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Background: In endothelial cells urocortin II has recently been found to activate nitric oxide synthase through cAMP-dependent and Ca2+-related pathway. Aim: The present study was therefore planned to determine the mechanisms of urocortin II effect on Ca2+ movements. Methods. In Fura-2 loaded porcine aortic endothelial cells (PAE), the effects of urocortin II on [Ca2+]c were analyzed and compared with those of various K+ channels agonists/antagonists. Results: In Fura-2 loaded PAE, urocortin II promoted a transient increase of [Ca2+]c mainly originating from an intracellular pool sensitive to thapsigargin and slightly from the extracellular space. In addition, urocortin II caused the hyperpolarization of plasma membrane through the opening of K+ channels, which contributed to the increased [Ca2+]c. These effects were abolished by the corticotropin releasing factor receptors (CRFR2) blocker, the adenylyl cyclase and Ca2+-calmodulin-kinase (CaMKII) inhibitors and by blockers of K+ channels. In addition, in PAE cultured in Na+-free medium or loaded with the plasma-membrane Ca2+ pump inhibitor the urocortin II-evoked Ca2+ transient was slower. Conclusion: The results obtained show that urocortin II affects intracellular Ca2+ homeostasis in PAE by both promoting a discharge of intracellular pool and by interfering with the operation of store-dependent channels through CRFR2-cAMP-CaMKII related signalling and K+ channels opening. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Urocortin II has previously been shown in anesthetized pigs to increase coronary blood flow through activation of the endothelial nitric oxide synthase (eNOS) pathway and involvement of the subtype 2 of corticotropin releasing factor receptors (CRFR2). However, little information has been available regarding the intracellular signalling through these receptors and leading to the release of nitric oxide (NO). Aim: The present study was therefore planned to determine the mechanism involved in such signalling. Methods: In porcine aortic endothelial cells (PAE) the effects of urocortin II on NO production and ERK, Akt, p38 and eNOS phosphorylation were examined in absence or presence of the adenylyl cyclase agonist forskolin and antagonist 2’5’ dideoxyadenosine, the Ca2+ ionophore A23187, the Ca2+-calmodulin-kinase inhibitor KN93, the CRFR2 blocker astressin 2B and of the protein kinases specific inhibitors UO126, wortmannin and SB203580. Results: Urocortin II caused a significant increase of NO production, which was amplified by forskolin and A23187 (P <0.05). All effects of urocortin II were abolished by l-NAME, 2’5’ dideoxyadenosine, KN93, astressin 2B and by pre-treatment of cells with UO126, wortmannin and SB203580. Western Blot analysis confirmed the involvement of ERK, Akt and p38 in the eNOS activation. Conclusion: In PAE urocortin II interaction with CRFR2 caused a cAMP-dependent and Ca2+-related phoshorylation of ERK, Akt and p38 leading to eNOS activation. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The endocannabinoid system reportedly plays a role in the pathogenesis of cardiovascular diseases. This system is expressed also in adipose tissue, which could thus be involved in cardiac disorders through modulation of metabolically triggered inflammation. The current study aims to determine the relevance of the endocannabinoid system in epicardial adipose tissue in heart disease., Methods: Expression of the endocannabinoid receptors CB1 and CB2, and of the endocannabinoid-degrading enzyme, fatty acid amidohydrolase, and activation of protein kinase A (PKA), phospholipase C (PLC), protein kinase C (PKC), endothelial nitric oxide synthase (eNOS) and inducible (i)NOS, and extracellular signal-regulated kinases 1 and 2 (ERK1/2) (a member of the reperfusion-injury salvage kinase pathway), were analyzed by Western blot in patients after coronary artery bypass surgery (ischemics; N = 18) or valve surgery (nonischemics; N = 15) and in preadipocytes isolated from epicardial adipose tissue., Results: In ischemics, the CB1-to-CB2 expression ratio shifted toward CB1 and was accompanied by higher PKA activation. In contrast, in nonischemics, CB2, fatty acid amidohydrolase, PLC and PKC, and ERK1/2 were upregulated. Moreover, NO production and iNOS-to-eNOS ratios were higher in preadipocytes from ischemics., Conclusions: These results show a different modulation and functioning of the endocannabinoid system in ischemics compared with nonischemics. Hence, while CB2, PLC and PKC, ERK1/2, and eNOS are more strongly expressed in patients without ischemic heart disease, high CB1 and PKA expression is associated with low survival intracellular pathway activation and high iNOS activation in ischemic heart disease patients. The changes in the endocannabinoid system in ischemics may contribute to cardiac dysfunction and therefore represents a potential therapeutic target., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: In normal individuals, carbohydrate ingestion increases sympathetic vasoconstrictor activity but causes net vasodilatation in the same vascular bed. This study quantified the effects of carbohydrate ingestion on muscle sympathetic nerve activity (MSNA) and vasoregulation in patients with congestive heart failure (CHF). We hypothesized that high resting levels of MSNA in patients with CHF would blunt further increases in MSNA following carbohydrate ingestion and that their sympathetic activation would restrain vasodilatation., Methods: Eleven patients with treated severe CHF and 11 age- and body mass index-matched normal controls (NCs) were studied for 2 hours after a high-carbohydrate meal. MSNA was measured by peroneal microneurography and calf blood flow by venous occlusion plethysmography., Results: Patients with CHF had higher (P < 0.03) baseline MSNA (67 ± 4.0 bursts/100 beats) than NCs (51 ± 5.8 bursts/100 beats) and lower (P < 0.001) baroreflex sensitivity (2.1 ± 0.58 ms/mm Hg) than NCs (7.4 ± 1.2 ms/mm Hg). Carbohydrate ingestion was associated with a significant increase in MSNA (P < 0.05) and calf blood flow (P < 0.01) with unchanged blood pressure in CHF patients. The magnitude of responses in CHF patients was not significantly different from that in NCs, but vasodilatation was delayed significantly (by 30 minutes)., Conclusions: Despite considerable resting sympathoexcitation and reduced baroreflex sensitivity, patients with CHF exhibited further increases in MSNA after carbohydrate ingestion, achieving levels similar to those after myocardial infarction. They also had temporally delayed vasodilatation, which could contribute to cachexia and muscle weakness in CHF patients. These observations suggest that high-carbohydrate meals may adversely affect CHF patients via altered autonomic tone and blood-flow patterns., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Neuroendocrine activation may be an important adjunctive mechanism for left ventricular hypertrophy (LVH) development. Controversy exists to as to whether LVH regression occurs due to blood pressure (BP) reduction alone or if adjunctive mechanisms play a role. We planned to test the hypothesis that for a similar BP reduction, LVH regression would be greater using a drug combination selected specifically to reduce neuroendocrine activity compared with one that did not., Methods: Forty-two patients with hypertension and cardiovascular magnetic resonance (CMR) proven LVH were allocated to one of two equipotent antihypertensive regimens for 6 months. Treatments were chosen on the basis of opposing mechanistic actions on the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS); one arm inhibitory (valsartan and moxonidine), the other neutral (bendroflumethiazide and amlodipine). The primary end point was absolute reduction in CMR-determined left ventricular mass (LVM)., Results: All BP indices were highly comparable at the start and end of the trial (P > 0.6 between groups). BP was reduced (always P < 0.0001) by 37/17  mmHg in the valsartan and moxonidine group and 38/19  mmHg in the bendroflumethiazide and amlodipine group. CMR quantified LVM was comparable between the two groups at baseline and decreased significantly in both treatment groups (P < 0.0001). Reduction in LVM was significantly greater in valsartan and moxonidine [-25.9  g; 95% confidence interval (CI) -31.6 to -20.2] compared with bendroflumethiazide and amlodipine (-18.3  g; -23.3 to -13.4) (P < 0.05)., Conclusion: The magnitude of LVH regression achieved by inhibiting the RAAS and SNS neuroendocrine pathways is greater than that produced by comparable BP reduction alone. This supports the hypothesis that neuroendocrine mechanisms are important in the regression of LVH.

