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 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.

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.

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.

Functional magnetic resonance imaging (fMRI) provides an indirect measure of cerebral activation that could be altered by factors directly affecting cerebral blood flow independent of changes in neuronal activation. Presently, we investigate how changes in blood pressure (BP) affect the activation detected with fMRI. fMRI scans were acquired in 33 rats under control conditions and following transient BP increases (norepinephrine, IV) or decreases (arfonad, IV) with and without electrical stimulation of the forepaw. Voxels correlating to either the stimulation or the change in BP time courses were identified. During transient hypertension, irrespective of forepaw stimulation, BP increases (i.e., >10 mm Hg) produced a transient increase in the blood oxygen level-dependent (BOLD) intensity resulting in a significant numbers of voxels correlating to the BP time courses (P < 0.05), and the number of these voxels increased as BP increased, becoming substantial at BP > 30 mm Hg. The activation patterns with BP increases and stimulation overlapped spatially resulting in an enhanced cerebral activation to simultaneous forepaw stimulation (P < 0.05). BP decreases (>10 mm Hg) produced corresponding decreases in BOLD intensity, causing significant numbers of voxels correlating to the BP decreases (P < 0.005), and these numbers increased as BP decreased (P < 0.001). The BP decreases and stimulation time courses and responses were distinct, and hypotension did not affect the detection of the activation response to forepaw stimulation. The results indicate that substantial hypertension accompanying a stimulation paradigm produces a BOLD response that enhances the cerebral activation detected, whereas hypotension does not affect the detection of neuronal activation but does produce responses that could be interpreted as a 'deactivation'.

In acute experiments on cats neural inotropic and lusitropic reactions of the heart to enhancement of pre- and afterload were assessed by changes in contractility and relaxation indices, which were preliminary chosen for their maximum specificity and sensitivity. The control cardiac responses to increased pre- and afterload were measured after treatment with ganglionic blocker arfonad. The myogenic component of these responses assessed under the action of arfonad was highly pronounced, therefore the neural inotropic and lusitropic reactions were measured as the difference between load-induced changes of indices in experiments with and without arfonad. Increased preload produced similar negative inotropic and lusitropic effects, while increased afterload produced a more pronounced negative inotropic effect, which indicated independent regulation of contractility and diastolic relaxation of the heart.

The possibility of using contraction and relaxation indices for evaluation of inotropic and loositropic influences on the heart was studied in experiments on cats. Increased pre- and afterload were used as the stimuli, which are simultaneously loading and reflexogenic. Under conditions of preserved innervation both stimuli elevated the indices selected according to the highest sensitivity/specificity ratio. Ganglionic blocker arfonad potentiated the effects of these stimuli. This attests to a considerable contribution of the myogenic component to the changes in the studied indices in response to increased pre- and afterload and to the existence of negative inotropic and loositropic influences on the heart under conditions of preserved innervation. These conclusions were supported when more specific indices were used: in most cases they decreased during load tests. Thus, when the contraction and relaxation indices are used for evaluation inotropic and loositropic influences on the heart, it seems reasonable either to compare heart responses under conditions of preserved or blocked innervation, or to apply more specific indices. Analysis of changes in most widely used indices (dP/dt)max and t showed that t reliably reflects neural loositropic influences, while the use of (dP/dt)max without proper control can be erroneous.

Sensitivity (response to epinephrine infusion) and specificity (response to changes in pre- and afterload) of some cardiac relaxation indices were compared in acute experiments on cats treated with ganglionic blocker arfonad. Some new indices proposed by us provide better characteristics than widely used relaxation time constant (t) and maximum first derivative of the left ventricular pressure (-dP/dt)max.

