma NE concentration correlated linearly with SNA in the NC group (slope: 2.17 ± 0.26 pg mL−1 %−1, intercept: 20.0 ± 18.2 pg mL−1) and also in the MI group (slope: 19.20 ± 6.45 pg mL−1 %−1, intercept: −239.6 ± 200.0 pg mL−1). The slope was approximately nine times higher in the MI than in the NC group (P < 0.01). Plasma Epi concentration positively correlated with SNA in the NC group (slope: 1.65 ± 0.79 pg mL−1 %−1, intercept: 115.0 ± 69.5 pg mL−1) and also in the MI group (slope: 7.74 ± 2.20 pg mL−1 %−1, intercept: 24.7 ± 120.1 pg mL−1). The slope was approximately 4.5 times higher in the MI than in the NC group (P < 0.05). Intravenous administration of desipramine (1 mg kg−1) significantly increased plasma NE concentration but decreased plasma Epi concentration in both groups, suggesting that neuronal NE uptake had contributed to the reduction in plasma NE concentration. These results indicate that high levels of plasma catecholamine in MI rats were still under the influence of baroreflex‐mediated changes in SNA, and may provide additional rationale for applying baroreflex activation therapy in patients with chronic heart failure.

Regulation of renin secretion and arterial pressure during prolonged baroreflex activation: influence of salt intake.

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as antihypertensive therapy for patients with resistant hypertension. However, the influence of variations in salt intake on blood pressure lowering during baroreflex activation (BA) has not yet been determined. As the sensitivity of arterial pressure to salt intake is linked to the responsiveness of renin secretion, we determined steady-state levels of arterial pressure and neurohormonal responses in 6 dogs on low, normal, and high salt intakes (5, 40, 450 mmol/d, respectively) under control conditions and during a 7-day constant level of BA. Under control conditions, there was no difference in mean arterial pressure at low (92±1) and normal (92±2 mm Hg) sodium intakes, but pressure increased 9±2 mm Hg during high salt. Plasma renin activity (2.01±0.23, 0.93±0.20, 0.01±0.01 ng angiotensin I/mL/h) and plasma aldosterone (10.3±1.9, 3.5±0.5, 1.7±0.1 ng/dL) were inversely related to salt intake, whereas there were no changes in plasma norepinephrine. Although mean arterial pressure (19-22 mm Hg) and norepinephrine (20%-40%) were lower at all salt intakes during BA, neither the changes in pressure nor the absolute values for plasma renin activity or aldosterone in response to salt were different from control conditions. These findings demonstrate that suppression of sympathetic activity by BA lowers arterial pressure without increasing renin release and indicate that changes in sympathetic activity are not primary mediators of the effect of salt on renin secretion. Consequently, blood pressure lowering during BA is independent of salt intake.

Quantitative indices of baroreflex-sympathoneural function: application to patients with chronic autonomic failure

Chronic autonomic failure syndromes such as Parkinson disease with orthostatic hypotension (PD+OH), multiple system atrophy (MSA), and pure autonomic failure (PAF) typically feature arterial baroreflex failure. Identifying baroreflex-sympathoneural failure from hemodynamic responses to the maneuver usually has been qualitative. We report quantitative methods for evaluating baroreflex-sympathoneural function, based on beat-to-beat systolic blood pressure (BPs) responses to the Valsalva maneuver. Using the trapezoid rule, we calculated the area under the curve (baroreflex area, BRA) between baseline systolic blood pressure (BPs) and the BPs for each beat in Phase II (BRA-II) and Phase IV (BRA-IV) in 136 autonomic failure patients and 171 controls. The sum of the areas was defined as total BRA (BRA-T). We compared individual values by the BRA approach with those by other measures. Mean values for log BRA-II, BRA-IV, and BRA-T were higher in PD+OH, PAF, and MSA than in controls (p<0.001 each). The log of BRA-T correlated negatively with the fractional orthostatic change in total peripheral resistance (r=-0.41, p<0.001), fractional orthostatic change in plasma norepinephrine (r=-0.27, p<0.001), orthostatic change in BPs (r=-0.62, p<0.001), fall in BPs in Phase II of the Valsalva (r=0.58, p<0.001), and log of baroreflex-cardiovagal slope (r=-0.40, p<0.001). Areas under receiver operating characteristic curves were 0.85 for BRA-T and 0.89 for BRA-IV (p<0.001). The BRA approach provides quantitative measures of baroreflex-sympathoneural function. Chronic autonomic failure syndromes entail deficiencies of both the cardiovagal and sympathoneural limbs of the arterial baroreflex.

