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

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

Asynchronous action potential discharge in human muscle sympathetic nerve activity.

What strategies are employed by the sympathetic system to communicate with the circulation? Muscle sympathetic nerve activity (MSNA) occurs in bursts of synchronous action potential (AP) discharge, yet whether between-burst asynchronous AP firing exists remains unknown. Using multiunit microneurography and a continuous wavelet transform to isolate APs, we studied AP synchronicity within human MSNA. Asynchronous APs were defined as those which occurred between bursts. Experiment 1 quantified AP synchronicity in eight individuals at baseline (BSL), -10 mmHg lower body negative pressure (LBNP), -40 mmHg LBNP, and end-expiratory apnea (APN). At BSL, 33 ± 12% of total AP activity was asynchronous. Asynchronous discharge was unchanged from BSL (67 ± 37 AP/min) to -10 mmHg LBNP (69 ± 33 AP/min), -40 mmHg LBNP (83 ± 68 AP/min), or APN (62 ± 39 AP/min). Across all conditions, asynchronous AP probability and frequency decreased with increasing AP size. Experiment 2 examined the impact of the ganglia on AP synchronicity by using nicotinic blockade (trimethaphan). The largest asynchronous APs were derecruited from BSL (11 ± 4 asynchronous AP clusters) to the last minute of the trimethaphan infusion with visible bursts (7 ± 2 asynchronous AP clusters). However, the 6 ± 2 smallest asynchronous AP clusters could not be blocked by trimethaphan and persisted to fire 100 ± 0% asynchronously without forming bursts. Nonnicotinic ganglionic mechanisms affect some, but not all, asynchronous activity. The fundamental behavior of human MSNA contains between-burst asynchronous AP discharge, which accounts for a considerable amount of BSL activity.NEW & NOTEWORTHY Historically, sympathetic nerve activity destined for the blood vessels supplying skeletal muscle (MSNA) has been characterized by spontaneous bursts formed by synchronous action potential (AP) discharge. However, this study found a considerable amount (~30% during baseline) of sympathetic AP discharge to fire asynchronously between bursts of human MSNA. Trimethaphan infusion revealed that nonnicotinic ganglionic mechanisms contribute to some, but not all, asynchronous discharge. Asynchronous sympathetic AP discharge represents a fundamental behavior of MSNA.

The role of the paravertebral ganglia in human sympathetic neural discharge patterns.

KEY POINTS: The mechanisms affecting recruitment patterns of postganglionic sympathetic nerves remain unclear. The divergent and convergent preganglionic innervation patterns of postganglionic neurons and the presence of differently sized postganglionic nerves suggest that the ganglia may participate in modifying the discharge patterns of single sympathetic postganglionic neurons innervating the skeletal muscle circulation. Whether the ganglia affect the ordered behaviour of varying sized postganglionic sympathetic neurons in humans has not been studied. Trimethaphan infusion produced an ordered pattern of action potential (AP) de-recruitment whereby the firing of larger, low probability APs present at baseline was abolished first, followed by progressive decreased probability of smaller APs. Although integrated sympathetic bursts were no longer detected after several minutes of trimethaphan, firing of the smallest APs was detected. These data suggest the ganglia affect the distribution of firing probabilities exhibited by differently sized sympathetic neurons. The ganglia may contribute to sympathetic neural emission patterns involved in homeostatic regulation. ABSTRACT: Do the ganglia contribute to the ordered behaviour of postganglionic neuronal discharge within the sympathetic nervous system? To further understand the functional organization of the sympathetic nervous system we employed the microneurographic approach to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to study postganglionic action potential (AP) behaviour during nicotinic blockade at the ganglia (trimethaphan camsylate, 1-7 mg min-1 ) in seven females (37 ± 5 years). Trimethaphan elicited a progressive reduction in sympathetic outflow characterized by fewer integrated bursts with decaying amplitude. Underlying trimethaphan-mediated attenuations in integrated MSNA were reductions in AP incidence (186 ± 101 to 29 ± 31 AP (100 beats)-1 ) and AP content per integrated burst (7 ± 2 to 3 ± 1 APs burst-1 ) (both P < 0.01) in the final minute of detectable bursting activity in the trimethaphan condition, compared to baseline. We observed an ordered de-recruitment of larger to smaller AP clusters active at baseline (14 ± 3 to 8 ± 2 active AP clusters, P < 0.01). Following cessation of integrated bursts in the trimethaphan condition, the smallest 6 ± 2 sympathetic AP clusters persisted to fire in an asynchronous pattern (49 ± 41 AP (100 beats)-1 ) in all participants. Valsalva's manoeuvre did not increase the incidence of these persistent APs (60 ± 42 AP (100 beats)-1 , P = 0.52), or recruit any larger APs in six of seven participants (6 ± 1 total AP clusters, P = 0.30). These data suggest that the ganglia participate in the ordered recruitment of differently sized postganglionic sympathetic nerves.

