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In rabbits methoxamine reversed the vasopressor effect of St 587 and abolished the EEG synchronizing action of St 587. The interaction on the blood pressure could be ascribed either to the different chemical structures of St 587 and methoxamine or to partial agonistic properties of St 587. The interaction on the EEG appears to be more complex.
The influence of methoxamine on the contractile tension of isolated rat abdominal aorta, and on its capacity to produce a platelet antiaggregating substance, were explored. Methoxamine stimulated platelet antiaggregation and diminished arterial tone. The last action was blocked by phentolamine as well as by inhibitors of cyclo-oxygenase and prostacyclinsynthetase.
The effect of a pure alpha-adrenergic agent, methoxamine on ventricular fibrillation (VF) amplitude and the relation between hemodynamic parameters and survival in a rodent cardiopulmonary resuscitation (CPR) model were studied. Our results suggested that: 1) VF amplitude decreased during untreated VF, but it increased during pericardial chest compression: 2) methoxamine significantly increased the mean aortic pressure (MAP) and coronary perfusion pressure (CPP) but not VF amplitude, and the survival also increased due to elevation of CPP; and 3) all surviving animals with successful defibrillation had a higher VF amplitude.
The effect of nitroglycerin combined with methoxamine in reducing infarct weight was studied in conscious dogs. Ten minutes after permanent left anterior descending (LAD) coronary artery occlusion, 10 dogs received nitroglycerin (450 micrograms bolus IV, then 300 micrograms/min for 4 hours) and methoxamine as needed to maintain blood pressure and heart rate. No dogs in heart failure. Ten control dogs received saline solution. Dogs were sacrificed 3 days later. The region at risk of infarction was delineated by simultaneously perfusing the aortic root with Evans blue and the distal LAD artery with saline solution under equal pressures. Slices of stained hearts were incubated with tetrazolium to identify infarct. Total weight of left ventricle (LV), risk region, and infarct was measured. Nitroglycerin-treated dogs showed no difference from control dogs in infarct weight (26.2 +/- 5.9 gm +/- SE vs 27.7 +/- 5.6 gm), percent risk region/LV (36.0 +/- 1.4% vs 37.9 +/- 3.1%), or present infarct/LV (23.5 +/- 5.2% vs 24.8 +/- 4.9%). In a subgroup with risk region/LV less than or equal to 35%, nitroglycerin reduced infarct weight by 45% (8.8 +/- 8.5% vs 15.9 +/- 7.9%), percent infarct/LV by 49% (7.1 +/- 6.8% vs 13.8 +/- 6.6%), and percent infarct/risk region by 41% (23.0 +/- 22.0% vs 38.9 +/- 15.9%). Because of the small number of dogs in the study, differences were not significant. In dogs with risk region/LV greater than 35%, nitroglycerin had no effect. Thus, in dogs without overt heart failure, nitroglycerin may salvage ischemic tissue within small areas at risk of infarction, but the results are not definitive. However, our results clearly demonstrate that in the absence of failure, nitroglycerin does not reduce the size of large infarcts.
Tha alpha-sympathomimetic agonists, clonidine, naphazoline, methoxamine, oxymetazoline and phenylephrine were used to further characterize the alpha-adrenoceptors mediating the positive inotropic effect in the isolated papillary muscle of the rabbit heart. The maximal inotropic effects of these amines were compared with the effect of isoprenaline and it was examined whether or not these amines compete for alpha-adrenoceptors. On the papillary muscle stimulated at 0.5 Hz, phenylephrine showed a high affinity (pD2 value=6.13) and produced the most pronounced intrinsic activity of the alpha-sympathomimetic amines. Therefore, the intrinsic activity of phenylephrine, in the presence of prindolol (3 X 10(-8) M), was used for comparison with those of the other alpha-agonists. Clonidine caused a positive inotropic effect: the intrinsic activity amounted to 0.32 of that of phenylephrine; the affinity was the highest among the amines tested (pD2 value=6.46); its effect was inhibited by 10(-6) M phentolamine. The affinity and the intrinsic activity of naphazoline were slightly lower than those of clonidine. Methoxamine showed a relatively high intrinsic activity (0.56) but the lowest affinity (4.68). Oxymetazoline did not cause any positive inotropic effect. Clonidine, naphazoline and oxymetazoline antagonized the positive inotropic effect of phenylephrine, mediated via the alpha-adrenocaptors in the presence of 3 X 10(-8) M prindolol, in a competitive manner. This observation suggests that these alpha-sympathomimetic amines compete with phenylephrine for the same receptor site. Thus the present results provide additional evidence for alpha-adrenoceptors mediating the positive inotropic actions of sympathomimetic amines in the rabbit papillary muscle.