Objectives: Hypertension and its subsequent cardiovascular complications have been associated with sympathetic neural activation, and their prevalence in women increases after the menopause. However, there have been no data on the level of sympathetic activation and its relationship to vascular blood flow following the menopause. Therefore, we planned to find out whether the behavior of muscle sympathetic nerve activity (MSNA) and calf blood flow (CBF) in women with and without essential hypertension (EHT) is changed following the menopause., Methods: Peroneal nerve activity was measured as mean frequency of single units and of multiunit bursts with simultaneously measured CBF in two matched groups of postmenopausal women with and without EHT in comparison with two matched groups of premenopausal women with and without EHT., Results: As expected, nerve activity was greater in the hypertensive than in normotensive groups and in postmenopausal than in premenopausal normotensive groups. We found that single unit frequency in postmenopausal hypertensives (65 ± 3.9 impulses/100 cardiac beats) was not significantly different from that in postmenopausal normotensives (54 ± 2.2 impulses/100 cardiac beats) or in premenopausal hypertensives (57 ± 2.8 impulses/100 cardiac beats). Similar results were obtained for burst frequency. In addition, a statistically significant negative correlation between the frequency of nerve activity and CBF was found only in postmenopausal normotensive (at least r =  -0.42, P < 0.04) and hypertensive women (at least r =  -0.45, P < 0.03)., Conclusion: These findings suggest that sympathetic nerve hyperactivity in postmenopausal women may have greater vascular effects than in premenopausal women, and could have implications in the management of EHT in postmenopausal women.