Influence of sympathetic nerve activity on aortic hemodynamics and pulse wave velocity in women.

Central (aortic) blood pressure, arterial stiffness, and sympathetic nerve activity increase with age in women. However, it is unknown if the age-related increase in sympathetic activity influences aortic hemodynamics and carotid-femoral pulse wave velocity (cfPWV), an index of central aortic stiffness. The goal of this study was to determine if aortic hemodynamics and cfPWV are directly influenced by sympathetic nerve activity by measuring aortic hemodynamics, cfPWV, and muscle sympathetic nerve activity (MSNA) in women before and during autonomic ganglionic blockade with trimethaphan camsylate. We studied 12 young premenopausal (23 ± 4 yr) and 12 older postmenopausal (57 ± 3 yr) women. These women did not differ in body mass index or mean arterial pressure (P > 0.05 for both). At baseline, postmenopausal women had higher aortic pulse pressure, augmented pressure, augmentation index adjusted for a heart rate of 75 beats/min, wasted left ventricular pressure energy, and cfPWV than young women (P < 0.05). During ganglionic blockade, postmenopausal women had a greater decrease in these variables in comparison to young women (P < 0.05). Additionally, baseline MSNA was negatively correlated with the reductions in aortic pulse pressure, augmented pressure, and wasted left ventricular pressure energy during ganglionic blockade in postmenopausal women (P < 0.05) but not young women. Baseline MSNA was not correlated with the changes in augmentation index adjusted for a heart rate of 75 beats/min or cfPWV in either group (P > 0.05 for all). Our results suggest that some aortic hemodynamic parameters are influenced by sympathetic activity to a greater extent in older postmenopausal women than in young premenopausal women.NEW & NOTEWORTHY Autonomic ganglionic blockade results in significant decreases in multiple aortic pulse wave characteristics (e.g., augmented pressure) and central pulse wave velocity in older postmenopausal women but not in young premenopausal women. Certain aortic pulse wave parameters are negatively influenced by sympathetic activity to a greater extent in older postmenopausal women.

Neural control of blood pressure in women: differences according to age.

PURPOSE: The blood pressure "error signal" represents the difference between an individual's mean diastolic blood pressure and the diastolic blood pressure at which 50% of cardiac cycles are associated with a muscle sympathetic nerve activity burst (the "T50"). In this study we evaluated whether T50 and the error signal related to the extent of change in blood pressure during autonomic blockade in young and older women, to study potential differences in sympathetic neural mechanisms regulating blood pressure before and after menopause. METHODS: We measured muscle sympathetic nerve activity and blood pressure in 12 premenopausal (25 ± 1 years) and 12 postmenopausal women (61 ± 2 years) before and during complete autonomic blockade with trimethaphan camsylate. RESULTS: At baseline, young women had a negative error signal (-8 ± 1 versus 2 ± 1 mmHg, p < 0.001; respectively) and lower muscle sympathetic nerve activity (15 ± 1 versus 33 ± 3 bursts/min, p < 0.001; respectively) than older women. The change in diastolic blood pressure after autonomic blockade was associated with baseline T50 in older women (r = -0.725, p = 0.008) but not in young women (r = -0.337, p = 0.29). Women with the most negative error signal had the lowest muscle sympathetic nerve activity in both groups (young: r = 0.886, p < 0.001; older: r = 0.870, p < 0.001). CONCLUSIONS: Our results suggest that there are differences in baroreflex control of muscle sympathetic nerve activity between young and older women, using the T50 and error signal analysis. This approach provides further information on autonomic control of blood pressure in women.