Methoxamine, an alpha 1-adrenoceptor agonist, significantly increased the overflow of ATP, ADP and AMP, but not adenosine, by a prazosin-sensitive mechanism in the rabbit pulmonary artery. Among the adenine nucleotides released, the amount of ATP was larger than those of the other two. Such release of adenine nucleotides was not induced by clonidine, an alpha 2-adrenoceptor agonist, and isoproterenol, a beta-adrenoceptor agonist. Methoxamine-induced release was observed in the absence of extracellular calcium, but was not observed at a low temperature, 27 degrees C. This suggests an extracellular calcium-independent and temperature-dependent ATP-releasing mechanism coupled with alpha 1-adrenoceptors in rabbit pulmonary artery.
To test the hypothesis that the increase in locomotor activity and the diversification of stimulus sampling observed during intrahippocampal microinfusions of norepinephrine are mediated by beta adrenergic receptors, rats were infused with either the beta agonist isoproterenol or the alpha-1 agonist methoxamine while being tested in a Behavioral Pattern Monitor. The behavioral profile induced by isoproterenol was qualitatively similar to that observed previously with norepinephrine. Methoxamine had no significant effects. The ability of isoproterenol to mimic the norepinephrine-induced blockade of the hyperactivity associated with intrahippocampal microinfusions of the cholinergic agonist carbachol was also tested. Carbachol produced hyperactivity which was attenuated by the coinfusion of isoproterenol. These results are consistent with the hypothesis that increases in diversive exploration and stimulus sampling induced by intrahippocampal norepinephrine are due to the activation of beta adrenergic receptors within the dentate gyrus.
The adrenergic responsiveness of right and left atria isolated from spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR) was studied. Right atria isolated from SHR showed subsensitivity to the chronotropic effect of noradrenaline (21.3-fold at the EC50 level, P < 0.05) and isoprenaline (12.0-fold, P < 0.05). However, atria isolated from RHR did not exhibit any significant alteration (P > 0.05) in sensitivity to the chronotropic effect of noradrenaline or isoprenaline. Chronotropic responsiveness to theophylline was not altered in right atria isolated from SHR or RHR. alpha 1-Mediated inotropic responses to noradrenaline and methoxamine were blunted in left atria isolated from SHR. Left atria isolated from RHR showed supersensitivity to the inotropic effect of noradrenaline (5.4-fold at the EC50 level, P < 0.05) and subsensitivity to the inotropic effect of methoxamine (6.0-fold, P < 0.05). It is concluded that the present results could, at least partially, explain the reduced cardiac output observed during established hypertension in SHR and the increased cardiac output observed in the initial phase of renal hypertension in RHR.
