Higher Norepinephrine Research Articles

Rhabdomyolysis after cerebral perfusion pressure-guided management in severe head injury

Intravenous infusion of norepinephrine is usually effective and safe to maintain adequate cerebral perfusion pressure for the management of posttraumatic intracranial hypertension. We report the case of a 17-year-old woman who suffered from traumatic intracranial bleeding and hypotension; she developed rhabdomyolysis, myoglobinuria and acute renal failure after receiving high dose norepinephrine postoperatively. Hemodialysis was begun 3 days after the onset of myoglobinuria when acute renal failure was noted, despite aggressive fluid supplementation and alkaline diuresis. After aggressive treatment and dialysis, the patient’s myoglobinuria and rhabdomyolysis gradually declined. Her kidneys eventually regained normal function. We consider that systemic hypotension may have been the leading cause for development of rhabdomyolysis, and vasoconstrictors such as norepinephrine aggravated this. We emphasise the potentially devastating consequences of rhabdomyolysis when a large dose of norepinephrine is given for the treatment of hypotension during cerebral perfusion pressure-guided management.

Sympathetic Neural Regulation of Heart Rate Is Robust against High Plasma Catecholamines

The sympathetic regulation of heart rate (HR) may be attained by neural and humoral factors. With respect to the humoral factor, plasma noradrenaline (NA) and adrenaline (Adr) can reportedly increase to levels approximately 10 times higher than resting level during severe exercise. Whether such high plasma NA or Adr interfered with the sympathetic neural regulation of HR remained unknown. We estimated the transfer function from cardiac sympathetic nerve stimulation (SNS) to HR in anesthetized and vagotomized rabbits. An intravenous administration of NA (n = 6) at 1 and 10 microg.kg(-1).h(-1) increased plasma NA concentration (pg/ml) from a baseline level of 438 +/- 117 (mean +/- SE) to 974 +/- 106 and 6,830 +/- 917 (P < 0.01), respectively. The dynamic gain (bpm/Hz) of the transfer function did not change significantly (from 7.6 +/- 1.2 to 7.5 +/- 1.1 and 8.1 +/- 1.1), whereas mean HR (in bpm) during SNS slightly increased from 280 +/- 24 to 289 +/- 22 (P < 0.01) and 288 +/- 22 (P < 0.01). The intravenous administration of Adr (n = 6) at 1 and 10 microg.kg(-1).h(-1) increased plasma Adr concentration (pg/ml) from a baseline level of 257 +/- 86 to 659 +/- 172 and 2,760 +/- 590 (P < 0.01), respectively. Neither the dynamic gain (from 8.0 +/- 0.6 to 8.4 +/- 0.8 and 8.2 +/- 1.0) nor the mean HR during SNS (from 274 +/- 13 to 275 +/- 13 and 274 +/- 13) changed significantly. In contrast, the intravenous administration of isoproterenol (n = 6) at 10 microg.kg(-1).h(-1) significantly increased mean HR during SNS (from 278 +/- 11 to 293 +/- 9, P < 0.01) and blunted the transfer gain value at 0.0078 Hz (from 5.9 +/- 1.0 to 1.0 +/- 0.4, P < 0.01). In conclusion, high plasma NA or Adr hardly affected the dynamic sympathetic neural regulation of HR.

.BETA.2- and .BETA.3-Adrenoceptor Polymorphisms Relate to Subsequent Weight Gain and Blood Pressure Elevation in Obese Normotensive Individuals