The high-frequency (HF) component of the heart rate variability (HRV) is regarded as an index of cardiac vagal responsiveness. However, when vagal tone is decreased, nonneural mechanisms could account for a significant proportion of the HF component. To test this hypothesis, we examined the HRV spectral power in 20 patients with mild chronic heart failure (CHF) and 11 controls before and during ganglion blockade with trimethaphan camsylate (3-6 mg/min iv). A small HF component was still present during ganglion blockade, and its amplitude did not differ between CHF patients and controls. The average contribution of nonneural oscillations to the HF component was 15% (range 1-77%) in patients with CHF and 3% (range 0. 7-30%) in healthy controls (P < 0.005). During controlled breathing at 0.16 Hz, however, it decreased to 1% (range 0.2-13%) in healthy controls and 5% (range 1-44%) in CHF patients. Our results indicate that the HF component can significantly overestimate cardiac vagal responsiveness in patients with mild CHF. This bias is improved by controlled breathing, since this maneuver increases the vagal contribution to HF without affecting its nonneural component.

Severe hypertension is a common clinical problem in the United States, encountered in various clinical settings. Although various terms have been applied to severe hypertension, such as hypertensive crises, emergencies, or urgencies, they are all characterized by acute elevations in BP that may be associated with end-organ damage (hypertensive crisis). The immediate reduction of BP is only required in patients with acute end-organ damage. Hypertension associated with cerebral infarction or intracerebral hemorrhage only rarely requires treatment. While nitroprusside is commonly used to treat severe hypertension, it is an extremely toxic drug that should only be used in rare circumstances. Furthermore, the short-acting calcium channel blocker nifedipine is associated with significant morbidity and should be avoided. Today, a wide range of pharmacologic alternatives are available to the practitioner to control severe hypertension. This article reviews some of the current concepts and common misconceptions in the management of patients with acutely elevated BP.

Blood pressure usually is reduced in patients with hypertensive intracerebral hemorrhage for the prevention of the expansion of the hematoma and recurrent hemorrhage in acute stage. However, disturbed autoregulation of cerebral circulation is expected, and decreased cerebral blood flow (CBF) caused by excessive hypotension has been pointed out. There are different mechanisms of action in hypotensives, thereby the influence of hypotension on CBF in patients with the thalamic hemorrhage was investigated using nitroglycerin (TNG), diltiazem hydrochloride (DH) and trimethaphan camsilate (TC). Average CBF in a hemisphere on the hematoma side, the hemisphere without hematoma, and around the hematoma showed a slight decline after administration of TNG or DH. However, CBF declined more, after TC than DH. DH and TNG are preferable in descending order to control blood pressure of patients with intracerebral hemorrhage in the acute stages in view of a smaller decline in CBF.

Coniine, an alkaloid from Conium maculatum (poison hemlock), is a known teratogen in many domestic species with maternal ingestion resulting in arthrogryposis of the offspring. We have previously shown that rats are not susceptible and rabbits only weakly susceptible to coniine-induced arthrogryposis. However, the chick embryo does provide a reproducible laboratory animal model of coniine-induced teratogenesis. The reason for this cross-species variation is unknown. The purpose of this study was to evaluate coniine binding to nicotinic receptors and to measure coniine metabolism in vitro between susceptible and non-susceptible species. Using the chick model, neither the peripheral nicotinic receptor antagonist d-tubocurarine chloride nor the central nicotinic receptor antagonist trimethaphan camsylate blocked the teratogenesis or lethality of 1.5% coniine (50 microliters/egg). Trimethaphan camsylate enhanced coniine-induced lethality in a dose-dependent manner. Neither nicotinic receptor blocker prevented nicotine sulfate-induced malformations but d-tubocurarine chloride did block lethality in a dose-dependent manner. Competition by coniine for [125I]-alpha-bungarotoxin to nicotinic receptors isolated from adult rat diaphragm and chick thigh muscle and competition by coniine for [3H]-cytisine to receptors from rat and chick brain were used to assess coniine binding to nicotinic receptors. The IC50 for coniine in rat diaphragm was 314 microM while that for chick leg muscle was 70 microM. For neuronal nicotinic receptors, the IC50s of coniine for maternal rat brain, fetal rat brain, and chick brain were 1100 microM, 820 microM, and 270 microM, respectively. There were no differences in coniine biotransformation in vitro by microsomes from rat or chick livers. Differences in apparent affinity of coniine for nicotinic receptors or differences in the quantity of the nicotinic receptor between the rat and chick may explain, in part, the differences in susceptibility of coniine-induced teratogenesis between these two species.