This study investigated whether maintenance of normotension using a methoxamine infusion would prevent activation of the stress response during halothane anaesthesia in ponies. After acepromazine premedication, anaesthesia was induced with thiopentone in six ponies, and maintained for 120 minutes with halothane in oxygen and ventilation to normocapnia. Methoxamine (M, 0.013+/-0.005 mg kg(-1) min(-1)) or saline (C) was infused throughout anaesthesia. Sequential blood samples were taken for cortisol and ACTH assay. During anaesthesia normotension (mean arterial blood pressure 101-124 mm Hg) was maintained in M, whilst hypotension developed in C (nadir 71+/-12 mm Hg). Cardiac output decreased in both groups but to a greater extent in M. Systemic vascular resistance increased more in M (max 2015+/-650 dyne.s cm(-5)) than C (max 939+/-285 dyne.s cm(-5)). Plasma cortisol increased in both groups but more slowly in M. Plasma ACTH did not change in either group. Maintenance of normotension via increased systemic vascular resistance did not prevent, but may have attentuated, the adrenocortical response to anaesthesia. Reduced cardiac output and presumed compromise to tissue perfusion appear as important a stimulus as hypotension. The equine stress response to halothane anaesthesia is likely to be multifactorial.
We report the case of a young man with a recurrent idiopathic priapism, successfully treated with methoxamine intracarvenosal self-injections. The patient was instructed in intracorporeal self-injection of this pure alpha-1 adrenergic agonist, which provided complete detumescence. The patient became asymptomatic after one month of domiciliary treatment. We conclude that intracavernosal self-administered methoxamine can be a useful treatment of recurrent idiopathic priapism.
The complete chiral separation of methoxamine and lobeline was achieved by capillary zone electrophoresis on an ethylbenzene-deactivated fused-silica capillary column and with cyclodextrins (CDs) as buffer additives. Among the CDs investigated in this study, i.e. alpha-CD, beta-CD, dimethyl-beta-CD, hydroxypropyl-beta-CD and gamma-CD, all the three beta-type CDs showed chiral recognition on the two drugs investigated. Under the investigated conditions, the baseline chiral separation of methoxamine can be achieved with 90 mM Tris-H3PO4 (pH 2.5) containing 11.5 mM of the three beta-type CDs, with dimethyl-beta-CD giving the best resolution, whereas the baseline chiral separation of lobeline can be realized by using 90 mM Tris-H3PO4 buffer (pH 2.5) containing 5.8 mM dimethyl-beta-CD or 29.5 mM hydroxypropyl-beta-CD.
A sensitive spectrophotometric assay has been developed for the determination of methoxamine in pure dosage form and in its pharmaceutical preparations. The method is based on the acidic oxidation of methoxamine with cerium(IV) in the micellar medium of sodium lauryl sulphate at 96 degrees C. The reaction yields a water-soluble purple product which can be quantified spectrophotometrically at 505 nm. The calibration curve was linear between 1.0 and 20 micrograms ml-1 with a limit of detection 0.5 microgram ml-1. The molar absorptivity at 505 nm is 8.3 X 10(3) iota mol-1 cm-1. The method is simple and rapid since the product is measured directly in solution without extraction.
A series of phenylethylamines related to methoxamine has been prepared and evaluated for direct alpha 1-receptor agonist activity. It has been observed that for open-chain compounds such as methoxamine, in which the amine-containing portion is free to adopt numerous conformations, an hydroxyl group is necessary for direct alpha 1-adrenergic activity. When the hydroxyl is removed, however, the direct component of activity is greatly reduced unless the amine is incorporated into a more sterically defined structure. From our studies we have concluded that in order for a phenylethylamine to be active as a direct alpha 1-receptor agonist it should have a beta nitrogen in a fully extended conformation relative to a substituted phenyl ring. For optimum potency, the nitrogen should be exocyclic to a saturated six-membered ring. It may be further incorporated exocyclic or endocyclic into an additional ring as long as the amine occupies a well-defined region of space relative to the aromatic portion of a molecule. The ED50 values of some of the more potent compounds as alpha 1-receptor agonists are on the order of 1 X 10(-7) M.
