Trimethaphan Research Articles

Ganglionic blockade modulates sympathetic neural discharge and neurocirculatory regulation in humans

This study investigated the impact of integrated muscle sympathetic nerve activity (MSNA) discharge patterns on human neurocirculatory regulation. In 13 healthy females (42 ± 15 years), the transduction of integrated MSNA (peroneal microneurography) into mean arterial pressure (MAP; arterial catheter) was studied during an intravenous infusion of a nicotinic ganglionic antagonist (trimethaphan camsylate, 1-7 mg/min). Neurovascular transduction (signal averaging) was studied based on the overall response, burst sequence (singlet, doublet, and triplet+), and burst amplitude (binned into tertials: small, medium, and large bursts). Data (mean ± SD) are reported for a 10-minute baseline (BSL), the one-minute period at the midpoint of the trimethaphan infusion with integrated MSNA bursts (TM-Mid), and the last minute of trimethaphan infusion with integrated MSNA bursts (TM-Last). During BSL, the MAP transduction responses were greatest for triplets+ (singlets: 0.9 ± 0.2 mmHg, doublets: 2.0 ± 0.6 mmHg, triplet+: 2.6 ± 0.9 mmHg; P < 0.01) and large bursts (small: 1.0 ± 0.3 mmHg, medium: 1.7 ± 0.5 mmHg, large: 2.2 ± 0.7 mmHg; P < 0.01). Trimethaphan infusion reduced integrated MSNA burst frequency resulting in a greater proportion of singlets (BSL: 45 ± 18 %, TM-Mid: 75 ± 23 %, TM-Last: 94 ± 20 %; P < 0.01), a lower proportion of doublets, and a lower proportion of triplets+ (BSL: 23 ± 19 %, TM-Mid: 9 ± 18 %, TM-Last: 0 ± 0 %; P < 0.01). Trimethaphan infusion reduced integrated MSNA burst amplitude resulting in a greater proportion of small bursts (BSL: 33 ± 0.2 %, TM-Mid: 60 ± 26 %, TM-Last: 78 ± 37 %; P < 0.01), a lower proportion of medium bursts, and a lower proportion of large bursts (BSL: 34 ± 1 %, TM-Mid: 17 ± 26 %, TM-Last: 1 ± 5 %; P < 0.01). Trimethaphan-mediated changes in MSNA burst frequency and amplitude were associated with reduced overall MAP transduction responses (BSL: 1.6 ± 0.5 mmHg, TM-Mid: 0.5 ± 0.2 mmHg, TM-Last: 0.3 ± 0.3 mmHg; P < 0.01). Linear regression analyses demonstrated that the trimethaphan-mediated reduction in the proportion of large bursts ( β = 0.02 ± 0.008 mmHg/%, R2 = 0.13, P = 0.03) more strongly affected sympathetic neurovascular transduction responses than reductions in the proportion of triplet+ burst sequences (P = 0.91). These findings suggest that time varying MSNA discharge patterns, particularly variations in burst amplitude, support human neurocirculatory regulation. This work was supported by the National Institutes of Health and the Natural Sciences and Engineering Research Council of Canada. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

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

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. 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, 1-7mgmin-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 APsburst-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± 41AP (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.

The Role of the Paravertebral Ganglia in Sympathetic Vasoconstrictor Neural Discharge Patterns