High blood pressure (BP) is a major determinant of cardiovascular events in obesity. The beta2- and beta3-adrenoceptor polymorphisms are associated with obesity and hypertension. In the present study, we examine the relationships of beta2- and beta3-adrenoceptor polymorphisms with further weight gain-induced BP elevation in obese subjects. Changes in BP, body weight, total body fat-mass, waist-to-hip ratio, plasma norepinephrine (NE) and leptin levels, and beta2(Arg16Gly)- and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured periodically over a 5-year period in 55 entry obese (body mass index [BMI]> or =25.0 kg/m(2)) normotensive (BP<140/90 mmHg) men. BP elevation and weight gain were defined as > or =10% increases from entry levels over 5 years in mean BP or BMI. Obese subjects with weight gain, BP elevation or weight gain-induced BP elevation had higher frequencies of the Gly16 allele of Arg16GIy and Arg64 allele of Trp64Arg. Subjects carrying the Gly16 or Arg64 alleles had significantly greater total fat-mass and waist-to-hip ratio at entry and over a 5-year period compared to the subjects who did not carry these polymorphisms. Subjects carrying the Gly16 allele had similar levels of plasma NE, higher levels of plasma leptin and a lower slope of the regression lines between plasma leptin and NE levels. Those carrying the Arg64 allele had higher plasma NE levels at entry and over a 5-year period compared to the subjects without the Arg64 allele, but plasma leptin levels and slopes were similar. The findings demonstrate that the Arg64 allele of the beta3-adrenoceptor polymorphisms relates to weight gain-induced BP elevation accompanying high plasma NE (heightened sympathetic activity) in obese men. The Gly16 allele of the beta2-adrenoceptor polymorphisms links to weight gain-induced BP elevation associated with leptin resistance. beta2- and beta3-adrenoceptor polymorphisms could predict the future BP elevation and further weight gain-induced BP elevation in originally obese subjects.

Norepinephrine-induced diastolic dysfunction with aortic valve opening under calcium-loading in rats

Heart failure associated with a high plasma level of norepinephrine (NE) has an extremely poor prognosis with NE being the most powerful predictor of all-cause mortality. An increase in the diastolic intracellular calcium level (Ca2+) occurs in left ventricular dysfunction; however, the cause-and-effect relationships among Ca2+loading, high plasma NE, and an increase in diastolic ventricular pressure is unclear. Here, we examined the relationship between diastolic dysfunction and NE with and without Ca2+loading in rats. Animals were studied in four groups: Ca2+loading for 45 min (Ca2+group), NE alone for 25 min (30 µg/kg/min NE for 25 min; NE group), Ca2+loading and NE for 25 min after Ca2+loading (Ca2+-NE group), and a vehicle group. Hemodynamics were examined using a micromanometer-tipped pressure catheter, and diastolic function was studied using Doppler echocardiography. Significantly increased left ventricular end-diastolic pressure (LVEDP) and decreased E and Ea waves and deceleration time (DCT) were found in the Ca2+-NE group, compared with the Ca2+and NE groups. There were no changes in left ventricular pressure (LVP) and LV ejection fraction (EF) among the four groups. NE-induced diastolic contracture (NEIDC) with aortic valve opening occurred in the diastole when LVP overshot the aortic pressure after co-administration of NE and Ca2+after Ca2+loading, and pulmonary hemorrhage was observed in all animals of the Ca2+-NE group. The results support the suggestion that NE may be an important factor in the development of diastolic dysfunction in ischemic heart disease. Drug Dev. Res. 67:511–518, 2006. © 2006 Wiley-Liss, Inc.

Refractory septic shock: Efficacy and safety of very high doses of norepinephrine

The aim of this study was to evaluate the safety, efficacy, and effects of administration of very high doses of norepinephrine (> 4 microg kg(-1) min(-1)) in catecholamine-resistant septic shock. We reviewed the charts of all patients with nonresponding to commonly used norepinephrine doses (< or = 4 microg kg(-1) min(-1)) septic shock from January 1999 to December 2002 in our Surgical Intensive Care Unit. All patients were treated with high norepinephrine doses (> 4 microg kg(-1) min(-1)), after initial resuscitation, so as to achieve a mean arterial pressure higher than or equal to 65 mmHg. During this 4-year period, 12 consecutive patients with catecholamine-resistant septic shock were included in our study. When compared with the values obtained prior to the administration of very high norepinephrine doses, the values of mean arterial pressure (p = 0.003) and systemic vascular resistance (p = 0.002) significantly increased after the administration of such doses, and additionally, lactate concentrations (p = 0.003) decreased. In contrast, no significant changes were observed regarding mean central venous pressure, pulmonary capillary wedge pressure, and pulmonary arterial pressure. Administration of high norepinephrine doses in our patients resulted in a survival rate of 33.4%. Management of catecholamine-resistant septic shock patients poses a challenging problem. Administration of very high norepinephrine doses is safe and effective and may improve survival of these patients with otherwise extremely high mortality rates.

