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© 2019 the American Physiological Society. 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.

Aging increases autonomic support of blood pressure; however, the impact of aerobic fitness on autonomic support of blood pressure has not been addressed in women. As such, we hypothesized that aerobic fitness would be related to the change in blood pressure during ganglionic blockade such that women with greater aerobic fitness would have a blunted fall in blood pressure during ganglionic blockade due to increased vagal tone. Thirteen young premenopausal and 13 older postmenopausal women completed a screening visit where aerobic fitness (maximal oxygen consumption, VO 2max ) was measured. On a separate study day, participants were instrumented for assessment of muscle sympathetic nerve activity, heart rate (electrocardiography), and beat by beat blood pressure (arterial catheter and pressure transducer) and underwent pharmacological blockade of the autonomic ganglia using trimethaphan camyslate. Heart rate, blood pressure, and muscle sympathetic nerve activity were analyzed before and during ganglionic blockade. In young women, there was a significant relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =0.761, P =0.003). In older women, there was no relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =−0.106, P =0.73). Measures of heart rate variability were related to fitness in young women, but not older women (root mean square of successive differences between normal heartbeats, r =0.713, P =0.006 versus r =−0.172, P =0.575). Our data suggest that in young women, autonomic support of blood pressure is attenuated in those that are highly fit; however, this relationship is not significant in older 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

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.

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.

© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society 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.

Obesity is an important risk factor for the development of insulin resistance. Initial compensatory mechanisms include an increase in insulin levels, which are thought to induce sympathetic activation in an attempt to restore energy balance. We have previously shown, however, that sympathetic activity has no beneficial effect on resting energy expenditure in obesity. On the contrary, we hypothesize that sympathetic activation contributes to insulin resistance. To test this hypothesis, we determined insulin sensitivity using a standard hyperinsulinemic euglycemic clamp protocol in obese subjects randomly assigned in a crossover design 1 month apart to receive saline (intact day) or trimetaphan (4 mg/min IV, autonomic blocked day). Whole-body glucose uptake ( M BW in mg/kg per minute) was used as index of maximal muscle glucose use. During autonomic blockade, we clamped blood pressure with a concomitant titrated intravenous infusion of the nitric oxide synthase inhibitor N -monomethyl-L-arginine. Of the 21 obese subjects (43±2 years; 35±2 kg/m 2 body mass index) studied, 14 were insulin resistant; they were more obese, had higher plasma glucose and insulin, and had higher muscle sympathetic nerve activity (23.3±1.5 versus 17.2±2.1 burst/min; P =0.03) when compared with insulin-sensitive subjects. Glucose use improved during autonomic blockade in insulin-resistant subjects ( M BW 3.8±0.3 blocked versus 3.1±0.3 mg/kg per minute intact; P =0.025), with no effect in the insulin-sensitive group. These findings support the concept that sympathetic activation contributes to insulin resistance in obesity and may result in a feedback loop whereby the compensatory increase in insulin levels contributes to greater sympathetic activation.

Impaired nitric oxide (NO) vasodilation (endothelial dysfunction) is associated with obesity and thought to be a factor in the development of hypertension. We previously found that NO synthesis inhibition had similar pressor effects in obese hypertensives compared with healthy control during autonomic blockade, suggesting that impaired NO vasodilation is secondary to sympathetic activation. We tested this hypothesis by determining the effect of autonomic blockade (trimethaphan 4 mg/min IV) on NO-mediated vasodilation (increase in forearm blood flow to intrabrachial acetylcholine) compared with endothelial-independent vasodilation (intrabrachial sodium nitroprusside) in obese hypertensive subjects (302 ). Acetylcholine and sodium nitroprusside were given at equipotent doses (10, 30, and 50 μg/min and 1, 2, and 3 μg/min, respectively) to 14 obese subjects (49±3.6 years, 34±1 kg/m 2 , 165/94±7/6 mm Hg), on separate occasions 1 month apart, randomly assigned. Autonomic blockade increased basal forearm blood flow (from 3.9±0.7 to 5.2±1.2 mL/100 mL per minute, P =0.078). As expected, NO-mediated vasodilation was blunted on the intact day compared with NO-independent vasodilation; forearm blood flow increased from 3.6±0.6 to 10.1±1.1 with the highest dose of nitroprusside, but only from 3.7±0.4 to 7.2±0.8 mL/100 mL per minute with the highest dose of acetylcholine, P P =0.58). Our results support the concept that sympathetic activation contributes to the impairment in NO-mediated vasodilation seen in obesity-associated hypertension and provides further rationale to explore it as a therapeutic target.

Approximately 50% of patients with autonomic failure (AF) suffer from supine hypertension, even those with very low plasma norepinephrine and renin. Because NO is arguably the most potent metabolic modulator of blood pressure, we hypothesized that impaired NO function contributes to supine hypertension in AF. However, we found that AF patients (n=14) were more sensitive to the pressor effects of the NO synthase inhibitor N G -monomethyl- l -arginine, suggesting increased NO function rather than deficiency; a lower dose of N G -monomethyl- l -arginine was needed to produce a similar increase in blood pressure in AF patients, as in healthy control subjects in whom AF was induced with the ganglionic blocker trimethaphan (171±37 mg versus 512±81 mg, respectively; P =0.001). Furthermore, potentiation of the actions of endogenous NO with the phosphodiesterase inhibitor sildenafil (25 mg PO) decreased nighttime supine systolic blood pressure from 182±11 to 138±4 mm Hg in 8 AF patients with supine hypertension ( P =0.012 compared with placebo). Finally, AF patients tolerated a greater degree of upright tilt during infusion of N G -monomethyl- l -arginine (56±6° versus 41±4° with placebo; n=7; P =0.014), an improvement in orthostatic tolerance similar to that obtained with equipressor doses of phenylephrine. In conclusion, AF patients do not have NO deficiency contributing to supine hypertension. Instead, they have increased NO function contributing to their orthostatic hypotension. Potentiation of NO could be used in the treatment of supine hypertension, and its inhibition offers a novel approach to improve orthostatic hypotension.

