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PubMed2004

Simultaneous quantitation of dexmedetomidine and glucuronide metabolites (G-Dex-1 and G-Dex-2) in human plasma utilizing liquid chromatography with tandem mass spectrometric detection.

Dexmedetomidine (Dex) (Precedex) is a novel lipophilic imidazole derivative with a high affinity for alpha-2 adrenergic receptors, which exhibits sedative, analgesic-sparing, and sympatholytic properties. The pharmacological effects and therapeutic benefits of this drug have drawn continued interest from the medical community. Here we report a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method to simultaneously measure the concentrations of dexmedetomidine and its glucoronide metabolites, G-Dex-1 and G-Dex-2, in human plasma samples. A solid-phase extraction method was developed to effectively extract Dex, G-Dex-1, and G-Dex-2 from plasma matrices. An isocratic chromatographic method was developed to achieve baseline separation of G-Dex-1 and G-Dex-2. The linear dynamic range evaluated was 19.08-1908.56 pg/mL for Dex, 65.17-6518.17 pg/mL for G-Dex-1, and 29.42-2943.28 pg/mL for G-Dex-2. The linear correlation coefficient (r) ranged from 0.9944-0.9979 for Dex, from 0.9966-0.9984 for G-Dex-1, and from 0.9939-0.9966 for G-Dex-2. The intra-assay coefficient of variation (CV) was between 2.5-12.5% for Dex, between 5.2-11.0% for G-Dex-1, and between 3.5-12.1% for G-Dex-2. The inter-assay precision of QC samples give % CV ranges from 6.5-9.3% for Dex, from 7.1-10.6% for G-Dex-1, and from 8.2-10.2% for G-Dex-2. The inter-assay accuracies ranged from 102.0-109.3% for Dex, from 95.4-105.6% for G-Dex-1, and from 98.7-115.0% for G-Dex-2.

Calibration↗

PubMed1993

Comparison of the effects of losulazine and reserpine on central aminergic neurons.

The purpose of this study was to examine the effects of both acute and chronic administration of the peripheral sympatholytic antihypertensive agent losulazine on central dopaminergic, noradrenergic, and 5-hydroxytryptaminergic neurons in the rat. For comparison, the acute effects of reserpine were also examined. Acute systemic administration of losulazine produced marked dose- and time-dependent decreases in dopamine and norepinephrine concentrations in regions outside the blood-brain barrier (i.e., the median eminence, intermediate lobe, and neural lobe), that were accompanied by an increase in plasma concentrations of prolactin and alpha-melanocyte-stimulating hormone. By comparison, losulazine caused a relatively modest, transient depletion of dopamine and norepinephrine (but not 5-hydroxytryptamine) in regions of the brain protected by the blood-brain barrier (i.e., the striatum, nucleus accumbens, and dorsomedial nucleus of the hypothalamus). In contrast to losulazine, acute systemic administration of reserpine caused a prolonged depletion of dopamine, norepinephrine, and 5-hydroxytryptamine in all brain and pituitary regions examined. These results suggest that regional differences in the response of aminergic neurons to acute administration of losulazine and reserpine reflect differences in the ability of these drugs to penetrate the blood-brain barrier. Chronic systemic administration of losulazine produced a similar decrease in dopamine and norepinephrine in the median eminence, intermediate lobe, and neural lobe, suggesting that tolerance does not develop to the ability of losulazine to deplete catecholamines in these regions. Chronic losulazine administration also decreased dopamine concentrations in the striatum, and norepinephrine concentrations in the dorsomedial nucleus, suggesting that losulazine may have cumulative effects on central catecholamine neurons terminating in these brain regions.

Animals↗

PubMed1991

Long-term treatment in arterial hypertension for protecting hypertrophic myocardium.