Multiple system atrophy: using clinical pharmacology to reveal pathophysiology.

Despite similarities in their clinical presentation, patients with multiple system atrophy (MSA) have residual sympathetic tone and intact post-ganglionic noradrenergic fibers, whereas patients with pure autonomic failure (PAF) and Parkinson disease have efferent post-ganglionic autonomic denervation. These differences are apparent biochemically, as well as in neurophysiological testing, with near normal plasma norephrine in MSA but very low levels in PAF. These differences are also reflected in the response patients have to drugs that interact with the autonomic nervous system. For example, the ganglionic blocker trimethaphan reduces residual sympathetic tone and lowers blood pressure in MSA, but less so in PAF. Conversely, the α2-antagonist yohimbine produces a greater increase in blood pressure in MSA compared to PAF, although significant overlap exists. In normal subjects, the norepinephrine reuptake (NET) inhibitor atomoxetine has little effect on blood pressure because the peripheral effects of NET inhibition that result in noradrenergic vasoconstriction are counteracted by the increase in brain norepinephrine, which reduces sympathetic outflow (a clonidine-like effect). In patients with autonomic failure and intact peripheral noradrenergic fibers, only the peripheral vasoconstriction is apparent. This translates to a significant pressor effect of atomoxetine in MSA, but not in PAF patients. Thus, pharmacological probes can be used to understand the pathophysiology of the different forms of autonomic failure, assist in the diagnosis, and aid in the management of orthostatic hypotension.

Sympathetic activation and nitric oxide function in early hypertension.

The purpose of this study was to determine if tonic restrain of blood pressure by nitric oxide (NO) is impaired early in the development of hypertension. Impaired NO function is thought to contribute to hypertension, but it is not clear if this is explained by direct effects of NO on vascular tone or indirect modulation of sympathetic activity. We determined the blood pressure effect of NO synthase inhibition with N(ω)-monomethyl-l-arginine (L-NMMA) during autonomic blockade with trimethaphan to eliminate baroreflex buffering and NO modulation of autonomic tone. In this setting, impaired NO modulation of vascular tone would be reflected as a blunted pressor response to L-NMMA. We enrolled a total of 66 subjects (39 ± 1.3 yr old, 30 females), 20 normotensives, 20 prehypertensives (blood pressure between 120/80 and 140/90 mmHg), 17 hypertensives, and 9 smokers (included as "positive" controls of impaired NO function). Trimethaphan normalized blood pressure in hypertensives, suggesting increased sympathetic tone contributing to hypertension. In contrast, L-NMMA produced similar increases in systolic blood pressure in normal, prehypertensive, and hypertensive subjects (31 ± 2, 32 ± 2, and 30 ± 3 mmHg, respectively), whereas the response of smokers was blunted (16 ± 5 mmHg, P = 0.012). Our results suggest that sympathetic activity plays a role in hypertension. NO tonically restrains blood pressure by ∼30 mmHg, but we found no evidence of impaired modulation by NO of vascular tone contributing to the early development of hypertension. If NO deficiency contributes to hypertension, it is likely to be through its modulation of the autonomic nervous system, which was excluded in this study.

beta2-Adrenoceptor gene variation and systemic vasodilatation during ganglionic blockade.

