Role of cardiac α1-adrenoreceptors for the torsadogenic action of IKr blocker nifekalant in the anesthetized atrioventricular block rabbit.

We analyzed role of cardiac α1-adrenoreceptors for the torsadogenic action of IKr blocker nifekalant in isoflurane-anesthetized atrioventricular block rabbits. Bradycardia was induced by atrioventricular node ablation, and the ventricle was electrically driven at a constant rate of 60 beats/min throughout the experiments to prevent rate-dependent modification by the IKr blocker in ventricular repolarization phase. Nifekalant (3 mg/kg per 10 min, n = 5) prolonged the duration of monophasic action potential (MAP90) by +178 ± 43 ms, increased the short-term variability of repolarization (STV) to 4.2 ± 1.2 ms, and induced torsade de pointes (TdP) in 1 animal. In the presence of methoxamine (n = 5), nifekalant prolonged the MAP90 by +328 ± 32 ms, increased the STV to 8.0 ± 1.0 ms, and induced TdP in 2 animals. In the presence of prazosin and methoxamine (n = 5), nifekalant prolonged the MAP90 by +267 ± 22 ms, increased the STV to 9.2 ± 3.6 ms, and induced no TdP. These results suggest that cardiac α1-adrenoreceptor activation by methoxamine essentially sensitizes the rabbit heart to nifekalant-induced QT interval prolongation, leading to the onset of TdP.

The efficacy and safety of pre-emptive methoxamine infusion in preventing hypotension by in elderly patients receiving spinal anesthesia: A PRISMA-compliant protocol for systematic review and meta-analysis.

BACKGROUND: Hypotension is frequent after spinal anesthesia, especially in elderly patients. Whether pre-emptive methoxamine infusion is effective and safe to prevent spinal anesthesia-induced hypotension is still a controversial issue, to dress this knowledge lack, we performed a systemic review and meta-analysis to evaluated it. PARTICIPANTS: Elderly patients undergoing spinal anesthesia. INTERVENTIONS: Administration of methoxamine prior to spinal anesthesia. METHODS: We searched PUBMED, Cochrane Library, EMBASE, China National Knowledge Infrastructure, Wanfang Database, and VIP Database, Chinese BioMedical Literature & Retrieval System from January 1st 1978 to February 28th 2022. Primary outcomes of interests included hemodynamic parameters, such as systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate. Secondary outcomes of interests included the incidence of intraoperative hypotension, bradycardia, nausea and vomiting, vasopressors requirement, intraoperative blood loss. For continuous or dichotomous variables, treatment effects were calculated as weighted mean difference or odds ratio, respectively. RESULTS: Our search yielded 8 randomized controlled trials including 480 patients, and 240 patients were allocated into methoxamine group and 240 into control group. Meta-analysis demonstrated that pre-emptive methoxamine infusion in preventing hypotension by in elderly patients receiving spinal anesthesia had higher blood pressures, lower heart rates. Compared with the control group, the incidence of perioperative hypotension in elderly patients was lower, and elderly patients had less requirement for vasopressor in methoxamine group. CONCLUSION: This meta-analysis demonstrated that pre-emptive methoxamine infusion in elderly patients receiving spinal anesthesia can improve blood pressure, slow down heart rate, reduce the incidence of hypotension and requirement for vasopressor. However, these findings should be interpreted rigorously. Further well-conducted trials are required to confirm this.

Augmentation index in the assessment of wave reflections and systolic loading.

BACKGROUND: Augmentation index (AIx) is used to quantify the augmented systolic aortic pressure that impedes ventricular ejection. Its use as an index of wave reflections is questionable. We hypothesize that AIx is quantitatively different from the reflection coefficient under varied physiological conditions. METHODS: 42 datasets of aortic pressure and flow waveforms were obtained during induced hypertension (methoxamine infusion) and vasodilation (nitroprusside infusion) in our mongrel dog experiments (n = 5) and from Mendeley data during various interventions (vasoconstrictors, vasodilators, pacing, stimulation, hemorrhage and hemodilution). Wave reflections and principal components of reflection coefficients were computed for comparison to AIx and heart rate normalized AIx. RESULTS: Principal reflection coefficient, Γ1, increased in hypertension and decreased in vasodilation, hemorrhage and hemodilution. AIx followed the trend in many cases but was consistently lower than Γ1 in almost all the subjects. The Bland-Altman analysis also showed that both AIx and normalized AIx underestimated Γ1. The relationship between augmentation index and reflection coefficient was explained by a linear regression model (r2 = 0.23, p < 0.01) in which AIx followed directional changes in Γ1 and the normalization of AIx resulted in a linear model that explained less variation in the relationship between AIx and Γ1. CONCLUSION: AIx is a reasonable clinical trend indicator, albeit not an accurate surrogate measure of the amount of wave reflections.