The cardiac organ manifestation of arterial hypertension comprises the myocardium itself with left-ventricular hypertrophy, the interstitium with perivascular and interstitial fibrosis, and the coronary circulation with disease of large and small coronary arteries. The consequences of the sum and interactions of these cardiac organ manifestations have an impact on left-ventricular systolic and diastolic function, the ischemic risk, and the occurrence of arrhythmias in hypertensive patients. As the prognosis of arterial hypertension is determined, to a considerable extent, by these cardiac complications, the aim of treatment of hypertensive heart disease is reversal of the myocardial hypertrophy in order to prevent later progression to hypertensive failure. A further goal of therapy is reversal of hypertensive coronary microangiopathy in order to improve the coronary reserve and to reduce the ischemic risk. Regression of hypertrophy can be induced by suitable antihypertensive drugs (calcium channel blockers of the dihydropyridine type, ACE inhibitors, and sympatholytic substances). While normal systolic function was maintained in the compensated stage of hypertensive hypertrophy and was not significantly influenced by antihypertensive therapy, diastolic function was impaired in a very early stage of arterial hypertension. Both the phase of isovolumic relaxation and the phase of early diastolic filling were imparied, while after long-term antihypertensive treatment with Ca-channel blockers of the dihydropyridine type or ACE inhibitors, only the latter one was improved. From preliminary results there is clinical evidence that hypertensive disease of small coronary arteries can be reversed after long-term antihypertensive treatment with a consequently improved coronary reserve and a reduced ischemic risk. Moreover, to what extent the prognosis of hypertensive heart disease can be improved by reversal of myocardial hypertrophy and disease of small coronary arteries is yet unknown.

Cardiomegaly↗

PubMed1991

Effects of nifedipine and moxonidine on cardiac structure in spontaneously hypertensive rats (SHR)--stereological studies on myocytes, capillaries, arteries, and cardiac interstitium.

Light and electron microscopic stereological studies were performed on the myocardium of spontaneously hypertensive rats (SHR) before and after treatment with nifedipine (27 mg/kg b.w./day) and the sympatholytic agent moxonidine (8 mg/kg b.w./day). The treated groups were compared with nontreated SHR and normotensive WKY (n = 10 in each group). When the therapy was started in 6-month old male SHR, blood pressure was increased and left ventricular hypertrophy had developed. On the other hand, pathologic changes of myocardial structure were not observed. After 3 months, the nontreated hypertensive rats showed cardiac fibrosis (volume density of fibrosis + 45%), activation and proliferation of interstitial cells (volume density of nonvascular interstitium + 240%), media hypertrophy of small arteries (total volume of arterial media in the left ventricle + 180%), reduced capillarization (length density of capillaries--11%), as well as focal degeneration of myocytes at the ultrastructural level. Both treatments showed similar effects on blood pressure, degree of hypertrophy, and cardiac structure. Blood pressure as well as degree of hypertrophy were significantly reduced (relative left ventricular weights: --25% and --16%). As far as myocardial fibrosis, capillarization, and regressive changes of myocytes are concerned a complete normalization was observed. Microarteriopathy and activation of nonvascular interstitial cells (first step in development of interstitial myocardial fibrosis) were significantly suppressed by therapy (total media volume --40%, volume density of nonvascular interstitium --38%), but the normal level of the normotensive control could not be maintained (+ 70%, + 111% vs WKY). This may be due to the slightly elevated systolic blood pressure despite therapy (+ 25%, vs WKY) or to hormonal factors in SHR which are independent of blood pressure. Since nifedipine and moxonidine are pharmacologically different drugs with different effects on sympathetic activity, one may cautiously conclude that increase in blood pressure itself is an important determinant of arterial, interstitial as well as myocellular alterations which are related to the pathogenesis of hypertensive heart muscle disease.

Animals↗

PubMed1975

The influence of topically applied bethanidine on intraocular pressure and pupil in the rabbit.