The causes of paroxysmal hypertension in patients in whom pheochromocytoma has been excluded ('pseudopheochromocytoma') usually remain unclear. Blood pressure disturbances and symptoms of catecholamine excess in these patients may reflect activation of the sympathetic nervous and adrenal medullary systems. We therefore examined sympathoadrenal function in patients with pseudopheochromocytoma compared with age-matched control subjects in whom there was no suspicion of pheochromocytoma.Plasma catecholamines and hemodynamics were examined in response to intravenous glucagon, yohimbine, and trimethaphan in 11 patients with pseudopheochromocytoma and a comparison group of nine normotensive and five hypertensive volunteers. Adrenomedullary function was also assessed by abdominal F-fluorodopamine positron emission tomography and measurements of plasma metanephrine, the O-methylated metabolite of epinephrine.Compared with controls, patients with pseudopheochromocytoma had normal plasma concentrations of norepinephrine, but 120% higher (P0.05) baseline plasma concentrations of epinephrine, 80% higher (P0.01) baseline plasma concentrations of metanephrine, and sixfold larger (P0.05) 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 (P0.005) and increases in blood pressure after yohimbine were threefold larger (P0.01) in pseudopheochromocytoma patients than in controls.Patients with pseudopheochromocytoma exhibit a pattern of normal sympathetic noradrenergic outflow, adrenomedullary activation, and augmented blood pressure responses to changes in the sympathoneural release of norepinephrine.

Cardiac β-receptor responsiveness is diminished by both aging and hypertension. However, concomitant decreases in the activity of counterregulatory mechanisms, such as the arterial baroreflex and neuronal catecholamine uptake, influence the ultimate cardiac responses to adrenergic agents in vivo. In the present study, we evaluated by echocardiography cardiac responses to intravenous infusion of epinephrine in 14 young and 18 older normotensive men and women and in 10 young and 17 older hypertensive men and women. To assess the relative contribution of intrinsic cardiac and counterregulatory components to the overall response, infusions were repeated combined with a ganglionic blocker in the young groups. Epinephrine-induced increases in heart rate were similar in the four groups. Increases in stroke volume, ejection fraction, and cardiac index were similar in the two hypertensive and two young normotensive groups. In contrast, they were attenuated in the older normotensive group, resulting in higher left ventricular responses in older hypertensive than in normotensive subjects. Heart rate and left ventricular responses to epinephrine in the presence of ganglionic blockade did not differ between the two young groups. Increases in plasma norepinephrine due to epinephrine infusion were larger in hypertensive than in normotensive subjects. One may conclude that compared with young normotensive subjects, in hypertensive subjects mechanisms increasing versus decreasing cardiac responses to epinephrine may remain in balance, and, compared with older normotensive subjects, older hypertensive subjects exhibit enhanced cardiac responses to sympathetic stimulation.

Obesity is associated with alterations in the autonomic nervous system that may contribute to the increase in blood pressure and resting energy expenditure present in this condition. To test this hypothesis, we induced autonomic withdrawal with the ganglionic blocker trimethaphan in 10 lean (32±3 years) and 10 obese (35±3 years) subjects. Systolic blood pressure fell more in obese compared with lean subjects (−17±3 versus −11±1 mm Hg; P =0.019) because of a greater decrease in total peripheral resistance (−310±41 versus 33±78 dynes/sec/cm −5 ; P =0.002). In contrast, resting energy expenditure decreased less in obese than in lean subjects, (−26±21 versus −86±15 kcal per day adjusted by fat-free mass; P =0.035). We confirmed that the autonomic contribution to blood pressure was greater in obesity after including additional subjects with a wider range of blood pressures. Systolic blood pressure decreased −28±4 mm Hg (95% CI: −38 to −18.0; n=8) in obese hypertensive subjects compared with lean (−9±1 mm Hg; 95% CI: −11 to −6; n=22) or obese normotensive subjects (−14±2 mm Hg; 95% CI: −18 to −10; n=20). After removal of autonomic influences, systolic blood pressure remained higher in obese hypertensive subjects (109±3 versus 98±2 mm Hg in lean and 103±2 mm Hg in obese normotensive subjects; P =0.004) suggesting a role for additional factors in obesity-associated hypertension. In conclusion, sympathetic activation induced by obesity is an important determinant to the blood pressure elevation associated with this condition but is not effective in increasing resting energy expenditure. These results suggest that the sympathetic nervous system could be targeted in the treatment of obesity-associated hypertension.

Impaired endothelial-derived NO (eNO) is invoked in the development of many pathological conditions. Systemic inhibition of NO synthesis, used to assess the importance of NO to blood pressure (BP) regulation, increases BP by ≈15 mm Hg. This approach underestimates the importance of eNO, because BP is restrained by baroreflex mechanisms and does not account for a role of neurally derived NO. To overcome these limitations, we induced complete autonomic blockade with trimethaphan in 17 normotensive healthy control subjects to eliminate baroreflex mechanisms and contribution of neurally derived NO. Under these conditions, the increase in BP reflects mostly blockade of tonic eNO. N G -Monomethyl- l -arginine (250 μg/kg per minute IV) increased mean BP by 6±3.7 mm Hg (from 77 to 82 mm Hg) in intact subjects and by 21±8.4 mm Hg (from 75 to 96 mm Hg) during autonomic blockade. We did not find a significant contribution of neurally derived NO to BP regulation after accounting for baroreflex buffering. To further validate this approach, we compared the effect of NOS inhibition during autonomic blockade in 10 normotensive individuals with that of 6 normotensive smokers known to have endothelial dysfunction but who were otherwise normal. As expected, normotensive smokers showed a significantly lower increase in systolic BP during selective eNO blockade (11±4.5 versus 30±2.3 mm Hg in normotensive individuals; P

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.

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 P r =−0.31 to −0.41, P P =0.006) and was related to the SBP responses to phenylephrine before GB ( R 2 =0.71, P 1 -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.

Background and Purpose— The aim of this study was to differentiate the mechanical effects of the Valsalva maneuver (VM) from the effects of changes in autonomic neural activity on cerebral hemodynamics in humans. Methods— Nine healthy subjects performed the VM before and after autonomic ganglionic blockade with trimethaphan. Blood pressure (BP) was measured in the radial artery with an indwelling catheter or at the finger by Finapres. Cerebral blood flow (CBF) velocity was measured in the middle cerebral artery with transcranial Doppler; end-tidal CO 2 was measured by mass spectrometry. Results— Before blockade, during phase II of the VM, BP was reduced by 27% and CBF velocity was reduced by 33% (magnitude of changes during phase II divided by baseline measurements before the VM, P Conclusions— After ganglionic blockade, cerebral autoregulation is unable to prevent the substantial fall in CBF induced by the marked reduction in BP during the VM. Enhanced phase IV increases in both CBF velocity and CVCI reflect the intrinsic characteristics of cerebral hyperemic responses, which are likely modified in part by the removal of vasoconstrictor effects of autonomic neural activity elicited during the VM.

