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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.

The hypothesis that cholinergic and nonadrenergic, noncholinergic parasympathetic nerves innervating the airways are subject to differential reflex regulation was addressed. Pronounced contractile and relaxant parasympathetic reflex responses could be evoked by intravenous histamine, laryngeal mucosal application of capsaicin, inhaled capsaicin, or electrical stimulation of the vagal afferent nerves projecting to the esophagus and abdominal viscera. These data suggest that activation of multiple vagal afferent nerve subtypes can initiate both cholinergic and noncholinergic parasympathetic reflexes in the airways. Conversely, hypoxia or activation of the diving response from the nose evoked only cholinergic contractile reflexes. All contractile and relaxant responses evoked by these stimuli were absent in vagotomized animals or in animals pretreated with the ganglionic blocker trimethaphan, confirming their reflex and parasympathetic nature. The data indicate that cholinergic and noncholinergic parasympathetic nerves regulating airway caliber in guinea pigs are comprised of two distinct parasympathetic pathways that are subject to differential reflex regulation. This previously unrecognized complexity of autonomic regulation of airway caliber has potentially important implications for the mechanisms of airways hyperresponsiveness.

Native brain and heterologously expressed rat alpha4beta2 nicotinic receptors (in Xenopus oocytes and CV-1 cells) were immunoisolated with the anti-alpha4 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 microM). 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 microM) less potently than it did to the receptors expressed in oocytes (IC(50) value of 16 microM) or CV-1 cells (IC(50) value of 55 microM). 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 alpha4beta2 receptors appear to have significantly different structural or chemical properties.

The effect of thyroid status on arterial baroreflex function and autonomic contributions to resting blood pressure and heart rate (HR) were evaluated in conscious rats. Rats were rendered hyperthyroid (Hyper) or hypothyroid (Hypo) with triiodothyronine and propylthiouracil treatments, respectively. Euthyroid (Eut), Hyper, and Hypo rats were chronically instrumented to measure mean arterial pressure (MAP), HR, and lumbar sympathetic nerve activity (LSNA). Baroreflex function was evaluated with the use of a logistic function that relates LSNA or HR to MAP during infusion of phenylephrine and sodium nitroprusside. Contributions of the autonomic nervous system to resting MAP and HR were assessed by blocking autonomic outflow with trimethaphan. In Hypo rats, the arterial baroreflex curve for both LSNA and HR was shifted downward. Hypo animals exhibited blunted sympathoexcitatory and tachycardic responses to decreases in MAP. Furthermore, the data suggest that in Hypo rats, the sympathetic influence on HR was predominant and the autonomic contribution to resting MAP was greater than in Eut rats. In Hyper rats, arterial baroreflex function generally was similar to that in Eut rats. The autonomic contribution to resting MAP was not different between Hyper and Eut rats, but predominant parasympathetic influence on HR was exhibited in Hyper rats. The results demonstrate baroreflex control of LSNA and HR is attenuated in Hypo but not Hyper rats. Thyroid status alters the balance of sympathetic to parasympathetic tone in the heart, and the Hypo state increases the autonomic contributions to resting blood pressure.

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.

Meal-induced insulin secretion is thought to be regulated primarily by absorbed nutrients and incretin hormones released from the gastrointestinal tract. In addition, the parasympathetic nervous system (PNS) is known to mediate preabsorptive, or cephalic phase, insulin secretion. Despite evidence that the PNS remains activated during the absorptive phase of the meal, its role in mediating postprandial insulin secretion has not been established. To study the role of the PNS in absorptive phase insulin release, we measured plasma concentrations of glucose as well as islet hormones and incretins in six healthy rhesus monkeys before and for 60 min after meals while they were infused with saline (control), atropine (muscarinic blockade), or trimethaphan (nicotinic blockade). During the infusion of saline, plasma levels of glucose, pancreatic polypeptide (PP), insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 increased promptly after meal ingestion and remained elevated throughout the 60 min of the study. The PP response was nearly abolished in animals treated with trimethaphan, indicating functional blockade of PNS input to the islet, and in contrast to the control study, there were minimal changes in plasma concentrations of glucose, incretin hormones, and insulin. Because trimethaphan inhibited glycemic and incretin stimuli in addition to blocking PNS input to the islet, it was not possible to discern the relative roles of these factors in the stimulation of insulin secretion. Atropine also significantly decreased PNS transmission to the islet, as reflected by PP levels similar to those observed with trimethaphan. Unlike the trimethaphan study, plasma glucose levels rose normally during atropine treatment and were similar to those in the control study over the course of the experiments (114 +/- 22 and 132 +/- 23 mmol/L.60 min, respectively). In addition, the rise in plasma glucagon-like peptide-1 following the meal was not suppressed by atropine, and the glucose-dependent insulinotropic polypeptide responses were only modestly decreased. Despite the significant increases in circulating glucose and incretins, plasma insulin levels were greatly attenuated by atropine, so that the 60 min responses were more comparable to those during trimethaphan treatment than to those in the control study (atropine, 3,576 +/- 1,284; trimethaphan, 4,128 +/- 2,616; control, 15,834 +/- 5,586 pmol/L.60 min; P: < 0.05). Thus, muscarinic blockade markedly suppressed the meal-induced insulin response despite normal postprandial glycemia and significant elevations of incretins. These results indicate that activation of the PNS during the absorptive phase of meals contributes significantly to the postprandial insulin secretory response.