Objective: Levosimendan has been reported to exert cardioprotection. In this study, we have examined the cardiac effects of different doses of intracoronary levosimendan on ischemia/reperfusion injuries, and the involvement of K(ATP) channels and nitric oxide (NO)., Methods: The experiments were performed in a total of 56 anesthetized pigs. In 21 pigs, 1.5, 5 and 12 μg min(-1) levosimendan was infused over 15 min into the coronary artery at the onset of 1 h reperfusion following 2-h ischemia and the effects on cardiac function, infarcted area, and on apoptosis/autophagy were examined. In addition, the activation of Akt and extracellular receptor kinase (ERK) was analyzed. The findings were compared with those obtained in a further 14 pigs where the highest dose levosimendan was infused after glibenclamide and l-nitro-arginine methyl ester (l-NAME)., Results: Intracoronary 1.5, 5 and 12 μg min(-1) levosimendan caused an increase of segmental shortening, dP/dt(max) and cardiac output of 7.8%, 22.6%, and 31.6%; 7.6%, 16.9%, and 21.6%; 2.8%, 5.9%, and 6.2%, respectively, from values measured at the end of ischemia. The beneficial effects elicited by levosimendan were still evident at the end of reperfusion when the increase of segmental shortening, dP/dt(max) and cardiac output caused by the three doses of levosimendan amounted to 3.7%, 13.3%, and 16.5%; 1.5%, 9.4%, and 11%; 1.4%, 2.7%, and 3.9%, respectively. When doses of 5 and 12 μg min(-1) levosimendan were used, a reduction of infarcted area to about 69% and 67% of area at risk was observed, and was significantly different from that of about 79% measured in control animals. In addition, after intracoronary levosimendan, the inhibition of apoptosis and activation of autophagy and a dose-related increase of the level of phosphorylation of ERK and Akt were observed. These responses were completely prevented by glibenclamide and significantly reduced by l-NAME., Conclusions: The results of this study show that intracoronary levosimendan reduces cell death induced by ischemia/reperfusion in a dose-dependent manner and activates survival signaling through K(ATP) channel opening and NO. These findings support interesting implications for cardioprotection in interventional cardiology and cardiac surgery., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: Sympathetic nerve hyperactivity has been associated with hypertension and heart failure and their cardiovascular complications. The α2-adrenergic receptors have been proposed to play a prominent role in the control of sympathetic neural output, and their malfunction to constitute a potential central mechanism for sympathetic hyperactivity of essential hypertension. Reports on the relationship between variant alleles of α2-adrenergic receptor subtypes and sympathetic drive or its effects, however, have not been consistent. Therefore, this study was planned to test the hypothesis that variant alleles of subtypes of α2-adrenergic receptors are associated with raised muscle sympathetic nerve activity (MSNA) in man., Methods: One hundred and seventy-two individuals, with a wide range of arterial pressure, were prospectively examined. Resting MSNA was quantified from multiunit bursts and from single units, and α2-adrenergic receptor subtypes were genotyped from DNA extracted from leucocytes and quantified by spectrophotometry., Results: No significant relationships between variant alleles of any of the α2A, α2B or α2C subtypes and raised muscle sympathetic activity were found. In contrast, MSNA showed a marked significant curvilinear relationship with age and systolic pressure; sex had a small but statistically significant effect. The α2-adrenergic receptor variants had a similar frequency when hypertensive and normotensive individuals were compared., Conclusion: Variant alleles of three α2-adrenergic receptor subtypes were not related to resting muscle sympathetic nerve hyperactivity, indicating that their functional differences shown in vitro are not reflected in sympathetic activity in man. Age had a marked effect likely influencing arterial pressure through sympathetic activity.