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 (BRB bolus ) and incremental infusion (BRB slope ) 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. BRB bolus (2.1±0.4 versus 5.1±0.7, P slope (1.6±0.2 versus 3.5±0.4, P bolus : r =−0.55, BRB slope : r =−0.69, P bolus : r =0.53; BRB slope : r =0.98, P bolus was also inversely related to the SBP response to phenylephrine before ganglionic blockade ( r =−0.78, P 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 α 1 –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.

We measured ventilation, arterial O2 saturation, end-tidal CO2 (PET,CO2), blood pressure (intra-arterial catheter or photoelectric plethysmograph), and flow velocity in the middle cerebral artery (CFV) (pulsed Doppler ultrasound) in 17 healthy awake subjects while they performed 20 s breath holds under control conditions and during ganglionic blockade (intravenous trimethaphan, 4.4 +/- 1.1 mg min-1 (mean +/- S.D.)). Under control conditions, breath holding caused increases in PET,CO2 (7 +/- 1 mmHg) and in mean arterial pressure (MAP) (15 +/- 2 mmHg). A transient hyperventilation (PET,CO2 -7 +/- 1 mmHg vs. baseline) occurred post-apnoea. CFV increased during apnoeas (by 42 +/- 3 %) and decreased below baseline (by 20 +/- 2 %) during post-apnoea hyperventilation. In the post-apnoea recovery period, CFV returned to baseline in 45 +/- 4 s. The post-apnoea decrease in CFV did not occur when hyperventilation was prevented. During ganglionic blockade, which abolished the increase in MAP, apnoea-induced increases in CFV were partially attenuated (by 26 +/- 2 %). Increases in PET,CO2 and decreases in oxyhaemoglobin saturation (Sa,O2) (by 2 +/- 1 %) during breath holds were identical in the intact and blocked conditions. Ganglionic blockade had no effect on the slope of the CFV response to hypocapnia but it reduced the CFV response to hypercapnia (by 17 +/- 5 %). We attribute this effect to abolition of the hypercapnia-induced increase in MAP. Peak increases in CFV during 20 s Mueller manoeuvres (40 +/- 3 %) were the same as control breath holds, despite a 15 mmHg initial, transient decrease in MAP. Hyperoxia also had no effect on the apnoea-induced increase in CFV (40 +/- 4 %). We conclude that apnoea-induced fluctuations in CFV were caused primarily by increases and decreases in arterial partial pressure of CO2 (Pa,CO2) and that sympathetic nervous system activity was not required for either the initiation or the maintenance of the cerebrovascular response to hyper- and hypocapnia. Increased MAP or other unknown influences of autonomic activation on the cerebral circulation played a smaller but significant role in the apnoea-induced increase in CFV; however, negative intrathoracic pressure and the small amount of oxyhaemoglobin desaturation caused by 20 s apnoea did not affect CFV.

Disabling orthostatic hypotension dominates the clinical picture of autonomic failure. Nonetheless, severe supine hypertension is observed in about 50% of patients. In patients with multiple system atrophy (Shy-Drager syndrome), supine hypertension is explained by residual sympathetic tone because it can be eliminated with the ganglionic blocker trimethaphan. The cause of hypertension in patients with pure autonomic failure is not known and its understanding may be relevant to essential hypertension. Supine hypertension complicates the treatment of these patients but can be managed by overnight administration of antihypertensive medications.

We studied the mechanisms and physiological relevance of the cephalic insulin response to meal ingestion in 12 healthy women (age 63 ± 0.4 years; BMI 27.7 ± 1.7 kg/m2). The ganglionic antagonist, trimethaphan, which impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia, or atropine or saline was given intravenously during the first 15 min after ingestion of a standard meal (350 kcal). During saline infusion, insulin levels increased during the first 10 min after meal ingestion, whereas the first increase in glucose was evident at 15 min. The preabsorptive 10-min insulin response was reduced by 73 ± 11% by trimethaphan (P = 0.009), accompanied by impaired reduction of glucose levels from 25 to 60 min after meal ingestion (Δglucose = –1.27 ± 0.5 [with saline] vs. 0.1 ± 0.4 mmol/l [with trimethaphan]; P = 0.008). This reduction at 25–60 min in glucose levels correlated significantly to the 10-min insulin response (r = 0.65, P = 0.024). The 10-min insulin response to meal ingestion was also reduced by atropine, but only by 20 ± 9% (P = 0.045), which was lower than the reduction with trimethaphan (P = 0.004). The preabsorptive insulin response was not accompanied by any increase in circulating levels of gastric inhibitory polypeptide (GIP) or glucagon-like peptide 1 (GLP-1). In conclusion, 1) the early preabsorptive insulin response to meal ingestion in humans can be largely attributed to autonomic activation mediated by noncholinergic and cholinergic mechanisms, 2) this cephalic insulin response is required for a normal postprandial glucose tolerance, and 3) GIP and GLP-1 do not contribute to the preabsorptive cephalic phase insulin response to meal ingestion.

Abstract —Recent studies suggest that activation of the sympathetic nervous system either directly or indirectly influences cerebrovascular tone in humans even within the autoregulatory range. In 6 healthy subjects (aged 29±4 years), we used transcranial Doppler sonography to determine cerebral blood flow velocity during sympathetic activation elicited through head-up tilt (HUT) and sympathetic deactivation through ganglionic blockade. Pa co 2 was manipulated through hyperventilation and CO 2 breathing (5%). With subjects in the supine position and during HUT, mean arterial pressure was not influenced by Pa co 2 . During ganglionic blockade, mean arterial pressure decreased markedly with hyperventilation (−13±1.9 mm Hg). Manipulation of sympathetic tone elicited only mild changes in cerebral blood flow (64±5.8 cm/s supine, 58±4.9 cm/s upright, and 66±6.2 cm/s during ganglionic blockade; P =0.07 by ANOVA). The slope of the regression between Pa co 2 and mean velocity was 1.6±0.18 cm/(s · mm Hg) supine, 1.3±0.14 cm/(s · mm Hg) during HUT, and 2.3±0.36 cm/(s · mm Hg) during ganglionic blockade ( P co 2 and ventilatory response to hypercapnia were also modulated by the level of sympathetic activity. Changes in sympathetic tone have a limited effect on cerebral blood flow at normal Pa co 2 levels. However, the sympathetic nervous system seems to attenuate the CO 2 -induced increase in cerebral blood flow. This phenomenon may indicate a moderate direct effect of the sympathetic nervous system on the cerebral vasculature. Furthermore, sympathetic activation tends to increase ventilation and thus can indirectly increase cerebrovascular tone.