Background Isoflurane improves outcome from near-complete forebrain ischemia in rats compared with fentanyl-nitrous oxide (N2O). Sympathetic ganglionic blockade with trimethaphan abolishes this beneficial effect. To evaluate whether anesthesia-related differences in cerebral blood flow (CBF) may explain these findings, this study compared regional CBF before, during, and after near-complete forebrain ischemia in rats anesthetized with either isoflurane (with and without trimethaphan) or fentanyl-nitrous oxide. Methods Fasted, normothermic isoflurane anesthetized Sprague-Dawley rats were prepared for near-complete forebrain ischemia (10 min of bilateral carotid occlusion and mean arterial pressure = 30 mmHg). After surgery, rats were anesthetized with either 1.4% isoflurane (with or without 2.5 mg of trimethaphan intravenously at onset of ischemia) or fentanyl-nitrous oxide (25 microgram. kg-1. h-1. 70% N2O-1). Regional CBF was determined (14C-iodoantipyrine autoradiography) before ischemia, 8 min after onset of ischemia, and 30 min after onset of reperfusion. Results Regional CBF did not differ significantly among groups at any measurement interval. Ischemia caused a marked flow reduction to 5% or less of baseline (P < 0.001) in selectively vulnerable regions, such as the cortex, caudoputamen and hippocampus, whereas flow in the brain stem and cerebellum was preserved. Reperfusion at 30 min was associated with partial restoration of flow to 35-50% of baseline values in ischemic structures. Conclusions The results indicate that improved histologic-behavioral outcome provided by isoflurane anesthesia cannot be explained by differential vasodilative effects of the anesthetic states before, during, or after severe forebrain ischemia. This study also shows severe postischemic delayed hypoperfusion that was not affected by choice of anesthetic or the presence of trimethaphan. Mechanisms other than effects on periischemic CBF must be responsible for beneficial effects of isoflurane in this model.

Some parasympathetic ganglionic cells are located in the epicardial fat pad between the medial superior vena cava and the aortic root (SVC-Ao fat pad) of the dog. We investigated whether the ganglionic cells in the SVC-Ao fat pad control the right atrial contractile force, sinus cycle length (SCL), and atrioventricular (AV) conduction in the autonomically decentralized heart of the anesthetized dog. Stimulation of both sides of the cervical vagal complexes (CVS) decreased right atrial contractile force, increased SCL, and prolonged AV interval. Stimulation of the rate-related parasympathetic nerves to the sinoatrial (SA) node (SAPS) increased SCL and decreased atrial contractile force. Stimulation of the AV conduction-related parasympathetic nerves to the AV node prolonged AV interval. Trimethaphan, a ganglionic nicotinic receptor blocker, injected into the SVC-Ao fat pad attenuated the negative inotropic, chronotropic, and dromotropic responses to CVS by 33∼37%. On the other hand, lidocaine, a sodium channel blocker, injected into the SVC-Ao fat pad almost totally inhibited the inotropic and chronotropic responses to CVS and partly inhibited the dromotropic one. Lidocaine or trimethaphan injected into the SAPS locus abolished the inotropic responses to SAPS, but it partly attenuated those to CVS, although these treatments abolished the chronotropic responses to SAPS or CVS. These results suggest that parasympathetic ganglionic cells in the SVC-Ao fat pad, differing from those in SA and AV fat pads, nonselectively control the atrial contractile force, SCL, and AV conduction partially in the dog heart.

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.

