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At least 19 recordsLinked to original sources

PubMed1981

Comparison of the effects of methoxamine with those of noradrenaline and phenylephrine on single cerebral cortical neurones.

1 The technique of microelectrophoresis was used to compare the actions of methoxamine, noradrenaline and phenylephrine on single neurones in the somatosensory cerebral cortex of the rat.2 Methoxamine evoked only excitatory responses on cortical neurones. The methoxamine-sensitive cells were also excited by phenylephrine; cells excited by methoxamine could either be excited or depressed by noradrenaline.3 Methoxamine appeared to be less potent than either noradrenaline or phenylephrine in evoking excitatory responses.4 Responses to methoxamine had a slower time course than responses to either noradrenaline or phenylephrine, both the latencies to onset and the recovery times being longer for responses to methoxamine than for responses to noradrenaline or phenylephrine.5 When the absolute mobilities of methoxamine, noradrenaline and phenylephrine were compared using an in vitro method, no significant differences were found between the mobilities of the three ionic species, suggesting that the three drugs have similar transport numbers. Thus the differences in potency between methoxamine and the other two drugs, and the difference between the time courses of responses to methoxamine and the other two drugs, are presumably of biological origin.6 The alpha-adrenoceptor antagonist, phenoxybenzamine, antagonized equally excitatory responses to methoxamine and noradrenaline, and responses to methoxamine and phenylephrine, without affecting responses to acetylcholine.7 When responses to methoxamine and noradrenaline and responses to methoxamine and acetylcholine were summated on the same cells, the net responses were smaller than those expected on the basis of additive effects; the deviation from additivity was greater in the case of the summation of responses to methoxamine and noradrenaline than in the case of summation of responses to methoxamine and acetylcholine. This observation is consistent with the hypothesis that the interaction between methoxamine and noradrenaline follows the model of competitive dualism, whereas the interaction between methoxamine and acetylcholine follows the model of functional synergism.8 The results suggest that methoxamine may act as a partial agonist at excitatory alpha-adrenoceptors on cerebral cortical neurones.

Animals↗

PubMed1999

Enhancement of bistability in spinal motoneurons in vivo by the noradrenergic alpha1 agonist methoxamine.

Enhancement of bistability in spinal motoneurons in vivo by the noradrenergic alpha1 agonist methoxamine. Like many types of motoneurons, spinal motoneurons in the adult mammal can exhibit bistable behavior. This means that short periods of excitatory input can initiate long periods of self-sustained firing and that equally short periods of inhibition can return the cell to the quiescent state. Usually, the presence of one of the monoamines (either serotonin or norepinephrine) is required for spinal motoneurons to express bistable behaviors. Because the decerebrate cat preparation has tonic activity in monoaminergic fibers that originate in the brain stem and project to spinal motoneurons, these cells sometimes exhibit bistable behavior. However, exogenous application of the noradrenergic alpha1 agonist methoxamine greatly enhances bistable behavior in the decerebrate. The goal of this study was to identify the mechanisms of this action of methoxamine. The total persistent inward current (IPIC) in spinal motoneurons in the decerebrate cat was measured from I-V functions generated by triangular voltage commands applied using discontinuous single electrode voltage clamp. The effect of methoxamine on IPIC was assessed by comparing its properties in a control cell sample without methoxamine to its properties in a sample of cells obtained after application of methoxamine. In most experiments, at least one cell was obtained from each sample. Our results showed that methoxamine approximately doubled the amplitude of IPIC without changing its onset voltage, its offset voltage, or its persistence. The reduced amplitude was a consistent finding within experiments and so was unlikely to be caused by interanimal variability. In addition, methoxamine depolarized motoneurons without altering their input conductances, so that a smaller amount of current was required to reach the onset voltage of IPIC. These effects of methoxamine were approximately equal in all cells. As a result of these changes, methoxamine greatly enhanced the tendency for motoneurons to become bistable. It is proposed that the methoxamine-induced increase in the amplitude of IPIC is effective in enhancing the duration of bistable firing because this increase makes IPIC more resistant to the deactivating effects of the afterhyperpolarizations between spikes.

