ABSTRACT
A CE method was developed and validated for the stereoselective determination of midodrine and desglymidodrine in Czapek culture medium to be applied to a stereoselective biotransformation study employing endophytic fungi. The electrophoretic analyses were performed using an uncoated fused-silica capillary and 70 mmol/L sodium acetate buffer solution (pH 5.0) containing 30 mmol/L heptakis (2, 3, 6-tri-O-methyl)-beta-CD as running electrolyte. The applied voltage and temperature used were 15 kV and 15 degrees C, respectively. The UV detector was set at 200 nm. The sample preparation was carried out by liquid-liquid extraction using ethyl acetate as extractor solvent. The method was linear over the concentration range of 0.1-12 microg/mL for each enantiomer of midodrine and desglymidodrine (r> or =0.9975). Within-day and between-day precision and accuracy evaluated by RSDs and relative errors, respectively, were lower than 15% for all analytes. The method proved to be robust by a fractional factorial design evaluation. The validated method was used to assess the midodrine biotransformation to desglymidodrine by the fungus Phomopsis sp. (TD2), which biotransformed 1.1% of (-)-midodrine to (-)-desglymidodrine and 6.1% of (+)-midodrine to (+)-desglymidodrine.
Subject(s)
Ascomycota/chemistry , Electrophoresis, Capillary/methods , Midodrine/analogs & derivatives , Midodrine/analysis , Ascomycota/metabolism , Asteraceae/microbiology , Culture Media , Linear Models , Midodrine/chemistry , Midodrine/metabolism , Reproducibility of Results , Sensitivity and Specificity , Stereoisomerism , TemperatureABSTRACT
The objective of this case is to describe the pharmacokinetics and toxicity of midodrine in overdose. A 20 year old female ingested up to 350 mg midodrine while recovering in hospital from another overdose. She developed vomiting and severe hypertension (blood pressure [BP], 210/100 mmHg). Remarkable findings included a heart rate with a range of 43-60 beats/min, spontaneous respirations (20 breaths/min), and oxygen saturations of >95 % on FiO2 25 %, and a GS of 8. She was admitted to intensive care and had a normal non-contrast CT brain. She was treated with a glyceryl trinitrate patch (5 mg) and observed for 36 h with subsequent BP reduction to 124/81 mmHg and improved in conscious state. Midodrine and desglymidodrine concentrations were measured with liquid chromatography tandem mass spectrometry and were detected with 2-h post-ingestion at concentrations of 158.4 and 169.7 ng/mL, respectively. The parent drug concentrations rapidly decreased with an elimination of half-life of 1.6 h, and the metabolite initially increased and then decreased. The peak in blood pressure appeared to coincide with peak metabolite concentrations. Midodrine in overdose can potentially cause severe hypertension and reflex bradycardia but given its short half-life treatment with vasodilator agents and supportive care is sufficient.
Subject(s)
Adrenergic alpha-1 Receptor Antagonists/poisoning , Bradycardia/chemically induced , Drug Overdose/therapy , Hypertension/chemically induced , Midodrine/poisoning , Blood Pressure/drug effects , Bradycardia/therapy , Drug Overdose/physiopathology , Female , Glasgow Coma Scale , Heart Rate/drug effects , Humans , Hypertension/therapy , Midodrine/analogs & derivatives , Midodrine/blood , Nitroglycerin/therapeutic use , Vasodilator Agents/therapeutic use , Young AdultABSTRACT
A simple, rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed for quantification of deglymidodrine in human plasma. The plasma samples were pretreated by protein precipitation with trichloroacetate. The chromatographic separation was performed on reversed phase Aquasil C18 column, and the plasma extraction was eluted with a mobile phase solution consisting of acetonitrile (containing 0.02% formic acid) and water (containing 0.02% formic acid). The molecular ion of analyte was detected in positive ionization by multiple reaction monitoring. The mass transitions of m/z 198.4--> 148.1 and m/z 212.4--> 162.3 were used for detection of deglymidodrine and its internal standard, respectively. The assay exhibited linear ranges from 0.25 to 32 ng/ml for the analyte in human plasma. Acceptable precision and accuracy were obtained for concentrations of quality control (QC) samples. The proposed method has been successfully used to analyze human plasma samples for application in oral pharmacokinetic study.
