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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↗

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↗

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↗

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↗

PubMed1987

Effects of a selective alpha 1-adrenoceptor agonist, methoxamine, on sexual behavior and penile reflexes.

Methoxamine, an adrenergic agonist with selectivity for the alpha 1-adrenoceptor, when administered intraperitoneally 10 minutes prior to mating tests (1 to 5 mg/kg), effected reductions in the ejaculatory threshold, evidenced by a decrease in the number of intromissions preceding ejaculation. In mounting tests after penile anesthetization, a test which specifically assesses sexual motivation, 3 mg/kg methoxamine was without a stimulatory effect. Further, in penile reflex tests (ex copula) 1 mg/kg methoxamine was without effect, whereas 5 mg/kg decreased the number of erections, cups and flips per test, and increased the incidence of seminal emission. These data indicate a facilitation of the ejaculatory mechanism, both in and ex copula, coupled with an inhibition of erectile responses for moderate doses of methoxamine. Treatment of male rats with the alpha 2-adrenoceptor agonist clonidine (0.25 mg/kg, IP, five minutes pretest) drastically reduced the number of animals exhibiting intromissive and ejaculatory behavior in mating tests. This suppressive effect of clonidine was not prevented by prior treatment with methoxamine (3 mg/kg, 10 minutes pretest and five minutes preclonidine). Further, ST-91, a polar analog of clonidine which does not readily enter the central nervous system, was without effect on male sexual behavior. Since (1) the effects of methoxamine administration are not of similar quality or magnitude to those reported earlier after yohimbine, an alpha 2-adrenoceptor antagonist, (2) since concurrent stimulation of alpha 1- (by methoxamine) and alpha 2- (by clonidine) adrenoceptors is followed by a suppression of sexual behavior similar to that seen after clonidine alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1975

Stimulation of adenosine 3',5'-monophosphate formation in rat cerebral cortical slices by methoxamine: interaction with an alpha adrenergic receptor.

Methoxamine elicits a rapid accumulation of adenosine 3',5'-monophosphate (cyclic AMP) in rat cerebral cortical slices with maximal effects at 100 muM. The accumulations of cyclic AMP elicited by this amine are completely blocked by the alpha adrenergic antagonists, phenoxybenzamine and dihydroergokryptine, partially blocked by the alpha antagonist, phentolamine, and unaffected by the beta blocking agent, propranolol, or by the local anesthetic, tetracaine. The magnitude of the accumulations of cyclic AMP elicited by methoxamine in cerebral cortical slices of four rat strains (F-344, ACI, BUF, and Sprague-Dawley) exhibit a strong negative correlation with spontaneous motor activity and a positive correlation with the magnitude of norepinephrine-elicited accumulations of cyclic AMP. The stimulatory interaction of methoxamine with alpha adrenergically regulated cyclic AMP-generating systems differs from the interaction of norepinephrine with alpha receptors as evidenced by the following observations: 1) the stimulatory effects of methoxamine and norepinephrine are nearly additive; 2) the stimulatory effects of methoxamine and adenosine are nearly additive, whereas the effects of norepinephrine and adenosine are much more than additive. Methoxamine, however, does not increase further the magnitude of accumulation of cyclic AMP elicited by a combination of norepinephrine and adenosine. The results are consonant with the interaction of methoxamine with alpha adrenergic receptors which are normally activated by norepinephrine only to a marginal extent. However, in the presence of adenosine, these receptors are now sensitive to activation by norepinephrine.

Adenosine↗

PubMed1992

The role of nitric oxide in the vascular hyporesponsiveness to methoxamine in portal hypertensive rats.

This study examined whether an increased activity of the endothelium-derived relaxing factor, nitric oxide, may account for the hyporesponsiveness to vasoconstrictors in portal hypertension. We performed dose-response curves to methoxamine, an alpha-adrenoceptor agonist, with and without N omega-nitro-L-arginine, a specific inhibitor of nitric oxide synthesis, in experimental portal hypertension. Partial portal vein-ligated or sham-operated rats were pretreated with a continuous intravenous infusion of either N omega-nitro-L-arginine (50 micrograms.kg-1.min-1) or saline. Thirty minutes after starting the infusion of N omega-nitro-L-arginine or saline an infusion of methoxamine (10, 30 and 100 micrograms.kg-1.min-1) was added. Total peripheral resistance was calculated from mean arterial pressure and cardiac index. Repeated measurements of cardiac index were performed by a thermodilution technique. In portal vein-ligated rats pretreated with saline, the increase in total peripheral resistance after methoxamine infusion was significantly less than that of sham-operated rats (0.2 +/- 0.1 vs. 1.0 +/- 0.3, 0.6 +/- 0.1 vs. 1.6 +/- 0.3 and 3.7 +/- 0.5 vs. 6.1 +/- 0.7 mm Hg.ml-1.min.100 gm, p less than 0.05, methoxamine 10, 30 and 100 micrograms.kg-1.min-1, respectively). In the presence of N omega-nitro-L-arginine, the change in total peripheral resistance after methoxamine infusion was similar in both groups (p greater than 0.05). In conclusion, this study demonstrates that a vascular hyporesponsiveness to methoxamine is present in portal vein-ligated rats and that this hyporesponsiveness is reversed by blockade of nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Effect of alpha 1-adrenoceptor stimulation with methoxamine and phenylephrine on spontaneously beating rabbit sino-atrial node cells.