Systemic intermedin (IMD)1-47 administration has been reported to result in vasodilation and marked hypotension through calcitonin-related receptor complexes. However, its effects on the coronary circulation and the heart have not been examined in vivo. The present study was therefore planned to determine the primary in vivo effect of IMD1-47 on coronary blood flow and cardiac function and the involvement of the autonomic nervous system and nitric oxide (NO). In 35 anesthetized pigs, IMD1-47, infused into the left anterior descending coronary artery at doses of 87.2 pmol/min, at constant heart rate and arterial blood pressure, augmented coronary blood flow and cardiac function. These responses were graded in a further five pigs by increasing the infused dose of IMD1-47 between 0.81 and 204.1 pmol/min. In the 35 pigs, the blockade of cholinergic receptors (intravenous atropine, 5 pigs), alpha-adrenoceptors (intravenous phentolamine, 5 pigs), and beta1-adrenoceptors (intravenous atenolol, 5 pigs) did not abolish the cardiac response to IMD1-47, the effects of which were prevented by blockade of beta2-adrenoceptors (intravenous butoxamine, 5 pigs), NO synthase (intracoronary N(omega)-nitro-l-arginine methyl ester, 5 pigs), and calcitonin-related receptors (intracoronary CGRP8-37/AM22-52, 10 pigs). In porcine coronary endothelial cells, IMD1-47 induced the phosphorylation of endothelial NO synthase and NO production through cAMP signaling leading to ERK, Akt, and p38 activation, which was prevented by the inhibition of beta2-adrenoceptors, calcitonin-related receptor complexes, and K+ channels. In conclusion, IMD1-47 primarily augmented coronary blood flow and cardiac function through the involvement of calcitonin-related receptor complexes and beta2-adrenoreceptor-mediated NO release. The intracellular signaling involved cAMP-dependent activation of kinases and the opening of K+ channels.

Aims: To determine whether the magnitude of post-acute myocardial infarction (AMI) sympathetic activation is greater in women (F-AMI) than men (M-AMI)., Methods and Results: Both sympatho-humoral activation and female gender are associated with worse outcome in the early phase following AMI. However, women have lower sympathetic output than men. We therefore examined matched groups of F-AMI (18) and M-AMI (18) patients 2-4 days following uncomplicated AMI, then 3 monthly to 9 months; matched normal control (NC) groups comprised M-NC (18) and F-NC (18). Muscle sympathetic nerve activity (MSNA) was measured by microneurography. Muscle sympathetic nerve activity was lower in the F-NC than M-NC (at least P < 0.05) and greater in the two AMI groups than their corresponding NC groups (at least P < 0.001). Muscle sympathetic nerve activity was similar in the F-AMI and M-AMI groups indicating a post-AMI increase in women of about twice that in men (P < 0.0001). Both AMI groups returned to corresponding NC (lower in women) levels by 9 months., Conclusion: Following uncomplicated AMI, women developed a relatively greater magnitude of sympathetic activation lasting until its resolution at 9 months. This is consistent with reports of their worse prognosis observed during this time period, with important potential clinical implications.

Various studies have suggested that the phytoestrogen genistein has beneficial cardioprotective and vascular effects. However, there has been scarce information regarding the primary effect of genistein on coronary blood flow and its mechanisms including estrogen receptors, autonomic nervous system, and nitric oxide (NO). The present study was planned to determine the primary effect of genistein on coronary blood flow and the mechanisms involved. In anesthetized pigs, changes in left anterior descending coronary artery caused by intracoronary infusion of genistein at constant heart rate and arterial pressure were assessed using ultrasound flowmeters. In 25 pigs, genistein infused at 0.075 mg/min increased coronary blood flow by about 16.3%. This response was graded in a further five pigs by increasing the infused dose of the genistein between 0.007 and 0.147 mg/min. In the 25 pigs, blockade of cholinergic receptors (iv atropine; five pigs) and alpha-adrenergic receptors (iv phentolamine; five pigs) did not abolish the coronary response to genistein, whose effects were prevented by blockade of beta(2)-adrenergic receptors (iv butoxamine; five pigs), nitric oxide synthase (intracoronary N(omega)-nitro-L-arginine methyl ester; five pigs) and estrogenic receptors (ERs; ERalpha/ERbeta; intracoronary fulvestrant; five pigs). In porcine aortic endothelial cells, genistein induced the phosphorylation of endothelial nitric oxide synthase and NO production through ERK 1/2, Akt, and p38 MAPK pathways, which was prevented by the concomitant treatment by butoxamine and fulvestrant. In conclusion, genistein primarily caused coronary vasodilation the mechanism of which involved ERalpha/ERbeta and the release of NO through vasodilatory beta(2)-adrenoreceptor effects.