Changes of plasma norepinephrine and serum N-terminal pro-brain natriuretic peptide after exercise training predict survival in patients with heart failure

BackgroundShort-term changes of neurohormones can give important prognostic information in heart failure (HF) patients. In this study, we evaluate whether changes in plasma Norepinephrine (NE) and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) after exercise training predict cardiac mortality in HF patients. Methods and resultsWe enrolled 221 HF patients (mean age 72.5±10.2year) followed-up for a mean period of 27.64±10.7months. All pts underwent a 3-month exercise training. Before training, clinical examination, echocardiography, peak VO2 determination, and blood draw for NT-proBNP and NE measurements were performed. Primary end-point was cardiac related mortality. Eighty-six-nine percent of patients were in NYHA class III, mean left ventricular ejection fraction (LVEF) was 32.5±10.4%, and mean peak VO2 was 12.36±1.45ml/kg/min. At baseline, mean NT-proBNP was 2111.4±1145.6pg/ml and mean NE was 641.8±215.3pg/ml. One hundred-one subjects died for cardiac causes. Training was associated with a significant increase of peak VO2 and LVEF, whereas NE, NT-proBNP, and heart rate decreased. Multiple Cox proportional hazards regression analysis was performed using delta% values (post vs pre-training) of LVEF, heart rate, NE, and NT-proBNP along with baseline covariates, revealing delta value of NE as the strongest predictor of cardiac mortality. Noteworthy, training reduced NT-proBNP in both survivor and non-survivor patients, while a lack of reduction of NE was observed in non survivors. ConclusionsIn our HF population, short-term changes of NE after exercise training independently predicted long-term cardiac mortality.

391 BETA2-ADRENOCEPTOR POLYMORPHISMS (ARG16GLY) IS RELATED TO RESISTANCE TO WEIGHT LOSS INDUCED IMPROVEMENTS OF CARDIAC- AND RENAL COMPLICATIONS

Background: Obesity is an independent risk factor for cardiovascular and renal complications. We previously reported that the Arg16Gly, β2-adrenoceptor (ADRB2) polymorphism, accompanying high plasma norepinephrine (NE) could predict future weight gain, BP elevation and renal injury. The 1st line of treatment for obesity is weight loss (WL). In this study, we evaluated the relationships between ADRB2 polymorphisms (Arg16Gly), prevalence of LVH and renal function (creatinine clearance) over 2 years with WL program. Methods: Obese Japanese men (n = 154) were measured BMI, BP, plasma NE, leptin, creatinine, creatinine clearance (CCr), LVH determined by ECG and ADRB2 polymorphisms (Arg16Gly, Gln27Glu) before and after WL program (low caloric diet + exercise) over 2 years. Significant WL was defined >10% WL of entry BMI. Results: Significant WL was noted in 97 (63%) subjects and the frequencies of Gly16 were 39% for WL group vs. 54% for non-WL group (P < 0.05). At entry, subjects with Gly16 allele had higher levels of plasma NE, leptin, creatinine, higher prevalence of LVH, and lower CCr compared to those without Gly16 allele. WL group had lower fat-mass, NE, leptin and creatinine and LVH prevalence and higher CCr at entry compare dto non-WL group. WL group had greater changes in BMI, fat-mass, creatinine and CCr, and greater % reductions in NE and leptin over a 2-year period. Changes in fat-mass correlated with changes in creatinine, CCr, NE and BP over 2 years. Changes in plasma NE correlated with changes in CCr. In multiple regression analysis, plasma NE, fat-mass and BP levels were determinants for prevalence of LVH at entry and 2-year period. Conclusions: ADRB2 polymorphisms (Arg16Gly) accompanying high plasma NE is related to the prevalence of LVH and improving CCr with WL. Arg16Gly associated with high plasma NE may play an important role in cardio- and renal-complications in obesity.