Patients with reflex sympathetic dystrophy have posttraumatic pain disproportionate to the injury and spreading beyond the distribution of any single peripheral nerve. We examined sympathetic neurocirculatory function and the role of sympathetic postganglionic nerve traffic in maintaining the pain in 30 patients with reflex sympathetic dystrophy. Most had had the condition for more than 1 year, and 14 had undergone sympathectomy for the pain. Positron emission tomographic scanning after administration of 13 N-ammonia was used to assess local perfusion, and 6-[ 18 F]fluorodopamine was used to assess sympathetic innervation. Rates of entry of norepinephrine in the regional venous drainage (spillovers) and regional plasma levels of L-dihydroxyphenylalanine (the immediate product of the rate-limiting enzymatic step in norepinephrine biosynthesis) and dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) were measured with and without intravenous trimethaphan for ganglion blockade. 13 N-Ammonia-derived radioactivity was less on the affected side than on the unaffected side, whereas 6-[ 18 F]fluorodopamine-derived radioactivity was symmetrical. Thus, perfusion-adjusted 6-[ 18 F]fluorodopamine-derived radioactivity was higher on the affected side. Norepinephrine spillover and arteriovenous increments in plasma levels of L-dihydroxyphenylalanine and dihydroxyphenylglycol did not differ significantly between affected and unaffected limbs, although 4 patients had noticeably less norepinephrine spillover and smaller arteriovenous increments in plasma dihydroxyphenylglycol on the affected side. Trimethaphan decreased the pain in only 2 of 12 nonsympathectomized patients. The results indicate that patients with chronic unilateral reflex sympathetic dystrophy have decreased perfusion of the affected limb, symmetrical sympathetic innervation and norepinephrine synthesis, variably decreased release and turnover of norepinephrine in the affected limb, and failure of ganglion blockade to improve the pain in most cases. These findings suggest augmented vasoconstriction, intact sympathetic terminal innervation, possibly impaired sympathetic neurotransmission, and pain usually independent of sympathetic neurocirculatory outflows.

UNLABELLED Rats exposed to forebrain ischemia have reduced injury when anesthetized with isoflurane versus fentanyl + N(2)O. The protection caused by isoflurane is reversed by trimethaphan. We hypothesized that these anesthetic-dependent effects on ischemic outcome can be associated with altered stress responses to ischemia. Rats were randomized to four treatments: isoflurane; fentanyl + N(2)O; isoflurane + trimethaphan; or isoflurane + metyrapone. Severe forebrain ischemia was then induced for 10 min. Plasma and brain corticosterone, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 were assayed. Plasma corticosterone concentrations were similar in the isoflurane and isoflurane + trimethaphan groups, but greater than in the fentanyl + N(2)O and isoflurane + metyrapone groups. Brain corticosterone was similar among all groups except isoflurane + metyrapone, in which values were markedly reduced. The addition of metyrapone to isoflurane also reduced plasma TNF-alpha; however, values among other groups were similar. There were no differences among groups for brain TNF-alpha. Plasma IL-6 concentrations were below the limit of detection. Brain IL-6 concentrations were increased by ischemia; however, there was no difference among groups. In conclusion, there were no differences between the isoflurane and isoflurane + trimethaphan groups for any of the measured stress markers. Further, there was little difference between the isoflurane and fentanyl + N(2)O groups, except for plasma corticosterone concentration. Accordingly, isoflurane neuroprotection and its reversal by trimethaphan appear to be independent of effects on the stress responses measured in this study. IMPLICATIONS Differential anesthetic effects on ischemic outcome are independent of effects on adrenergic/noradrenergic responses to ischemia. The absence of a consistent differential effect of anesthetics on either corticosterone or cytokine responses to ischemia serves to further refute the hypothesis that isoflurane neuroprotection can be attributed to dampening of adverse stress responses to ischemic insults.

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.

Local cerebral perfusion pressure (CPP), a crucial parameter that should allow a better assessment of the haemodynamic compromise in cerebrovascular diseases, is not currently measurable by non-invasive means. Experimental and clinical studies have suggested that the regional ratio of cerebral blood flow to cerebral blood volume (CBF:CBV), as measured by PET, represents an index of local CPP in focal ischaemia. The present study was designed to evaluate further the reliability of the CBF:CBV ratio during manipulations of CPP by deliberately varying mean arterial pressure (MAP) in the anaesthetized baboon. Cortical CBF, CBV, cerebral metabolic rate for oxygen (CMRO2) and oxygen extraction fraction were measured by PET using the (15)O steady-state technique in 10 anaesthetized baboons. Five baboons (Group A) underwent four PET examinations at different levels of MAP: base line (101 +/- 6 mmHg) followed by moderate hypotension (58 +/- 3 mmHg) and, in a separate experiment, minor hypotension (72 +/- 3 mmHg) followed by profound hypotension (34 +/- 5 mmHg). Trimetaphan was used to lower MAP to minor and moderate levels while profound hypotension was achieved by the combined effects of trimetaphan and lower-body negative pressure. Five other baboons (Group B) were subjected to hypertension (121 +/- 2 mmHg) induced by metaraminol and were compared with their base line state (81 +/- 10 mmHg). While CBF displayed significant changes with varying MAP, i.e. decrease and increase with hypotension and hypertension, respectively (-11% from base line to moderate hypotension compared with -20%, from minor to profound hypotension and +31% from base line to hypertension), CBV was more variable and did not significantly change, except with profound hypotension when the increase was significant (+13%). The CBF:CBV ratio decreased significantly at all stages of hypotension (-21 and -31%) and was significantly increased during hypertension (+30%). Importantly, the CBF:CBV ratio demonstrated a significant correlation with MAP (rho = 0.78, Spearman's rank correlation coefficient, P < 0.01). No major changes in CMRO2 were noted during either hypotension or hypertension. Our results demonstrate that, under physiological conditions, cortical CBF:CBV is significantly correlated with CPP, itself a function of MAP. In the investigated range of MAP, the relationships between CBF:CBV and MAP appear to be linear. These findings further argue for the reliability of CBF:CBV as an index of CPP in situations where increases or decreases of MAP without superimposed changes in cerebrovascular tone are encountered, and they confirm the potential usefulness of this regional ratio for clinical investigations and management in cerebrovascular diseases.