We planned to determine the primary effects and mechanisms of urocortin II, a member of the corticotrophin-releasing factor (CRF) family highly expressed in the cardiovascular system, on coronary blood flow and myocardial function in vivo. Urocortin II was infused into the left anterior descending coronary artery in 25 anaesthetized pigs whilst measuring haemodynamic variables, coronary blood flow, ventricular dP/dt(max) cardiac output and percentage of segmental shortening. This infusion was repeated after blockade of the autonomic nervous system, nitric-oxide synthase (NOS) or subtype 2 of the CRF receptors. In all experiments changes in heart rate and aortic blood pressure were prevented. Intra-coronary urocortin II increased, within 60 s, coronary blood flow (15+/-3.2%, P<0.05), dP/dt(max) (12.7+/-2.6%, P<0.05), cardiac output (16+/-2.3%, P<0.05) and percentage of segmental shortening (19.8+/-3.8%, P<0.05). Blockade of NOS abolished only the coronary effects whereas blockade of subtype 2 of the CRF receptors abolished all cardiac and coronary effects. It was shown for the first time that urocortin II administration primarily increases coronary blood flow and myocardial function through the release of nitric oxide and activation of subtype 2 of the CRF receptors in the anaesthetized pig. This provides a mechanism through which a local increase of urocortin II levels can help improve a compromised cardiovascular function.

Prolactin has been associated with many effects and has been implicated in the pathogenesis of pregnancy-related hypertensive disorders, although little is known about its vascular effects. The present study was designed to determine the primary effect of prolactin on regional vascular beds and the mechanisms involved. In 37 anesthetized pigs, the infusion of 0.17 mug/kg min of prolactin at constant heart rate and arterial pressure decreased coronary, mesenteric, renal, and iliac blood flow. This response was graded in further five pigs by increasing the infused dose of the hormone between 0.017 and 1 mug/kg min. In 22 of the 37 pigs, blockade of cholinergic receptors (five pigs) and of alpha-adrenoceptors (five pigs) did not affect the prolactin-induced vascular response, which was abolished by blockade of beta(2)-adrenoceptors (five pigs) and by blockade of vascular nitric oxide (NO) synthase (seven pigs). In 15 of the 37 pigs the increases in measured blood flows caused by iv infusion of isoproterenol (five pigs) and by intraarterial administration of acetylcholine (five pigs) and of sodium nitroprusside (five pigs) were significantly reduced by infusion of prolactin. Moreover, the treatment of porcine aortic endothelial cells by prolactin caused a reduction of NO production and of the phosphorylation of ERK, Akt, and p38, which was prevented by the concomitant treatment by the beta(2)-adrenergic agonist albuterol. The present study showed that iv infusion of prolactin primarily caused coronary, mesenteric, renal, and iliac vasoconstriction. These effects were brought about by the inhibition of a vasodilatory beta(2)-adrenergic receptor-mediated effect related to the NO intracellular pathway.

Background: Sympathetic activation occurs in hypertension (HT) and after acute myocardial infarction (AMI) and is related to greater cardiovascular risk. Also, AMI in patients with HT (AMI-HT) carries greater risk than that in normal subjects (AMI-NT). We therefore planned to determine whether the sympathetic activation and its duration after AMI are greater in patients with antecedent HT than in patients with normal arterial pressure (NT)., Methods: In 68 matched subjects with uncomplicated AMI-HT (n = 17), AMI-NT (n = 17), HT (n = 17), and NT (n = 17), we measured resting muscle sympathetic nerve activity (MSNA) as the mean frequency of multiunit bursts (m-MSNA) and single units (s-MSNA). In AMI groups data were obtained 2 to 4 days after AMI and then at 3-month intervals until MSNA returned to levels found in HT and NT., Results: The AMI-HT had greater (at least P < 0.05; ANOVA) s-MSNA (99 +/- 3.5 impulses/100 cardiac beats) than AMI-NT (84 +/- 2.8 impulses/100 cardiac beats). During follow up, s-MSNA hyperactivity in AMI-HT was always greater than in AMI-NT, and returned to values found in HT and NT (84 +/- 3.5 impulses/100 cardiac beats and 62 +/- 4.4 impulses/100 cardiac beats, respectively) 9 months after AMI. Similar results were obtained for m-MSNA., Conclusions: AMI in hypertensives resulted in greater MSNA levels lasting at least 6 months longer than AMI in normotensives. This indicates that AMI further augmented the MSNA hyperactivity of HT and that this could be one mechanism involved in the reported worse prognosis in AMI-HT.