We treated two patients affected by retrograde ejaculation (RE) with the pure alpha1-adrenergic agonist methoxamine; the drug was self-administered intramuscularly by the patients 30 min prior to intercourse or masturbation. A previous trial with oral imipramine had been ineffective in both patients. Sperm count increased substantially, particularly in the first patient who had insulin-dependent diabetes and was seeking fertility. In this patient, total ejaculated sperm increased from 22 millions to 488 and 419.5 millions on two different occasions, with good motility; two clinical pregnancies were obtained in the partner of this patient after 3 and 4 months of treatment, respectively. The second patient did not desire fertility. In both patients, no side effects were seen except for slight piloerection; blood pressure values increased slightly, and heart rate was unchanged. We conclude that self-administered methoxamine can be a useful, noninvasive and inexpensive treatment of RE, when oral agents are ineffective.
We describe three cases of electromechanical dissociation under anaesthesia that were unresponsive to doses of intravenous epinephrine given according to current Advanced Life Support guidelines, but which responded immediately to the intravenous administration of the pure alpha agonist, methoxamine. We suggest a possible mechanism to explain this finding and review the literature on vasopressor drugs used for cardiopulmonary resuscitation during electromechanical dissociation. An intravenous alpha agonist, such as methoxamine 20 mg, should be considered for any case of cardiac arrest secondary to electromechanical dissociation which is unresponsive to epinephrine given according to current guidelines.
Non-invasive methods for assessment of the vascular effects of antimigraine drugs were evaluated with respect to their utility, variability and sensitivity in a double-blind, placebo-controlled, three-period crossover study in six healthy volunteers using an intravenous vasoconstrictor, methoxamine, as a probe drug. Changes in the internal diameter of the brachial and radial arteries were measured using ultrasound which had low between-day and within-day coefficients of variation. Peak systolic velocity (PSV), time-averaged velocity (TAV), total flow, resistance (RI) and pulsatility indices (PI) were measured by Doppler from one arterial wave form. Whilst PSV and TAV increased with methoxamine, because of bradycardia, changes in PI and RI were difficult to interpret. An automatic oscillometric cuff, a mercury-in-silastic strain gauge method and the "Finapres", finger arterial blood pressure monitor were used to follow changes in systolic blood pressure (SBP). The strain gauge technique underestimated arm SBP compared to the oscillometric method but clearly showed drug-related increases whilst the Finapres did not reflect changes in blood pressure detected by the other methods.
Non-cholinergic, non-adrenergic vasodilation has been studied by transmural field stimulation of the isolated rat hepatic artery and compared with responses in the splenic artery. In the hepatic artery with rubbed endothelium, transmural stimulation caused a contracture that was blocked by phentolamine and potentiated after capsaicin. After pretreatment with guanethidine in order to deplete the neuronal stores of noradrenaline, the methoxamine-contracted hepatic artery was significantly relaxed by transmural stimulation; more efficiently than the splenic artery. This relaxation of the hepatic artery was attenuated following a 30 min exposure to capsaicin and largely blocked by tetrodotoxin (TTX). The relaxation by exogenous CGRP was independent of a functional endothelium. In contrast, vasodilation by substance P (SP) and neurokinin A (NKA), was completely dependent on an intact endothelium. Exogenous CGRP caused a near-complete relaxation of the methoxamine-contracted hepatic artery both before and after capsaicin treatment. CGRP was a more efficient relaxant of the hepatic than the splenic artery. These findings show that responses to transmural stimulation of the hepatic artery are modulated after pretreatment with capsaicin, indicating release of relaxing substances such as CGRP, presumably from capsaicin-sensitive neuronal stores. In conclusion, CGRP is a likely mediator of neuronal vasodilation in the rat liver, independent of the state of the endothelium.
Thirty-six patients who presented for transurethral prostatic resection were allocated randomly to one of two groups. Patients in group A were given methoxamine 10 mg i.m., 15 min before spinal anaesthesia. Patients in group B acted as a control group. All patients received spinal anaesthesia. Preoperative administration of methoxamine 10 mg i.m. decreased blood loss significantly and improved haemodynamic stability compared with the control group.