Adrenergic alpha-Agonists↗

PubMed1982

Effects of alpha-adrenoceptor antagonists administered intraventricularly on central hypotensive action of clonidine and on central hypertensive action of methoxamine in rabbits.

In urethane-anesthetized rabbits blood pressure was lowered by intraventricular clonidine (30 microgram) and increased by intraventricular methoxamine (1 mg). Clonidine is well known to cause hypotension by acting on central alpha-adrenoceptors. The hypertensive effect of intraventricular methoxamine was not observed in cord-sectioned rabbits, in guanethidine-treated adrenalectomized rabbits and in phentolamine-treated rabbits, indicating the effect was central in origin. These responses to intraventricularly administered clonidine and methoxamine were examined in rabbits pretreated intraventricularly with various alpha-adrenoceptor antagonists believed to exhibit preference for alpha 1- or alpha 2-adrenoceptors in the peripheral tissues. Pretreatment with 250 microgram of yohimbine and with 500 microgram of piperoxan inhibited the clonidine hypotension, but pretreatment even with 2 mg of either of these drugs did not affect the methoxamine hypertension. In contrast, pretreatment with 8 microgram of prazosin inhibited the methoxamine effect, whereas pretreatment even with 1 mg of prazosin did not affect the clonidine effect. Pretreatment with 8 microgram of thymoxamine inhibited the methoxamine effect, while it was necessary to increase the doses for each drug up to 4 to 8 times to oppose the clonidine effect. Pretreatment with 2 mg of labetalol inhibited the methoxamine effect but was ineffective against clonidine. Pretreatment with 500 microgram of phentolamine was effective in antagonizing the clonidine effect but twice the dose was needed to inhibit the methoxamine effect. From the findings that the hypertensive effect of methoxamine and the hypotensive effect of clonidine were inhibited differently by various alpha-adrenoceptor antagonists and that the selectivity of these antagonists for the methoxamine and clonidine effect is similar, respectively, to that for alpha 1- and alpha 2-adrenoceptors in the peripheral tissues, we concluded that the methoxamine hypertension and the clonidine hypotension are due to the stimulation of alpha 1- and alpha 2- adrenoceptors in the brain, respectively.

Adrenergic alpha-Agonists↗

PubMed1975

Frequency-dependence of the positive inotropic effect of methoxamine and naphazoline mediated by alpha-Adrenoceptors in the isolated rabbit papillary muscle.

Under the conditions of different stimulation frequencies the inotropic effects of the alpha-adrenoceptor stimulationg agents, methoxamine, naphazoling and oxymetazoline were studied on the isolated rabbit papillary muscle. 1. On the papillary muscle stimulated at 0.5 Hz methoxamine in concentrations from 10(-5)M caused a significant and dose-dependent positive inotropic effect. At 10(-3)M methoxamine decreased the developed tension. With increasing frequency of stimulation (0.5--1--1.5Hz), the positive inotropic effect became smaller, while the negative inotropic one was more pronounced. The time course of the disappearance of the negative inotropic effect of methoxamine by washout differed from that of the positive inotropic effect: the negative component disappeared within 30 min, whereas the positive one lasted for about 100 min. The positive inotropic effect of noradrenaline (10(-6)M), in contrast ot that of methoxamine, was not influenced by the frequency under the same conditions of stimulation. Also naphazoline (10(-5)M) caused a significant positive inotropic effect on the papillary muscle stimulated at 0.5 Hz, while oxymetazoline induced exclusively a negative inotropic effect. 2. The positive inotropic effect of metoxamine (10(-4)M) as well as of naphazoline (10(-5)M) evoked at a frequency of 0.5 Hz was abolished by phentolamine (10(-6)M). Methoxamine (10(-4)M) induced a significant negative inotropic effect in the presence of phentolamine. Phentolamine antagonized the positive inotropic effect of methoxamine in a non-competitive manner: the pD2-value was 7.76. 3. In the presence of methoxamine (10(-4)M) the developed tension in the lower range (0.05--1 Hz) of the frequency-force relationship was enhanced, while that in the higher range (greater that 1.5 Hz) was decreased. The enhancement was abolished by phentolamine (10(-6)M). 4. Papaverine (2x10(-5)M) did not affect the positive inotropic effect of methoxamine. 5. The present results show that methoxamine and naphazoline induced a positive inotropic effect via alpha-adrenoceptor in the ventricular myocardium of the rabbit. These effects were caused only at low, but not at high frequencies of stimulation.