Dose-dependent effects of intravenous methoxamine infusion during hip-joint replacement surgery on postoperative cognitive dysfunction and blood TNF-α level in elderly patients: a randomized controlled trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD), common in elderly patients, is thought to be closely associated with intraoperative instability of hemodynamics and excessive excretion of tumor necrosis factor-α (TNF-α). Methoxamine is a blood-pressure increasing drug commonly used for maintaining intraoperative hemodynamics. Methoxamine potentially promotes TNF-α expression, leading to an increased risk of POCD. This study aimed to investigate the dose-dependent effect of methoxamine on the incidence of early POCD and blood TNF-α level. METHODS: This single-center prospective double-blind controlled clinical trial included a total of 300 adult patients (75-90 years old, American Society of Anesthesiologists class II-III) who underwent unilateral hip-joint replacement surgery under epidural anesthesia. Patients were randomly divided into three methoxamine groups (M1, M2, and M3), and one control group (n = 75 per group). During surgery, M1, M2, and M3 patients received intravenous infusion of methoxamine at 2, 3, or 4 µg·kg-1·min-1, respectively; the control group received saline of same volume at the same infusion rate. All patients received standard transfusion to maintain stable circulation. Hemodynamics, cardiovascular events, and serum TNF-α levels were monitored. Mini Mental State Examination was performed both before and after surgery to diagnose POCD. RESULTS: The primary outcome of this study was the incidence of POCD, which was higher in the M3 group (18.7%) than in the control group (5.3%), the M1 group (6.7%), or the M2 group (6.7%) (all P < 0.05). The secondary outcomes were the postoperative blood TNF-α level and intraoperative hemodynamic parameters. The postoperative TNF-α level was found to be higher than baseline in all groups and was highest in M3 patients (P < 0.05). The intraoperative hemodynamic parameters showed improved stability in the M1 and M2 groups compared with the control group. However, in the M3 group, abnormally increased intraoperative blood pressure, cardiac output, and systolic stroke volume were observed. CONCLUSIONS: Intravenous infusion of methoxamine at 2-3 µg·kg-1·min-1 can maintain stable hemodynamics in elderly patients during epidural anesthesia for hip-joint replacement surgery, without increasing the incidence of POCD. Increasing the dose to 4 µg·kg-1·min-1 provided no further advantages but induced adverse effects on the intraoperative hemodynamics. TRIAL REGISTRATION: Chinese Clinical Trial Register (Unique identifier: ChiCTR-INR-15007607 , retrospectively registered 18 Dec 2015).

Libertas: a phase II placebo-controlled study of NRL001 in patients with faecal incontinence showed an unexpected and sustained placebo response.

PURPOSE: Faecal incontinence (FI) is distressing, significantly reduces quality of life (QoL) and has few pharmacological treatments. The α1-adrenoceptor agonist NRL001 (1R,2S-methoxamine hydrochloride) improves anal sphincter tone. NRL001 efficacy was evaluated by changes in Wexner scores at week 4 vs. baseline in NRL001-treated patients compared with placebo. Impact of NRL001 on QoL and safety were also assessed. METHODS: Four hundred sixty-six patients received NRL001 (5, 7.5 or 10 mg) or placebo as suppository, once daily over 8 weeks. Wexner score, Vaizey score and QoL were analysed at baseline, week 4 and week 8. FI episodes and adverse events were recorded in diaries. RESULTS: At week 4, mean reductions in Wexner scores were -3.0, -2.6, -2.6 and -2.4 for NRL001 5, 7.5, 10 mg and placebo, respectively. All reduced further by week 8. As placebo responses also improved, there was no significant treatment effect at week 4 (p = 0.6867) or week 8 (p = 0.5005). FI episode frequency improved for all patients, but not significantly compared with placebo (week 4: p = 0.2619, week 8: p = 0.5278). All patients' QoL improved, but not significantly for all parameters (p > 0.05) except depression/self-perception at week 4 (p = 0.0102) and week 8 (p = 0.0069), compared with placebo. Most adverse events were mild and judged probably or possibly related to NRL001. CONCLUSIONS: All groups demonstrated improvement in efficacy and QoL compared with baseline. NRL001 was well-tolerated without serious safety concerns. Despite the improvement in all groups, there was no statistically significant treatment effect, underlining the importance of relating results to a placebo arm.

Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights.

AIMS: The application of α-adrenoceptor agonists can improve faecal incontinence symptoms. The aim of this study was to investigate the pharmacokinetic and systemic effects of NRL001 administered as different strengths in 1 or 2 g suppositories. METHODS: This randomised, double-blind, placebo controlled study included 48 healthy subjects. Group 1 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 5, 7.5 or 10 mg NRL001, or matching placebo. Group 2 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 10, 12.5 or 15 mg NRL001, or matching placebo. Doses were given in an escalating manner with placebo at a random position within the sequence. RESULTS: Tmax was at ~4.5 h post-dose for all NRL001 doses. Median AUC0-tz , AUC0-∞ and Cmax increased with increasing dose for both suppository sizes. The estimate of ratios of geometric means comparing 2 g with 1 g suppository, and regression analysis for dose proportionality, was close to 1 for the variables AUC0-tz , AUC0-∞ and Cmax (P > 0.05). For both suppository sizes, 20-min mean pulse rate was significantly decreased compared with placebo with all doses (P < 0.05). Blood pressure decreased overall. There were 144 adverse events (AEs) and no serious AEs reported during the study. All AEs were mild in severity. CONCLUSIONS: The regression analysis concluded that the doses were dose proportional.

A randomised, controlled, crossover study to investigate the pharmacodynamics, pharmacokinetics and safety of 1R,2S-methoxamine hydrochloride (NRL001) in healthy elderly subjects.

AIMS: This study aimed to assess the effects of a single dose of 10 mg NRL001 (the 1R,2S stereoisomer of methoxamine hydrochloride) in a 2 g suppository on pharmacodynamic and pharmacokinetic (PK) variables, and safety, in a healthy elderly population. METHODS: This was a Phase I, single-centre, randomised, double-blind, placebo-controlled crossover study during which subjects received a single 2 g suppository of 10 mg NRL001 and a matching placebo in two separate treatment periods. The main outcome measures were Holter-, vital signs- and electrocardiogram-derived cardiovascular variables; plasma PK analysis; and safety assessments. RESULTS: Twenty-six subjects were dosed with study medication. Statistically significant reductions in Holter-derived heart rate (HR), vital signs-derived HR and diastolic blood pressure (BP) were observed comparing NRL001 with placebo treatment, and also with increasing NRL001 plasma concentration. No statistically significant relationships were observed between NRL001 concentration and systolic BP, mean arterial pressure or QTC interval (both Bazett's and Fridericia's correction). Thirty-nine adverse events were reported in 20 (76.9%) subjects, mostly after dosing with NRL001. CONCLUSION: Administration of NRL001 suppositories led to decreases in HR when compared with placebo data. NRL001 was well tolerated with a good safety profile during the study. Healthy elderly subjects did not show significantly different biological responses to NRL001 suppositories compared with younger healthy volunteers in previous studies.

Libertas: rationale and study design of a multicentre, Phase II, double-blind, randomised, placebo-controlled investigation to evaluate the efficacy, safety and tolerability of locally applied NRL001 in patients with faecal incontinence.