Regional infusions of beta(2)-adrenoceptor (ADRB2) agonist have generally shown that individuals homozygous for Gly16 produces greater vasodilatation than those homozygous for Arg16. Systemic infusions have shown an opposite effect on systemic vascular resistance (SVR), possibly confounded by baroreflexes or interactions between single nucleotide polymorphism (SNP) positions 16 and 27. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (Terb) during ganglionic blockade. Forty healthy young adults were recruited according to the double homozygous haplotypes: Arg16 + Gln27 (n = 13), the rare Gly16 + Gln27 (n = 6), and Gly16 + Glu27 (n = 21). Arterial pressure was measured by brachial arterial catheter, and cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3-7 mg min(1)), continuous phenylephrine was titrated to restore blood pressure to baseline. Terb was infused i.v. at 33 and 67 ng kg(1) min(1) for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR (P = 0.06). For SNP position 16, the highest dose of Terb produced lower SVR in Gly16 (mean +/- s.e.m.: 7.5 +/- 0.4) vs. Arg16 (8.9 +/- 0.7 units; P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs. Arg16 (P = 0.05). We conclude that during ganglionic blockade, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16 + Glu27 homozygotes, with greater influence from Gly16, providing further evidence that ADRB2 gene variation influences vasodilatation.

Jugular venous overflow of noradrenaline from the brain: a neurochemical indicator of cerebrovascular sympathetic nerve activity in humans.

A novel neurochemical method was applied for studying the activity of sympathetic nerves in the human cerebral vascular system. The aim was to investigate whether noradrenaline plasma kinetic measurements made with internal jugular venous sampling reflect cerebrovascular sympathetic activity. A database was assembled of fifty-six healthy subjects in whom total body noradrenaline spillover (indicative of whole body sympathetic nervous activity), brain noradrenaline spillover and brain lipophlic noradrenaline metabolite (3,4-dihydroxyphenolglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG)) overflow rates were measured. These measurements were also made following ganglion blockade (trimethaphan, n = 6), central sympathetic inhibition (clonidine, n = 4) and neuronal noradrenaline uptake blockade (desipramine, n = 13) and in a group of patients (n = 9) with pure autonomic failure (PAF). The mean brain noradrenline spillover and brain noradrenaline metabolite overflow in healthy subjects were 12.5 +/- 1.8, and 186.4 +/- 25 ng min(-1), respectively, with unilateral jugular venous sampling for both. Total body noradrenaline spillover was 605.8 ng min(-1) +/- 34.4 ng min(-1). As expected, trimethaphan infusion lowered brain noradrenaline spillover (P = 0.03), but perhaps surprisingly increased jugular overflow of brain metabolites (P = 0.01). Suppression of sympathetic nervous outflow with clonidine lowered brain noradrenaline spillover (P = 0.004), without changing brain metabolite overflow (P = 0.3). Neuronal noradrenaline uptake block with desipramine lowered the transcranial plasma extraction of tritiated noradrenaline (P = 0.001). The PAF patients had 77% lower brain noradrenaline spillover than healthy recruits (P = 0.06), indicating that in them sympathetic nerve degeneration extended to the cerebral circulation, but metabolites overflow was similar to healthy subjects (P = 0.3). The invariable discordance between noradrenline spillover and noradrenaline metabolite overflow from the brain under these different circumstances indicates that the two measures arise from different sources, i.e. noradrenaline spillover originates from the cerebral vasculature outside the blood-brain barrier, and the noradrenaline metabolites originate primarily from brain noradrenergic neurons. We suggest that measurements of transcranial plasma noradrenaline spillover have utility as a method for assessing the sympathetic nerve activity of the cerebral vasculature.

Aging Alters the Relative Contributions of the Sympathetic and Parasympathetic Nervous System to Blood Pressure Control in Women.