Effects of methoxamine and phenylephrine on the action potential and the membrane currents in spontaneously beating rabbit sino-atrial node cells were examined by means of a two-microelectrode voltage-clamp technique. Both methoxamine and phenylephrine (10(-4) mol/l) prolonged the cycle length (CL) and the action potential duration (APD), significantly. At concentrations higher than 3 x 10(-4) mol/l, phenylephrine increased the maximum rate of rise of action potential (Vmax) but methoxamine reduced it. Both agents depolarized the maximum diastolic potential (MDP). These changes in the action potential parameters occurred in a concentration-dependent manner. In the presence of phentolamine (10(-5) mol/l), methoxamine (3 x 10(-4) mol/l) did not modify the action potential parameters. Also, phenylephrine did not affect them during exposure to phentolamine (10(-5) mol/l) and pindolol (10(-7) mol/l). In voltage-clamp experiments, at 10(-3) mol/l both methoxamine and phenylephrine slightly increased the slow inward current (Isi), but decreased the time-dependent outward current (Ik). The steady-state activation variable of Ik (p infinity) was unaffected by these agents. The hyperpolarization-activated current (Ih) was suppressed in the presence of methoxamine, but enhanced in the presence of phenylephrine. An additional application of pindolol (10(-7) mol/l) during exposure to phenylephrine (10(-3) mol/l) depressed the action potential amplitude (APA) and Vmax, and prolonged CL slightly. Under the same condition, all the membrane currents (Isi, Ik and Ih) were decreased. In addition, the time courses of decay for Isi were not modified in the absence and the presence of phenylephrine (10(-3) mol/l) and phenylephrine plus pindolol (10(-7) mol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1975

The time course of the effects of beta- and alpha-adrenoceptor stimulation by isoprenaline and methoxamine on the contractile force and cAMP level of the isolated rabbit papillary muscle.

In the isolated papillary muscle of the rabbit the time course of the effects of selective beta- and alpha-adrenoceptor stimulation by isoprenaline and methoxamine, respectively, on the contractile force and on the level of 3',5'-cyclic AMP (cAMP) was determined. 1. Isoprenaline (3 times 10(-7) M) increased significantly the content of cAMP at 15 sec and elevated it to the maximal level-about twice the control value-at 30 sec after its administration, while the developed tension of the papillary muscle was also increased significantly at 15 sec and reached gradually its maximum at 90 sec. 2. Compared with isoprenaline methoxamine (10(-4) M) increased the developed tension very slowly: the maximal response was reached after 20 min. The level of cAMP, on the other hand, was changed neither before nor during the induction of the positive inotropic effect of methoxamine. 3. The phosphodiesterase inhibitor papaverine (10(-5) M) inhibited the PDE activity of the papillary muscle by about 40% after an incubation of 1 hr, and increased the level of cAMP significantly. The effects of isoprenaline on the contractile forced and on the level of cAMP were considerably enhanced by papaverine: the content of cAMP was increased by isoprenaline (3 times 10(-7) M) to about 3 times the control value and also its positive inotropic effect was significantly greater than in controls without papaverine. On the other hand, the positive inotropic effect of methoxamine (10(-4) M) was not affected by papaverine (10(-5) M). Furthermore, in the papillary muscle treated with papaverine the level of cAMP was significantly reduced by methoxamine: the papaverine-induced increase of cAMP was abolished by methoxamine. 4. The present results are compatible with the hypothesis that cAMP is involved as a mediator in the positive inotropic effect induced by beta-adrenoceptor stimulation, and indicate further that the stimulation of alpha-adrenoceptors evokes its positive inotropic effec through a mechanism other than that elicited by beta-adrenoceptor stimulation, i.e., independent of cAMP.

Animals↗

PubMed1987

The effect of epinephrine versus methoxamine on regional myocardial blood flow and defibrillation rates following a prolonged cardiorespiratory arrest in a swine model.

Recent studies in swine have shown that larger doses of epinephrine than those currently employed for cardiopulmonary resuscitation (CPR) significantly improve regional myocardial blood flow following prolonged cardiac arrest. The dose-response effect of a pure alpha-adrenergic agonist, methoxamine, on regional myocardial blood flow has not been investigated in this setting. This study compared the effect of high-dose epinephrine with graded doses of methoxamine on regional myocardial blood flow, oxygen delivery/utilization, and defibrillation rates during CPR. Twenty swine were instrumented for regional myocardial blood flow measurements using radiolabeled tracer microspheres. Measurements of regional myocardial blood flow, oxygen delivery, and oxygen consumption were made during normal sinus rhythm. Ventricular fibrillation was then induced. Following 10 minutes of ventricular fibrillation, CPR was initiated with a pneumatic compressor. Regional myocardial blood flow, oxygen delivery, and oxygen consumption were then measured during CPR. Following 3 minutes of CPR, the swine were allocated to one of four treatment groups (five per group): group I, epinephrine 0.2 mg/kg; group II, methoxamine 0.1 mg/kg; group III, methoxamine 1.0 mg/kg; and group IV, methoxamine 10.0 mg/kg. One minute after drug administration, regional myocardial blood flow, oxygen delivery, and oxygen consumption measurements again were made. Three and one half minutes after drug administration, defibrillation was attempted. Regional myocardial blood flow following drug administration was compared using an analysis of covariance. Epinephrine (0.2 mg/kg) significantly improved myocardial blood flow (P less than .002) for all tissues examined compared with all doses of methoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

A comparison of epinephrine and methoxamine for resuscitation from electromechanical dissociation in human beings.