Subject(s)
Midodrine/analogs & derivatives , Adult , Calibration , Chromatography, Liquid , Humans , Male , Mass Spectrometry , Midodrine/blood , Midodrine/pharmacokinetics , Reproducibility of ResultsABSTRACT
A specific, rapid, sensitive and selective ultra-performance liquid chromatography - tandem mass spectrometry has been developed for the simultaneous determination of midodrine and desglymidodrine in human plasma. The analytes and its deuterated analogs were quantitatively extracted from 100µL of human plasma by solid phase extraction technique. Separation of analytes was achieved on the Waters Acquity UPLC BEH C18 (50×2.1mm, 1.7µm) column using acetonitrile-4.0mM ammonium formate, pH 2.5(90:10, v/v) as mobile phase. The protonated analytes were quantified by selected reaction monitoring in the positive ionization mode by triple quadrupole mass spectrometer. The calibration plots were linear over the concentration range of 0.050-50.0ng/mL. The intra-batch and inter-batch precision (%CV) across quality control levels was <4.0 and the% mean relative recovery was ≥96%. Various other parameters like stability in different conditions; matrix effect and reproducibility of the method were performed in accordance with the guidelines specified by the USFDA for bioanalytical method development and validation. The developed method was successfully administered to the pharmacokinetics study of 5 mg midodrine tablet in 12 healthy subjects. Reproducibility of assay was proved by reanalysis of 48 incurred samples.
Subject(s)
Midodrine/analogs & derivatives , Midodrine/blood , Tandem Mass Spectrometry/methods , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Cross-Over Studies , Humans , Midodrine/analysis , Tandem Mass Spectrometry/standards , Therapeutic Equivalency , Time FactorsABSTRACT
OBJECTIVE: Midodrine is an α-agonist prodrug of desglymidodrine used for the management of hypotension, and can also be used for hepatorenal syndrome and cirrhotic patients with tense ascites. The objective of the present work was to study the clinical pharmacokinetic parameters of midodrine and its active metabolite desglymidodrine in cirrhotic patients with tense ascites, which may help in dose selection and improve treatment outcome. METHOD: This was a prospective, open-label, single-dose, parallel-group study. At first, a pilot study was performed on one healthy volunteer by taking serial blood samples at scheduled time intervals to validate the method of analysis and sampling times. The full study was then conducted by selecting 12 cirrhotic patients with tense ascites in one group and taking nine blood samples. We also selected five healthy volunteers as the control group and took 11 blood samples. RESULTS: Statistically significant differences were observed between the healthy volunteer group and the patients group in the area under the concentration versus time curve (AUC0-t) and maximum plasma concentration (Cmax) values of midodrine and desglymidodrine. Based on the results of the pharmacokinetic analysis, the patient group was further subdivided into those receiving the interacting drug ranitidine (five patients) and those not receiving the interacting drug (seven patients). CONCLUSIONS: Pharmacokinetic parameters of midodrine can differ significantly in cirrhotic patients with tense ascites from those in healthy individuals. Drug monitoring, dose adjustments, and drug-drug interactions should all be considered during therapy in this vulnerable patient group.
Subject(s)
Adrenergic alpha-Agonists/pharmacokinetics , Ascites/drug therapy , Liver Cirrhosis/drug therapy , Midodrine/analogs & derivatives , Prodrugs/pharmacokinetics , Adult , Case-Control Studies , Female , Humans , Male , Middle Aged , Midodrine/pharmacokinetics , Pilot Projects , Prospective StudiesABSTRACT
Midodrine (MD) is a prodrug that is converted after oral administration to Desglymidodrine (DMD). In this study, an LC-MS/MS assay was developed and validated for investigation of the pharmacokinetics of MD and DMD in non azotemic patients with liver cirrhosis and tense ascites. Results were compared to those noted with healthy volunteers following the adminstration of a single oral dose of MD. Sample preparation was performed by liquid-liquid extraction using t-butyl methyl ether. HPLC separation was carried out using RP C18 column (4.6mm×50mm, 5µm). Isocratic elution was performed using methanol:0.2% formic acid (70:30, v/v) as the mobile phase, at a flow rate of 0.7mL/min. Tandem mass spectrometric detection was employed at positive electrospray ionization in MRM mode for the determination of MD and DMD. Analysis was carried out within 1.0min over a concentration range of 0.50-40.00ng/mL for the prodrug and its active metabolite. The assay was validated according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained. The applicability of the assay for the determination of the pharmacokinetic parameters of MD and DMD and personalized therapy was demonstrated in healthy volunteers and ascitic patients. Results revealed significant differences in pharmacokinetic parameters among the studied groups. Such differences were explained on the basis of the medical condition and co-adminstered medications exerting possible drug-drug interaction. Results confirmed the need for implementation of reliable analysis tools for therapeutic dose adjustment.