Autonomic support of blood pressure increases with age in humans. Large differences exist in the dose of trimethaphan (TMP) required for ganglionic blockade in young and older women. We asked whether differences in the dose of TMP required to achieve ganglionic blockade are because of differences in the relative contributions of the sympathetic and parasympathetic nervous system in control of blood pressure with age. Muscle sympathetic nerve activity (microneurography, peroneal nerve), heart rate (HR), and blood pressure were recorded before and during incremental doses of TMP camsylate until ganglionic blockade was achieved (absence of muscle sympathetic nerve activity and <5-bpm increase in HR during a valsalva maneuver; final TMP dose, 1-7 mg/min). HR variability was analyzed from the ECG waveform (WinCPRS). The dose of TMP required to achieve ganglionic blockade is positively related to basal HR variability, where women with high HR variability require a higher dose of TMP to achieve ganglionic blockade. In contrast, baseline muscle sympathetic nerve activity is inversely related with the dose of TMP required to achieve ganglionic blockade, such that women with high basal muscle sympathetic nerve activity required a lower dose of TMP. As such, the change in HR with ganglionic blockade was positively related, and the change in mean arterial pressure was inversely related, with the dose of TMP required to achieve ganglionic blockade. These data suggest loss of parasympathetic tone and increased sympathetic tone with aging contribute to the increase in blood pressure with age in women and dictate the dose of TMP that is necessary to achieve ganglionic blockade.

Autonomic ganglionic blockade does not prevent reduction in cerebral blood flow velocity during orthostasis in humans.

BACKGROUND AND PURPOSE: The underlying mechanisms for reductions in cerebral blood flow (CBF) during orthostasis are not completely understood. This study tested the hypothesis that sympathetic activation causes cerebral vasoconstriction leading to reductions in CBF during lower body negative pressure (LBNP). METHODS: CBF velocity, arterial pressure, and end-tidal CO(2) were measured during LBNP (-30 to -50 mm Hg) in 11 healthy subjects before and after autonomic ganglionic blockade with trimethaphan. Arterial partial pressure of CO(2) also was measured in a subgroup of 5 subjects. Mean arterial pressure during LBNP after blockade was maintained by infusion of phenylephrine. RESULTS: Before blockade, mean arterial pressure did not change during LBNP. However, CBF velocity was reduced in all subjects by 14% (P<0.05). Systolic and pulsatile (systolic-diastolic) CBF velocity were reduced by 18% and 28%, respectively, associated with significant reductions in pulse arterial pressure and end-tidal CO(2) (all P<0.05). After blockade, mean arterial pressure during LBNP was well-maintained and even increased slightly with infusion of phenylephrine. However, reductions in mean, systolic, and pulsatile CBF velocity, pulse arterial pressure, and ETCO(2) were similar to those before blockade. In contrast to reductions in end-tidal CO(2), arterial partial pressure of CO(2) did not change during LBNP. CONCLUSIONS: These data, contrary to our hypothesis, demonstrate that sympathetic vasoconstriction is not the primary mechanism underlying reductions in CBF during moderate LBNP. We speculate that diminished pulse arterial pressure or pulsatile blood flow may reduce cerebral vessel wall shear stress and contribute to reductions in CBF during orthostasis through flow mediated regulatory mechanisms.

Early estimation of myocardial damage in conscious dogs and patients with evolving acute myocardial infarction.