Sympathetic neurocirculatory failure (SNF) features orthostatic hypotension and abnormal beat-to-beat blood pressure (BP) responses to the Valsalva maneuver. This article describes a new sign of SNF, based on changes in BP after premature ventricular contractions (PVCs). Records of supine beat-to-beat BP at rest were reviewed from 22 patients with SNF and 52 control subjects. Records were also taken during intravenous infusion of the ganglion blocker trimethaphan from 38 control subjects. In all 10 control subjects who had PVCs, after the postextrasystolic beat, mean arterial pressure increased progressively to levels higher than before the PVC, peaking at about the eighth beat. In contrast, in all 13 patients with SNF who had PVCs, after the postextrasystolic beat, BP decreased to less than baseline and then increased gradually back to baseline. In all 3 control subjects who had at least one PVC before trimethaphan infusion and another during trimethaphan infusion, the post-PVC pressure pattern during trimethaphan infusion resembled that in SNF patients. Because of a brief increase in sympathetic cardiovascular outflows, after a PVC, BP increases progressively to greater than pre-PVC values, mimicking the pressure overshoot after release of the Valsalva maneuver. Just as the absence of the overshoot of BP after release of the Valsalva maneuver supports a diagnosis of SNF, so does the absence of the overshoot after a PVC.

Dopamine in the circulation occurs mainly as dopamine sulfate, the sources and physiological significance of which have been obscure. In this study, plasma concentrations of dopamine sulfate were measured after a meal, after fasting for 4 days, and during i.v. L-DOPA, nitroprusside, or trimethaphan infusion in volunteers; after dopamine infusion in patients with L-aromatic-amino-acid decarboxylase deficiency; in arterial and portal venous plasma of gastrointestinal surgery patients; and in patients with sympathetic neurocirculatory failure. Meal ingestion increased plasma dopamine sulfate by more than 50-fold; however, prolonged fasting decreased plasma dopamine sulfate only slightly. L-DOPA infusion produced much larger increments in dopamine sulfate than in dopamine; the other drugs were without effect. Patients with L-aromatic amino acid decarboxylase deficiency had decreased dopamine sulfate levels, and patients with sympathetic neurocirculatory failure had normal levels. Decarboxylase-deficient patients undergoing dopamine infusion had a dopamine sulfate/dopamine ratio about 25 times less than that at baseline in volunteers. Surgery patients had large arterial-portal venous increments in plasma concentrations of dopamine sulfate, so that mesenteric dopamine sulfate production accounted for most of urinary dopamine sulfate excretion, a finding consistent with the localization of the dopamine sulfoconjugating enzyme to gastrointestinal tissues. The results indicate that plasma dopamine sulfate derives mainly from sulfoconjugation of dopamine synthesized from L-DOPA in the gastrointestinal tract. Both dietary and endogenous determinants affect plasma dopamine sulfate. The findings suggest an enzymatic gut-blood barrier for detoxifying exogenous dopamine and delimiting autocrine/paracrine effects of endogenous dopamine generated in a "third catecholamine system."

Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared effects of mecamylamine (10 mg p.o.), a central and peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10-40 microg/kg per min i.v.), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 microg/kg nicotine by nasal spray and then tested on generalization of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 microg/kg) following antagonist/placebo pretreatment. Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in part by its central effects.

Our aim was to study the relationship between cerebral blood flow (CBF) responses to induced hypotension and to CO2 inhalation in patients with occlusive disease of the carotid or middle cerebral arteries. In 13 patients (8 men, 5 women) aged 31-73 years (mean +/- 1 SD = 63.2 +/- 10.6), regional CBF values during the resting state (CBFrest), 7% CO2 inhalation (CBFhypercapnia), and hypotension induced by 10-20 microg/kg/min intravenous trimethaphan (CBFhypotension) were measured using positron-emission tomography (PET) with H2(15)O. The % CBF change during induced hypotension (% CBFhypotension) was defined as (CBFhypotension - CBFrest)/CBFrest multiplied by 100. The % CBF change during CO2 inhalation (% CBFhypercapnia) was defined as (CBFhypercapnia - CBFrest)/CBFrest/mm Hg arterial partial pressure of CO2 x 100. We defined symptomatic hemispheres as those with a stenotic or occlusive lesion with neurological symptoms or signs and asymptomatic hemispheres as those which had a similar lesion and/or were influenced by the collateral flow pattern without neurological symptoms. In the territory of the occlusive lesion, % CBFhypotension correlated significantly with % CBFhypercapnia (r = 0.793, P0.002) in the symptomatic hemispheres. In the brain regions in which trimethaphan did not induce a reduction in CBF. % CBFhypercapnia was 6.13 +/- 1.79. In those in which % CBFhypotension ranged from 0 to -5, from -5 to -10, and more than -10%, % CBFhypercapnia was 4.05 +/- 1.99, 3.21 +/- 1.17, and 1.73 +/- 1.61, respectively, with significant differences between each pair of groups. In the asymptomatic hemispheres, % CBFhypotension also correlated with % CBFhypercapnia (r = 0.979, P0.0001). Failure to maintain CBF during induced hypotension was associated with diminished cerebrovascular vasoreactivity to hypercapnia in patients with arterial disease. This may indicate that failure of autoregulation can be assessed by the CBF response to both induced hypotension and CO2 inhalation. From the technical point of view, estimation of the CO2 response may be useful for assessing failure of autoregulation.

The effects of controlled hypotension induced with trimethaphan (TMP), nitroglycerin (TNG) or prostaglandin E1 (PGE1) during sevoflurane anaesthesia on hepatic function were studied in 28 patients undergoing spinal fusion surgery. Patients were randomly divided into three groups to receive TMP (group A, n = 10), TNG (group B, n = 10) or PGE1 (group C, n = 8). Anaesthesia was maintained with N2O and sevoflurane. The mean arterial blood pressure was maintained at 60 mmHg for 90 min. Measurements included arterial ketone body ratio (AKBR-acetoacetate/3-hydroxybutyrate), SGOT, SGPT, LDH, blood glucose and blood gases were made. Measurements were taken before hypotension, 60 min and 90 min after starting hypotension, 60 min after recovery from hypotension and on the post-operative day. AKBR showed no significant change. SGOT, SGPT and LDH were within normal limits. Controlled hypotension induced with TMP, TNG or PGE1 under sevoflurane anaesthesia in surgical patients did not cause hepatocellular damage.