Animals↗

PubMed1994

Dissociation of the positive inotropic effect of methoxamine from the hydrolysis of phosphoinositide in rabbit ventricular myocardium: a comparison with the effects of phenylephrine and the subtype of the alpha-1 adrenoceptor involved.

The effects of methoxamine on the contractile force and the hydrolysis of phosphoinositide (PI) were examined and compared with those of phenylephrine in the rabbit ventricular myocardium. Methoxamine, as well as phenylephrine, caused the concentration-dependent accumulation of [3H]inositol monophosphate in rabbit ventricular slices. The maximal responses of the two drugs were equivalent, but methoxamine was approximately 10 times less potent than phenylephrine. The extents and time courses of accumulation of [3H]inositol phosphates induced by 10(-4) M methoxamine and 10(-5) M phenylephrine were very similar, whereas the positive inotropic effect (PIE) of methoxamine developed much more slowly and its extent was much smaller than that of phenylephrine. The maximal inotropic response achieved with 10(-4) M methoxamine was one third of that achieved with phenylephrine. The PIE of methoxamine induced by a single administration was markedly attenuated when the same dose was given by cumulative administration. The concentration-response curve for the PIE of phenylephrine was shifted to the right and downward in the presence of methoxamine in a concentration-dependent manner. These results indicate that methoxamine accelerates the hydrolysis of PI as effectively as does phenylephrine, but it has a smaller PIE because of its depressant effect on the process subsequent to acceleration of the hydrolysis of PI induced by alpha-1 adrenoceptors. The accumulation of [3H]inositol 1,4,5-trisphosphate induced either by methoxamine or by phenylephrine was abolished by 10(-5) M chlorethylclonidine, whereas the maximal inhibition induced by WB 4101 was 60%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

L-Erythro-methoxamine is more potent than phenylephrine in effecting contraction of internal anal sphincter in vitro.

BACKGROUND: Topical phenylephrine has been shown to increase resting anal canal pressure in normal and incontinent individuals. However, high concentrations of gel (10-40 per cent) are required that may cause local side-effects. The aim of this study was to determine whether methoxamine, another alpha-1-adrenoceptor agonist, might be a more potent alternative to phenylephrine. METHODS: Porcine internal anal sphincter (IAS) tissue was cut into strips, suspended in a superfusion organ bath and allowed to equilibrate. Strips were subjected to each drug under test for 20 s, sufficient to obtain stable tone. Phenylephrine, methoxamine (1 : 1 : 1 : 1 ratio of its four isomers) and each of the individual isomers of methoxamine were evaluated in turn. RESULTS: In vitro, methoxamine racemate and phenylephrine were similarly potent in causing contraction of IAS strips (mean(s.e.m.) dose giving half maximal effect (EC(50)) at 74.7(16.5) versus 58.3(13.4) micro M respectively; P = 0.443). However, one of the methoxamine isomers, L-erythro-methoxamine (EC(50) 17.6(3.7) micro M), was significantly more potent than the other three isomers, methoxamine racemate and phenylephrine (P = 0.002). CONCLUSION: L-Erythro-methoxamine is four times more potent than phenylephrine and is a possible treatment for incontinence. Trials are under way to examine the efficacy of L-erythro-methoxamine in vivo.

Adrenergic alpha-Agonists↗

PubMed1999

Non-specific action of methoxamine on Ito, and the cloned channels hKv 1.5 and Kv 4.2.