The present work was planned to study the effects of non-noxious gastric distension on hemodynamic variables and on cardiovascular hindbrain areas detected by means of c-Fos immunoreactivity, to determine the afferent and central mechanisms involved. In anesthetized rats, innocuous stomach distension increased arterial blood pressure and heart rate and induced c-Fos immunoreactivity within nucleus tractus solitarii, nucleus ambiguus, ventrolateral medulla and lateral reticular nucleus. Bilateral vagotomy abolished the pressor response and c-Fos immunoreactivity in nucleus ambiguus and ventrolateral medulla. Also, c-Fos immunoreactivity was significantly decreased in nucleus tractus solitarii and lateral reticular nucleus. After bilateral splanchnicotomy the pressor and tachycardic responses caused by gastric distension were reduced. c-Fos immunoreactivity in nucleus tractus solitarii, lateral reticular nucleus and nucleus ambiguus was reduced in comparison to the intact rats. In ventrolateral medulla a preferential localization of c-Fos immunoreactivity was found within its caudal portion. It was shown that such gastric distension, known to activate low threshold mechanoreceptors, induced cardiovascular effects via both vagal and splanchnic afferents and involving their central convergence and interaction in modulating the baroreceptor buffer system.

Hypertension is a major cardiovascular risk factor in the metabolic syndrome (MS) in which the presence of insulin resistance, glucose intolerance, abnormal lipoprotein metabolism, and central obesity all confer an increased risk. Because essential hypertension (EHT), insulinemia, and visceral fat are associated with sympathetic hyperactivity, which is itself known to increase cardiovascular risk, the aim of this study was to see if MS is a state of sympathetic nerve hyperactivity and if the additional presence of EHT intensifies this hyperactivity. In 69 closely matched subjects, comprising hypertensive MS (MS+EHT, 18), normotensive MS (MS-EHT, 17), hypertensives without MS (EHT, 16), and normotensive controls without MS (NC, 18), we measured resting muscle sympathetic nerve activity (MSNA) as assessed from multiunit discharges and from single units with defined vasoconstrictor properties (s-MSNA). The s-MSNA in MS+EHT (76+/-3.1 impulses/100 beats) was greater (at least P<0.01) than in MS-EHT (62+/-3.2 impulses/100 beats) and in EHT (60+/-2.3 impulses/100 beats), and all these were significantly greater (at least P<0.01) than in NC (46+/-2.7 impulse/100 beats). The multi-unit MSNA followed a similar trend. These findings suggest that MS is a state of sympathetic nerve hyperactivity and that the additional presence of hypertension further intensifies this hyperactivity. The degree of sympathetic hyperactivity seen in this study could be argued at least partly to contribute to the higher cardiovascular risk and metabolic abnormalities seen in MS+EHT patients.

Although the beta1-adrenergic blocking agent atenolol is an established antihypertensive therapy, its effect on peripheral sympathetic vasoconstrictor drive has remained controversial. In patients with hypertension, atenolol therapy has been reported to either increase or have no effect on peripheral vascular resistance, despite other reports showing no change or a decrease in peripheral sympathetic drive. This study was designed, in patients with untreated essential hypertension (EHT), to quantify changes in simultaneously measured peroneal muscle sympathetic nerve activity (MSNA) and calf vascular resistance (CVR) accompanying atenolol therapy. MSNA was quantified as the mean frequency of single units (s-MSNA) and as multiunit bursts (MSNA bursts) using the technique of microneurography, and CVR was measured using a standard plethysmographic technique. Firstly, by comparing two age- and body weight- matched groups, each of 14 patients with hypertension, we found that the group on atenolol therapy (treated-HT) had similar MSNA values counted over the same number of cardiac beats and similar CVR levels (at least P>0.40) to the group without therapy (untreated-HT). Secondly, we examined 10 EHT patients before and after 8+/-0.4 weeks of oral atenolol therapy (HT-A) in comparison to seven control patients with hypertension and no treatment (HT-C) who were examined over a similar period of time. We found that the measures of MSNA and CVR did not significantly change in both groups. We conclude that the arterial pressure lowering effect of atenolol was not related to significant changes in central vasoconstrictor sympathetic drive to the periphery.