To estimate the ultimate extent of myocardial damage during evolving myocardial infarction in conscious dogs and patients, we analyzed early serum creatine phosphokinase (CPK) changes with nonlinear curve-fitting techniques. In experiments with dogs, serial serum CPK changes were fit to a log-normal function by the least squares method; the extent of the completed infarct was calculated by analysis of observed serum CPK changes and verified by measurement of myocardial CPK depletion 24 h after coronary occlusion. Early prediction of myocardial damage was based on projected serum CPK values from best fit curves based on data obtained during the first 5 h after initial elevation of enzyme activity. The correlation between predicted and observed values was close (r > 0.96, n = 11). In 11 additional conscious animals subjected to coronary occlusion, isoproterenol was administered continuously as soon as damage had been estimated from projected serum CPK values. The extent of the completed infarct was assessed by analysis of all serial serum CPK values and verified by analysis of myocardial CPK depletion 24 h after coronary occlusion. In each experiment the calculated completed infarct size exceeded infarct size projected before administration of isoproterenol (average increase = 44+/-10 [SE]%). When similar calculations were applied in experiments with eight dogs treated with propranolol, myocardial salvage was detected in 50% of the animals. In 30 patients with uncomplicated acute myocardial infarction the extent of the completed infarct, measured by analysis of CPK activity in serum samples obtained every 2 h, was compared with damage estimated from CPK values projected by the best fit log-normal curve derived from data obtained during the first 7 h after the initial serum CPK elevation. The estimate of damage based on early data correlated closely with the extent of infarction calculated from all available serial serum CPK values (r = 0.93, n = 30). Thus, the extent of the completed infarct could be estimated accurately during the early evolution of infarction. In patients with spontaneous extension of infarction manifested by chest pain and electrocardiographic changes, the calculated extent of the completed infarct exceeded that predicted. Conversely, salvage of myocardium, after reduction of myocardial oxygen requirements by administration of trimethaphan, was reflected by reduction of the extent of the calculated completed infarct with respect to that predicted from early serum CPK changes.

Studies of the mechanism of contralateral polyuria after renal artery stenosis.

Acute renal artery stenosis in hydropenic dogs caused a contralateral increase in urine volume and free water clearance without change in glomerular filtration, renal blood flow, or osmolar clearance. The increase in urine volume was not dependent on the development of hypertension since it occurred in animals pretreated with trimethaphan but was dependent upon angiotensin since it was presented with angiotensin blockade with Saralasin. The effect was not caused by angiotensin inhibiting antidiuretic hormone release since the polyuria occurred in hypophysectomized animals receiving a constant infusion of 10 muU/kg per min of aqueous Pitressin. Since the rise in urine volume was associated with an increase in renal vein prostaglandin E concentration and was prevented by pretreatment with indomethacin (5 mg/kg) the results suggest that the rise in plasma angiotensin after renal artery stenosis causes an increase in contralateral prostaglandin E synthesis with resultant antagonism to antidiuretic hormone at the collecting tubule.

Sympathetic control of lower esophageal sphincter function in the cat. Action of direct cervical and splanchnic nerve stimulation.

The purpose of this study was to determine the effect of direct stimulation of the sympathetic nerves on the lower esophageal sphincter (LES) in the anesthetized cat. Neither unilateral nor bilateral cervical sympathectomy, or splanchnicectomy significantly modified basal LES pressure in animals with intact vagi, or animals having undergone bilateral cervical vagotomy. Electrical stimulation of the cut, peripheral, cervical sympathetic trunk increased mean arterial blood pressure, but had no effect on LES pressure or LES relaxation as induced by vagal stimulation. Stimulation of the central end of the cervical sympathetic trunk had no effect on LES pressure. Stimulation of the central end of the cut splanchnic nerve produced a decrease in LES pressure with a maximal response of 69.1+/-16.0% (mean+/-SEM). This inhibitory response was not modified by either propranolol or bilateral cervical vagotomy. Stimulation of the peripheral end of the cut, greater splanchnic nerve gave an increase in LES pressure with a maximal response of 38.2+/-7.19 mm Hg. Guanethidine, in the presence or absence of the adrenal glands, significantly augmented this excitatory response. This response was also slightly increased by phentolamine alone at 10 V, 1 Hz, but was not altered by propranolol. The excitatory response was completely antagonized by atropine or by trimethaphan camsylate. Stimulation of the peripheral end of the splanchnic nerve inhibited LES relaxation as induced by vagal stimulation. The results of this study suggest that: (a) the LES in the cat is not affected by either central or peripheral stimulation of the cervical sympathetic trunk; (b) the central portion of the splanchnic nerve carries an afferent inhibitory response to the LES through yet unknown pathways; (c) the peripheral splanchnic nerve carries an atropine-sensitive excitatory response to the LES; and (d) the splanchnic nerves may modulate LES relaxation as induced by vagal stimulation.