The alpha1-adrenoceptor agonist methoxamine acted independently of receptor activation to reduce Ito and the sustained outward current in rat ventricular myocytes, and hKv 1.5 and Kv 4.2 cloned K+ channel currents. Two hundred microM methoxamine reduced Ito by 36% in the presence of 2 microM prazosin, and by 37 and 38% after preincubation of myocytes with either N-ethylmaleimide or phenoxybenzamine (n=6). The EC50 values at +60 mV for direct reduction of Ito, hKv 1.5, and Kv 4.2 by methoxamine were 239, 276, and 363 microM, respectively, with Hill coefficients of 0.87-1.5. Methoxamine accelerated Ito and Kv 4.2 current inactivation in a concentration- and voltage-dependent manner. Apparent rate constants for methoxamine binding and unbinding gave Kd values in agreement with EC50 values measured from dose-response relations. The voltage-dependence of block supported charged methoxamine binding to a putative intracellular site that sensed approximately 20% of the transmembrane electrical field. In the presence of methoxamine, deactivating Kv 4.2 tail currents displayed a distinct rising phase, and were slowed relative to control, such that tail current crossover was observed. These observations support a dominant mechanism of open channel block, although closed channel block could not be ruled out. Single-channel data from hKv 1.5 patches revealed increased closed times with blank sweeps and decreased burst duration in the presence of drug, and a reduction of mean channel open time from 1.8 ms in control to 0.4 ms in 500 microM methoxamine. For this channel, therefore, both open and closed channel block appeared to be important mechanisms for the action of methoxamine.

Adrenergic alpha-Agonists↗

PubMed1992

Improvement in exercise performance by inhalation of methoxamine in patients with impaired left ventricular function.

BACKGROUND: Bronchial hyperresponsiveness to cholinergic stimuli such as the inhalation of methacholine is common in patients with impaired left ventricular function. Such hyperresponsiveness is best explained by cholinergic vasodilation of blood vessels in the small airways, with extravasation of plasma due to high left ventricular filling pressure. Because this vasodilation may be prevented by the inhalation of the vasoconstrictor agent methoxamine, we studied the effect of methoxamine on exercise performance in patients with chronic left ventricular dysfunction. METHODS: We studied 19 patients with a mean left ventricular ejection fraction of 22 +/- 4 percent and moderate exertional dyspnea. In the first part of the study, we performed treadmill exercise tests in 10 patients (group 1) at a constant maximal workload to assess the effects of 10 mg of inhaled methoxamine on the duration of exercise (a measure of endurance). In the second part of the study, we used a graded exercise protocol in nine additional patients (group 2) to assess the effects of inhaled methoxamine on maximal exercise capacity and oxygen consumption. Both studies were carried out after the patients inhaled methoxamine or placebo given according to a randomized, double-blind, crossover design. RESULTS: In group 1, the mean (+/- SD) duration of exercise increased from 293 +/- 136 seconds after the inhalation of placebo to 612 +/- 257 seconds after the inhalation of methoxamine (P = 0.001). In group 2, exercise time (a measure of maximal exercise capacity) increased from 526 +/- 236 seconds after placebo administration to 578 +/- 255 seconds after methoxamine (P = 0.006), and peak oxygen consumption increased from 18.5 +/- 6.0 to 20.0 +/- 6.0 ml per minute per kilogram of body weight (P = 0.03). CONCLUSIONS: The inhalation of methoxamine enhanced exercise performance in patients with chronic left ventricular dysfunction. However, the improvement in the duration of exercise at a constant workload (endurance) was much more than the improvement in maximal exercise capacity assessed with a progressive workload. These data suggest that exercise-induced vasodilation of airway vessels may contribute to exertional dyspnea in such patients. Whether or not inhaled methoxamine can provide long-term benefit in patients with heart failure will require further study.

Administration, Inhalation↗

PubMed1989

Differential inhibitory effects of nitroglycerin on contractile responses to the alpha-adrenoceptor agonists, methoxamine and clonidine, in rabbit aorta.