Rebound Weight Gain as Associated With High Plasma Norepinephrine Levels That Are Mediated Through Polymorphisms in the β2-Adrenoceptor

A successful weight loss program is essential treatment for obesity-related diseases, but it is well known that the majority of individuals do not succeed in weight loss maintenance. The present study evaluates hormonal mechanisms and the relationship of beta2-adrenoceptor polymorphisms involved in individuals who regain weight after initially successful weight loss. Overweight Japanese men (n = 154) were enrolled in a 24-month weight loss program. Body mass index (BMI), total body fat mass, plasma norepinephrine (NE) and leptin levels, and beta2-adrenoceptor polymorphisms (Arg16Gly, Gln27Glu) were measured every 6 months for the 24-month period. Maintenance of weight loss was defined as significant weight loss (>or=10% reduction) from entry weight at 6 months and maintenance of the weight loss for an additional 18 months. Rebound weight gain was defined as significant weight loss at 6 months but subsequent regain of body weight during the next 18 months. The results showed that 37 subjects maintained weight loss during 24 months, whereas 36 subjects had rebound weight gain. The BMI at entry and calorie intake and physical activity at each period were similar between the two groups. Subjects who maintained weight loss had at entry a significantly lower fat mass and plasma NE levels compared to those with rebound weight gain. Body fat mass, NE, and leptin levels at entry predicted the degree of change in body weight during the 24-month study period. Subjects with rebound weight gain had a significantly higher frequency of the Gly16 allele for the beta2-adrenoceptor polymorphism compared to subjects who had a 24-month maintenance of weight loss. Subjects carrying the Gly16 allele also had significantly higher plasma NE, leptin, and body fat mass levels and a greater waist-to-hip ratio both at entry and throughout the study. A high initial degree of body fat mass and high plasma NE levels as determined by the Gly16 allele for the beta2-adrenoceptor polymorphisms predict those individuals who will have rebound weight gain after their initial successful weight loss.

Low plasma vasopressin/norepinephrine ratio predicts septic shock

To evaluate if low plasma vasopressin and high norepinephrine concentrations predict grave prognosis of sepsis, a prospective sample of consecutive patients visiting the emergency department of a university teaching hospital who met the American College of Chest Physicians criteria of sepsis or severe sepsis was enrolled. Besides septic workup, we measured serum vasopressin and norepinephrine concentrations to correlate the impending outcome. One hundred eighty-two patients aged 27 to 99 years met the inclusive criteria and were classified as those with septic shock (n = 72), severe sepsis (n = 56), and those with sepsis only (n = 54) according to the outcome within 6 hours. Thirty healthy subjects were included as control. The plasma vasopressin level at baseline was significantly lower for those who finally developed septic shock (septic shock group, 3.6 ± 2.5 pg/mL; 95% confidence interval [CI], 3.0-4.2 pg/mL; severe sepsis group, 21.8 ± 4.1 pg/mL, 95% CI, 20.7-22.9 pg/mL; sepsis group, 10.6 ± 6.5 pg/mL, 95% CI, 8.8-12.4 pg/mL, P < .001), whereas the norepinephrine level was highest for the same group (septic shock group, 3650 ± 980 pg/mL, 95% CI, 3420-3880 pg/mL; severe sepsis group, 3600 ± 1000 pg/mL, 95% CI, 3330-3870 pg/mL; sepsis group, 1720 ± 320 pg/mL, 95% CI, 1630-1810 pg/mL). The vasopressin/norepinephrine ratio was significantly lower for the patients with final diagnosis of septic shock ( P < .001). The mean interval between the time of samples drawn and the time of the most severe occurring sequelae was 2.4 ± 0.8 hours. Receiver operating characteristic analysis revealed that the vasopressin/norepinephrine ratio 1 × 10 −3 had a sensitivity of 97% (95% CI, 90%-99%) and a specificity of 85% (95% CI, 78%-91%) for detecting impending septic shock. Low serum vasopressin/norepinephrine ratio can predict impending septic shock.