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.

We hypothesized that selective control of ventricular contractility might be mediated by postganglionic parasympathetic neurons in the cranial medial ventricular (CMV) ganglion plexus located in a fat pad at the base of the aorta. Sinus rate, atrioventricular (AV) conduction (ventricular rate during atrial pacing), and left ventricular contractile force (LV dP/dt during right ventricular pacing) were measured in eight chloralose-anesthetized dogs both before and during bilateral cervical vagus stimulation (20-30 V, 0.5 ms pulses, 15-20 Hz). Seven of these dogs were tested under beta-adrenergic blockade (propranolol, 0.8 mg kg(-1) i.v.). Control responses included sinus node bradycardia or arrest during spontaneous rhythm, high grade AV block or complete heart block, and a 30% decrease in contractility from 2118 +/- 186 to 1526 +/- 187 mm Hg s(-1) (P0.05). Next, the ganglionic blocker trimethaphan (0.3-1.0 ml of a 50 microg ml(-1) solution) was injected into the CMV fat pad. Then vagal stimulation was repeated, which now produced a relatively small 5% (N.S., P0.05) decrease in contractility but still elicited the same degree of sinus bradycardia and AV block (N = 8, P0.05). Five dogs were re-tested 3 h after trimethaphan fat pad injection, at which time blockade of vagally-induced negative inotropy was partially reversed, as vagal stimulation decreased LV dP/dt by 19%. The same dose of trimethaphan given either locally into other fat pads (PVFP or IVC-ILA) or systemically (i.v.) had no effect on vagally-induced negative inotropy. Thus, parasympathetic ganglia located in the CMV fat pad mediated a decrease in ventricular contractility during vagal stimulation. Blockade of the CMV fat pad had no effect on vagally-mediated slowing of sinus rate or AV conduction.

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.

Background Although pulmonary function is minimally changed by neuraxial blockade in most cases, ventilatory arrest may ensue in rare cases. The authors examined the mechanism of apnea in a rabbit model of sudden ventilatory arrest during the combination of epidural anesthesia and hypoxia. Methods Rabbits were studied during alpha-chloralose sedation and spontaneous ventilation through a tracheostomy tube. Heart rate and mean arterial pressure were monitored by intraarterial cannulation. Respiratory rate and tidal volume were measured by pneumotachograph. Responses were recorded during administration of oxygen at inspired oxygen concentrations of 11% for 2.5 min and 0% for 40 s, before and after either thoracolumbar epidural blockade (0.4 ml/kg lidocaine, 1.5%) or intramuscular lidocaine (15 mg/kg). In a third group of animals, epinephrine was given intravenously during epidural blockade to return mean arterial pressure to baseline values before hypoxia. In a fourth group of animals, which did not get lidocaine, sympathetic blockade and hypotension were produced with intravenously administered trimethaphan rather than epidural blockade. Results Thoracolumbar epidural anesthesia decreased mean arterial pressure from 76 +/- 4 mmHg (mean +/- SE) to 42 +/- 2 mmHg. Apnea during hypoxia occurred in 90% of these animals (nine of ten) but in only 11% of animals (one of nine) after intramuscularly administered lidocaine (P < 0.01). Treatment of epidural hypotension with epinephrine prevented apnea (zero of nine animals). Apnea during hypoxia occurred in 50% (three of six) of animals given trimethaphan. Apnea in all groups was sudden in onset, with no preceding decreases in respiratory rate or tidal volume. Conclusions Epidural anesthesia results in a narrowed margin of safety for oxygen delivery to the brain and predisposes subjects to ventilatory arrest during hypoxia. This results from the combined effects of decreased blood oxygen content, which is due to decreased inspired oxygen concentration superimposed on circulatory depression due to neural blockade.