Changes in Plasma Norepinephrine to Combat-Related Stimuli among Vietnam Veterans with Posttraumatic Stress Disorder. Edward B. Blanchard, PhD, Lawrence C. Kolb, MD, Annabel Prins, MS, Sherman Gates, MD, and Guy C. McCoy, MD (1991). Reprinted from the J Nerv Ment Dis. 179

Changes in Plasma Norepinephrine to Combat-Related Stimuli among Vietnam Veterans with Posttraumatic Stress Disorder. Edward B. Blanchard, PhD, Lawrence C. Kolb, MD, Annabel Prins, MS, Sherman Gates, MD, and Guy C. McCoy, MD (1991). Reprinted from the J Nerv Ment Dis. 179

Understanding the Neurobiology of Fear Conditioning and Emergence of Posttraumatic Stress Disorder Psychobiology

In this article, we discuss the historical evolution of posttraumatic stress disorder (PTSD) after the Vietnam War, with a focus on an article by Blanchard, Kolb, Prins, Gates, and McCoy (J Nerv Ment Dis 179:371-373, 1991) published in this Journal in 1991 entitled Changes in Plasma Norepinephrine to Combat-Related Stimuli Among Vietnam Veterans With Posttraumatic Stress Disorder. In this commentary, we discuss the significance of this brief article and the developments in the PTSD field before, during, and after the Blanchard publication. Within this context, we discuss the eventual recognition in both the clinical and scientific fields that PTSD had a major neurobiological foundation. Finally, we examine the key implication of these discoveries from an epidemiological, a clinical, and a public health perspective.

Exertional dyspnea-related acidotic and sympathetic responses in patients with sequelae of pulmonary tuberculosis

The objective of this study was to investigate whether exertional dyspnea correlates with exercise responses, especially arterial blood pH and plasma norepinephrine (NE) changes, in patients with sequelae of tuberculosis (TBsq). Cardiopulmonary exercise testings were performed in 49 TBsq patients and 9 controls. Each group had a break point in the dyspnea, plasma lactate, and plasma NE changes during exercise, all of which occurred at a similar exercise point. In TBsq patients in both exercise phases before and after the dyspnea break point, the dyspnea-slope (DeltaBorg scale/Deltaminute ventilation) correlated with the pH-slope (DeltapH/Deltaoxygen uptake) (r = -0.616, p < 0.0001; r = -0.629, p < 0.0001, respectively, before and after the break point) and with the NE-slope (DeltaNE/Deltaoxygen uptake) (r = 0.443, p = 0.0012; r = 0.643, p < 0.0001, respectively, before and after the break point). In TBsq patients during exercise, increases in circulating NE levels and exertional acidosis were correlated with exertional dyspnea.

Sympathoadrenal function in patients with paroxysmal hypertension: pseudopheochromocytoma

The causes of paroxysmal hypertension in patients in whom pheochromocytoma has been excluded ('pseudopheochromocytoma') usually remain unclear. Blood pressure disturbances and symptoms of catecholamine excess in these patients may reflect activation of the sympathetic nervous and adrenal medullary systems. We therefore examined sympathoadrenal function in patients with pseudopheochromocytoma compared with age-matched control subjects in whom there was no suspicion of pheochromocytoma. Plasma catecholamines and hemodynamics were examined in response to intravenous glucagon, yohimbine, and trimethaphan in 11 patients with pseudopheochromocytoma and a comparison group of nine normotensive and five hypertensive volunteers. Adrenomedullary function was also assessed by abdominal F-fluorodopamine positron emission tomography and measurements of plasma metanephrine, the O-methylated metabolite of epinephrine. Compared with controls, patients with pseudopheochromocytoma had normal plasma concentrations of norepinephrine, but 120% higher (P < 0.05) baseline plasma concentrations of epinephrine, 80% higher (P < 0.01) baseline plasma concentrations of metanephrine, and sixfold larger (P < 0.05) increases in plasma epinephrine after glucagon. Adrenal 18F-fluorodopamine-derived radioactivity did not differ between groups. Compared with changes in plasma norepinephrine, falls in blood pressure after trimethaphan were 13-fold larger (P < 0.005) and increases in blood pressure after yohimbine were threefold larger (P < 0.01) in pseudopheochromocytoma patients than in controls. Patients with pseudopheochromocytoma exhibit a pattern of normal sympathetic noradrenergic outflow, adrenomedullary activation, and augmented blood pressure responses to changes in the sympathoneural release of norepinephrine.