Perioperative management of a child with severe hypertension from a catecholamine secreting neuroblastoma

Increased catecholamine secretion from neuroblastomas can occasionally be demonstrated, but severe hypertension is uncommon. We report the perioperative management of a 5 year old child with stage III adrenal neuroblastoma who presented with malignant hypertension and high norepinephrine and dopamine levels. Hypertensive crises occurred during anesthesia for surgical biopsy and during chemotherapy. After blood pressure control using phenoxybenzamine and enalapril, doxazosin was used successfully as the preoperative alpha-adrenergic receptor antagonist for surgical tumor resection.

Moods in everyday situations: effects of menstrual cycle, work, and stress hormones

Objective This study examined women's mood responsiveness on work and off days during different phases of the menstrual cycle. Methods Self-reports of negative, positive, and energy dimensions of mood were obtained throughout the day on two work and two off days during the luteal and follicular phases of the menstrual cycle in 203 women nurses. Individual differences in daytime and nighttime epinephrine, norepinephrine, and cortisol were assessed. Results High daytime norepinephrine, epinephrine, and cortisol levels were associated with higher ratings of stress and tired, and with lower ratings of happy. The phase of the menstrual cycle and the day factor (workday, off day) were also associated with mood differences, and the direction of the effects depended on hormone levels and hormone sampling period. Conclusion The experience of moods is affected by the arousal-related interaction of hormone levels with the phase of the menstrual cycle and occupational stress.

Clinical Epidemiology of Major Nontraditional Risk Factors in Peritoneal Dialysis Patients

End-stage renal disease (ESRD) is a situation with a cardiovascular (CV) risk profile of almost unique severity. While traditional risk factors dominate the scene in the general population, in chronic kidney disease (CKD), nontraditional risk factors play an increasingly important role, being perhaps dominant in ESRD patients. We review the role inflammation [C-reactive protein (CRP)], hyperhomocysteinemia, high plasma norepinephrine, and accumulation of the endogenous inhibitor of the nitric oxide synthase asymmetric dimethylarginine (ADMA) in the high all-cause and CV mortality of patients on continuous ambulatory peritoneal dialysis (CAPD). The association between CRP and clinical outcomes in patients on peritoneal dialysis (PD) was examined in six studies totaling 692 subjects. The largest of these studies in Caucasians indicates that the independent risk of CV events in patients in the top CRP quartile is about five times higher than in the bottom quartile. Seven prospective studies, including over 1000 hemodialysis and 176 CAPD patients, reported both positive and negative associations between homocysteine and mortality and/or CV events. Because homocysteine circulates bound to albumin, negative associations--rather than negating the vasculotoxicity of homocysteine--most likely reflect the very deleterious effects of malnutrition. Plasma norepinephrine is higher in CAPD than in hemodialysis patients, and multivariate analyses suggest the difference quantitatively entails a 16% higher risk of incident CV events. Likewise, ADMA is more elevated in CAPD patients and such an elevation corresponds to a 15% increase in risk. Nontraditional risk factors are far more prevalent in ESRD patients than in the general population. ADMA and norepinephrine may play a greater role in CV risk in CAPD than in hemodialysis patients.