Action potentials (APs) of varying sizes and firing probabilities, that are synchronized into bursts of efferent traffic, characterize recordings of muscle sympathetic nerve activity (MSNA). Recent evidence points to ordered recruitment of these APs but the sites of this control remain unknown. This study investigated the role of the paravertebral ganglia in sympathetic AP emission patterns using pharmacological blockade of ganglionic NN‐nicotinic receptors via trimethaphan camsylate (TM; n = 7 females, 37 ±5 years, 112 ±2/70 ±3 mmHg, 22 ±1 kg/m2). Heart rate (HR; ECG), blood pressure (BP; arterial catheter) and MSNA (microneurography) were recorded during baseline, TM infusion (1–7 mg/min) and Valsalva's manoeuvre. MSNA APs were detected from the filtered raw signal using a wavelet deconstruction approach and were binned in clusters (Scott's rule) based on peak‐to‐peak amplitude (K‐means). In the final minute of MSNA burst detection during TM, HR increased (57 ±11 to 66 ±12 bpm) and mean BP decreased (97 ±7 to 90 ±7 mmHg) (both P &lt; 0.01 compared to baseline). Relative to baseline, TM elicited a progressive reduction in total sympathetic outflow (833 ±458 to 157 ±120 AU/min), characterized by fewer integrated bursts (30 ±14 to 9 ±8 bursts/100 beats) with decaying amplitude (49 ±3 to 31 ±3 AU) (all P &lt; 0.01). Underlying TM‐mediated attenuations in integrated MSNA were reductions in AP incidence (186 ±101 to 29 ±31 AP/100beats) and AP content per integrated burst (7 ±2 to 3 ±1 APs/burst) (all P &lt; 0.01). Compared to baseline, the total number of active AP clusters was reduced with TM (14 ±3 to 9 ±3 AP clusters), resulting in fewer unique clusters per burst (4 ±1 to 3 ±1 AP clusters/burst) (both P &lt; 0.01). Relative to baseline, most participants demonstrated a reduction in the within‐burst firing probability of all AP clusters, with the largest two to six AP clusters ceasing to fire in the last minute before integrated bursting activity was abolished. Following cessation of integrated MSNA bursts, the smallest 6 ±2 sympathetic AP clusters (range: 4 – 8 AP clusters) persisted to fire in an asynchronous pattern (49 ±41 AP/100beats) in all participants. Valsalva's Maneuver did not increase the incidence of these persistent small APs (60 ±42 AP/100beats, P = 0.52), or instigate any larger APs (previously active at baseline) in six of seven participants (6 ±1 total AP clusters, P = 0.30). These data suggest: 1) the paravertebral ganglia may contribute to the heterogeneity in the firing probabilities of varying sized postganglionic sympathetic APs active under baseline conditions, and 2) the presence of non‐synchronized sympathetic APs that express resistance to blockade with trimethaphan.Support or Funding InformationSupported by the Natural Sciences and Engineering Research Council (NSERC) of Canada, Discovery Grant #217916‐2013.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

From Coenzyme R to “Arfonad” and from Vitamin H to Hypotension

From Coenzyme R to “Arfonad” and from Vitamin H to Hypotension

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.

Abstract 018: Sympathetic Contribution to Obesity Hypertension: Differential Hemodynamic Mechanisms between Prehypertension and Hypertension

Sympathetic activation contributes to blood pressure (BP) elevation in obesity, but it is unknown whether this contribution differs between obese prehypertensives (PreHTN) and obese hypertensives (HTN). We, therefore, assessed hemodynamic parameters during autonomic withdrawal with the ganglionic blocker trimethaphan (TMT) in 15 lean normotensives (NTN; 34±3 yrs., BMI 23.4±0.4), 11 obese PreHTN (38±2 yrs., BMI 33.6±0.8) and 14 obese HTN (40±1 yrs., BMI 33.8±0.7). As expected, baseline supine systolic BP (SBP) was higher in PreHTN and HTN compared to NTN (P&lt;0.01, Figure A). HTN, however, had lower supine SBP on the study day compared to their seated levels at screening (127±4 mmHg vs. 142±5; P=0.04) presumably due to lower sympathetic tone at supine rest. Autonomic blockade lowered SBP similarly in PreHTN (-23±4 mmHg) and HTN (-24±4 mmHg) compared to NTN (-8±3 mmHg; P&lt;0.01), but the “intrinsic” SBP in the absence of autonomic influences remained slightly higher in HTN compared to the other groups. Baseline systemic vascular resistance (SVR) was similarly increased in PreHTN and HTN compared to NTN (P&lt;0.01, Figure B), but it normalized after TMT only in PreHTN. Conversely, the BP drop in HTN was due to a decrease in cardiac output (CO; Figure C) and stroke volume (SV; -37±2 vs. PreHTN -25±2 and NTN -26±3%; P&lt;0.01). In conclusion, the autonomic contribution to BP elevation differed between obese PreHTN and HTN. Obesity prehypertension was due to a sympathetically driven increase in SVR, whereas obesity hypertension was due to a non-autonomic increase in SVR associated with impaired sympathetic modulation of CO and SV presumably due to sympathetic contraction of splanchnic capacitance.