Electromechanical dissociation (EMD) is an organized electrical depolarization of the heart without synchronous myocardial fiber shortening and, therefore, without cardiac output. Patients in EMD have a poor prognosis for resuscitation and long-term survival. The beneficial effect in resuscitation of epinephrine, the adrenergic agent currently recommended, has been shown to depend on stimulation of alpha-adrenergic vasoconstriction. The beta-adrenergic inotropic and chronotropic effects of epinephrine are theoretically detrimental by increasing myocardial oxygen consumption and subendocardial ischemia. The purpose of our study was to determine whether the pure alpha agonist methoxamine was superior to epinephrine in human beings in EMD as determined by survival at one hour. These two agents were compared in a prospective, randomized, and double-blinded study involving 80 patients with EMD of various causes seen in the emergency department and internal medicine inpatient service. The advanced cardiac life support (ACLS) algorithm (current at the time of our study) for resuscitation from EMD was used, with the blinded study drug (epinephrine 1 mg or methoxamine 10 mg) administered where the algorithm calls for epinephrine. Calcium and isoproterenol also were used in the majority of cases according to ACLS standards but never prior to the use of methoxamine or epinephrine. Survival data are summarized as: survival less than one hour, 22 patients receiving methoxamine, 22 receiving epinephrine; one to six hours, 15 patients receiving methoxamine, 13 patients receiving epinephrine; six to 12 hours, one patient receiving epinephrine; more than 24 hours but not surviving to discharge, three patients receiving methoxamine, two patients receiving epinephrine; and survival to discharge, one patient receiving epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Differential interactions of clonidine and methoxamine with the postsynaptic alpha-adrenoceptor of rabbit main pulmonary artery.

We investigated the dependence upon extracellular Ca2+ of contractile responses of the isolated rabbit main pulmonary artery to the alpha-adrenoceptor subtype-selective agonists clonidine (alpha 2) and methoxamine (alpha 1). The calcium-entry blocker verapamil caused a weak, surmountable antagonism of contractile responses to methoxamine, whereas the concentration-response curve of clonidine was antagonized in a noncompetitive manner with a marked depression of maximal responses. Withdrawal of Ca2+ from the physiological saline solution virtually abolished contractile responses to clonidine, without significantly affecting methoxamine-induced responses. We, therefore, determined if clonidine and methoxamine were interacting with the same population of vascular postsynaptic alpha-adrenoceptors. We found that the alpha 1-antagonist prazosin and the alpha 2-antagonist yohimbine caused competitive blockade of contractile responses to both agonists. However, the potency of both antagonists was significantly greater against clonidine than methoxamine. This may reflect a heterogeneity in the population of postsynaptic alpha-adrenoceptors of the rabbit main pulmonary artery. On the other hand, the difference in extracellular Ca2+ sensitivity of clonidine- and methoxamine-induced contractions may be explained as a differential mode of stimulation of the postsynaptic alpha 1-adrenoceptor, possibly through separate, interacting recognition sites for both agonists.

Animals↗

PubMed1976

Actions of methoxamine and tryptamine and their interactions with cyproheptadine and phenoxybenzamine on cat spinal cord segmental reflexes.

The effects of norepinephrine, methoxamine and tryptamine were assessed on the monosynaptic and polysynaptic segmental reflexes in the unanesthetized, decerebrated acute spinal cat. Their selectivity of action was determined by studying the interactions of methoxamine and tryptamine with two antagonists, cyproheptadine and phenoxybenzamine. Potentials were evoked by stimulating either the L7 or S1 dorsal root and were recorded from the corresponding ipsilateral ventral root. Norepinephrine did not affect reflex activity, whereas methoxamine facilitated both the monosynaptic and polysynaptic potentials in a dose-related manner when infused over 20 minutes. Tryptamine facilitated both the monosynaptic and polysynaptic reflex potentials. This increase was dose related for the monosynaptic reflex but not for the polysynaptic reflex. Phenoxybenzamine blocked the facilitatory effects of methoxamine and did not antagonize the effects of tryptamine on the segmental reflex. The facilitatory effects of tryptamine were effectively blocked by cyproheptadine. Cyproheptadine failed to reduce the polysynaptic response to methoxamine, although it partially antagonized the monosynaptic facilitation. These findings demonstrate that methoxamine and tryptamine facilitate the segmental reflex by different modes of action and provide additional evidence for noradrenergic and tryptaminergic systems in the spinal cord.

Animals↗