Sympathoadrenal function in patients with paroxysmal hypertension

The cause of paroxysmal hypertension in patients in who pheochromocytoma has been excluded (“pseudopheochromocytoma”) usually remains a mystery. We hypothesized that sympathoadrenal activation would explain these blood pressure (BP) disturbances. Plasma catecholamines and hemodynamics were examined in response to i.v. glucagon, isoproterenol, yohimbine, and trimethaphan in 8 patients with pseudopheochromocytoma and a comparison group of 9 normotensives and hypertensives. Adrenal medullary function was further examined by 18F-fluorodopamine positron emission tomography and measurements of plasma metanephrine, a metabolite of epinephrine produced within the adrenals. Patients with pseudopheochromocytoma had greater increases in BP after yohimbine and greater falls in BP in response to trimethaphan than controls. Exaggerated BP responses were associated with smaller changes in plasma norepinephrine. Heart rate responses to isoproterenol were also exaggerated. Patients had larger glucagon-induced increases in plasma epinephrine and a tendency to elevated baseline plasma levels of epinephrine, metanephrine, and cortisol compared to controls. Prominent adrenal uptake of 18F-fluorodopamine in some patients was consistent with adrenal medullary enlargement. In conclusion, increased release of norepinephrine by sympathetic nerves does not appear to contribute to the BP disturbances in most patients with pseudopheochromocytoma. Increased functional activity of the adrenal medulla and exaggerated adrenoceptor-mediated cardiovascular responses appear more likely causes of the paroxysmal hypertension.

The Effects of a Sliding Scale Diuretic Titration Protocol in Patients With Heart Failure

Patients with heart failure (HF) are often instructed to temporarily adjust their diuretic dose. This approach has become routine in some HF management programs; however, no study has specifically examined the effects of a patient-directed flexible diuretic protocol. For the purposes of this study, patients were randomized into a usual care (UC) group (n = 31) or a flexible diuretic titration (DT) group (n = 35). The DT group completed a 6-item diuretic titration protocol once a day, for 3 months. The 6-minute walk distance, plasma B-type natriuretic peptide (NT-BNP), plasma norepinephrine (NE), and quality of life (QOL) were measured at baseline and at 3 months. Hospitalizations, emergency department (ED) visits, and mortality rates were measured at 3 months. Compared to baseline, at 3 months, there was a significant increase in the DT group's 6-minute walk distance (646 +/- 60 ft vs 761 +/- 61 ft, P = .01) and total QOL score (53 +/- 5 vs 38 +/- 5, P = .001), whereas these parameters remained unchanged within the UC group. There were significantly less ED visits in the DT group compared with those in the UC group (3% vs 23%, P = .015). No differences were found between the groups in HF-related hospitalizations or mortality. Within both groups, no differences were found between baseline and 3-month NE or NT-BNP plasma values. Patients with heart failure who used a sliding scale diuretic titration protocol had significant improvements in their exercise tolerance and QOL, had fewer ED visits, and had no change in plasma NE or NT-BNP levels.

Low Frequency Regular Exercise Improves Flow-Mediated Dilatation of Subjects with Mild Hypertension

Although exercise is recommended for the primary prevention of hypertension, and although it is generally known to have a beneficial effect on endothelial function, working individuals often find it difficult to maintain a consistent exercise regimen. In the present study, therefore, we examined the effects of infrequently performed exercise on flow-mediated dilatation (FMD), which is an index of endothelial function, in 15 subjects with hypertension (mild hypertensives) and 10 normotensive subjects (normotensives). All subjects performed mild bicycle exercise twice a week for 12 weeks. To assess the FMD, the diameter of the brachial artery was measured using ultrasound at baseline, during reactive hyperemia, and following sublingual administration of nitroglycerin. Measurement of these parameters was performed twice, at the beginning and the end of the exercise program. At the baseline, FMD was significantly lower in the mild hypertensives than in the normotensives. Nitroglycerin-mediated dilatation (NTG-D) was similar in the two groups. The exercise decreased blood pressure in the mild hypertensives, and increased high-density lipoprotein (HDL) cholesterol in both groups. The exercise improved FMD without altering NTG-D in the mild hypertensives, but did not result in any change in the normotensives. Multiple regression analysis revealed that the elevation in FMD was positively associated with changes in HDL cholesterol, and negatively associated with changes in plasma norepinephrine and systolic blood pressure. These findings suggest that regular exercise at a low frequency improves FMD, and thereby endothelial function, and lowers blood pressure in mild hypertensives.