The vasoinhibitory action of nitroglycerin was examined on contractile responses to methoxamine and clonidine in isolated rabbit aorta. Nitroglycerin at 10(-5) M, but not 10(-6)-10(-8) M, shifted the concentration response curve for methoxamine to the right. Nitroglycerin (10(-8)-10(-5) M), however, noncompetitively inhibited responses to clonidine in a concentration dependent manner. Nitroglycerin (10(-5) M) had no effect on responses to potassium (10-70 mM), but slightly inhibited responses to Ca2+ (0.1-5 mM) in a Ca2+-free medium containing potassium. Nifedipine (10(-6) and 10(-5) M), however, almost abolished responses to both potassium and Ca2+ but had no effect on responses to either methoxamine or clonidine. Agonist-antagonist interactions using prazosin and yohimbine revealed that responses to both methoxamine and clonidine were due to activation of alpha 1-adrenoceptors. Results with phenoxybenzamine suggested that the aorta has more receptor reserve for methoxamine than for clonidine. Furthermore, in tissues pretreated with phenoxybenzamine, nitroglycerin (10(-5) M) inhibited the maximal contractile response to methoxamine (3 x 10(-4) M). The maximal response to clonidine in tissues pretreated with phenoxybenzamine was not affected by nitroglycerin (10(-8) M). Nitroglycerin (10(-9)-10(-4) M) had greater inhibitory effect on residual responses to clonidine (10(-5) M) than that to methoxamine (10(-5) M) in a Ca2+-free medium containing EGTA. The contractile responses to Ca2+ (2 mM) in a Ca2+-free medium containing EGTA, nifedipine, and either methoxamine (5 x 10(-7) M) or clonidine (3 x 10(-7) M) were inhibited by nitroglycerin (10(-9) - 10(-5) M). The effect of nitroglycerin was greater on responses in the presence of clonidine than methoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

Neurohypophyseal and pituitary-adrenocortical responses to the alpha 1 agonist methoxamine in humans.

To test the hypothesis that the release of neurohypophyseal peptides into plasma in humans is stimulated by a central nervous system (CNS) alpha 1 adrenergic mechanism, we measured the responses of arginine vasopressin (AVP) and oxytocin (OT) to intravenous methoxamine, an alpha 1 agonist which enters the CNS following peripheral administration. The potential confound of baroreceptor inhibition of AVP release by the pressor effect of methoxamine was addressed by measuring the plasma AVP response to infusion of norepinephrine (NE), an alpha 1 agonist which does not enter the CNS and which produced an equivalent pressor effect. We also assessed the pituitary adrenocortical system responses to methoxamine and norepinephrine infusions by measuring plasma ACTH and cortisol concentrations. In addition, plasma NE and epinephrine were measured. Methoxamine, but not NE, increased plasma AVP compared to placebo infusion. Neither methoxamine nor NE affected plasma OT. The AVP elevation was delayed until more than 60 min after the methoxamine infusion began and the peak AVP level occurred 30 min after cessation of the infusion. In contrast, ACTH and cortisol increased early during methoxamine infusion and ACTH returned to baseline promptly after the infusion ceased. Although it is possible that the AVP response to methoxamine reflected stimulation of AVP release at a CNS level, it is also possible that the AVP increase represented a rebound response to withdrawal of methoxamine.

Adrenal Cortex↗

PubMed1993

Methoxamine inhibits noradrenaline release through activation of alpha 1- and alpha 2-adrenoceptors in rat isolated kidney: involvement of purines and prostaglandins.

The effects of the alpha 1-adrenoceptor agonist methoxamine and the alpha 2-adrenoceptor agonist bromoxidine (UK 14034) on the stimulation induced (S-I) outflow of radioactivity at 100 Hz/6 pulses from rat isolated kidney preincubated with 3H-noradrenaline were investigated. Methoxamine (0.3-30 mumol/l) inhibited S-I outflow of radioactivity to a maximum of 83% with a pEC50 of 5.85 (5.71-5.94). UK 14304 (0.0003-0.3 mumol/l) inhibited S-I outflow of radioactivity to a maximum of 99% with a pEC50 of 8.35 (8.26-8.47). alpha-Adrenoceptor antagonist affinities (pKD) against methoxamine and UK 14304 at prejunctional alpha-adrenoceptors were determined. The concentration response curve of methoxamine was shifted to the right by the alpha 1/alpha 2B-adrenoceptor antagonist prazosin (0.1 mumol/l) with a pKD of 7.41 and that of UK 14304 by prazosin (0.3 mumol/l) with a pKD of 6.24. The alpha 2-adrenoceptor antagonist rauwolscine (0.1 mumol/l) shifted the concentration response curve of UK 14304 potently to the right with a pKD of 8.34. The concentration response curve of methoxamine was shifted also to the right by rauwolscine (0.1 mumol/l) and the alpha 2-adrenoceptor antagonist idazoxan (0.1 mumol/l), however, both antagonists suppressed the maximum response of methoxamine to 46% and 56%, respectively. A ten times lower concentration of rauwolscine (0.01 mumol/l) did not shift the concentration response curve of methoxamine but the inhibitory effect of methoxamine still reached only a maximum of 59%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1993

Methoxamine enhances the release of endogenous noradrenaline from rabbit ear artery: possible involvement of ATP.