We have investigated in 30 patients the metabolic and hormonal responses to middle ear surgery using induced hypotension to a mean arterial pressure of 55 mm Hg. A standardized anaesthetic technique of propranolol, thiopentone-vecuronium-isoflurane was used in all patients and hypotension induced with sodium nitroprusside, trimetaphan camsylate or additional isoflurane. All patients showed a classic stress response with an increase in circulating blood glucose, cortisol and growth hormone concentrations. Blood lactate and plasma uric acid concentrations changed little during operation, suggesting that tissue oxygenation was adequate. However, the former declined after operation, possibly as a result of the concomitant use of propranolol. There were no significant differences between the three hypotensive techniques in their effects on the hormonal and metabolic response, although the increase in blood glucose concentration in the trimetaphan group was obtunded. We conclude that induced hypotension for middle ear surgery induced an endocrine and metabolic response of small magnitude and short duration.

Trimethaphan camsylate is a potent antihypertensive drug used to induce systemic arterial hypotension in patients undergoing major surgery and to treat severe systemic hypertension. The pharmacokinetics and pharmacodynamics of trimethaphan administered in the usual clinical dosages have been previously reported. The effects of trimethaphan when administered in very high doses of 500-1000 times the usual dose have not been reported.

The authors sought to develop a model for assessing in vivo regulation of cerebral vasoregulation by nitric oxide (NO), originally described as endothelial-derived relaxing factor, and to use this model to establish the role of NO in the regulation of cerebral blood flow (CBF) in primates. By using regional intraarterial perfusion, the function of NO in cerebral vasoregulation was examined without producing confounding systemic physiological effects. Issues examined were: whether resting vasomotor tone requires NO; whether NO mediates vasodilation during chemoregulation and autoregulation of CBF; and whether there is a relationship between the degree of hypercapnia and hypotension and NO production. Twelve anesthetized (0.5% isoflurane) cynomolgus monkeys were monitored continuously for cortical CBF, PaCO2, and mean arterial pressure (MAP), which were systematically altered to provide control and experimental curves of chemoregulation (CBF vs. PaCO2) and autoregulation (CBF vs. MAP) during continuous intracarotid infusion of 1) saline and 2) an NO synthase inhibitor (NOSI), either L-n-monomethyl arginine or nitro L-arginine. During basal conditions (PaCO2 of 38-42 mm Hg) NOSI infusion of internal carotid artery (ICA) reduced cortical CBF from 62 (saline) to 53 ml/100 g/per minute (p<0.01), although there was no effect on MAP. Increased CBF in response to hypercapnia was completely blocked by ICA NOSI. The difference in regional (r)CBF between ICA saline and NOSI infusion increased linearly with PaCO2 when PaCO2 was greater than 40 mm Hg, indicating a graded relationship of NO production, increasing PaCO2, and increasing CBF. Diminution of CBF with NOSI infusion was reversed by simultaneous ICA infusion of L-arginine, indicating a direct role of NO synthesis in the chemoregulation of CBF. Hypotension and hypertension were induced with trimethaphan camsylate (Arfonad) and phenylephrine at constant PaCO2 (40 +/- 1 mm Hg). Autoregulation in response to changes in MAP from 50 to 140 mm Hg was unaffected by ICA infusion of NOSI. In primates, cerebral vascular tone is modulated in vivo by NO; continuous release of NO is necessary to maintain homeostatic cerebral vasodilation; vasodilation during chemoregulation of CBF is mediated directly by NO production; autoregulatory vasodilation with hypertension is not mediated by NO; and increasing PaCO2 induces increased NO production.