In order to observe the reaction of cochlear blood flow (CBF) to trimetaphan (TMP)-induced hypotension, CBF was measured with laser-Doppler flowmetry in 7 human subjects during general anaesthesia for middle ear surgery. All subjects showed a decrease in mean arterial pressure (MAP) during intravenous infusion of TMP, followed by a gradual return to the baseline level after termination of the infusion. The CBF generally followed the MAP changes with the same pattern. Three of the seven subjects demonstrated a CBF change larger than the maximum MAP change, indicating the lack of a local autoregulatory mechanism in CBF. On the other hand, CBF changes were smaller in magnitude than the maximum change in MAP for the rest of the subjects, suggesting an autoregulatory mechanism in CBF. However, since the audiograms from these subjects indicated profound damage along the cochlear basal turn probably due to middle ear inflammation, concomitant vascular damage in this region offers another possible explanation for the inappropriate CBF changes. The present observations may also suggest that deliberately TMP-induced hypotension has a potentially harmful effect on CBF during otological surgery that attempts to preserve or improve hearing.

Abstract —Systemic administration of adrenergic agonists and nitric oxide donors is used extensively to determine cardiovascular receptor sensitivity. Conclusions regarding receptor sensitivity in the presence of the baroreflex may be misleading. In 8 normal volunteers, we determined the heart rate and blood pressure changes after incremental bolus doses of isoproterenol, phenylephrine, and sodium nitroprusside before and during neuronal nicotinic cholinergic (N N -cholinergic) blockade with trimethaphan. Results are given as median (25th/75th percentile). With trimethaphan, the baroreflex slope (as determined by bolus doses of nitroprusside and phenylephrine) decreased from 24 (22/26) to 0.00 (0.00/0.09) ms/mm Hg ( P P P P P N -cholinergic blockade. Estimation of adrenoreceptor sensitivity and sensitivity to nitric oxide donors by systemic administration of agonists is severely confounded by baroreflexes. Uncoupling of the baroreflex by N N -cholinergic blockade may be a useful method to obtain an integrated measure of adrenergic receptor sensitivity and sensitivity to nitric oxide donors in humans. This approach would permit the comparison of normal and abnormal physiological states without the “noise” of baroreflex buffering.

It is recognized that the brain plays a pivotal role in the maintenance of blood pressure and the control of myocardial function. By combining direct sampling of internal jugular venous blood with a noradrenaline isotope dilution method, for examining neuronal transmitter release, and microneurographic nerve recording, we were able to quantify the release of central nervous system noradrenaline and its metabolites and investigate their association with efferent sympathetic nervous outflow in healthy subjects and patients with pure autonomic failure. To further investigate the relationship between brain noradrenaline, sympathetic nervous activity and blood pressure regulation we examined brain catecholamine turnover, based on the internal jugular venous overflow of noradrenaline and its principal central nervous system metabolites, in response to a variety of pharmacological challenges. A substantial increase was seen in brain noradrenaline turnover following trimethaphan, presumably resulting from a compensatory response in sympathoexcitatory forebrain noradrenergic neurones in the face of interruption of sympathetic neural traffic and reduction in arterial blood pressure. In contrast, reduction in central nervous system noradrenaline turnover accompanied the blood pressure fall produced by intravenous clonidine administration, thus representing the blood pressure lowering action of the drug. Following vasodilatation elicited by intravenous adrenaline infusion, brain noradrenaline turnover increased in parallel with elevation in muscle sympathetic nervous activity. While it is difficult to assess the source of the noradrenaline and metabolites determined in our studies, available evidence implicates noradrenergic cell groups of the posterolateral hypothalamus, amygdala, the A5 region and the locus coeruleus as being involved in the regulation of sympathetic outflow and autonomic cardiovascular control.

Carbon monoxide (CO), an activator of soluble guanylate cyclase and generated enzymatically by heme oxygenase-2 (HO-2), is thought to function as an intra- and intercellular neurotransmitter in the central and peripheral nervous system. In the present study, the distribution of HO-2 in airway nerves from both humans and guinea pigs was assessed. HO-2 was found in all neuronal perikarya of the intrinsic ganglia of guinea-pig airways and in all ganglion nerve cell bodies localized to the trachea and bronchi of humans. By contrast, nerve fibers innervating the smooth muscle, lamina propria, and epithelium of the airways in both species were devoid of HO-2 immunoreactivity. HO-1, the inducible isoform of heme oxygenase, was not found in airway nerves. The pattern of distribution of HO-2 observed suggests that CO might serve as a modulator of synaptic neurotransmission in the lung and airways rather than as a bona fide neurotransmitter in the smooth muscle, vasculature, or glands. Consistent with this hypothesis, 8-bromo-cyclic guanosine monophosphate (cGMP) (30 microM), a stable, pharmacologically active analog of cGMP, markedly inhibited vagally-mediated cholinergic contractions of the isolated guinea-pig trachea. In subsequent studies, however, neither inhibiting heme oxygenase with zinc protoporphyrin-IX (30 microM) nor inhibiting the soluble isoform of guanylate cyclase with ODQ (3 microM) had measurable effects on vagally-mediated cholinergic contractions of the trachea. These results indicate that CO could play a modulatory role in efferent (parasympathetic) synaptic neurotransmission in the airways, but under normal conditions may not be activated to an appreciable extent during periods of elevated vagal activity.