Aging Enhances Autonomic Support of Blood Pressure in 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<0.05). Muscle sympathetic nerve activity bursts were abolished by trimethaphan within minutes. Older women had a greater decrease in mean arterial pressure (-29±2 versus -9±2 mm Hg; P<0.01) and total peripheral resistance (-10±1 versus -5±1 mm Hg/L per minute; P<0.01) during trimethaphan. Baseline muscle sympathetic nerve activity was associated with the decrease in mean arterial pressure during trimethaphan (r=-0.74; P<0.05). In summary, our results suggest that autonomic support of blood pressure is greater in older women compared with young women and that elevated sympathetic nerve activity in older women contributes importantly to the increased incidence of hypertension after menopause.

Greater autonomic support of blood pressure in older women

In young women, tonic autonomic nervous system activity contributes less to resting blood pressure than that in men. It is unknown whether the autonomic support of blood pressure increases in postmenopausal women, therefore we examined the effect of autonomic blockade on blood pressure and how this relates to baseline muscle sympathetic nerve activity (MSNA) in women. Five young (23±4 yr) and 6 older (57±3 yr) women were examined before and during autonomic blockade using trimethaphan camsylate (TM). MSNA burst frequency and burst incidence were higher in older women (24±2 vs. 14±3 bursts/min; 41±3 vs. 23±5 bursts/100hb, respectively; p&lt;0.05). Older women had a greater drop in mean arterial pressure (MAP; −25±2 vs. −8±3 mmHg; p&lt;0.01) and total peripheral resistance (−0.7±0.1 vs. −0.2±0.1 AU; p&lt;0.01) during autonomic blockade. MSNA bursts were abolished by TM within minutes. Baseline burst frequency and burst incidence were associated with the decrease in MAP during autonomic blockade (r=−0.64, r=−0.63; respectively; p&lt;0.05). In conclusion, autonomic blockade reduces MAP to a greater extent in older women, and this decrease in blood pressure is associated with resting levels of MSNA. Our results suggest that autonomic support of blood pressure is greater in older women compared to young women. Elevated sympathetic nerve activity may explain the increased incidence of hypertension after menopause.

Higher aortic wave reflection is mediated in part by greater autonomic support in older women

Aortic wave reflection increases with age, and is influenced by numerous factors, including sympathetic nerve activity. The purpose of this study was to examine the effect of autonomic blockade using trimethaphan camsylate on indices of aortic wave reflection in young (23±4 yr) and older postmenopausal (57±3 yr) women and determine if aging alters these interactions. Arterial tonometry was used to non‐invasively measure arterial waveforms from the radial artery before and during trimethaphan infusion. Aortic augmentation index (AIx), augmented pressure, and left ventricular wasted energy (Ew) were higher in older women compared to young women at baseline (p&lt;0.05). Mean arterial pressure was similar between young (93±5 mmHg) and older women (91±2 mmHg) at baseline. AIx (Δ −12±5%), augmented pressure (Δ −11±4 mmHg), and Ew (Δ −2364±1020 dyne·cm2·sec) decreased after autonomic blockade in older women (p&lt;0.05 for all). In addition, the age‐related differences in AIx and aortic wave reflection persisted during autonomic blockade (p&lt;0.05). In conclusion, autonomic blockade reduces augmentation index and aortic wave reflection in older women. Our results suggest that sympathetic activity contributes to the higher aortic wave reflection observed in older women.

Aging and the effect of autonomic blockade on central and peripheral pulse wave velocity