The urinary bladder is a compliant organ, high compliance being essential for useful urine storage. The extent to which the sympathetic nervous system promotes the storage of urine by increasing bladder compliance is unclear. The aim of the present study was to determine the range of bladder volumes over which the sympathetic nervous system increased bladder wall compliance. In supine, anaesthetized cats, the bladder was filled at twice the rate of natural filling, the continence cycle being interrupted at five stages. These stages were when the bladder had become globular, during prodromal contractions, soon after non-micturating contractions had commenced, approximately two-thirds of the way through the continence cycle and just prior to micturition. During each of these interruptions, bladder volume was held constant while pelvic nerve afferent activity and bladder pressure were recorded. Recordings were obtained before and during the intravenous infusion of trimethaphan, the resulting partial ganglion blockade decreasing arterial pressure by a third. Bladder pressure as well as afferent nerve activity increased significantly when the sympathetic drive was transiently blocked, indicating that there had been a prevailing net sympatho-inhibitory effect promoting bladder wall relaxation. This effect was observed during prodromal contractions and continued until the onset of micturition. This net sympatho-inhibitory effect is a potential therapeutic path for the treatment of bladder storage disorders.

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.

We studied the formation of vasomotor reflexes in hypokinesia and responses of the brain vessels to the action of GABA, hypotension, and hypercapnia. We found that the response of the brain vessels to GABA is delayed and the mechanisms which supported an adequate cerebral vasculation are distorted in hypotension. At the same time the disturbance of the reflectory reaction of the brain vessels in the course of forming the vasomotor reflexes and the absence of significant changes in response to GABA were noticed. The capability of GABA of inhibiting cerebral blood circulation arising in hypokinesia is shown.

Present study is designed to examine an effect of Stobadine, a new cell-protective agent with antiarrhythmic properties, on survival, electron microscopic changes in microvasculatory bed of selected brain areas and acid-base parameters of arterial blood after global brain ischemia and reperfusion. Forty dogs (weighting 6 to 15 kg) were anesthetized using pentobarbital i.v. (5%, 35 mg/kg). An intubation and controlled ventilation was performed. One catheter was placed into v. femoralis (for drug administration), another to a. femoralis (for blood samples) and third one into the left common carotid artery (continuous brain blood feeding pressure measurement). Each dog underwent an surgical obstruction of principal brain-supplying arteries and immediate administration of hypotensive agent (Arfonad, 0.062%) resulting in 7 minutes lasting global brain ischemia (brain feeding pressure 1.0-1.5 kPa). If survived, animals were killed at one (perfusion-fixed for electron microscopy) or three days after ischemia. Ultrastructural changes were evaluated at 24 hour of recirculation (control and S2 groups only). Vehicle or 1, 2 or 5 mg/kg of Stobadine (group S1, S2, S5 resp.) i.v. was given 30 minutes prior to ischemia. Significantly longer survival was observed in group S2 (8 of 11 until 72 hour) as compared to control group (none of 7, p < 0.005 by Student's t-test). The ultrastructural changes of blood-brain barrier structures were none or minimal in S2 (single damage type), but in control group three major types of capillary damages has appeared at 24 hour after insult. They include intravascular coagulopathy (type I), no-reflow (type II) phenomenon with astrocyte edema, and capillary necrosis (type III) finally. Stobadine pretreated animals experienced hypercapnia, elevated arterial O2 and slight deeper acidemia (depending on dosage) as compared to control group. Respiratory compensation of metabolic acidosis was present in control group, but lacking in all stobadine pretreated animals. Stobadine at 2 mg/kg improves survival (Student p < 0.005, Mantel-Cox p < 0.05, Fischer p = 0.004). Stobadine has a protective effect on neurons and structures of blood-brain barrier (endothel, astrocytes, basement membrane) seen in electron microscope.