Sympathoadrenal function in patients with paroxysmal hypertension: pseudopheochromocytoma.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men.

BACKGROUND: Short-term and tonic regulation of arterial blood pressure (BP) differ in premenopausal women and men of similar age. The autonomic nervous system (ANS) plays a critical role in BP regulation. METHODS AND RESULTS: To test the hypothesis that women have lower tonic ANS support of BP (reduction in intra-arterial BP during acute ganglionic blockade [GB] with intravenous trimethaphan) and less effective baroreflex buffering (BRB) of BP (potentiation of the systolic BP [SBP] response to bolus phenylephrine during versus before GB) than men, 51 healthy adults, 22 premenopausal women (aged 28+/-1 years, mean+/-SE) and 29 men (aged 27+/-1 years), were studied. Women had lower baseline SBP and plasma catecholamine concentrations than men (P<0.05). Tonic ANS support of BP was approximately 50% to 65% lower in the women (P<0.001). The reductions in BP during GB were related to baseline plasma catecholamine concentrations (r=-0.31 to -0.41, P<0.05). Acute BRB of BP was 47% smaller in the women (3.3+/-0.5 versus 6.3+/-0.9, P=0.006) and was related to the SBP responses to phenylephrine before GB (R2=0.71, P<0.0001). Systemic alpha1-adrenergic vascular responsiveness (SBP response to bolus phenylephrine during GB) was not different (women 21.5+/-2 mm Hg versus men 18.6+/-2 mm Hg, P=0.3). CONCLUSIONS: Premenopausal women have lower tonic sympathoadrenal activity-related ANS support of BP and less effective BRB of BP than men of similar age. The lower tonic ANS support of BP could contribute to the lower chronic BP levels of premenopausal women, whereas attenuated BRB of BP may help explain less effective BP regulation in women in response to vasoactive drugs and acute stress.

Neuropharmacologic distinction of neurogenic orthostatic hypotension syndromes.

BACKGROUND: Neurogenic orthostatic hypotension (OH) characterizes pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson disease (PD) with autonomic failure. We used neuropharmacologic probes that might distinguish these diseases based on loss of sympathetic noradrenergic nerves in PAF and PD + OH but not in MSA, and related the results to neurochemical and neuroimaging findings in the same patients. METHODS: Patients with neurogenic OH (PD + OH; N = 35), MSA (N = 41), and PAF (N = 12) received iv trimethaphan (TRI), which inhibits sympathetic nerve traffic, or yohimbine (YOH), which stimulates sympathetic traffic. Dependent measures included blood pressure, plasma norepinephrine (NE) levels, and interventricular septal myocardial radioactivity after iv injection of the sympathoneural imaging agent, 6-[F]fluorodopamine. RESULTS: The PD + OH and PAF groups had smaller pressor responses to YOH (12 +/- 8 and 13 +/- 1 mm Hg) and depressor responses to TRI (-14 +/- 8 and -17 +/- 7 mm Hg) than did the MSA group (43 +/- 8 mm Hg, -57 +/- 8 mm Hg; P = 0.01, P = 0.03). The PD + OH and MSA groups did not differ in NE responses to YOH and TRI. The depressor response to TRI, the pressor response to YOH, and the blood pressure difference between YOH and TRI all correlated positively with myocardial 6-[F]fluorodopamine-derived radioactivity. CONCLUSIONS: The PD + OH resembles PAF and differs from MSA in hemodynamic responses to drugs that alter NE release from sympathetic nerves. The results fit with sympathetic noradrenergic denervation in PD + OH and PAF but not in MSA.