Background: The sympathetic activation that follows acute myocardial infarction (AMI) has been associated with increased morbidity and mortality. Because the prognosis after anterior AMI (ant-AMI) is worse than that after inferior AMI (inf-AMI), we planned to determine whether the magnitude of sympathetic hyperactivity differs between the two., Methods and Results: Thirty-nine patients with uncomplicated AMI, comprising 2 matched groups of 17 patients with ant-AMI, and 22 patients with inf-AMI were examined. Measurements were obtained 2 to 4 days after AMI and compared with 20 normal subjects (NC) who were matched in terms of age and body weight to the AMI groups. Resting muscle sympathetic nerve activity was quantified from multiunit bursts (MSNA) and from single units (s-MSNA). Both groups of AMI patients were matched with regard to hemodynamic variables, left ventricular function, and infarct size. Both groups had greater (at least P<0.01) sympathetic nerve activity than NC (60+/-4.3 bursts/100 cardiac beats and 68+/-4.9 impulses/100 cardiac beats), but the magnitude of sympathetic nerve hyperactivity in ant-AMI (81+/-4.0 bursts/100 cardiac beats and 91+/-4.9 impulses/100 cardiac beats) was similar (P>0.05) to that in inf-AMI (80+/-3.2 bursts/100 cardiac beats and 90+/-4.0 impulses/100 cardiac beats), Conclusions: Both ant-AMI and inf-AMI resulted primarily in a similar magnitude of sympathetic nerve hyperactivity. These findings suggest that the worse prognosis after ant-AMI compared with after inf-AMI would not be related primarily to the degree of sympathetic hyperactivity.

Objectives: We planned to examine the relationship between neurovascular compression (NVC) of the rostral ventrolateral medulla (RVLM) and the magnitude of central sympathetic hyperactivity in normal subjects and in patients with untreated and uncomplicated essential hypertension (EHT)., Background: Previously it has not been possible to establish a definitive relationship between EHT and NVC of the RVLM, a location containing efferent sympathetic vasoconstrictor neurons. Furthermore, the relationship between NVC and magnitude of sympathetic nerve hyperactivity has not been adequately examined, despite the knowledge that hyperactivity varies according to EHT severity., Methods: In 83 subjects, we used magnetic resonance imaging to detect NVC and, independently, peroneal microneurography to quantify muscle sympathetic nerve activity (MSNA), expressed as the mean frequency of multi-unit discharge (m-MSNA) and of single units (s-MSNA). Subjects were classified according to arterial pressure values into groups with normal (NT) (n = 24) or high-normal (HN) (n = 14) arterial pressure and mild (EHT-1) (n = 26) or severe (EHT-2/3) (n = 19) EHT., Results: A significantly greater sympathetic activity was found in 23 subjects with NVC, compared with 60 subjects without NVC. The prevalence of NVC and the magnitude of sympathetic hyperactivity were greater in the EHT-1 group (p < 0.05) than in the other three groups. There was no significant difference in confounding variables between the groups. Although increased sympathetic activity was strongly predictive of NVC, this was not significantly related to baroreceptor sensitivity controlling the pulse interval (cardiac baroreceptor reflex sensitivity)., Conclusions: Neurovascular compression of the RVLM may cause central sympathetic activation in normal and hypertensive populations and therefore has significant implications regarding the pathogenesis of EHT.

Background: The magnitude of sympathetic hyperactivity in essential hypertension (EHT) varies with its severity and complications. There are no data on sympathetic nerve activity in borderline (BHT) or white-coat hypertension (WHT) relative to the various stages of EHT, despite suggestions that both lead to established EHT and organ damage through sympathetic mechanisms. We planned to determine the magnitude of sympathetic nerve activity in patients with BHT and WHT in relation to normality and various stages of sustained EHT., Methods: We examined 90 untreated subjects comprising matched groups with BHT (n = 13), WHT (n = 12), Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure EHT stage 1 (EHT-1 n = 12), EHT stages 2 and 3 (EHT-2/3 n = 14), high-normal pressure (HN n = 14), and normal pressure (NT n = 13), as well as a group with EHT complicated by left ventricular hypertrophy (EHT+LVH n = 12). We quantified muscle sympathetic nerve activity as the mean frequency of multiunit discharge (MSNA) and that of single-units (s-MSNA)., Results: We found a greater (at least P <.01) mean central sympathetic frequency in BHT (75 +/- 5.8 impulses/100 beats), EHT-1 (76 +/- 4.0 impulses/100 beats), and EHT+LVH (79 +/- 4.3 impulses/100 beats) than in EHT-2/3 (57 +/- 3.1 impulses/100 beats), WHT (52 +/- 3.6 impulses/100 beats), HN (42 +/- 3.9 impulses/100 beats), and NT (33 +/- 3.6 impulses/100 beats). BHT hyperactivity was closer to that of EHT, whereas WHT was closer to NT., Conclusions: Central sympathetic activity was greatest in BHT, early stage, and complicated EHT, and as such is likely to play an integral role in the development of hypertension and its complications. Sympathetic hyperactivity occurs in WHT, but to a lesser extent than in BHT.