Bethanidine sulphate was administered topically to the eyes of conscious rabbits using a 0.5%, 1%, 2% and 5% solution of the drug. The intraocular pressures and pupil sizes were measured in the right treated and left control eyes at 0,1,2,3, 6 and 24 hrs. With all concentrations a pressure decrease with a maximum between 3 and 6 hrs after topical treatment occured. The 5% solution of bethanidine sulphate showed a delayed effect which was submaximal when compared to the 2% bethanidine solution. Using the 1% and 2% solution a ppressure decrease probably due to systemic action of the drug happened in the untreated control eyes. In all experiments the pressure responses had disappeared after 24 hrs in the treated and untreated eyes respectively. By means of the experimental conditions in this study no significant pupillary reactions were found after bethanidine application. The tension effect of 0.5% adrenaline borate remained essentially unchanged when repeated with additional 1% topical bethanidine. Some aspects of sympatholytic drug action on the intraocular pressure in the rabbit are discussed.

Animals↗

PubMed1979

Possible subdivision of postsynaptic alpha-adrenoceptors mediating pressor responses in the pithed rat.

Additional evidence has been obtained indicating a possible subclassification of postsynaptic alpha-adrenoceptors into alpha 1 - and alpha 2 -subtypes. The pressor responses to the alpha-adrenoceptor agonists L-phenylephrine and guanfacine were quantified after i.v. administration to pithed rats. The alpha-sympatholytic drug yohimbine (1 mg/kg) displaced both dose-response curves to the right, but the effect was greatest for guanfacine. After prazosin (0.1 mg/kg) a 53-fold shift to the right was noticed for the dose-response characteristic of L-phenylephrine. Prazosin antagonized the effect of only the higher doses of guanfacine. The findings indicate that L-phenylephrine and prazosin preferentially interact with alpha 1 -adrenoceptors as agonist and antagonist, respectively. Yohimbine proved less selective than prazosin, but preferentially blocks postjunctional alpha 2 -adrenoceptors in the vascular wall. The results obtained with guanfacine may be interpreted to indicate that this drug acts on alpha 2 -adrenoceptors at lower doses and additionally stimulates alpha 1 -adrenoceptors at higher ones. Preliminary findings with corynanthine and rauwolscine support this interpretation.

Animals↗

PubMed1983

Effect of diuretics and calcium antagonists on circulatory parameters and plasma catecholamines during mental stress.

In a model of mental stress the influence of nifedipine and hydrochlorothiazide on stress-induced changes in blood pressure, heart rate, and plasma catecholamines was studied in normal persons. The drugs were used to investigate whether substances with antihypertensive but no particular sympatholytic properties were capable of suppressing emotionally induced stress reactions. In all subjects blood pressure and heart rate increased significantly during mental stress, and this effect was not inhibited either by nifedipine or hydrochlorothiazide. In the hydrochlorothiazide group plasma noradrenaline levels were significantly higher than in controls in the resting state and during the stress reaction, whereas in the nifedipine group no difference was observed. It is concluded that nifedipine or hydrochlorothiazide do not inhibit emotional stress reactions in normotensive persons.

Adult↗

PubMed1981

Chronic treatment with the new potent vasodilator Ro 12-4713 in moderate to severe hypertension: effects on blood pressure, endocrine function, sodium and plasma volume.

The antihypertensive efficacy and endocrine profile of the new antihypertensive agent, Ro 12-4713, were evaluated in 23 patients (17 men and 6 women) with moderate to severe arterial hypertension. Following addition of Ro 12-4713 to pre-existing therapy with diuretics and beta-blockers or sympatholytics, blood pressure in most of the patients was normalized within one month by a daily dose of 60 to 120 mg. Heart rate was only slightly increased. Orthostatic hypotension was not observed. Weight gain or oedema formation occurred in 14 patients within the first four weeks, but could be controlled satisfactorily by intensified diuretic therapy. Increased hair growth occurred in most of the patients. After a mean duration of treatment of 2.8 months, plasma volume and plasma and urine sodium were unaltered, and plasma potassium was slightly decreased. Plasma renin activity was doubled, whereas plasma aldosterone concentrations were unaltered. Plasma norepinephrine levels were high before and increased only slightly during chronic Ro 12-4713 treatment, whereas urinary norepinephrine excretion was unchanged. Plasma and urinary epinephrine were unaltered by Ro 12-4713. Ro 12-4713 appears to be a potent vasodilator for the combination treatment of hypertension in men.