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.

Activation of the vagus nerve leads to decreases in sinoatrial (SA) rate, atrioventricular (AV) conduction, and myocardial contractility. Previous data are consistent with the hypothesis that vagal control of cardiac rate and AV conduction are mediated by two anatomically separated and physiologically independent parasympathetic intracardiac ganglia located in fat pads on the surface of the right and left atria, respectively. These data suggested that vagal control of ventricular contractility might be mediated through another intracardiac ganglion. We examined the ventricles of cat hearts histologically for the presence of ganglia. Multiple small basophilic ganglia composed of a few neurons, and an occasional larger ganglion were found embedded in the epicardial fat surrounding the cranial margin of the anterior surface of the left ventricle, near the juncture with the right ventricle, which we refer to as the CV ganglion. In anesthetized cats, right cervical vagal stimulation decreased SA rate by 44 +/- 5%, decreased the rate of AV conduction by 68 +/- 14%, and reduced ventricular contractility by 19.5 +/- 5.7%. Vagally induced negative inotropism was almost completely prevented by microinjection of a ganglionic blocking drug into the CV ganglion. However, these injections into the CV ganglion did not significantly effect vagally induced decreases in either SA rate or AV conduction. We conclude: (1) that ganglia are found in a fat pad on the surface of the left ventricle of the cat heart and (2) that the CV ganglion selectively mediates the negative inotropic effect of vagal stimulation on the left ventricle. Greater understanding of the physiological functions of intracardiac neuronal circuits may help in developing new strategies to treat disorders of cardiac contractility such as congestive heart failure.

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.

Autonomic activation mediates the majority of the increase of glucagon secretion during insulin-induced hypoglycemia in several species including dogs, mice, and rats. However, the role of the autonomic nervous system to increase glucagon during hypoglycemia in humans remains controversial, and investigations in nonhuman primates have not been previously conducted. The autonomic contribution to glucagon secretion during hypoglycemia in a nonhuman primate was examined by two independent pharmacological approaches. Glucagon responses to clamped insulin-induced hypoglycemia were compared in conscious rhesus monkeys in the presence or absence of ganglionic blockade with trimethaphan, or during combined muscarinic and adrenergic receptor blockade with atropine, propranolol, and tolazoline. Insulin-induced hypoglycemia (plasma glucose = 1.9 +/- 0.1 mmol/l) activated parasympathetic nerves to the pancreas as assessed by increased plasma pancreatic polypeptide (PP) levels (delta = 135.0 +/- 36.8 pmol/l, P < 0.01), produced sympathoadrenal activation as assessed by elevations of plasma epinephrine (EPI) (delta = 22.3 +/- 2.95 nmol/l, P < 0.0005) and norepinephrine (NE) (delta = 3.72 +/- 0.77 mmol/l, P < 0.0025) and increased plasma immunoreactive glucagon (IRG) (delta = 920 +/- 294 ng/l, P < 0.025). Nicotinic ganglionic blockade with trimethaphan prevented parasympathetic (deltaPP = 16.5 +/- 16.3 pmol/l, P < 0.01 vs. control) and sympathoadrenal (deltaEPI = 1.52 +/- 0.98 nmol/l; deltaNE = -0.62 +/- 0.24 mmol/l, both P < 0.0025 vs. control) activation during hypoglycemia and inhibited the IRG response by 70% (delta = 278 +/- 67 ng/l, P < 0.025 vs. control). Combined muscarinic and adrenergic receptor blockade reduced parasympathetic activation (deltaPP = 48.3 +/- 16.3 pmol/l, P < 0.01 vs. control) and inhibited the IRG response by a similar degree to ganglionic blockade (deltaIRG = 284 +/- 60 ng/l, P < 0.025 vs. control). These results demonstrate by two independent pharmacological approaches that autonomic activation makes a substantial contribution to increased glucagon secretion during hypoglycemia of approximately 2.0 mmol/l in a species of nonhuman primate.

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.

We compared the effects of deliberate hypotension induced with trimethaphan on renal function and renal tubular damage under combined epidural and light-enflurane anesthesia (epidural group) and enflurane anesthesia alone (enflurane group). The mean arterial blood pressure was maintained at 50–55 mm Hg for 2.5 h in both groups using continuous infusion of trimethaphan. The urine volume and free water clearance were significantly greater in the epidural group than in the enflurane group [1.8±1.8 (SD)vs 0.4±0.3 ml·kg−1·h−1 and 0.81±1.30vs −0.15±0.22 ml·min−1, respectively] (P

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.