Decreased tyrosine hydroxylase activity in the adrenals of spontaneously hypertensive rats

Higher activity of the peripheral sympathetic nervous system, accompanied by higher tyrosine hydroxylase activity is frequently and consistently reported in human essential hypertension as well as in animal models of hypertension. However, results obtained in the adrenals, particularly in young animals before the development of hypertension, are scarce and controversial. In the present study tyrosine hydroxylase activity and catecholamine content in the adrenals of spontaneously hypertensive rats and of age-matched control Wistar Kyoto rats were evaluated before, during and after the development of hypertension (5, 12 and 22-week-old animals). Results show that both tyrosine hydroxylase activity and total amine content in the adrenals of spontaneously hypertensive rats were significantly reduced (35% reduction) at all studied ages. Determination of the kinetic parameters for tyrosine hydroxylase in the adrenals of 5 week-old spontaneously hypertensive rats revealed a 38% reduction in V max values (13.4 versus 21.3 nmol L-DOPA/mg prot/h in age-matched controls) accompanied by lower levels of expression of both tyrosine hydroxylase total protein and phosphoSer40 observed by Western-Blot. In contrast, norepinephrine content in both plasma and tail artery were significantly higher in the spontaneously hypertensive strain. In conclusion, contrary to the higher peripheral sympathetic activity, tyrosine hydroxylase activity and catecholamine content in the adrenals of spontaneously hypertensive rats are markedly reduced before, during and after the development of hypertension. End product, long-term feedback inhibition by the high norepinephrine plasma levels could be responsible for this reduction, establishing yet another regulatory mechanism of tyrosine hydroxylase operating in adrenal cromaffin cells.

Adipose tissue cytokines, insulin sensitivity, inflammation, and cardiovascular outcomes in end-stage renal disease patients

From an evolutionary perspective, Darwinian selection has favored insulin-resistant individuals, ie, those with a trait ensuring brain functioning in situations of extreme fuel deprivation. The ability to mount a powerful inflammatory response to infection was another survival advantage in our ancestors, and we now have solid evidence showing that these 2 traits, insulin resistance and inflammation (as measured by serum C-reactive protein [CRP]), are associated in modern human beings. In an analysis of 192 nondiabetic hemodialysis patients, leptin and adiponectin were related in an opposite fashion with insulin sensitivity in end-stage renal disease (ESRD) and interacted in determining insulin resistance in these patients. The risk of insulin resistance was about 6 times higher in ESRD patients with an unfavorable combination of the 2 adipokines (high leptin and low adiponectin) than in those with a favorable combination (low leptin and high adiponectin). Low adiponectin but not high leptin predicted incident cardiovascular events in this cohort. Neither leptin nor adiponectin were associated with CRP in a cross-sectional analysis, but they were linked in an opposite fashion to CRP in a longitudinal study in 21 patients with acute inflammation secondary to infection. High sympathetic activity predicts adverse cardiovascular outcomes in ESRD. Of note, we found that the risk for cardiovascular events is more than 3 times higher in patients with high sympathetic activity and low adiponectin than in those with high adiponectin and low sympathetic activity. The adipocyte hormones leptin and adiponectin are associated in an opposite fashion to insulin sensitivity and inflammation in ESRD patients. Relatively lower plasma adiponectin levels are associated with a higher rate of incident cardiovascular events. Finally, low adiponectin and high norepinephrine seem to be interacting factors in the dismal cardiovascular outcomes with ESRD.

Endoluminal pelvic perfusion with norepinephrine causes only minor systemic effects and diminishes the increase in pelvic pressure caused by perfusion