The nucleus of the solitary tract (NTS) was systematically explored in the alpha-chloralose-anesthetized rat for sites that elicited changes in mean arterial pressure (MAP) and heart rate (HR) during microinjections (20 nl) of phosphate-buffered saline (PBS; pH 7.2-7.4) or NaCl solutions containing various concentrations of NaCl (104-326 mM). Decreases in MAP (range 7-83 mmHg) and HR (range 10-70 bpm) were consistently elicited from sites in the caudal medial and commissural subnuclei of NTS. Microinjection of PBS or NaCl into other NTS subnuclei or area postrema did not elicit cardiovascular responses. Microinjection of LiCl in PBS elicited cardiovascular responses that were significantly smaller than those elicited by microinjection of NaCl in PBS at the same NTS site. Injections of either a hyperosmotic (400 mOsm/kg) or a hyposmotic (204 mOsm/kg) solution of mannitol into NaCl-sensitive sites did not elicit cardiovascular responses. Finally, most of the sites in NTS that elicited cardiovascular responses during microinjection of glutamate (1 M) did not respond to microinjections of PBS. Administration of atropine methyl bromide had no effect on the magnitude of the depressor response to injections of PBS into NTS, but significantly attenuated (32%) the HR response. Subsequent administration of the ganglionic blockers hexamethonium bromide or arfonad abolished both the depressor and bradycardic responses. These data suggest that within a restricted region of the caudal NTS there exists a pool of neurons sensitive to changes in extracellular Na+ concentrations that, when activated by the sodium, elicit vasodepressor responses as a result of sympathoinhibition and bradycardia as a result of vagal excitation and sympathoinhibition.

A 42-year-old male was hospitalized in the surgical ward for abdominal pain due to stenosis of the splenic flexure of the colon and abscess around the stenosis. After segmental colectomy, the patient received intravenous continuous infusion of trimetaphan (Arfonad) to control his blood pressure. Twenty hours later, he developed bradycardia and hypotension followed by syncope. An electrocardiogram revealed marked prolongation of the QT interval and a prominent U wave associated with sinus bradycardia and/or sinus pause with junctional rhythm. Torsades de pointes type polymorphic ventricular tachycardia was the cause of the syncope, which appeared to be pause-dependent long QT syndrome caused by the ganglionic blocking action of trimetaphan in the presence of a hyperadrenergic state.

Acetylcholine (ACh) is the major neurotransmitter released from the efferent fibers in the cochlea onto the outer hair cells (OHCs). The type of ACh receptor on OHCs and the events subsequent to receptor activation are unclear. Therefore we studied the effect of agonists and antagonists of the ACh receptor on isolated OHCs from the guinea pig. OHCs were recorded from in whole cell voltage and current clamp configuration. ACh induced an increase in outward K+ current (IACh) which hyperpolarized the OHCs. No desensitization to ACh application was observed. Cs+ replaced K+ in carrying the IACh. The IACh is Ca(2+)-dependent, time and voltage sensitive, and different from the IKCa induced by depolarization of the membrane potential. When tested at 100 microM, several agonists also induced outward current responses (acetylcholine > suberyldicholine > or = carbachol > DMPP) whereas nicotine, cytisine and muscarine did not. The IACh response to 10 microM ACh was blocked by low concentrations of traditional and non-traditional-nicotinic antagonists (strychnine > curare > bicuculline > alpha-bungarotoxin > thimethaphan) and by higher concentrations of muscarinic antagonists (atropine > 4-DAMP > AF-DX 116 > pirenzepine). Pharmacologically, the ACh receptor on OHCs is nicotinic.

A model which assesses the closed-loop interaction between heart period (HP) and arterial pressure (AP) variabilities and the influence of respiration on both is applied to evaluate the sources of low frequency (LF approximately 0.1 Hz) and high frequency (HF, respiratory rate approximately 0.25 Hz) in conscious dogs (n = 18) and humans (n = 5). A resonance of AP closed-loop regulation is found to amplify LF oscillations. In dogs, the resonance gain increases slightly during baroreceptor unloading (mild hypotension obtained with nitroglycerine (NTG) i.v. infusion, n = 8) and coronary artery occlusion ((CAO), n = 6), and it is abolished by ganglionic transmission blockade ((ARF), Arfonad i.v. infusion, n = 3). In humans, this gain is considerably increased by passive tilt. Different, possibly central, sources of LF oscillations are also evaluated, finding a strong rhythmic modulation of HP during CAO. At HF, a direct respiratory arrhythmia is dominant in dogs at control, while it is considerably reduced during CAO. On the contrary, in humans, a strong influence of respiration on AP is shown which induces a reflex respiratory arrhythmia. An index of the gain of baroreceptive response, alpha cl, was decreased by NTG and CAO, and virtually abolished by chronic arterial baroreceptive denervation (TABD, n = 4) and ARF.