Subject(s)
Adrenergic alpha-1 Receptor Agonists/blood , Chromatography, High Pressure Liquid/methods , Midodrine/analogs & derivatives , Tandem Mass Spectrometry/methods , Adrenergic alpha-1 Receptor Agonists/metabolism , Ascites/drug therapy , Drug Monitoring/methods , Humans , Limit of Detection , Liquid-Liquid Extraction/methods , Liver Cirrhosis/drug therapy , Midodrine/blood , Midodrine/metabolism , Prodrugs/metabolism , Prodrugs/pharmacokineticsABSTRACT
Midodrine is an orally active adrenergic agonist useful in the treatment of hypotension. We have investigated the pharmacodynamics of its active metabolite after oral midodrine therapy in nine patients with severe orthostatic hypotension. Peak plasma levels of the metabolite were reached in 60 to 90 minutes and ranged from 25 to 56 ng/ml. The mean values for distribution volume, plasma clearance, and t1/2 were 4.0 L/kg, 23 ml/min/kg, and 2.1 hours, respectively. Heart rate increased after 5 to 10 mg doses and the increases were statistically significant (P less than 0.05) at 120 minutes. An apparent increase in blood pressure was not statistically significant. The patients said that they felt better.
Subject(s)
Ethanolamines/therapeutic use , Hypotension, Orthostatic/drug therapy , Midodrine/therapeutic use , Administration, Oral , Adult , Aged , Blood Pressure/drug effects , Chromatography, Liquid , Dopamine/blood , Epinephrine/blood , Female , Heart Rate/drug effects , Humans , Kinetics , Male , Middle Aged , Midodrine/analogs & derivatives , Midodrine/blood , Midodrine/metabolism , Norepinephrine/blood , Shy-Drager Syndrome/drug therapyABSTRACT
The effects of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethane sulfonanilide hydrochloride), an alpha 1A-adrenoceptor-selective agonist, on intraurethral pressure and blood pressure were investigated in anesthetized dogs. In addition, the contractile effects of NS-49 on the isolated dog urethra and carotid artery were compared with those of non-selective alpha 1-adrenoceptor agonists. Intravenously (i.v.) administered NS-49 at 0.3 microgram/kg or more significantly increased intraurethral pressure in a dose-dependent manner. Much higher doses of NS-49 were needed to increase blood pressure. In contrast, ST-1059 (1-(2',5'-dimethoxyphenyl)-2-aminoethanol) (an active metabolite of midodrine) at 30 micrograms/kg or more significantly increased both intraurethral pressure and blood pressure. NS-49 was 11-fold more selective for intraurethral pressure than ST-1059, NS-49, ST-1059, phenylephrine and noradrenaline caused concentration-dependent contraction of the isolated dog urethra. NS-49 caused only a slight contraction of the dog carotid artery even at high concentrations, whereas the reference drugs caused contractions of the artery with high efficacy. The alpha 1A-adrenoceptor-selective antagonists 5-methyl-urapidil and WB-4101 also showed high affinity for alpha 1-adrenoceptors in the dog urethra in inhibiting [3H]prazosin binding. In conclusion, the alpha 1A-selective agonist NS-49 selectively increased intraurethral pressure in dogs, and produced selective contraction of the dog urethra. These results suggest that the alpha 1A-adrenoceptor subtype is responsible for the contraction of the urethra and the regulation of intraurethral pressure, and that NS-49 might be useful for the treatment of stress incontinence with little effect on the cardiovascular system.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Anilides/pharmacology , Muscle, Smooth/drug effects , Receptors, Adrenergic, alpha-1/physiology , Urethra/drug effects , Animals , Blood Pressure/drug effects , Carotid Arteries/drug effects , Dogs , Dose-Response Relationship, Drug , Female , In Vitro Techniques , Liver/metabolism , Male , Midodrine/analogs & derivatives , Midodrine/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth/physiology , Muscle, Smooth, Vascular/drug effects , Prazosin/pharmacology , Pressure , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-1/metabolism , Submandibular Gland/metabolism , Urethra/physiologyABSTRACT
Human alpha1-acid glycoprotein (alpha1-AGP) has been used as a chiral stationary phase (CSP) for the enantioseparation of midodrine and deglymidodrine racemates in the same HPLC run. The imobilized AGP resulted as the best chiral selector for the enantioresolution of two compounds. Due to the modification of alpha1-AGP characters as a result of changing the composition of the mobile phase, an attempt study of the watery mobile phase (ionic strength and pH of the buffer, nature and concentration of the organic modifier) allowed for an increase in the enantioselectivity of the chromatographic system and an optimization of the resolution base-line of both enantiomeric pairs.