To evaluate the effect of endoluminal norepinephrine (NE) on transport pressures of the normal upper urinary tract of the pig and on plasma levels of NE in relation to possible systemic effects. Six anaesthetized pigs weighing approximately 39 kg were studied. Transparenchymally, two 6-F catheters were introduced into the renal pelvis bilaterally to measure pressure and perfusion. Ultrasonic flow probes recorded renal arterial blood flow, and a transurethral 10-F catheter drained the bladder and monitored diuresis. In all six animals, the bilateral pelvic pressure response was examined at increasing perfusion rates (2, 4, 6, 8, 10 and 15 ml/min) and with increasing doses of NE (0, 5, 50 and 100 microg/ml). Arterial blood samples were analysed for NE, epinephrine and blood glucose. The systemic blood pressure, heart rate and electrocardiogram were registered. At all the investigated concentrations, endoluminal NE significantly diminished the increase in pelvic pressure caused by pelvic perfusion at all flow rates. At the lowest concentration of NE, no significant increase in the plasma level of NE was observed and the blood pressure did not increase. During perfusion with 50 and 100 microg/ml NE, plasma levels of NE increased significantly from 487+/-398 to 1798+/-910 and 2961+/-2093 pg/ml, respectively. This was accompanied by significant rises in mean systolic blood pressure from a baseline value of 95+/-10 mmHg to 111+/-20 and 118+/-23 mmHg, respectively. Heart rate, renal arterial blood flow and plasma levels of epinephrine and glucose did not change. Endoluminal NE diminished the increase in pelvic pressure caused by pelvic perfusion even at concentrations too low to cause significant changes in NE plasma levels or systemic effects. Very high NE concentrations in the perfusion fluid caused increased plasma levels and a modest but significant increase in blood pressure. Administration of endoluminal NE may be useful in upper urinary tract stone treatment and endoscopy.

Pathogenesis and etiology of essential hypertension: role of dietary carbohydrate

The development of essential hypertension (EH) is proposed to be the result of a cascade of metabolic alterations, with high insulin levels/hyperinsulinemia and an abnormal reaction to the vasodilatory effect of insulin as the initiating factors. It is well established that insulin causes vasodilatation of peripheral resistance vessels. In normal subjects, this insulin-induced vasodilatation and decrease of the peripheral vascular resistance (PVR) is compensated by an SNS-mediated re-vasoconstriction in order to avoid hypotension, with the net effect of a slight decrease in blood pressure and no significant effect on peripheral vascular resistance. In contrast, in genetically predisposed subjects, prone to the development of essential hypertension, the insulin-induced vasodilatation is compensated by an increased heart rate and cardiac output (to avoid hypotension), mediated by an abnormal sympathetic overactivity, (characterised by high norepinephrine spillover rates and (frequently) a hyperdynamic circulation), while the PVR remains low during the early phase of developing EH. During the course of chronic hypertension, the SNS-overactivity leads to progressive trophic alterations of vessel walls, and structural and functional vascular remodeling, with narrowing of arterial resistance vessels and an increasing PVR. Vascular remodeling and lumen narrowing not only affect peripheral resistance vessels, but also kidney vessels. Narrowing and decreased distensibility of preglomerular kidney vessels lead to chronic activation of the Renin-Angiotensin-Aldosterone-System, with reinforcement and fixation of hypertension. High-glycemic index nutrition is suggested to play a key role in the etiology of hypertension: The chronic stimulus of pancreatic beta-cells due to high-glycemic index nutrition may cause cell hypertrophy and dysfunction, resulting in postprandial hyperinsulinemia, and -- in susceptible subjects -- the development of EH. Since significant evidence suggests that hyperinsulinemia also represents a key factor for the development of obesity, insulin resistance and the metabolic syndrome, the well-known common association of EH and these metabolic alterations becomes quite understandable.

Radionuclide Imaging Metabolic Activity of Brown Adipose Tissue in a Patient with Pheochromocytoma

We describe a patient with extra-adrenal pheochromocytoma and high plasma norepinephrine levels. Radionuclide images of this patient obtained using (18)F-fluorodeoxyglucose and (123)I-metaiodobenzylguanidine revealed bilateral tracer accumulation in the shoulder and lower neck. The regions of radiotracer uptake corresponded to the location of human brown adipose tissue (BAT). Excessive sympathetic stimulation by high circulating catecholamine concentrations augmented the metabolic activity and tracer uptake in the BAT. This study showed that radionuclide imaging can noninvasively visualize human BAT in terms of metabolic and functional activity.