Despite evidence that the autonomic nervous system (ANS) makes a significant contribution to increased glucagon secretion during insulin-induced hypoglycemia in several animal species, including a recent study in nonhuman primates, the role of the ANS in mediating this important counterregulatory response in humans remains controversial. Therefore, glucagon responses to insulin-induced hypoglycemia were examined in seven nondiabetic women (BMI, 28.0 +/- 2.0 kg/m2) with and without the presence of the ganglionic nicotinic receptor antagonist trimethaphan. Trimethaphan impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia and in the adrenal medulla and, therefore, markedly impairs autonomic activation during insulin-induced hypoglycemia. The studies were performed in random order at least 4 weeks apart. Trimethaphan was infused at a variable rate (0.3-0.6 mg/min) to modestly lower blood pressure (approximately 10 mmHg) without producing hypotension. Regular human insulin was infused (0.28 pmol x m(-2) x min(-1)) with a variable rate glucose infusion to lower the plasma glucose from 4.9 +/- 0.2 to 2.6 +/- 0.2 mmol/l in the control study and from 4.9 +/- 0.2 to 2.5 +/- 0.2 mmol/l in the trimethaphan study. Trimethaphan impaired parasympathetic and sympathoadrenal activation during insulin-induced hypoglycemia as assessed by 70% reductions of the plasma pancreatic polypeptide response and epinephrine response (both P < 0.05 vs. control study). Glucagon secretory responses during insulin-induced hypoglycemia were assessed as peak responses and as the area under the curve (AUC) above baseline values during insulin-induced hypoglycemia. Plasma glucagon increased in the control study from 44 +/- 5 ng/l to a peak of 76 +/- 9 ng/l (delta = 32 +/- 8 ng/l; P < 0.005 vs. baseline) and in the trimethaphan study from 41 +/- 3 to 50 +/- 7 ng/l (delta = 10 +/- 5 ng/l; P < 0.02 vs. control subjects). The glucagon response to insulin-induced hypoglycemia as assessed by the AUC was 948 +/- 272 ng x 1(-1) x 45 min(-1) in the control study (P < 0.01 vs. baseline), but was reduced by 75% in the trimethaphan study (AUC = 203 +/- 94 ng x 1(-1) x 45 min(-1); P < 0.02 vs. control subjects). Trimethaphan did not affect the glucagon response to arginine administration. These results demonstrate that the ANS mediates the majority of the glucagon response to insulin-induced hypoglycemia of 2.5 mmol/l in postmenopausal nondiabetic women.

The autonomic nervous system plays a central role in both acute and chronic blood pressure regulation in humans. The activity of the sympathetic branch of the autonomic nervous system is positively associated with peripheral resistance, an important determinant of mean arterial pressure in men. In contrast, there is no association between sympathetic nerve activity and peripheral resistance in women before menopause, yet a positive association after menopause. We hypothesized that autonomic support of blood pressure is higher after menopause in women. We examined the effect of ganglionic blockade on arterial blood pressure and how this relates to baseline muscle sympathetic nerve activity in 12 young (25±1 years) and 12 older postmenopausal (61±2 years) women. The women were studied before and during autonomic blockade using trimethaphan camsylate. At baseline, muscle sympathetic nerve activity burst frequency and burst incidence were higher in the older women (33±3 versus 15±1 bursts/min; 57±5 versus 25±2 bursts/100 heartbeats, respectively; P P P r =−0.74; P

To assess the relative roles of neural and nonneural mechanisms in respiratory sinus arrhythmia (RSA) at rest and during exercise (steady-state supine cycle ergometry at 25% of peak oxygen uptake), we studied 10 healthy men (mean age 21 +/- 1 yr) before (control) and during ganglion blockade (GB) with trimetaphan camsylate (3–5 mg/min i.v.). GB was confirmed by the abolition of the reflex bradycardia in response to intravenous phenylephrine and of the blood pressure rise with the cold pressor test. RSA was calculated from the power of the spectral component of the R-R interval variability centered at the breathing frequency. GB decreased but did not abolish RSA. At rest, this nonneural component of RSA was negligible, accounting for < 1% of the control RSA. During GB, exercise did not affect RSA significantly. However, because control RSA was decreased by exercise, the proportion of nonneural RSA increased by 32% (range from 17 to 75%). These results indicate that as the vagal tone decreases with exercise, an increasing proportion of RSA is due to nonneural mechanisms.

To evaluate influences on blood volume distribution, atrial natriuretic peptide concentrations (ANP) and thoracic and leg electrical impedance at 2.5 (TI2.5 and LI2.5, respectively) and 100 kHz (TI100 and LI100, respectively) were monitored during administration of ketanserin, noradrenaline and trimetaphan combined with lower body negative pressure (LBNP) in 12 subjects. Administration of clinically relevant doses of ketanserin alone did not induce changes in mean arterial pressure (MAP) or in the central blood volume, as electrical impedance and ANP concentrations did not change. During continued infusion of ketanserin an increase in MAP from a mean of 90 (range 83-108) to 113 (range 98-138) mmHg was induced by noradrenaline, but TI2.5 [mean 45.6 (range 39.3-54.2)] and TI100 [mean 33.8 (range 27.5-38.5) omega] remainded stable until ganglionic blockade and LBNP were applied, when they increased by a mean of 3.1 (range 2.0-6.1) and 2.7 (range 1.1-4.2) omega, respectively (P0.05). Conversely, LI2.5 [mean 79.6 (range 74.1-89.4)] and LI100 [mean 56.7 (range 52.4-63.3) omega] decreased by a mean of 3.2 (range 1.2-8.0) and 2.3 (range 0.9-3.9) omega, ANP from a mean of 27.7 (range 10.2-62.7) to 12.7 (range 7.1-27.5) pmol.l-1 and MAP fell to a mean of 62 (range 42-70) mmHg (P0.05). The heart rate was a mean of 75 (range 69-77) beats.min-1 and did not change until LBNP, when it increased to a mean of 102 (range 78-104) beats.min-1, as presyncopal symptoms appeared. The data indicated that serotonergic blockade by ketanserin and alpha-sympathetic stimulation by noradrenaline did not affect blood volume distribution in normal humans, but that ganglionic blockade combined with LBNP reduced the central blood volume as leg volume increased; during central hypovolaemia tachycardia induced by ganglionic blockade did not prevent the fall in MAP, and thereby the appearance of presyncopal symptoms.