Subject(s)
Midodrine/analogs & derivatives , Midodrine/chemistry , Orosomucoid/chemistry , Chemistry Techniques, Analytical , Chromatography, High Pressure Liquid , Humans , In Vitro Techniques , Midodrine/analysis , Molecular Structure , StereoisomerismABSTRACT
The distribution of selective alpha 1-adrenoceptor agonist 1-(2',5'-dimethoxyphenyl)-2-glycinamidoethanol hydrochloride, midodrine, and its active metabolite 1-(2',5'-dimethoxyphenyl)-2-aminoethanol, DMAE, was evaluated on bladder and urethra of 8-weeks and 52-weeks old female rats. Prior to the intravenous injection of 14C-labeled midodrine and DMAE, bilateral ureters were ligated to prevent drug uptake from the urinary tract. In 8-weeks rats, 14C-midodrine activity was significantly (p less than 0.01) higher in the bladder than in the femoral muscle, which served as a control for drug distribution. Similarly, higher uptake of 14C-DMAE was observed in the bladder than in the femoral muscle (p less than 0.01) and the urethra (p less than 0.05). In 52-weeks rats, there was no significant difference of midodrine uptake among these tissues. However, significantly higher uptake of 14C-DMAE was observed in the urethra than in the femoral muscle (p less than 0.05). Compared with midodrine, the concentration of DMAE was significantly increased in the bladder of 8-weeks rat and in the urethra of 52-weeks rats (respectively, p less than 0.05). In autoradiogram, the grains corresponding to midodrine and DMAE were diffusely distributed on the smooth muscles of bladder (mainly bladder neck and trigone) and urethra. The grains were also recognized on the vessels and perivascular areas of these tissues. These findings support that midodrine and DMAE could be effective for stress incontinence, because these drugs are known to bind specifically to alpha 1-adrenoceptor.
Subject(s)
Adrenergic alpha-Agonists/pharmacokinetics , Midodrine/pharmacokinetics , Urethra/metabolism , Urinary Bladder/metabolism , Animals , Female , Midodrine/analogs & derivatives , Rats , Rats, Inbred Strains , Tissue DistributionABSTRACT
A high-performance liquid chromatography (HPLC) method is presented for the simultaneous determination of midodrine and desglymidodrine (DMAE) in Czapek-Dox culture medium, to be used in biotransformation studies by fungi. The HPLC analysis was conducted using a Lichrospher 100 RP18 column, acetonitrile-40 mmol/L formic acid solution (60:40, v/v) as mobile phase, and ultraviolet detection at 290 nm. The sample preparation was conducted by liquid-liquid extraction using ethyl acetate as extractor solvent. The method was linear over the concentration range of 0.4-40.0 µg/mL for midodrine (r ≥ 0.9997) and DMAE (r ≥ 0.9998). Within-day and between-day precision and accuracy were evaluated by relative standard deviations (≤ 8.2%) and relative errors (-7.3 to 7.4%), respectively. The validated method was used to assess midodrine biotransformation by the fungi Papulaspora immersa Hotson SS13, Botrytis cinerea UCA 992 and Botrytis cinerea 2100 under static and shaken conditions. Under shaken conditions, the biotransformation of midodrine to DMAE was more efficient for all studied fungi, especially for the fungus Botrytis cinerea 2100, which converted 42.2% of midodrine to DMAE.