Abnormalities of Neurohormonal and Cardiac Autonomic Nervous Activities Relate Poorly to Functional Status in Fontan Patients

Impaired cardiac autonomic nervous activities and increased neurohumoral activities (CANA, NHA) characterize Fontan patients. However, the clinical significance of these changes is not clearly understood. Our purpose was to clarify the clinical significance of the CANA and NHA in stable Fontan patients. We divided 22 atriopulmonary connection (APC) and 75 total cavopulmonary connection (TCPC) patients into 4 subgroups according to New York Heart Association (NYHA) class (1.8+/-0.6) and measured various CANA and NHA indices. All NHA indices were elevated in the symptomatic patients (P<0.001). Natriuretic peptides were higher in the APC than in the TCPC patients, and the hemodynamics showed no correlation with brain natriuretic peptide in the APC patients. Low arterial oxygen saturation and impaired hemodynamics greatly influenced all elevated NHA indices (P<0.01), except for plasma renin activity, in the TCPC patients. Impaired CANA indices did not relate to NYHA class, although surgeries were associated with lower heart rate variability. In addition to poor correlation between NHA and CANA, age and ventricular morphology had no impact on all CANA and NHA indices, except for high norepinephrine in right ventricular Fontan patients. Although symptomatic Fontan patients exhibit higher NHA, CANA is not related to either NYHA class or NHA. APC itself is responsible for higher natriuretic peptides, and arterial oxygen desaturation has a great impact on elevated NHA in the TCPC patients. These characteristics of the NHA and CANA differ from those of heart failure patients with biventricular physiology.

Extraneuronal enzymatic degradation of myocardial interstitial norepinephrine in the ischemic region.

Catechol O-methyltransferase (COMT) is believed to exert degradative action at high norepinephrine (NE) levels. Although COMT exists in cardiac tissues, the contribution of cardiac COMT activity to regional NE kinetics, particularly in ischemia-induced NE accumulation, remains unclear. We investigated the role of cardiac COMT in NE kinetics in the ischemic region. We implanted a microdialysis probe into the left ventricular myocardium of anesthetized rabbits and induced myocardial ischemia by 60-min coronary artery occlusion. We monitored myocardial interstitial levels of NE and its metabolites in the presence and absence of a COMT inhibitor. We intraperitoneally administered entacapone (10 mg/kg) 120 min before control sampling. In control, entacapone increased interstitial dihydroxyphenylglycol (DHPG, intraneuronal NE metabolite by monoamine oxidase (MAO)) levels and decreased interstitial normetanephrine (NMN, extraneuronal NE metabolite by COMT) and 3-methoxy-4-hydroxyphenylglycol (MHPG, extraneuronal DHPG metabolite by COMT) levels, but did not change interstitial NE levels. Coronary occlusion increased NE levels to 165+/-48 nM at 45-60 min of occlusion. This increase was accompanied by increases in DHPG and NMN levels (11.3+/-1.1 and 9.3+/-1.3 nM at 45-60 min of occlusion). Entacapone augmented the ischemia-induced NE and DHPG responses (333+/-51 and 22.9+/-2.4 nM at 45-60 min of occlusion). In contrast, the ischemia-induced NMN response was suppressed by entacapone (2.0+/-0.4 nM at 45-60 min of occlusion). Reperfusion decreased interstitial NE levels and increased interstitial DHPG and NMN levels. Entacapone suppressed changes in NE and NMN levels, but augmented the increase in dialysate DHPG. Myocardial ischemia evoked increases in myocardial interstitial NE and NMN levels. COMT inhibition augmented the increase in NE (substrate of COMT) levels and suppressed the increase in NMN (metabolite by COMT) levels. In the ischemic heart, COMT contributes to the removal of accumulated NE in the myocardium.