Background: Essential hypertension (EHT) is a major cardiovascular risk factor, and the additional presence of type 2 diabetes mellitus (DM2) increases this risk. However, although the sympathetic nerve hyperactivity of EHT is known to play a role in cardiovascular risk, the level of sympathetic nerve activity is known neither in DM2 nor in hypertensive type 2 diabetic patients (EHT+DM2). Therefore, we planned to quantify the vasoconstrictor sympathetic nerve activity in patients with EHT+DM2 and with DM2 relative to that in matched groups with EHT and normal blood pressure (NT)., Methods and Results: In 68 closely matched subjects with EHT+DM2 (n=17), DM2 (n=17), EHT (n=17), and NT (n=17), we measured resting muscle sympathetic nerve activity as the mean frequency of multiunit bursts (MSNA) and of single units (s-MSNA) with defined vasoconstrictor properties. The s-MSNA in EHT+DM2 (97+/-3.8 impulses/100 beats) was greater (at least P<0.001) than in EHT (69+/-3.4 impulses/100 beats) and DM2 (78+/-4.1 impulses/100 beats), and all these were significantly greater (at least P<0.01) than in NT (53+/-3.3 impulses/100 beats) despite similar age and body mass index. The MSNA followed a similar trend. In addition, the level of insulin was also raised in EHT+DM2 (20.4+/-3.6 microU/mL) and DM2 (18.1+/-3.1 microU/mL; at least P<0.05) compared with HT or NT., Conclusions: Patients with EHT+DM2, EHT, or DM2 had central sympathetic hyperactivity, although plasma insulin levels were raised only in EHT+DM2 and DM2. The combination of EHT and DM2 resulted in the greatest sympathetic hyperactivity and level of plasma insulin, and this hyperactivity could constitute a mechanism for the increased risks of this condition.

Background: It is unclear whether pregnancy-induced hypertension (PIH) and preeclampsia (PE) are separate conditions or represent opposite ends of a spectrum of a single disease entity. Sympathetic hyperactivity exists in both PIH and PE; however, only the latter is characterized by multiorgan involvement, particularly renal impairment. As there is evidence in hypertension that target organ damage is associated with increased sympathetic drive, this study was designed to test the hypothesis that the magnitude of sympathetic hyperactivity in PE is greater than that in PIH., Methods: Microneurography was used to compare peripheral sympathetic neural discharge, its reflex control and end-organ effect (plethysmographic measurement of calf blood flow) in 33 women with PIH, PE, and normal pregnancy (NP) who were matched for age, body weight, and gestation., Results: As expected, patients with PIH and PE had higher levels of mean arterial pressure than those with NP. The frequency of sympathetic neural discharge was greater in the hypertensive disorders of pregnancy compared with NP; however, it was not increased in PE compared with PIH as might be expected., Conclusions: Based on the study results, PE is not associated with greater sympathetic hyperactivity than PIH, suggesting that any renal impairment in PE involves mechanisms that are not solely dependent on sympathetic hyperactivity.

Objectives: This study planned to establish whether sympathetic hyperactivity exists in white-coat hypertension (WHT) in the clinical setting, relative to matched groups with normotension (NT) and untreated essential hypertension (EHT)., Background: White-coat hypertension differs from EHT by the presence of normal ambulatory blood pressure. Sympathetic hyperactivity exists in patients with EHT in the clinical setting and is believed to contribute to the development of target organ damage. Similar organ damage has been reported in WHT, yet little is known about sympathetic neural activity in this condition., Methods: Using microneurography, we examined groups of 12 matched subjects with WHT, EHT and NT during the same clinical setting to quantify muscle sympathetic nerve activity as multiunit discharge (MSNA) and single units (s-MSNA)., Results: The s-MSNA in WHT (54 +/- 4.2 impulses/100 beats) was greater (p < 0.05) than in NT (37 +/- 5.4 impulses/100 beats) despite similar age and body mass index (BMI). The EHT values of s-MSNA (73 +/- 5.2 impulses/100 beats) were significantly (p < 0.05) greater than in WHT despite similar age, BMI and blood pressure levels. The MSNA followed a similar trend. White-coat hypertension had a similar cardiac baroreceptor reflex sensitivity to NT, but this was impaired in EHT relative to both NT and WHT., Conclusions: It was shown, in the clinical setting, that central sympathetic hyperactivity exists in WHT, albeit to a lesser degree than EHT. These findings suggest that WHT may not be entirely benign and that the observed sympathetic hyperactivity may be responsible for development of target organ damage in this group of patients.