To determine whether vasodilators such as sodium nitroprusside (SNP) and trimethaphan (TMP) produce a pressure difference between the radial artery and the brachial artery during epidural plus general anesthesia or simple general anesthesia.Randomized study and prospective study.Operating rooms of two hospitals.36 and 6 adult patients in the first and second studies, respectively, who received spherical acetabular osteotomy with induced hypotensive anesthesia.In the first study, 18 patients received epidural plus general anesthesia (epidural group) and 18 patients received general anesthesia alone (general group). All patients received the hypotensive drugs for more than 50 minutes each. In the second study, 6 patients received TMP-induced hypotension for 20 minutes under epidural plus general anesthesia.In the first study, radial intra-arterial blood pressure (RIBP) and tonometric blood pressure (TBP) calibrated with oscillometric blood pressure of the arm were compared. In the second study, RIBP and the brachial intra-arterial blood pressure (BIBP) were compared. In the first study, the bias between RIBP and TBP for systolic, mean and diastolic blood pressure were significantly less during TMP-induced hypotension in the epidural group (-11.5 +/- 2.5 (mean +/- SD), -6.0 +/- 3.1, and -2.8 +/- 3.7 mmHg, respectively] than during SNP-induced hypotension in the epidural group and SNP- and TMP-induced hypotension in the general group (p0.01). The precision of systolic and mean pressures were significantly greater during TMP-induced hypotension in the epidural group (11.8 +/- 2.3 and 7.1 +/- 1.9 mmHg, respectively) than the other three hypotension groups (p0.01). In the second study, the bias between RIBP and BIBP for systolic, mean, and diastolic pressures were significantly less (p0.01), and precision was significantly greater during hypotension than during normotension (p0.01).Our results demonstrate that TMP decreases the direct radial artery systolic and mean pressures to levels below the brachial artery systolic and mean pressures in patients who received epidural plus general anesthesia.

Haemodynamic changes during induced hypotension depend upon the hypotensive agent used. We investigated if, using transoesophageal echocardiography (TEE), we could identify the haemodynamic differences between trimethaphan and prostaglandin E1. Twenty-nine patients undergoing total hip replacement were selected for study. Hypotension was induced to a mean arterial pressure of 8.0-9.3 kPa with either trimethaphan (5-20 micrograms.kg-1.min-1) or prostaglandin E1 (0.5-2.0 micrograms.kg-1.min-1). The left atrial dimension, cardiac output, fractional shortening, pulmonary venous flow and mitral valve flow were evaluated using TEE. During induced hypotension, left atrial dimension decreased in both trimethaphan and prostaglandin E1 groups (P0.05). In the trimethaphan-treated patients systolic velocity in pulmonary venous flow decreased from 41.9 +/- 4.8 cm.sec-1 before induced hypotension to 27.8 +/- 4.2 cm.sec-1 by 30 min after stable hypotension had been established (P0.01). The late/early ratio of peak velocity in mitral blood flow decreased in prostaglandin E1 treated patients. Cardiac output increased from 4.2 +/- 0.5 L.min-1 to 5.3 +/- 0.4 L.min-1 during 30 min hypotension with prostaglandin E1 administration (P0.05), but cardiac output decreased from 5.0 +/- 0.5 to 3.5 +/- 0.4 L.min-1 with trimethaphan (P0.01). The differences in haemodynamic variables could be attributed to the venule dilatation effect of trimethaphan. We conclude that it was possible to detect the haemodynamic differences between trimethephan and prostaglandin E1 using TEE.

In patients with hypertensive intracerebral hemorrhage, changes in regional cerebral blood flow (rCBF) following drug-induced blood pressure reduction were examined by SPECT. METHODS. The subjects were 68 patients with hypertensive intracerebral hemorrhage. The site of cerebral hemorrhage was the thalamus in 28 patients, and the putamen in 40 patients. RCBF was measured by SPECT using the 133Xe inhalation method. To reduce blood pressure, trimethaphan camsilate (an autonomic ganglion blocker) and diltiazem hydrochloride (a calcium antagonist) were used. RESULTS. 1. In the acute period, mean CBF declined as the mean arterial blood pressure declined by more than 20% in both the putaminal and the thalamic hemorrhage group (p < 0.01). 2. During the chronic period, a greater reduction in blood pressure was needed to induce mean CBF reduction. 3. Neither of the two drugs significantly reduced the mean arterial blood pressure, but the group receiving trimethaphan demonstrated a 7.9 approximately 7.5% decreased in CBF, group while the receiving diltiazem showed a 2.2 approximately 2.4% decrease (p < 0.05). CONCLUSIONS. In patients with hypertensive intracerebral hemorrhage, a 20% or more drug-induced decrease in blood pressure resulted in a decrease in mean CBF. During the acute period of intracerebral hemorrhage, blood pressure showed reduced by 20%. Clinically, diltiazem was more effective than trimethaphan.

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 Nω-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.

Objectives To assess age-related changes in the cardiac chronotropic and inotropic responses and arterial responses to β-receptor stimulation and the potential role of the arterial baroreflex on these responses. Methods and Results Isoproterenol alone was infused in 14 young subjects (age, 30 ± 2 years) and 15 older healthy volunteers (age, 60 ± 2 years) and together with ganglionic blockade (trimethaphan) in eight young and eight older subjects. Isoproterenol was infused at 3 to 4 incremental rates. Cardiac function was assessed by echocardiography and peripheral arterial responses were measured by venous occlusion plethysmography. Before ganglionic blockade, isoproterenol at infusion rates from 0.005 to 0.03 µg/kg/min caused similar changes in heart rate, ejection fraction, and mean normalized systolic ejection rate in the young and older subjects. With concomitant use of trimethaphan, isoproterenol at infusion rates from 0.0025 to 0.01 µg/kg/min caused in young subjects a larger increase in heart rate (29 ± 2 beats/min [young] versus 20 ± 3 [older] at peak infusion; p = 0.03), ejection fraction (11% ± 2% [young] versus 6% ± 1% [older]; p < 0.01), and mean normalized systolic ejection rate (1.13 ± 0.2 ml/sec [young] versus 0.48 ± 0.09 [older]; p < 0.01). Whereas percentage changes in total peripheral resistance were larger in the young subjects, there were no significant age-related differences in the responses of forearm blood flow and resistance before or after ganglionic blockade. Conclusions These results indicate an age-related decrease in β-receptor responsiveness of both sinoatrial node and ventricular myocardium that is masked by a concomitant decrease in the baroreflex control of the heart. Clinical Pharmacology and Therapeutics (1994) 56, 543–553; doi:10.1038/clpt.1994.176

The responses of regional cerebral blood flow (CBF) to decrease in arterial blood pressure were studied in eight patients with arteriovenous malformations using the Xe-133 inhalation method. Measurements were performed twice for each study; before and during hypotension induced by trimethaphan camsylate (Arfonad). In all cases, there were regions where cerebral blood flow increased remarkably in response to hypotension. When the studies were repeated in five cases after total resection of the malformations, increase in the cerebral blood flow in response to hypotension was not observed. The underlying mechanisms that operate in such paradoxical blood pressure-flow relationship are discussed.

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.