Prognostic impact of serum matrix metalloproteinase-3 in patients with idiopathic dilated cardiomyopathy

Hypothesis: We hypothesized that increased matrix metalloproteinases (MMPs) activity could be associated with higher incidence of future cardiac events of patients with idiopathic dilated cardiomyopathy (DCM), and evaluated the prognostic ability of serum MMPs compared with other prognostic predictors in DCM. Methods: We measured serum levels of MMP-2, MMP-3, and MMP-9 using ELISA in 35 patients with DCM and 20 healthy control subjects. Moreover, plasma levels of high sensitive C-reactive protein, norepinephrine, and brain natriuretic peptide (BNP) were also measured. The primary end point was the composite incidence of cardiac death and hospitalizations for worsening heart failure. Results: Serum levels of MMP-2, MMP-3, and MMP-9 were significantly higher in patients with DCM than in control subjects (all p < 0.05). During the mean follow-up periods of 25 ± 12 months, 7 patients had major cardiac events; sudden cardiac death in 2 and hospitalizations for worsening heart failure in 5. On multivariate analysis of six markers, only plasma BNP and serum MMP-3 were significant independent predictors of cardiac events in patients with DCM (p = 0.015 and p = 0.026, respectively). According to the Kaplan-Meier analysis, cardiac event-free rates were significantly lower in high MMP-3 group (MMP-3 > 55 ng/ml) than in low MMP-3 group (MMP-3 < 55 ng/ml) (p = 0.027). Conclusions: Our study may address the capability of serum MMP-3 for predicting the prognosis of patients with DCM.

Relationship between overnight neuroendocrine activity and morning haemostasis in working men.

Sustained effects of SNS (sympathetic nervous system) and HPAA (hypothalamic-pituitary-adrenal axis) hyperactivity on haemostasis have not been investigated. In the present study, we tested for an association of overnight urinary catecholamine and cortisol excretion with morning plasma levels of fibrinogen, PAI-1 (plasminogen activator inhibitor-1) and D-dimer. Participants (639 male industrial employees) with a complete dataset were studied (age, 41+/-11 years; mean+/-S.D.). Subjects collected overnight urinary samples and had a fasting morning blood sample drawn. Measurement of urinary adrenaline (epinephrine), noradrenaline (norepinephrine) and cortisol were dichotomized to perform multivariate analyses of (co)variance. Haemostatic parameters were measured by ELISA. Fibrinogen was higher in men with high adrenaline (F(7,631)=5.68, P=0.018; where the subscripted value represents the degrees of freedom) and high noradrenaline (F(7,631)=4.19, P=0.041) compared with men with low excretion of the respective hormones. PAI-1 was higher in men with high cortisol than in men with low cortisol (F(7,631)=4.77, P=0.029). Interaction revealed that subjects with high cortisol/low noradrenaline had higher PAI-1 than subjects with low cortisol/high noradrenaline (P=0.038). Subjects with high adrenaline/high noradrenaline had higher D-dimer than subjects with high adrenaline/low noradrenaline (P=0.029), low adrenaline/high noradrenaline (P=0.022) and low adrenaline/low noradrenaline (not significant). When covariance for several confounders of haemostatic function was determined, the main effect of adrenaline on fibrinogen and the interaction between adrenaline and noradrenaline for D-dimer maintained significance. Although overnight SNS hyperactivity was associated independently with morning hypercoagulability, the relationship between the activity of HPAA and haemostasis was mediated by traditional cardiovascular risk factors.

Pharmacological Activity of Taxus baccata

Crude extracts prepared from the heartwood of Taxus baccata L. were evaluated for their antiplatelet and vasorelaxing effect. The ethanol extract of the heartwood of T. baccata (1) and their fractions, CHCl3 (2) and CHCl3 non-soluble extract (3) were preincubated with platelets, and then thrombin, arachidonic acid (AA), collagen or platelet-activating factor (PAF) was added for testing antiplatelet activity. In other set of experiments, all extracts were tested on high potassium or norepinephrine (NE) depolarized isolated rat thoracic aorta for investigating the vasorelaxing effect. All tested extracts showed a significant inhibitory effect on platelet aggregation induced by AA, collagen and PAF at a concentration of 400 µg/ml, but not thrombin. However, not all extracts relaxed NE-induced vasocontraction, extracts 1 and 2 showed a weak inhibitor effect on high potassium depolarized smooth muscle. To the best of our knowledge, this is the first report on antiplatelet activity and vasorelaxing effect of the heartwood of T. baccata.