Sodium nitroprusside (SNP) has been used to control the proximal hypertension associated with thoracic aortic cross-clamping (TACC) during thoracic aortic surgery. It worsens neurologic outcome, presumably by further decreasing distal arterial pressure and increasing cerebrospinal fluid (CSF) pressure, thereby worsening the spinal cord perfusion pressure (SCPP). Trimethaphan does not increase CSF pressure. Therefore, the present study investigates the effect of trimethaphan versus SNP to control proximal hypertension during TACC on neurologic outcome. Two groups, each with eight mongrel dogs, were studied. All animals underwent descending TACC for 45 min. The mean proximal aortic blood pressure was maintained at 95-100 mm Hg by the use of SNP or trimethaphan. Distal aortic pressure was allowed to vary. The dogs were neurologically evaluated 24 and 48 h later by a blinded observer. During cross-clamping, there was no difference in mean proximal aortic pressure between groups. After 10 min of cross-clamping, distal aortic pressure was higher (P < 0.01), CSF pressure was lower (P < 0.01), and SCPP was higher (P < 0.005) in the trimethaphan group as compared with the SNP group (group effect). Neurologic outcome as assessed by Tarlov's score was better at 24 and 48 h in the trimethaphan group (P < 0.05). Histopathologic injury trended with worsened neurologic outcome. We conclude that 1) trimethaphan produced higher SCPP than SNP, and 2) neurologic outcome was better in the trimethaphan group.

The nicotinic antagonists d-tubocurarine and trimethaphan camsylate competitively inhibit GABA-induced currents. Hexamethonium, mecamylamine and dihydro-beta-erythroidine, other nicotinic antagonists, do not affect GABA-elicited currents. The trimethaphan effect is completely reversed by a putative convulsant receptor antagonist, alpha-isopropyl-alpha-methyl-gamma-butyrolactone, which implies that the trimethaphan binding site may be closely associated with the convulsant site. However, nicotine was ineffective in competing for either the d-tubocurarine or trimethaphan effect at the GABAA receptor. From these observations, we propose that the nicotinic and GABAA receptor ionophore complexes share similar configurational patterns that accommodate some of the same molecules. Possible mechanisms for the trimethaphan and d-tubocurarine blockades are discussed.

Local cerebral blood flow (CBF) during three types of profound hypotension were compared using the quantitative autoradiographic [14]-C iodo-anti-pyrine method. Rats were rendered hypotensive to a mean arterial pressure of 30 mm Hg for 30 min by haemorrhage, trimetaphan or nitroprusside during 0.8% halothane anaesthesia. During haemorrhagic hypotension, mean local CBF was reduced significantly in all except two pontine regions. This reduction in flow ranged from 83% to 41% compared with the normotensive control group, with the neocortex and telencephalon most affected. During trimetaphan-induced hypotension, local CBF was reduced to the same degree and in the same pattern as that during haemorrhagic hypotension. In contrast, during nitroprusside-induced hypotension, local CBF in many regions of the brain was well maintained (57–101%); although local CBF was significantly below control in all cortical and telencephalic regions, it was significantly greater in the majority of these regions than in the other two hypotensive groups. We conclude that local CBF was significantly reduced in the neocortex and telencephalon by hypotension of this degree induced by all three methods, but nitroprusside preserved local CBF significantly better than the other methods, in these, as in most other regions.

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

Neuroanatomic studies describing forebrain projections to the lateral parabrachial nucleus suggest a central integrative role in cardiovascular regulation. We performed this study to examine the role of this pontine nucleus in the maintenance of one-kidney, figure-8 renal-wrap hypertension. Bilateral ibotenic acid ablation of the lateral parabrachial nucleus was performed 4 weeks after induction of hypertension or sham operation. In hypertensive rats, ablation produced a significant reduction in mean arterial pressure from 160 +/- 4 to 118 +/- 2 mm Hg and a transient but significant increase in heart rate from 381 +/- 5 to 408 +/- 8 beats per minute on the first day after ablation; arterial pressure returned to preablation values by day 5 after ablation. In sham-operated, normotensive animals, arterial pressure was not altered by ablation, and a transient but significant increase in heart rate from 384 +/- 8 to 419 +/- 7 beats per minute was again observed. Before ablation, trimethaphan administration produced a significantly greater drop in arterial pressure in hypertensive (delta-72.8 +/- 4.6 mm Hg) versus normotensive (delta-55.7 +/- 4.1 mm Hg) animals. This effect was eliminated on day 1 after ablation yet returned on day 4 after ablation. In blood samples obtained before ablation and on days 1 and 4 after ablation, circulating plasma catecholamine concentrations in both groups remained unchanged. These observations suggest that, because of possible alternate neural compensatory mechanisms, lateral parabrachial nucleus ablation produces a significant yet transient reversal of renal-wrap hypertension. Thus, the lateral parabrachial nucleus may contribute to the increased sympathetic nervous system function associated with this model.