Pulse wave velocity (PWV) and sympathetic nerve activity increase with age. However, it is unknown if the age‐related increase in sympathetic activity influences PWV. We determined the effect of autonomic blockade on peripheral and central arterial stiffness in young (23 ± 4 yr) and older, postmenopausal (57 ± 3 yr) women before and during administration of trimethaphan camsylate. Arterial tonometry was used to measure carotid‐radial (peripheral) and carotid‐femoral (central) PWV. The groups did not differ in height, weight, BMI, or mean arterial pressure (MAP). At baseline, peripheral PWV did not differ between the groups. However, central PWV was significantly greater in older women compared with young women (8.2 vs. 6.1 m/s, respectively; p&lt;0.05). Trimethaphan infusion caused a substantial drop in MAP; therefore, we corrected PWV for the change in MAP. Peripheral PWV was greater in older women compared with young women (0.12 vs. 0.08 m/s·mmHg−1; p&lt;0.05). In addition, central PWV remained higher in older women during trimethaphan infusion (0.11 vs. 0.08 m/s·mmHg−1 in young; p&lt;0.05). In conclusion, central PWV was greater in older women before and during autonomic blockade, whereas peripheral PWV was only higher in the older women after autonomic blockade. This suggests that peripheral PWV is influenced by sympathetic activity to a greater extent in young vs. older women.Funded by NIH

Neuronal Source of Plasma Dopamine

Determinants of plasma norepinephrine (NE) and epinephrine concentrations are well known; those of the third endogenous catecholamine, dopamine (DA), remain poorly understood. We tested in humans whether DA enters the plasma after corelease with NE during exocytosis from sympathetic noradrenergic nerves. We reviewed plasma catecholamine data from patients referred for autonomic testing and control subjects under the following experimental conditions: during supine rest and in response to orthostasis; intravenous yohimbine (YOH), isoproterenol (ISO), or glucagon (GLU), which augment exocytotic release of NE from sympathetic nerves; intravenous trimethaphan (TRI) or pentolinium (PEN), which decrease exocytotic NE release; or intravenous tyramine (TYR), which releases NE by nonexocytotic means. We included groups of patients with pure autonomic failure (PAF), bilateral thoracic sympathectomies (SNS-x), or multiple system atrophy (MSA), since PAF and SNS-x are associated with noradrenergic denervation and MSA is not. Orthostasis, YOH, ISO, and TYR increased and TRI/PEN decreased plasma DA concentrations. Individual values for changes in plasma DA concentrations correlated positively with changes in NE in response to orthostasis (r = 0.72, P < 0.0001), YOH (r = 0.75, P < 0.0001), ISO (r = 0.71, P < 0.0001), GLU (r = 0.47, P = 0.01), and TYR (r = 0.67, P < 0.0001). PAF and SNS-x patients had low plasma DA concentrations. We estimated that DA constitutes 2%-4% of the catecholamine released by exocytosis from sympathetic nerves and that 50%-90% of plasma DA has a sympathoneural source. Plasma DA is derived substantially from sympathetic noradrenergic nerves.

A novel pharmacologic alternative to ganglionic blockade: cardiovascular responses to systemic terbutaline

The ganglionic blocker trimethaphan (TMP) is no longer produced; alternatives are needed to inhibit baroreflex control of the circulation during systemic hemodynamic studies. We tested the hypothesis that combination anti‐cholinergic glycopyrrolate (Gly) and α2 receptor agonist dexmedetomidine (Dex) would inhibit baroreflex buffering in response to vasodilation to a similar degree as ganglionic blockade with TMP. In 2 separate trials, 5 males received an I.V. bolus and infusion of Gly‐Dex, and 11 males received TMP infusion. To offset the fall in blood pressure with TMP, phenylephrine (PE) was used to raise pressure to pre‐TMP baseline. Terbutaline was then infused for 15 minutes at 2 doses (33 and 67 ng/kg/min). Heart rate (HR), blood pressure (BP, oscillometric cuff for Gly‐Dex, brachial arterial line for TMP+PE), and cardiac output (CO, acetylene breathing) were recorded. Resting HR was higher with Gly‐Dex (mean ± SEM: 93±7mmHg) than TMP+PE (74±3mmHg, p&lt;0.001) but resting BP, CO, stroke volume (SV), and total peripheral resistance (TPR) were similar between Gly‐Dex and TMP+PE. The cardiovascular responses to terbutaline were similar between Gly‐Dex and TMP+PE, except for the increase in CO which was significantly greater in the TMP + PE group. We conclude that Gly‐Dex is a viable pharmacologic alternative to TMP in physiologic measures of BP and TPR during vasodilator infusions.