The effect of methoxamine, an alpha 1-adrenoceptor agonist, on the electrically-evoked release of endogenous noradrenaline was examined in the isolated rabbit ear artery. Noradrenaline was quantified by high performance liquid chromatography-electrochemical detection. The release of adenine nucleotides and nucleosides by methoxamine was examined using high performance liquid chromatography-fluorescence detection. The release of noradrenaline evoked by electrical field stimulation (EFS) at 4 Hz was reduced by tetrodotoxin 0.3 mumol/l and clonidine 1 mumol/l by approximately 80% and 50%, respectively. On the other hand, methoxamine at 10 but not 1 mumol/l enhanced the release of noradrenaline to approximately twice the control, and the enhancement was prevented by prazosin 1 mumol/l. The facilitatory action of methoxamine was also abolished after desensitization of P2-purinoceptors by alpha,beta-methylene ATP 30 mumol/l as well as by the presumed P2-purinoceptor antagonist suramin given at 10 mumol/l. Exogenous ATP 10 mumol/l significantly enhanced the EFS-evoked release of noradrenaline, and the enhancement was abolished by alpha,beta-methylene ATP and suramin. None of the drugs changed the spontaneous outflow of noradrenaline. These results indicate that endogenous ATP, acting at prejunctional purinoceptors, may participate in the facilitatory effect of methoxamine. Indeed, methoxamine 10 mumol/l significantly enhanced the spontaneous outflow of ATP and, less so, ADP. The methoxamine evoked release of ATP and ADP was antagonized by prazosin 1 mumol/l. It is concluded that methoxamine releases endogenous ATP from postjunctional sites which then, via prejunctional purinoceptors, facilitates action potential-evoked release of noradrenaline in rabbit ear artery.

Adenine Nucleotides↗

PubMed1993

Methoxamine-induced rhythmic activity in rabbit anococcygeus muscle.

1. Methoxamine 0.5 microns induced an extremely regular rhythmic activity in isolated rabbit anococcygeus muscle. 2. Prazosin had an inhibitory effect on methoxamine-induced rhythmic contractions. IC50 of prazosin was 7.94 nM. 3. The methoxamine-induced contractions are dependent on extracellular calcium and can be inhibited by the omission of calcium from media or the introduction of verapamil (IC50 = 0.11 microM) or nifedipine (IC50 = 0.21 microM). 4. Application of reserpine made the preparations 40-fold more sensitive to methoxamine. 5. It can be concluded that rhythmic contractions produced by methoxamine are mediated through stimulatory action of methoxamine on alpha-I adrenoceptors and depend on extracellular calcium. 6. Lithium made the muscle more sensitive to methoxamine action. In preincubated muscles with 1, 3 and 5 mM lithium the initiation of contractions occurred at 1.5 x 10(-7), M, 5 x 10(-8) M and 1.5 x 10(-8) M of methoxamine, respectively.

Adrenergic alpha-Agonists↗

PubMed1989

Randomized study of epinephrine versus methoxamine in prehospital ventricular fibrillation.

Experimental data suggest that a pure alpha-agonist, such as methoxamine, may improve the outcome of patients in ventricular fibrillation. A double-blind, randomized, prospective study was conducted in a paramedic system comparing the use of methoxamine with epinephrine in enhancing conversion of ventricular fibrillation while otherwise following American Heart Association protocols. One hundred two patients in ventricular fibrillation not responding to initial defibrillations with a pulsatile rhythm were randomized into one of two groups, each containing 51 patients. Equipressor doses of epinephrine (0.5 mg) and methoxamine (5 mg) were given intravenously and repeated according to American Heart Association guidelines. The mean age, sex ratio, and mean paramedic response times were comparable for the two groups. The mean time at scene until conversion was 22 +/- 10 minutes for methoxamine and 17 +/- 7 minutes for epinephrine (P = NS). The methoxamine group received 3.1 +/- 1.4 doses as compared with 2.8 +/- 1.3 doses for the epinephrine group (P = NS). Conversion rate, defined as the percentage of patients who developed a pulse during resuscitation, was 27.5% for the methoxamine group and 49.0% for the epinephrine group (P less than or equal to .03). Successful resuscitation, defined as the conveyance of a patient to an emergency department with a pulse and rhythm, was 17.7% for the methoxamine group and 39.2% for the epinephrine group (P less than or equal to .02). Save rate, defined as the percentage of patients discharged alive after hospitalization, was 7.8% for the methoxamine group and 19.6% for the epinephrine group (P less than or equal to .07).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials as Topic↗