Adult↗

PubMed1982

Comparative evaluation of the new vasodilator carprazidil and minoxidil in the treatment of moderate to severe hypertension.

The efficacy and side effects of the new vasodilator carprazidil and the established vasodilator minoxidil were compared in 18 hypertensive patients inadequately controlled by 2 to 4 conventional drugs; the latter included diuretics, beta-blockers and/or sympatholytics and, in half the cases, vasodilators, such as hydralazine, diazoxide or the postsynaptic alpha-blocker prazosin. The vasodilators were withdrawn and, using a crossover design all patients received carprazidil (mean final dose 88 mg) and minoxidil (20 mg) for an average period of 5 to 6 months. The effects of the 2 agents appeared to be qualitatively and quantitatively similar. Both tended to cause sodium retention and an increase in heart rate, which required an increased dose of diuretic in one third of the cases or of a beta-blocker in a quarter. With this approach mean body weight and blood volume were not altered in the established phase of carprazidil or minoxidil treatment; heart rate and plasma norepinephrine tended to be only minimally increased, plasma renin was slightly increased, and plasma aldosterone and epinephrine were largely unchanged. Supine and upright blood pressure were reduced from initial values of 189/113 and 167/ 113 mm Hg, to 149/95 and 138/95 mm Hg (-18 and - 17%), respectively, during carprazidil, and to 154/95 and 141/96 mm Hg (-17 and - 15%) during minoxidil therapy. Hypertrichosis occurred with both agents in almost all patients, and limits their more prolonged use in females. No adverse side effects on haematological parameters, liver or renal function were observed, nor was antinuclear antibody detected. It is concluded that carprazidil and minoxidil are equivalent vasodilator agents in the treatment of severe hypertension, particularly in males.

Adult↗

PubMed1990

Subjective experiences associated with thermal biofeedback treatment of hypertension.

Reports of subjective experiences of 73 hypertensive patients who were treated with thermal biofeedback for hand warming were obtained over 16 treatment sessions. Most of the differential responding in subjective report occurred in the first 5 sessions. Differences in reports of throbbing were associated with medication status during treatment (presence of sympatholytic antihypertensive agent). From 4 to 9% of patients report negative subjective experiences at any one session. When short-term clinical successes (either elimination of medication or reduction of BP) were compared with short-term failures, it was found that successes reported more warmth, more likelihood of falling asleep, and more dreamlike experiences. The latter were more likely to occur suddenly for the successes. Correlational analyses revealed consistent positive associations between reports of warmth and relaxation with highest temperature achieved in the session and consistent negative associations between experiencing physical sensations and degree of temperature change within the session.

Adult↗

PubMed1980

[Comparison of oral diazoxide and minoxidil in refractory hypertension].

The efficacy and side effects of two potent vasodilatators, namely diazoxide and minoxidil given orally, were compared in 11 patients who had hypertension refractory to conventional drug treatment. The latter included diuretics, betablockers and/or sympatholytics, and either dihydralazine or prazosin. In a crossover approach, dihydralazine and prazosin were withdrawn and replaced by diazoxide or minoxidil. In nine patients the diazoxide phase preceded the minoxidil treatment, while in two it followed minoxidil treatment. Before introduction of the more potent vasodilators blood pressure averaged 181/107 mm Hg in the supine and 161/103 mm Hg in the upright position. Both, oral diazoxide (median dose 400 mg/d( and minoxidil (medium dose 17.5 mg/d) produced similar decreases (p < 0.02) in mean arterial pressure (-15%) in the supine and (-11 vs. -12%) in the upright position. They caused a comparable tendency for sodium retention and weight gain which could be satisfactorily controlled with increased diuretic therapy, except in one patient. Hypertrichosis occurred with both drugs, but tended to be somewhat milder with diazoxide. Electrocardiograms remained generally unchanged. Plasma glucose levels were increased during diazoxide treatment in six patients necessitating interruption of this therapy in four patients. It is concluded that the antihypertensive potency and most side effect of orally administered diazoxide are comparable to those of minoxidil, except for diazoxide-related hyperglycemia which may limit the use of this substance.