Baroreflex buffering is reduced with age in healthy men.

BACKGROUND: Baroreflex buffering is an important mechanism in arterial blood pressure control. The effect of healthy (physiological) aging on tonic baroreflex buffering in humans is unknown. METHODS AND RESULTS: Baroreflex buffering was determined in 27 young (aged 25+/-1 years) and 16 older (aged 65+/-1 years) healthy normotensive men by measuring the potentiation of the systolic blood pressure (SBP) responses to a phenylephrine bolus (BRBbolus) and incremental infusion (BRBslope) during compared with before ganglionic blockade with trimethaphan. The SBP responses to phenylephrine either were not different or greater in the older men before ganglionic blockade, but smaller during ganglionic blockade. BRBbolus (2.1+/-0.4 versus 5.1+/-0.7, P<0.001) and BRBslope (1.6+/-0.2 versus 3.5+/-0.4, P<0.0001) were approximately 115% smaller in the older men. Baroreflex buffering was not consistently related to mean levels or variability of blood pressure or heart rate, or to cardiovagal baroreflex sensitivity, but correlated with muscle sympathetic nerve activity (BRBbolus: r=-0.55, BRBslope: r=-0.69, P<0.005) and the SBP responses to phenylephrine during ganglionic blockade (BRBbolus: r=0.53; BRBslope: r=0.98, P<0.0001). BRBbolus was also inversely related to the SBP response to phenylephrine before ganglionic blockade (r=-0.78, P<0.0001). CONCLUSIONS: Physiological aging in men is associated with a marked reduction in baroreflex buffering. The decrease in baroreflex buffering with aging is related to increases in basal sympathetic nerve activity and reductions in systemic alpha1-adrenergic vascular responsiveness. These findings are helpful for interpreting changes in baroreflex buffering in older patients with cardiovascular disease, as well as changes in responsiveness to vasoactive drugs with aging.

Catechol-o-methyltransferase and blood pressure in humans.

BACKGROUND: Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown. METHODS AND RESULTS: We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was approximately 3.5 times greater than the maximal response to entacapone. CONCLUSIONS: COMT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering. Patients with multiple system atrophy allow for the characterization of subtle manipulations of norepinephrine turnover and blood pressure regulation in small numbers of subjects.

Modulation of QT interval during autonomic nervous system blockade in humans.

BACKGROUND: It is thought that the autonomic nervous system modulates QT interval, but traditional autonomic blockade combining propranolol and atropine has produced conflicting results. We used the alternative approach of interrupting neurotransmission at the level of autonomic ganglia to determine its effect on the QT interval. METHODS AND RESULTS: We infused trimethaphan at increasing doses (0.5 to 10 mg/min IV) while monitoring heart rate, heart rate variability spectra, QT interval, and blood pressure in 10 normal volunteers, 9 patients with multiple system atrophy (MSA), and 8 patients with pure autonomic failure (PAF). The QT interval was corrected for heart rate using Bazett's formula (QTc). Patients with PAF had very low heart rate variability and a prolonged QTc at baseline (465+/-8 ms) compared with patients with MSA (448+/-6 ms) and normal subjects (432+/-6 ms). In normal subjects, trimethaphan dose-dependently prolonged QTc (to 469+/-7 ms), decreased RR interval (995+/-45 to 670+/-35 ms), and abolished heart rate variability. In MSA patients, trimethaphan also prolonged QTc (to 463+/-7 ms) and reduced heart rate variability but did not significantly change RR interval (from 813+/-38 to 801+/-39). CONCLUSIONS: Autonomic blockade prolongs QT interval in normal subjects to a similar duration as in PAF patients. Furthermore, blocking residual autonomic tone in PAF patients is associated with a further increase in QT interval length. Patients with MSA have greater residual sympathetic tone and greater prolongation of the QT interval during ganglionic blockade than PAF patients.