We have studied 20 patients undergoing local resection of intraocular melanoma during hypotensive anaesthesia, allocated randomly to receive either manual control by an experienced anaesthetist or closed-loop computer control of an infusion of a 5:1 mixture of trimetaphan camsylate (TMP) and sodium nitroprusside (SNP). There were no significant differences in the smallest systolic and diastolic arterial pressures obtained, heart rate or infusion requirements between the two groups, but the duration of both the infusion and the operation were significantly longer in the computer-controlled group (P0.05). The quality of control of arterial pressure was assessed by the percentage of time spent at pressures greater and less than the prescribed target values, and was satisfactory in both groups during the critical period of profound hypotension. We conclude that the computer-controlled infusion performed satisfactorily during profound hypotension compared with an experienced anaesthetist.

In essential hypertension sympathetic nerve firing is commonly increased. A central nervous system origin has been presumed but not tested directly. To estimate cerebral norepinephrine release in essential hypertension, spillover of norepinephrine into the cerebrovascular circulation was measured by isotope dilution, with high internal jugular venous sampling. Norepinephrine was released into the cerebrovascular circulation in both hypertensive patients and healthy volunteers and was present after administration of the ganglion blocker trimethaphan and in patients with sympathetic nervous failure, indicating that brain neurons and not cerebrovascular sympathetic nerves were the probable source. Although differing among hypertensive patients, norepinephrine spillover on average was higher in the hypertensive patients (153 +/- 41 pmol/min) than in healthy subjects (59 +/- 12 pmol/min; p less than 0.05), and was elevated in six of 17 patients, in whom the accompanying whole body norepinephrine spillover rate was higher than in the remaining 11 patients (p less than 0.01). To test for a possible link between brain norepinephrine release and human sympathetic nervous function, the effect of the tricyclic antidepressant desipramine (0.3 mg/kg i.v.) on both brain and whole body norepinephrine spillover was measured in healthy volunteers. Desipramine lowered the cerebrovascular spillover of norepinephrine, its precursor dihydroxyphenylalanine, and its metabolite dihydroxyphenylglycol by 50-80% and produced a mean fall of 35% in whole body norepinephrine spillover. One interpretation of these results is that human sympathetic nerve firing is dependent on norepinephrine release within the brain and that increased cerebral norepinephrine release may possibly be present in some patients with essential hypertension, underlying their higher sympathetic nerve firing rates.

Acute hypertensive responses during nitrous oxide-opioid-relaxant anesthesia are a common clinical problem. In adult men undergoing radical prostatectomy procedures and anesthetized with a standardized technique, we evaluated the effectiveness of alfentanil, isoflurane, and trimethaphan in treating acute hemodynamic and stress hormone responses to surgical stimulation. Stress hormone concentrations were measured 1 min before skin incision, after the onset of an acute hypertensive response, and after returning the mean arterial pressure to within 10% of the preincision values with one of the three treatment modalities. Pretreatment plasma alfentanil concentrations (151 ± 47 to 156 ± 47 ng. ml-1) and end-tidal nitrous oxide concentrations (66 ± 2 to 68 ± 2%) were similar in all three groups. Acute hypertensive events were associated with significantly increased concentrations of catecholamines and vasopressin (anti-diuretic hormone [ADH]). Whereas intravenous alfentanil returned all hormone concentrations to preincision values, norepinephrine and glucose concentrations were significantly increased after adjunctive isoflurane administration. Although trimethaphan decreased the norepinephrine concentration, the epinephrine, β-endorphin, cortisol, ADH, and glucose concentrations were significantly increased compared to preincision values. However, the persistent elevation in the posttreatment ADH concentration in the trimethaphan group was the only significant difference between the three groups. Mean (± standard deviation) times to awakening (2.8 ± 3.3 to 3.8 ± 4.2 min), extubation (8.1 ± 4.8 to 10.3 ± 8.5 min), and orientation (19.6 ± 20.4 to 24.6 ± 19.1 min) were similar in all three groups. Naloxone was required more frequently in patients in the alfentanil (35%) and isoflurane (24%) groups than in the trimethaphan group (4%). However, fewer alfentanil-treated patients required antihypertensive therapy in the postanesthesia care unit (12% vs. 48% and 38% in the isoflurane and trimethaphan groups, respectively). Postoperative analgesic requirements and hospital discharge times were similar in all three groups. We conclude that the choice of adjunctive therapy to maintain hemodynamic stability during balanced anesthesia did not appear to effect outcome after radical prostatectomy procedures.

Despite the rich innervation of the cerebral vasculature by both sympathetic and parasympathetic nerves, the role of autonomic control in cerebral circulation and, particularly, cerebral hemodynamics is not entirely clear. Previous animal studies have reported inconsistent results regarding the effects of electrical stimulation or denervation on cerebral blood flow (CBF), cerebral pressure-flow relationship, and cerebral vessel response to metabolic stimuli. Moreover, with the advance of transcranial Doppler ultrasound (TCD), which yields accurate measurements of CBF velocity (CBFV) with high time resolution, it has been found that in humans CBFV in the middle cerebral artery decreased substantially during lower body negative pressure (LBNP) and head-up tilt in the absence of systemic hypotension, which suggests the presence of cerebral vasoconstriction associated with augmented sympathetic nerve activity during orthostatic stress. These observations were based on assessing static measures of cerebral circulation, i.e., mean values of artevial blood pressure (ABP) and CBF with a low time resolution.

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.

This study was performed to examine changes in local cerebral blood flow during hypotensive anaesthesia with either prostaglandin E1 (PGE1) or trimethaphan (TMP). Local cerebral blood flow (LCBF), mean blood pressure (MBP), heart rate (HR), and hourly urine output (UO) were studied in 51 patients undergoing cerebral aneurysm surgery with neuroleptanalgesia (NLA). The incidence of vasospasm after aneurysm surgery, and outcome (Glasgow Outcome Scale) at discharge were evaluated. Measurements of LCBF were made using a thermal gradient blood flow meter. The dose of PGE1 or TMP was adjusted to maintain MBP at about 70 mmHg, and LCBF was studied during and after PGE1 or TMP administration. Hypotensive drugs were discontinued at the completion of aneurysm clipping. After starting PGE1 or TMP, MBP decreased immediately, but HR did not change in either group. The LCBF decreased 30 min after the start of TMP administration and increased immediately after its discontinuation, whereas PGE1 did not affect LCBF. Urine output increased during PGE1 administration but was unchanged during TMP. Neither drug affected surgical outcome or the incidence of vasospasm. These results suggest that PGE1 may be preferable to trimethaphan for hypotensive anaesthesia in cerebral aneurysm surgery because LCBF is maintained.