Blood Glucose↗

PubMed1988

Beta-blocker effects on sexual function in normal males.

Among the antihypertensives currently in use, the sympatholytic drugs (e.g., central alpha-agonists, beta-blockers) and diuretics are most commonly associated with sexual side effects. Previous reports of sexual dysfunction associated with these drugs have been based entirely on retrospective and self-report data. This is the first study to date to investigate beta-blocker effects on sexual function by means of physiological (NPT), subjective, and hormonal measures. Four beta-blockers with different ancillary properties (atenolol, metoprolol, pindolol, propranolol) were evaluated in a placebo-controlled, double-blind, Latin-square design. Thirty healthy male volunteers received, in counterbalanced order, each of the four drugs and 1 week of placebo testing. Significant drug effects on both total and free testosterone were found during treatment with all four beta-blockers, although it appeared that the nonselective drugs (pindolol, propranolol) were associated with the greatest reduction in testosterone. No significant effects were found on measures of cortisol or cholesterol. Analysis of NPT and self-report data yielded inconclusive results, perhaps due to the confounding effects of sleep disruption and the brief duration of treatment in this study. Inspection of individual records, however, suggested that some subjects may be especially vulnerable to sexual dysfunction in association with propranolol.

Adrenergic beta-Antagonists↗

PubMed1991

The sympathetic nervous system in hypertension due to unilateral renal artery stenosis in man.

The contribution of neurogenic mechanisms in maintaining hypertension was investigated in 13 patients with unilateral renal artery stenosis (twelve with normal, one with grossly elevated plasma renin levels) by determining the haemodynamic and hormonal responses to the centrally acting sympatholytic agent, clonidine. The same patients were studied after captopril to determine the dependency of their blood pressure on the direct peripheral effects of angiotensin-II. Sixteen patients with essential hypertension (normal plasma renin) were additionally studied after clonidine. After clonidine, blood pressure fell markedly in patients with renal artery stenosis (17 +/- 3%) and essential hypertension (18 +/- 2%). In both groups, clonidine lowered cardiac output by a reduction in stroke volume and heart rate; forearm vascular resistance was unchanged but digital skin vascular resistance fell. Plasma noradrenaline levels were normal in both groups and fell after clonidine; plasma renin activity and aldosterone levels were unchanged. After captopril, blood pressure fell minimally (5 +/- 3%) in renal artery stenosis patients; cardiac output fell and forearm and digital skin vascular resistance were unchanged. Plasma renin activity rose, plasma aldosterone fell and plasma noradrenaline was unchanged after captopril. In the patient with grossly elevated renin levels, blood pressure fell minimally (6%) after clonidine, but unlike others fell profoundly (37%) after captopril. We conclude that, in the majority of our renal artery stenosis patients, despite the elevated blood pressure, sympathetic nervous activity was not reduced. Central neurogenic mechanisms appear to play an important role in maintaining raised blood pressure. In the same patients the peripheral effects of angiotensin-II did not maintain vascular tone or hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Dihydroergotoxine, an ergot alkaloid without marked hypotensive effect, improves blood flow and metabolism in the underperfused canine myocardium.