PubMed1985

Inhibition of methoxamine-induced bronchoconstriction by ipratropium bromide and disodium cromoglycate in asthmatic subjects.

We compared the effects of pretreatment with saline, ipratropium bromide, and disodium cromoglycate (DSCG) on bronchoconstriction induced by methoxamine--an alpha-adrenoceptor agonist, in asthmatic subjects. All 12 patients bronchoconstricted in response to methoxamine after saline. The PD20 (the dose of methoxamine causing a 20% fall in forced expiratory volume in 1 s [FEV1]) ranged from 0.3-18 mumol. Ipratropium bromide (200 micrograms administered by aerosol) significantly inhibited (P less than 0.05) the response to methoxamine in all patients without producing significant changes in the mean baseline lung function. The mean PD20 for methoxamine after saline was 6.8 mumol and 95% confidence limits (CL) were 3.6, 12.7 mumol. The mean PD20 for methoxamine after ipratropium bromide was 35.4 (95% CL 28.8, 43.6) mumol. DSCG also produced significant (P less than 0.05) shifts to the right in the methoxamine dose response curves, but did not affect resting airway calibre as measured by the FEV1. The mean PD20 for methoxamine increased from 3.3 mumol (95% CL 1.1, 10.0 mumol) after saline to 25.1 mumol (95% CL 14.1, 44.6) after DSCG pretreatment. These findings suggest that alpha-adrenoceptors in the airways of asthmatic subjects may be located at sites other than smooth muscle--possibly on mast cells but more likely on nerve endings and/or parasympathetic ganglia.

Adult↗

PubMed1990

The effects of methoxamine and epinephrine on survival and regional distribution of cardiac output in dogs with prolonged ventricular fibrillation.

This study compares the effects of methoxamine, a pure alpha 1-agonist, and epinephrine on cerebral and myocardial blood flow, central hemodynamics, and survival in a randomized placebo-controlled fashion during prolonged ventricular fibrillation (VF) in a canine model. Twenty-four anesthetized and ventilated adult mongrel dogs were instrumented for regional blood flow determinations using radio-labeled microspheres. The dogs were randomized to receive either 20 mg of methoxamine as a single intravenous bolus or repeated boluses of 0.02 mg/kg of epinephrine, 0.2 mg/kg of epinephrine, or normal saline solution placebo beginning at three minutes following induction of VF and initiation of closed chest cardiac massage (CCCM). Organ blood flow measurements were determined during normal sinus rhythm and after five and 20 minutes of VF. All six dogs receiving methoxamine were successfully resuscitated in contrast to only one in each of the epinephrine-treated groups and none of the dogs receiving placebo (p less than .01). Although epinephrine was associated with significantly higher blood pressures than placebo during cardiopulmonary resuscitation (CPR), blood pressures achieved with methoxamine were significantly higher than those observed in the other three treatment groups (p less than .001). Cerebral blood flow was significantly higher with both methoxamine and high-dose epinephrine (p less than .05). Mean left and right ventricular myocardial flows were highest with methoxamine but this did not achieve statistical significance. In contrast, organ flows measured in the animals receiving the lowest dose of epinephrine were not significantly higher than those associated with placebo. Cardiac output after 20 minutes of CPR was significantly lower with high-dose epinephrine than with methoxamine or placebo (p less than .05). Our results suggest that methoxamine significantly improves regional cerebral blood flow and survival during CPR and although high-dose epinephrine is associated with comparable improvements in regional cerebral blood flow, this treatment is associated with deterioration in central hemodynamics during prolonged VF and does not enhance survival.

Animals↗

PubMed1993

Differential attenuation of the responses to adenosine and methoxamine in isolated rabbit aorta.