Pharmacologic Probes to Differentiate Chronic Autonomic Failure Syndromes

Objective: The current clinical classification of chronic autonomic failure (CAF) recognizes four primary forms—pure autonomic failure (PAF), multiple system atrophy (MSA), Parkinson disease (PD), and autoimmune autonomic ganglionopathy (AAG). We provide a pathophysiologic classification scheme, based on neuropharmacologic probes: tyramine (TYR), trimethaphan (TRI) or pentolinium (PEN), yohimbine (YOH), acetylcholine (ACh, quantitative sudomotor axon reflex test, QSART), and 6‐[18F]fluorodopamine (18F‐DA) scanning.Methods: CAF groups received i.v. TYR, TRI/PEN, YOH, or 18F‐DA or ACh by iontophoresis. Blood pressure (BP) and dihydroxyphenylglycol (DHPG) responses were measured.Results: PAF involved low cardiac 18F‐DA‐derived radioactivity and attenuated (Atten.) increments (Inc.) to TYR and YOH and decrements (Dec.) to TRI/PEN, in contrast with normal reponses in AAG and MSA. MSA involved augmented (Aug.) responses to YOH and TRI/PEN and normal (Nl.) cardiac 18F‐DA, in contrast with Atten. in PD+NOH.Conclusions: Pharmacologic probes provide a pathophysiologic classification of chronic autonomic failure that can be utilized in individual patients.

Autonomic Cardiovascular Control During a Novel Pharmacologic Alternative to Ganglionic Blockade

The purpose of this study was to compare ganglionic blockade with trimethaphan (TMP) and an alternative drug strategy using combined muscarinic antagonist (glycopyrrolate, GLY) and alpha-2 agonist (dexmedetomidine, DEX). Protocol 1: incremental phenylephrine was administered during control and combined GLY-DEX, or control and TMP on two control combined GLY and DEX or TMP infusion on two randomized days. Protocol 2: muscle sympathetic nerve activity (MSNA) and the baroreflex MSNA relationship was determined before and after GLY-DEX. Blood pressure was higher with GLY-DEX (99+/-3 mm Hg) and lower with TMP (78+/-3 mm Hg) relative to control (GLY-DEX: 90+/-2 mm Hg; TMP: 91+/-2 mm Hg; P<0.05). Incremental phenylephrine increased pressure during GLY-DEX (P<0.01 vs control) and TMP (P<0.01 vs control) to a similar degree. Both GLY-DEX and TMP infusion inhibited norepinephrine release (P<0.01 vs control). GLY-DEX inhibited baseline MSNA (P<0.05) and baroreflex changes in MSNA (P<0.01). We conclude that the GLY-DEX alternative drug strategy can be used as a reasonable alternative to pharmacologic ganglionic blockade to examine autonomic cardiovascular control.

Alternative to ganglionic blockade with anticholinergic and alpha-2 receptor agents

The ganglionic blocking agent trimethaphan (TMP) is no longer produced. Therefore, a need exists for alternative pharmacological approaches to investigate baroreflex control of the circulation. The aim of the present study was to examine baroreflex-mediated cardiovascular responses during the administration of a muscarinic receptor antagonist (glycopyrrolate; GLY: ) and a selective alpha-2 receptor agonist (dexmedetomidine; DEX: ) and to compare responses to ganglionic blockade with TMP. We hypothesized that combined GLY-: DEX: would inhibit the baroreflex similar to TMP. Ten volunteers participated in two study days and were instrumented with pulse oximeter, nasal cannula, ECG, continuous blood pressure monitoring (Finapres), and I.V. catheter for drug infusions. Each study day consisted of a control condition followed by either combined GLY: -DEX: or TMP on alternating days. A Valsalva maneuver was performed under each condition with every subject and six subjects received bolus phenylephrine (25 mug) during GLY: -DEX: and TMP. Combined GLY: -DEX: increased (P < 0.05) blood pressure (99 +/- 4 mmHg) and heart rate (99 +/- 3 bpm) relative to control condition (BP: 90 +/- 2 mmHg; HR: 64 +/- 3 bpm) and TMP infusion decreased (P < 0.05) blood pressure (79 +/- 3 mmHg) while increasing heart rate (88 +/- 3 bpm). Valsalva maneuver elicited a persistent drop in arterial pressure (no phase IIb recovery) with the absence of a phase IV overshoot during both GLY: -DEX: and TMP conditions. Phenylephrine increased systolic pressure 34 +/- 4 mmHg under GLY: -DEX: and 23 +/- 3 mmHg with TMP (P < 0.05). Heart rate only decreased 1 +/- 2 bpm during GLY: -DEX: and 1 +/- 1 bpm with TMP. Taken together, our results suggest that GLY: -DEX: is a reasonable alternative to TMP for baroreflex inhibition.