Regional myocardial blood flow was assessed in 6 anaesthetized dogs using radiolabelled microspheres. Lactate, H+, and O2 content were measured in arterial and local venous blood, obtained from the area supplied by the circumflex branch of the left coronary artery (LCX). Constriction of LCX by 67% led to considerable hemodynamic changes indicative of depressed global myocardial function. A significant release of lactate from the underperfused part of the left ventricle was recorded. Infusion of 0.7 micrograms/kg dihydroergotoxine over a period of 5 min induced a decrease in heart rate, left ventricular dp/dt max, and cardiac output, a sustained increase in total peripheral and femoral resistance and a transient increase in mean arterial blood pressure. Dihydroergotoxine markedly reduced lactate release and even, in some cases, induced lactate uptake and led to a significant increase in the endocardial blood flow both in the underperfused and normally perfused left ventricle. It is concluded that dihydroergotoxine, due to its ability to reduce myocardial oxygen demand and owing to its alpha-sympatholytic activity, which is not accompanied by any marked decrease in arterial blood pressure, causes improvement in blood flow in the underperfused myocardium and a marked amelioration of the impaired metabolic processes.

Animals↗

PubMed1989

Prevalence of debrisoquine oxidation phenotypes in glaucoma patients.

The oxidation of debrisoquine, a sympatholytic antihypertensive agent, exhibits genetic polymorphism. The debrisoquine/4-OH-debrisoquine metabolic ratio (MR) separates the population to poor (PM, MR greater than 12.6) and extensive (EM, MR less than 12.6) metabolizers. 5-10% of the caucasians belong to the PM phenotype. The oxidation of many other drugs, like timolol, correlates with the debrisoquine phenotype. We determined the debrisoquine phenotype in 102 glaucoma patients. The majority of the patients was treated with ophthalmic timolol. Five patients were classified as PMs. However, two of them were on quinidine, a well known inhibitor of debrisoquine oxidation. The prevalence of debrisoquine PM phenotype in glaucoma patients was 2.9% (excluding patients on quinidine) or 4.9% (with patients on quinidine). The figures are slightly lower than the mean value reported for the normal Finnish population. However, both figures lay within the 95% confidence limits of the prevalence of PM phenotype in the normal Finnish population. The beta-blocking activity of oral timolol is increased in PMs. The significance of timolol oxidation phenotype during ocular timolol therapy warrants further investigation.

Cross-Sectional Studies↗

PubMed1986

The effect of anticholinergic drugs on the inner eye muscles.

Using 12 healthy volunteers, we tested the para-sympatholytic effects on the eye. In a randomized crossover double-blind trial, hyoscine-N-butylbromide was tested against saline. Before (20 or 40 mg IV) and up to 45 min after the injection, pupillar light reaction, accommodation, visual acuity, and nyctometer values were measured. The range of accommodation diminishes according to dosage: 9-15 min after the injection, the inhibition is maximum; 45 min after the injection, only a small effect remains, even using the 40 mg dosage. Pupillary reaction is little affected by either dosage, and the pupil diameters at the end of the reaction are only slightly greater after the injection of either dosage than after placebo injection. The time constant of the reaction remains unchanged. Visual acuity and nyctometer values remain unchanged under the influence of hyoscine-N-butylbromide. The results are discussed with respect to the potential ability of a patient to meet the requirements of modern traffic. According to our findings, there are no ophthalmologically-based reasons for an emmetropic person to assume impaired driving abilities after a single injection of hyoscine-N-butylbromide of up to 40 mg. If the accommodative capacity of a patient is impaired whose hyperopia is not fully corrected, the ability to drive in modern traffic may be impaired. After a single dose of 20 mg hyoscine-N-butylbromide (i.e., 1 ampule Buscopan), the impairment of even these patients does not last longer than about 45 min.

Accommodation, Ocular↗

PubMed1990

CNS side effects of centrally-active antihypertensive agents: a prospective, placebo-controlled study of sleep, mood state, and cognitive and sexual function in hypertensive males.