This article describes the functional antagonism between the responses to adenosine (through adenosine A2 receptors) and methoxamine (through alpha-1 adrenoceptors) in the adventitia- and endothelium-denuded isolated rabbit thoracic aorta. Rings were contracted with different concentrations of methoxamine and cumulative relaxation concentration-response curves (CRC) to adenosine were constructed. This protocol allowed the authors to rearrange the same data, which yielded contractile CRCs to methoxamine in the presence of adenosine. A 32-fold increase in the [methoxamine] markedly attenuated the maximal response to adenosine (80% decrease) and shifted the CRC to adenosine 10-fold to the right. By contrast, a 3000-fold increase in the [adenosine] shifted the CRC to methoxamine 3.25-fold to the right and attenuated the maximal response by a modest 18%. Analysis of these data by the operational model of agonism indicated that the efficacy parameter, tau, for adenosine or methoxamine was reduced by 99% or 71%, respectively, under these conditions. The agonist dissociation constant, KA, for adenosine (80 microM) or methoxamine (33 microM) by functional antagonism was also estimated. Use of an irreversible alpha-1 adrenoceptor antagonist allowed for the estimation of the KA for methoxamine by the receptor inactivation method using the operational model (40 microM), the Furchgott equation (48 microM) and the nested equations (42 microM) described by James et al. These results suggest that this tissue preparation is a good model to study functional antagonism quantitatively and that the functional antagonism between the responses mediated by these two receptors allows for the reliable estimation of the agonist dissociation constant for alpha-1 adrenoceptor agonists.

Adenosine↗

PubMed1995

Comparison of the effects of desipramine on noradrenaline- and methoxamine-evoked venoconstriction in man.

1. The dorsal hand vein compliance technique was used to investigate the dual effect of tricyclic antidepressants at the noradrenergic synapse (i.e. noradrenaline uptake blockade leading to potentiation and alpha 1-adrenoceptor blockade leading to antagonism of the effect of noradrenaline). The effects of a single oral dose (100 mg) of desipramine (DMI) on venoconstrictor responses to locally infused noradrenaline and methoxamine, a selective alpha 1-adrenoceptor agonist with little affinity for the uptake mechanism, were examined. 2. Eight healthy male volunteers participated in four weekly experimental sessions. Each session was associated with one of the following treatment conditions: noradrenaline/DMI, noradrenaline/placebo, methoxamine/DMI, methoxamine/placebo. Subjects were allocated randomly to treatments and sessions according to a double-blind balanced design. Noradrenaline acid tartrate (0.33-33 ng min-1) and methoxamine hydrochloride (0.0135-135 micrograms min-1) were infused into the superficial dorsal hand vein; each dose was infused for 5-7 min with 5 min intervening washout periods. Systolic and diastolic blood pressure and pulse rate were recorded before the infusion and immediately after the infusion of the highest dose. Salivation, an index of anticholinergic activity of the antidepressant, was measured by the dental roll technique. 3. Both noradrenaline and methoxamine produced dose-dependent venoconstriction: the geometric mean ED50 for noradrenaline was 4.41 ng min-1 and for methoxamine was 2558 ng min-1; the potency ratio (noradrenaline/methoxamine) was 2884. DMI shifted the dose-response curve for noradrenaline to the left (ANOVA: P < 0.025), resulting in a dose-ratio of 0.26. DMI did not affect the dose-response curve for methoxamine significantly; the dose ratio was 1.24. 4. None of the local infusions and/or systemic treatments had any significant effects on supine systolic and diastolic blood pressure and pulse rate. 5. DMI caused a substantial (47.6%) reduction in salivary output that significantly differed from the slight statistically insignificant increase (5.8%) of salivary output recorded after placebo. 6. These results show that a single oral dose (100 mg) of DMI causes significant potentiation of the response to noradrenaline without significantly affecting the response to methoxamine. The potentiation is likely to be due to uptake blockade since the response to methoxamine was not affected. Furthermore, the lack of significant antagonism of the response to methoxamine indicates that a single oral dose (100 mg) of DMI does not cause sufficient alpha 1-adrenoceptor blockade to be detected as a pharmacodynamic change in our test system.

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