Subject(s)
Ascomycota/metabolism , Batch Cell Culture Techniques/methods , Botrytis/metabolism , Chromatography, High Pressure Liquid/methods , Culture Media/analysis , Midodrine/analogs & derivatives , Midodrine/metabolism , Ascomycota/growth & development , Batch Cell Culture Techniques/instrumentation , Biotransformation , Botrytis/growth & development , Culture Media/metabolism , Midodrine/analysisABSTRACT
The pharmacokinetics of midodrin (alpha-2,5-dimethoxyphenyl-beta-glycinamidoethanol hydrochloride, ST 1085) and its main metabolite ST 1059 (alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride) have been investigated in 12 male healthy volunteers. 2.5 mg midodrin hydrochloride were applied intravenously, as drinking solution or as tablet (Gutron) according to a randomized cross-over design. Plasma and urine samples collected up to 24 h after application were analyzed by high-performance liquid chromatography with fluorescence detection. The mean maximum concentration in plasma for midodrin was ca. 10 ng/ml 20-30 min after oral administration, for ST 1059 ca. 5 ng/ml after 1 h. Midodrin was eliminated with a terminal half-life of 0.5 h. The half-life of ST 1059 was determined to be 3 h. The mean area under the plasma-level vs. time curve (AUC) of ST 1059 after administration of 2.5 mg midodrin i.v. was 28.7 ng X h/ml, and as drinking solution or as tablet 25.7 and 25.6 ng X h/ml, respectively. The data of 10 volunteers could be used for the calculations of the bioavailability of ST 1059 by the AUC. Assuming an interval of equivalence of 0.75-1.25 because of the relatively small number of volunteers, the three galenical formulations are considered to be equivalent.
Subject(s)
Adrenergic alpha-Agonists/metabolism , Ethanolamines/metabolism , Midodrine/metabolism , Administration, Oral , Adrenergic alpha-Agonists/administration & dosage , Adrenergic alpha-Agonists/blood , Adult , Biological Availability , Chromatography, High Pressure Liquid , Humans , Injections, Intravenous , Kinetics , Male , Midodrine/administration & dosage , Midodrine/analogs & derivatives , Midodrine/bloodABSTRACT
ST 1059, the pharmacologically active metabolite of midodrine, is a powerful vasoconstrictor compound, acting by stimulation of alpha-receptors. It elicited 80% of noradrenaline-induced contraction of human veins.
Subject(s)
Dihydroergotamine/pharmacology , Ethanolamines/pharmacology , Etilefrine/pharmacology , Midodrine/pharmacology , Norepinephrine/pharmacology , Phenylephrine/analogs & derivatives , Vasoconstrictor Agents , Humans , In Vitro Techniques , Midodrine/analogs & derivatives , Muscle, Smooth, Vascular/drug effects , Veins/drug effectsABSTRACT
Midodrine hydrochloride is a peripheral alpha(1)-adrenoreceptor agonist that induces venous and arterial vasoconstriction. Midodrine, after oral or intravenous administration, undergoes enzymatic hydrolysis and releases deglymidodrine, a pharmacologically active metabolite. Midodrine and deglymidodrine have a chiral carbon in the 2-position. To investigate the bioactivity of racemates and enantiomers of the drug and metabolite, three chromatographic chiral stationary phases, Chiralcel OD-H, Chiralcel OD-R, and alpha(1)-AGP, were evaluated for enantiomeric resolution. Good enantioseparation of midodrine racemate was obtained using the Chiralcel OD-H column. This stationary phase was then used to collect separately the midodrine enantiomers. By alkaline hydrolysis of rac-midodrine and each separated enantiomer, rac-deglymidodrine and its enantiomers were prepared. The control of the enantiomeric purity was carried out by alpha(1)-AGP stationary phase, while the hydrolysis of rac-midodrine and its enantiomers was controlled by capillary electrophoresis using trimethyl-beta-cyclodextrin as chiral selector. The pharmacological activity of the two racemates and the two enantiomeric pairs was tested in vitro on a strip of rabbit descending thoracic aorta. The tests continued that the activity of the drug and metabolite is due only to the (-)-enantiomer because neither of the (+)-enantiomers is active.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Midodrine/analogs & derivatives , Midodrine/chemistry , Midodrine/pharmacology , Adrenergic alpha-Agonists/chemistry , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/pathology , Carbon/chemistry , Dose-Response Relationship, Drug , Electrophoresis, Capillary , Hydrolysis , Models, Chemical , Rabbits , StereoisomerismABSTRACT