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.

Experiments were done in the chloralose-anesthetized, paralyzed, and artificially ventilated rat to determine the cardiovascular responses elicited during chemical stimulation of bed nucleus of the stria terminalis (BST) and to investigate the components of the peripheral autonomic nervous system that mediate these responses. Neurons in BST were selectively stimulated by the microinjection (10-20 nl) of the excitatory amino acid L-glutamate (1 M). Stimulation of BST elicited decreases in mean arterial pressure (n = 105) of -6 to -55 mmHg. These depressor responses were on occasion (n = 60) accompanied by decreases in heart rate ranging between -10 and -40 beats/min. The largest depressor responses were consistently elicited from a crescent-shaped region of BST around the dorsolateral, lateral, and ventrolateral surfaces of the anterior commissure. Intravenous administration of the muscarinic receptor blocker, atropine methylbromide, had no affect on the magnitude of the mean arterial pressure and heart rate responses. On the other hand, administration (intravenous) of the nicotinic receptor blocker, hexamethonium bromide or arfonad, abolished both the depressor response and cardiac slowing during stimulation of BST. These data suggest that the BST depressor and the bradycardia responses are mediated by inhibition of both sympathetic vasoconstrictor fibers to the vasculature and cardioacceleratory fibers to the heart, respectively.

Six patients with massive hypertensive intracerebral hemorrhage and showing progression of consciousness-disturbance were treated by CT-guided stereotactic surgery. Serious complications or the age of these patients prevented evacuation of the hematomas by craniotomy under general anesthesia. The increase in the size of the intracerebral hematoma suggested by the progression of the consciousness-disturbance on admission was stopped by controlling the blood pressure. Stereotactic evacuation of the hematoma was performed using Komai's CT stereotactic apparatus 1-4 days after the onset. On the CT slice showing the maximum size of the hematoma, two target points showing each center or two circles which cover the greater part of the hematoma were determined, and then two drainage tubes were inserted into the two target points of the hematoma through two burr holes, and the hematoma was aspirated with a syringe. Postoperatively, every 12 hours, a solution of 60,000IU urokinase in 100 ml saline was irrigated into the hematoma cavity with aspiration of the hematoma, and finally 10 ml urokinase solution was left in the hematoma cavity. By 2-4 repetitions of this procedure, 83-91% of the estimated hematoma volume was evacuated using urokinase (120,000-240,000IU) for 1-2 days. Therefore, all of the cases showed improvement in the consciousness level without rebleeding or progression of serious complications. For large hypertensive intracerebral hematomas in aged patients or patients with serious complications, this stereotactic surgery can be carried out safely and rapidly through two drainage tubes using urokinase after 24 hours from the onset.

The central nervous system provides feedback regulation at several points within the peripheral auditory apparatus. One component of that feedback is inhibition of cochlear hair cells by release of acetylcholine (ACh) from efferent brainstem neurons. The mechanism of hair cell inhibition, and the character of the presumed cholinergic receptor, however, have eluded understanding. Both nicotinic and muscarinic, as well as some non-cholinergic ligands can affect the efferent action. We have made whole-cell, tight-seal recordings from short (outer) hair cells isolated from the chick's cochlea. These are the principal targets of cochlear efferents in birds. ACh hyperpolarizes short hair cells by opening a cation channel through which Ca2+ enters the cell and subsequently activates Ca(2+)-dependent K+ current (Fuchs & Murrow 1991, 1992). Both curare and atropine are effective-antagonists of cholinergic inhibition at 3 microM, whereas trimethaphan camsylate and strychnine block at 1 microM. The normally irreversible nicotinic antagonist, alpha-bungarotoxin, reversibly blocked the hair cell response, as did kappa-bungarotoxin. The half-blocking concentration for alpha-bungarotoxin was 26 nM. It is proposed that the hair cell AChR is a ligand-gated cation channel related to the nicotinic receptor of nerve and muscle.