Nitroglycerin inhibits platelet aggregation in vitro, but its effect on thrombosis and platelet function in vivo is controversial. This study assessed the effect of nitroglycerin on primary thrombus formation in response to vessel wall injury and secondary thrombus formation, or rethrombosis, after lysis of an existing thrombus. In the first protocol the right carotid artery was instrumented with a flow probe, stenosis, an anodal electrode, and a proximal infusion line. A 300 microA anodal current was used to induce endothelial injury and subsequent thrombotic occlusion of the vessel. Anisoylated plasminogen streptokinase activator complex (APSAC; 0.05 U/kg intraarterially) was injected proximal to the thrombus 30 minutes after occlusion. After APSAC, nitroglycerin (1 microgram/kg/min intraarterially, n = 7) or vehicle (n = 6) was infused proximal to the thrombus for 3 hours. Reocclusion occurred in two of seven nitroglycerin-treated dogs and six of six vehicle-treated dogs (p < 0.05). In the second protocol both carotid arteries were instrumented as described previously. Anodal current (300 microA, 180 minutes) was applied to the right carotid (n = 12) artery to determine control times to occlusion. The left carotid artery served as the test vessel, receiving either nitroglycerin (1 microgram/kg/min intraarterially, n = 6) or trimethaphan (0.05 mg/kg/hr intraarterially, n = 6). Trimethaphan was used to produce controlled hypotension to match the approximately 10% decrease in mean arterial blood pressure that was observed during nitroglycerin infusion. Control arteries and those treated with trimethaphan formed occlusive thrombi in all instances. Nitroglycerin infusion resulted in a lower incidence of occlusion (1 of 6; p < 0.05 vs control value) and inhibited ex vivo platelet aggregation to adenosine diphosphate and arachidonic acid (p < 0.05). Local infusion of nitroglycerin reduced the formation of primary thrombi, independent of the hypotensive effect of the drug, and exerted systemic effects on platelet aggregation. Furthermore, platelet inhibition with nitroglycerin reduced the incidence of secondary thrombus formation (rethrombosis) after thrombolysis. The results suggest that a potential benefit of nitroglycerin therapy may be derived from its ability to inhibit thrombotic events in patients with unstable angina or myocardial infarction.

Purpose: Infrarenal aortic cross-clamping performed during vascular reconstructive procedures is often accompanied by systemic supraclamp hypertension. Much of the disease and death that attend aortic cross-clamping centers around hypertension. Many different strategies have been developed to attenuate intraoperative hypertension, and a host of pharmacologic agents are regularly used to lessen the heart-related, cerebral, and systemic effects of clamp-induced hypertension. This study was performed to evaluate two such strategies: the intravenous administration of either trimethaphan camsylate or nitroprusside. Methods: We used a highly controllable and reproducible model of aortic cross-clamping in which we have previously shown the hypertension associated with clamping to be an active process mediated by means of a reflex arc. Ten dogs, five treated with nitroprusside (NP group) and five treated with trimethaphan camsylate (TC group), underwent 90 minutes of aortic cross-clamping. During this 90-minute period each group received 30 minutes of antihypertensive therapy. Results: Control mean arterial pressure ± SEM was 80 ± 5 mm Hg for both groups and increased to 140 ± 5 mm Hg with clamp application. With antihypertensive treatment the elevation in mean arterial pressure produced by cross-clamping was reduced to preclamp levels in the TC group and only partially (52%) in the NP group, despite very high doses of nitroprusside. Cardiac output (CO) increased in the NP group by 115% and decreased by 36% in the TC group. This increase in CO translates into a large (101%) increase in cardiac minute work for the NP group. Conclusions: The attenuation of clamp-induced hypertension by nitroprusside is associated with a dramatic increase in CO and cardiac work whereas the use of trimethaphan camsylate is not. The use of this ganglionic blocker may be more appropriate in this setting. (J VASC SURG 1994;19:707-16.)