Neuropharmacologic Distinction of Neurogenic Orthostatic Hypotension Syndromes

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. 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. 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. 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.

Pharmacological differences between immunoisolated native brain and heterologously expressed rat α4β2 nicotinic receptors

Native brain and heterologously expressed rat α4β2 nicotinic receptors (in Xenopus oocytes and CV-1 cells) were immunoisolated with the anti-α4 antibody mAb 299 and their pharmacological properties were compared using [ 3H](±)epibatidine, the novel N-alkylnicotinium analog N- n-octylnicotinium iodide (NONI), and the ganglionic antagonist trimethaphan (TRM). The equilibrium dissociation constant ( K d) for [ 3H](±)epibatidine binding to the native and heterologously expressed receptors ranged from 13 to 21 pM. The Hill coefficients for [ 3H](±)epibatidine binding to the native and expressed receptors ranged from 0.8 to 1.1 and were consistent with a single high-affinity site. NONI inhibited 30 pM [ 3H](±)epibatidine binding to the native and expressed receptors with similar potency (IC 50 values of 6–7 μM). However, [ 3H](±)epibatidine dissociated 2–3 times more slowly from the native, than from the expressed receptors and TRM inhibited 30 pM [ 3H](±)epibatidine binding to the native receptors (IC 50 value of 330 μM) less potently than it did to the receptors expressed in oocytes (IC 50 value of 16 μM) or CV-1 cells (IC 50 value of 55 μM). The differences between the native and expressed [ 3H](±)epibatidine dissociation rate constants and IC 50 values for TRM were significant for both host cell types, although the values for the CV-1-expressed receptors were closer to the native ones than were those for the oocyte-expressed receptors. Thus, the epibatidine and trimethaphan binding sites in native and expressed α4β2 receptors appear to have significantly different structural or chemical properties.

Effects of controlled hypotension with sevoflurane anaesthesia on hepatic function of surgical patients

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 under-going 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.

The effect of CGRP-induced hypotension on organ blood flow during halothane anesthesia in dogs: a comparison with trimetaphan.

Calcitonin gene-related peptide (CGRP) is an endogenous 37-amino-acid peptide which is a powerful vasodilator of the splanchnic circulation. To elucidate the effects of CGRP-induced hypotension on the organ blood flow, we compared the renal, hepatic, and pancreatic organ flows of CGRP-induced hypotension with those of trimetaphan (TMP) in halothane-anesthetized dogs. Systemic hemodynamics and organ blood flow were determined in 18 mongrel dogs allocated to one of two groups: CGRP group (n=10) and TMP group (n=8). CGRP of TMP was infused at a rate sufficient to decrease the mean arterial pressure (MAP) to near 60 mmHg from the baseline values for a 60 min-hypotensive period. Organ blood flow was measured using the hydrogen clearance technique. The decrease in MAP was approximately 50% of baseline values (P<0.01). The hypotension induced by either CGRP or TMP was associated with a reduction (P<0.01) in systemic vascular resistance in both groups. Cardiac index (CI) in the CGRP group did not change significantly throughout the experiment. On the other hand, CI decreased at 30 min (P<0.01) and 60 min (P<0.01) during the hypotensive period in the TMP group. No changes were observed in renal, hepatic, and pancreatic blood flows in the CGRP group. Renal blood flow in the TMP group did not change significantly throughout the experiment. In contrast, hepatic blood flow resulted in a significant decrease (P<0.01) during TMP-induced hypotension. Pancreatic blood flow decreased during the hypotensive period (P<0.01) and at 30 min (P<0.05) after termination of TMP. These findings show that CGRP does not adversely affect renal, hepatic, and pancreatic organ blood flows even in the presence of profound hypotension in halothane-anesthetized dogs. The results of this study suggest that CGRP may preserve organ blood flow during induced hypotension.