In urethane anaesthetized rats 1 mg/kg i.v. alpha-2,5-dimethoxyphenyl-beta-glycinamidoethanol hydrochloride (midodrine, Gutron) or 0.1 mg/kg of its main metabolite alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride (ST 1059) do not increase the uterine motility while these doses elevate the arterial blood pressure, 5 mg/kg midodrine or 0.3 mg/kg ST 1059 increase the uterine motility with concomitant increases in blood pressure and decreases in heart rate. It is concluded that midodrine does not enhance the uterine activity in doses clinically used for the treatment of hypotensive circulatory disorders.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Ethanolamines/pharmacology , Midodrine/pharmacology , Uterine Contraction/drug effects , Animals , Blood Pressure/drug effects , Female , Midodrine/analogs & derivatives , Rats , Rats, Inbred StrainsABSTRACT
We have developed an experimental urinary incontinence model in anesthetized female rabbits, in order to study the effects of alpha-adrenergic receptor agonists on it in vivo. Micturition was induced artificially by electrical stimulation of the abdomen of rabbits receiving a continuous infusion of glucose-free. Tyrode's solution into the urinary bladder. Alpha-1 adrenergic agonists, phenylephrine (1 mg/kg, i.v.) and the newly synthesized agent ST-1059 (1 mg/kg, i.v.) and its prodrug midodrine (10 mg/kg), which was intraduodenally administered, elevated the bladder pressure and arrested micturition induced by electrical stimulation. Prazosin (0.1 mg/kg, i.v.) inhibited these effects of phenylephrine. The effect of an alpha-2 agonist, clonidine (1 mg/kg, i.v.), on micturition induced by electrical stimulation was not clearly defined. This study demonstrates that alpha-1 adrenergic agonists can arrest artificially-induced micturition via urethral contraction. This method may be useful for evaluating the effect of a drug on urethral leakage in vivo.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Midodrine/analogs & derivatives , Midodrine/pharmacology , Urinary Incontinence/physiopathology , Urination/drug effects , Adrenergic alpha-Antagonists/pharmacology , Animals , Electric Stimulation , Female , Rabbits , Urinary Bladder/drug effectsABSTRACT
The alpha-adrenoceptor agonist ST-1059 (2-amino-1-(2,5-dimethoxyphenyl) ethanol), the alpha 1-adrenoceptor agonist methoxamine, the alpha 2-adrenoceptor agonist clonidine and a nonselective alpha-adrenoceptor agonist norepinephrine, all increase cardiac output and dose-dependently increase arterial blood pressure in spinally anesthetized ganglion-blocked dogs. The increase in cardiac output may be the result of an increased venous return via the contraction of capacitance vessels, and the vasopressor responses are attributed to an increase in total peripheral resistance. The increases in cardiac output and pressor responses induced by ST-1059 and methoxamine were antagonized by the alpha 1-adrenoceptor antagonist prazosin (0.3 mg/kg i.v.), but those induced by clonidine were not inhibited. In contrast, the alpha 2-adrenoceptor antagonist yohimbine (0.3 mg/kg i.v.) had little or no effects on the increase in cardiac output or the pressor responses induced by ST-1059 and methoxamine, but strongly attenuated those of clonidine. Prazosin and yohimbine inhibited the norepinephrine-induced increase in cardiac output and pressor responses. These results suggest that the increases in cardiac output and blood pressure induced by ST-1059 were mediated by postjunctional alpha 1-adrenoceptor stimulation, such as by methoxamine, but that those induced by clonidine were mediated by postjunctional alpha 2-adrenoceptor stimulation in dogs. Not only the postjunctional alpha 1-adrenoceptors but also the postjunctional alpha 2-adrenoceptors may play an important role in the constriction of venous beds, as well as of the arterioles in spinally anesthetized ganglion-blocked dogs.