Many epidemiological studies have suggested a high correlation between the use of tobacco and ethanol, the two most frequently abused psychoactive drugs. Recently, we reported behavioral interactions between (-)-nicotine, (-)-cotinine and ethanol within the CNS. The present report is a confirmation and an extension of that study. Using a 2 g/kg ethanol-induced motor incoordination (EIMI) as the test response, possible behavioral interactions between (-)-nicotine, (-)-cotinine and ethanol and between (-)-nicotine, (-)-cotinine and adenosine agonist + ethanol in the cerebellum were investigated. (-)-Nicotine, 0.625, 1.25 and 5 ng intracerebellarly (ICB) significantly attenuated EIMI in a dose-related manner. Likewise, ICB injection of 1.25, 2.5, and 5 ng (-)-cotinine, a major metabolite of nicotine, significantly attenuated EIMI after the same i.p. dose of ethanol as in case of (-)-nicotine but less markedly compared to (-)-nicotine. No change in normal motor coordination was observed when the highest dose of (-)-nicotine or (-)-cotinine was injected ICB followed by saline control, suggesting selectivity of their behavioral interactions with ethanol. The attenuation of EIMI by (-)-nicotine and (-)-cotinine was blocked by ICB hexamethonium (1 microgram) and trimethaphan (100 ng), the purported nicotinic-cholinergic antagonists. Finally, the ICB injection of adenosine agonists, N6-cyclohexyladenosine (CHA) or 5'-N-ethylcarboxamidoadenosine (NECA), produced marked accentuation of EIMI which was significantly antagonized by ICB (-)-nicotine and (-)-cotinine. The data obtained in the present study suggested, for the first time, a cerebellar adenosinergic-nicotinic cholinergic interaction and modulation of EIMI. The data also suggested participation of cerebellar nicotinic-cholinergic receptors in EIMI.

We tested the hypothesis that hyperglycemic exacerbation of incomplete forebrain ischemia is mediated by increased extracellular dopamine levels. Normoglycemic and hyperglycemic Sprague-Dawley rats (eight each) with previously placed coaxial striatal microdialysis probes underwent 12 min of forebrain ischemia produced by bilateral carotid artery occlusion and trimethaphan-induced hypotension. Microdialysis was performed before, during, and for 6 h after ischemia, then perfusion-fixation was performed. Hyperglycemic rats had more severe postischemic damage in the caudate-putamen, neocortex, and hippocampus. Extracellular striatal dopamine levels were increased by ischemia, but were unaffected by hyperglycemia. These data show that hyperglycemic exacerbation of ischemic striatal damage does not depend on elevated extracellular dopamine levels.

1. The guinea-pig trachea was isolated with its extrinsic innervation intact and pinned to the bottom of a water-jacketed dissecting dish filled with warmed, oxygenated Krebs solution. The trachea was not separated from the oesophagus. Isometric tension was measured in a segment of the rostral portion of the trachea. 2. Stimulation of the vagus nerves caudal to the nodose ganglia elicited contractions of the trachealis that were blocked by the muscarinic receptor antagonist atropine. Following addition of atropine and contraction of the trachealis with prostaglandin F2 alpha (PGF2 alpha), vagus nerve stimulation elicited non-adrenergic, non-cholinergic relaxations. Both responses elicited by stimulation of the vagi were abolished by cutting the recurrent laryngeal nerves and were considered parasympathetic in nature as they were sensitive to the autonomic ganglion blockers trimetaphan and hexamethonium. 3. Experiments were designed in which ganglionic blockers were added to the buffer bathing the entire preparation or, alternatively, added only to the buffer perfusing the tracheal lumen. When given equal access to the trachea and oesophagus, hexamethonium was 56-fold more potent an inhibitor of vagally mediated relaxations of the trachealis than vagally mediated contractions. Selective administration of hexamethonium to the buffer perfusing the tracheal lumen did not decrease the potency of the ganglionic blocker versus vagally mediated contractions. By contrast, even at a concentration of 1 mM, intratracheally administered hexamethonium failed to inhibit vagally mediated relaxations by 50%. Comparable results were obtained using trimetaphan. 4. Consistent with previous observations, removing the portion of the oesophagus contiguous with the region of the trachea at which isometric tension was measured abolished parasympathetic relaxations of the trachealis. Oesophagus removal was without effect on parasympathetic nerve-induced contractions. Removing the dorsal half of the oesophagus or the mucosa and submucosa of the oesophagus did not affect the parasympathetic relaxant innervation. 5. The compound action potential of guinea-pig recurrent laryngeal nerves evoked by vagus nerve stimulation consisted of three distinct peaks representing populations of axons with fast, intermediate and slow conduction velocities. The voltage-response characteristics of vagally mediated contractions were identical to those of the compound action potential peak representing fibres with intermediate (10 m/s) conduction velocities. By contrast, the voltage-response characteristics of the vagally mediated relaxations were best correlated with the compound action potential peak representing fibres with slow (0.4-3 m/s) conduction velocities.(ABSTRACT TRUNCATED AT 400 WORDS)

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.