Sympathetic nervous system activation, antivenin administration and cardiovascular manifestations of scorpion envenomation

We performed two-dimensional echocardiograms and determined plasma norepinephrine levels on admission and at 24 h after hospitalization, in 16 children with scorpion envenomation. All patients came from areas where scorpions have been identified as Tityus zulianus and received antivenin at the site of the accident or upon admission. Based on the presence or absence of cardiovascular manifestations, patients were divided into two groups. Group A: 10 patients had cardiovascular manifestations of pulmonary edema. Four patients had mild pulmonary edema (Left ventricular ejection fraction: 0.43±0.19) and six had moderate to severe pulmonary edema (Ejection fraction: 0.31±0.09. p=NS, M±SD). Plasma norepinephrine was elevated on admission (1279±824) and decreased at 24 h in seven of eight patients (474±140 pg/ml, p<0.03). Group B: Six patients had no cardiovascular manifestations. These patients had normal chest X-rays and normal echocardiograms. Plasma norepinephrine was not elevated (188±180 pg/ml). Time interval from the accident to antivenin administration was significantly longer in Group A compared to Group B (4.5±3.3 vs 1.2±0.4 h, p<0.03) and correlated directly with the absolute change in plasma norepinephrine ( r=0.76, p<001). Consequently, we strongly recommend very early administration of antivenin in the medical management of scorpion envenomation by T. zulianus.

Weight reduction and pharmacologic treatment in obese hypertensives

This study was conducted to evaluate the mechanisms of weight loss-induced blood pressure (BP) reduction focusing, in particular, on the contributions of sympathetic nervous system activity, fasting plasma insulin, and leptin to BP levels, and to delineate the additional influence of antihypertensive drug therapy. Each of five groups of obese hypertensives were treated with the long-acting calcium channel blocker (CCB) amlodipine, the angiotensin converting enzyme (ACE) inhibitor enalapril with or without a weight reduction program, or a weight reduction program alone. The goal BP was less than 140/90 mm Hg for the pharmacologic treatment groups. The weight reduction program groups with or without pharmacologic treatment were divided into two groups; weight loss groups who succeeded in weight reduction (≥10%) and nonweight loss groups who failed in weight reduction (<10%) in the first 6 months. The final dose of CCB and ACE inhibitor were less in the combined pharmacologic and weight loss groups than in the pharmacologic treatment alone groups or in the pharmacologic and nonweight loss groups. In the weight reduction groups regardless of pharmacologic treatment, the percent reductions from baseline in plasma insulin, leptin, and norepinephrine (NE) were greater in the weight loss groups (≥10%) than in the nonweight loss groups (<10%). The reductions in plasma NE, insulin, and leptin were significantly greater and earlier in combined pharmacologic and weight loss groups than in the pharmacologic treatment alone groups. In ACE inhibitor groups, the reductions in plasma NE, in insulin, and especially in leptin were greater than the other groups. In the CCB alone group, reductions in insulin and leptin occurred, but there was no change in plasma NE. Reductions in insulin and leptin in CCB groups were less and occurred later than in the ACE inhibitor groups or the weight reduction alone group. These results show that weight loss associated with favorable metabolic improvements and these improvements are amplified when combined with pharmacologic treatment. Therefore, weight loss should be regarded as an essential component of any treatment program for obesity-related hypertension. A novel finding from this study is that ACE inhibition had a striking effect to lower plasma leptin. Suppression of sympathetic activity, insulinemia, and leptinemia appeared to play a role in the BP reduction accompanying weight loss.