A prospective, placebo-controlled, comparative evaluation was conducted on two widely prescribed, sympatholytic antihypertensive agents with known CNS effects. In order to separately assess these effects in younger and older male hypertensives, patients were assigned to either of two treatment studies based on age. For study I, 24 males aged 31-59 (mean = 49.8; SD = 7.4) with mild hypertension (mean DBP = 100.2 mm Hg; SD = 8.0) received 3 months of treatment with propranolol (20-80 mg bid), clonidine (0.1-0.3 mg bid), or double-blind placebo in a counterbalanced, crossover design. For study II, 23 elderly hypertensive males (mean DBP = 102.6 mm Hg; SD = 8.2) aged 60-78 years (mean = 65.1; SD = 4.6) were randomized to propranolol (20-40 mg bid) or double-blind placebo therapy. Patients received cognitive testing, mood assessments, and all-night polysomnographic evaluations before and after each treatment period. Multivariate analysis of EEG sleep data was statistically significant for study I, with significant univariate effects on four of the six primary sleep variables: total sleep time was reduced, sleep maintenance decreased, REM latency increased, and percent total REM time was reduced. A similar MANOVA analysis for the effects of treatment on the sleep of older patients (study II) was not significant. However, propranolol administration was found to be associated with a significant decline in cognitive performance in these patients. Significant mood effects were observed with each of the study drugs, and nocturnal penile tumescence (NPT) was significantly decreased in both younger and older patients. Overall, this research suggests that distinct patterns of CNS effects are associated with each of the antihypertensive agents studied.

Adult↗

PubMed1997

Does sympathetic activation blunt nitric oxide-mediated hyperemia in the human forearm?

To determine if the vasodilating substance nitric oxide (NO) interferes with the ability of sympathetic nerves to regulate blood flow in humans, forearm blood flow (FBF) was measured during brachial artery infusions of acetylcholine (ACh) to evoke endothelial NO release, and during infusions of the NO donor nitroprusside (NTP) in five healthy volunteers. Sympathetic activity was increased by application of lower body suction and antagonized by brachial artery infusions of phentolamine. In the control condition, FBF was 2.4 +/- 0.4 ml/100 ml per min and rose by 16.9 +/- 3.6 ml/100 ml per min during ACh at 16 micrograms/min and by 17.0 +/- 4.3 ml/100 ml per min at 64 micrograms/min. With suction, FBF was 1.7 +/- 0.6 ml/100 ml per min (p < 0.05 versus control) and rose by 11.4 +/- 3.2 ml/100 ml per min during ACh at 16 micrograms/min (p < 0.05 versus control). After phentolamine, FBF was 3.8 +/- 0.5 ml/100 ml per min at baseline (p < 0.05 versus control) and the increases in flow with ACh at either 16 or 64 micrograms/min were identical to control. During the control NTP trial, FBF rose by 6.3 +/- 1.1 ml/100 ml per min with NTP at 2.5 micrograms/min and by 12.1 +/- 1.4 ml/100 ml per min at 10 micrograms/min. Suction blunted and phentolamine augmented the increases in flow with NTP by approximately 50% (p < 0.05). Due to the unexpected results with ACh, the effects of suction and pharmacological sympathectomy with both phentolamine and bretylium on ACh-mediated dilation were evaluated with lower doses of ACh (8 and 32 micrograms/min) in six additional studies. Again, altered sympathetic activity had inconsistent effects on the rise in FBF with ACh administration. The effects of altered sympathetic activity on the blood flow responses to NTP indicate that sympathetic activity can modulate NO-mediated vasodilation, suggesting that NO does not have a major sympatholytic effect in the human forearm. That sympathetic activity did not consistently alter ACh-mediated vasodilation suggests that vasodilating mechanisms, in addition to NO release, can be activated by arterial administration of ACh in the human forearm.

Acetylcholine↗