AIMS: Faecal incontinence affects up to 8% of adults. Associated social isolation and subsequent depression can have devastating effects on quality of life (QoL). Faecal incontinence is an underreported health problem as the social isolation and stigma that patients experience makes it difficult for sufferers to discuss their condition with a physician. There have been few well-designed, placebo-controlled clinical trials of treatment for faecal incontinence and little clinical evidence is available to inform the most appropriate management strategies. Libertas, a robustly designed study will investigate the efficacy and safety of NRL001 (1R,2S-methoxamine), an α1 -adrenoceptor agonist, in the treatment of faecal incontinence. METHODS: Libertas is a multicentre, Phase II, double-blind, randomised, placebo-controlled, parallel group study. Patient recruitment took place across 55 study centres in Europe. Patients suffering with faecal incontinence were randomised into four groups (approximately 110 each) to receive once daily self-administered doses of NRL001 (5, 7.5 or 10 mg or placebo in a suppository formulation) for 8 weeks. The primary objective of Libertas is to assess the impact of once daily administration of NRL001 on the severity and frequency of incontinence episodes as assessed by the Wexner score at 4 weeks, compared with placebo. Secondary outcomes include measures of efficacy of NRL001 compared with placebo following 8 weeks treatment; safety and tolerability; evaluation of plasma pharmacokinetics; establishment of any pharmacokinetic/pharmacodynamic relationship to adverse events; dose-response relationship; the efficacy of NRL001 therapy at 4 and 8 weeks assessed by the Vaizey score; and QoL using the Faecal Incontinence Quality of Life and the EQ-5D-5L Healthcare Questionnaires following 4 and 8 weeks NRL001 therapy. Overall patient satisfaction with the treatment will also be evaluated. DISCUSSION: This is the first randomised controlled study to investigate the efficacy and safety of a selective α1 -adrenoceptor agonist for the treatment of faecal incontinence. Furthermore, this is the first time the impact of NRL001 on assessments of QoL, health outcomes and patient satisfaction will be assessed. Innovative strategies were developed to meet the challenge of recruiting patients for this study, for example, media advertising, posters and mailshots as allowed by each study centre.

Dexmedetomidine and clonidine inhibit ventricular tachyarrhythmias in a rabbit model of acquired long QT syndrome.

BACKGROUND: Agents with α-2 adrenoreceptor (AR) agonistic action have reportedly suppressed tachyarrhythmias. METHODS AND RESULTS: We hypothesized that α-2 AR agonists would have an inhibitory effect on abnormal repolarization-related ventricular tachyarrhythmias (VTs). To test this hypothesis, the effects of 2 clinically available α-2 AR agonists (dexmedetomidine and clonidine) on the occurrence of VTs were assessed in a methoxamine-sensitized rabbit model of acquired long QT syndrome (Study 1: n=45). In control rabbits, administration of methoxamine and nifekalant almost invariably caused VTs (14/15). In contrast, incidence of VT significantly decreased during the treatment with dexmedetomidine (1µg·kg(-1)·min(-1): 5/12 [P<0.01 vs. control]) or with clonidine (33.3µg·kg(-1)·min(-1): 10/18 [P<0.01]). To verify that VTs in this animal model are triggered by early afterdepolarization (EAD), the monophasic action potential on the left ventricular surface was recorded in 28 open-chest rabbits (Study 2). EAD-like hump was less frequently detected during treatment with clonidine or dexmedetomidine (2/14) than in saline-treated rabbits (9/10, P<0.005). Presence of a hump was significantly related to the advent of VTs (P<0.05). CONCLUSIONS: Agents with α-2 AR agonistic action have an inhibitory effect on VTs in a rabbit model of long QT syndrome. Alpha-2 AR agonists, especially dexmedetomidine, may be a therapeutic choice for abnormal repolarization-related VTs that are resistant to conventional treatment.

Assessment of the ion channel-blocking profile of the novel combined ion channel blocker AZD1305 and its proarrhythmic potential versus dofetilide in the methoxamine-sensitized rabbit in vivo.

AZD1305 is a novel antiarrhythmic agent under clinical evaluation for management of atrial fibrillation. This study assessed its ion channel-blocking potency by the whole cell patch-clamp technique in vitro and its proarrhythmic liability in anesthetized methoxamine-sensitized rabbits in comparison with dofetilide. AZD1305 predominantly blocked the hERG, the L-type calcium and the hNav1.5 currents in a concentration-dependent manner. In vivo AZD1305 increased the QT interval (from 145 +/- 8 to 196 +/- 18 ms, P < 0.01) without inducing ventricular extrasystoles or torsades de pointes (TdP). In contrast, dofetilide prolonged the QT interval from 161 +/- 3 to 256 +/- 15 ms (P < 0.001) and caused TdP in 12/17 rabbits (P < 0.01 vs. AZD1305). During AZD1305 and dofetilide infusion, the QTend-peak interval maximally increased by 14 +/- 4 and 30 +/- 6 ms (P < 0.05 vs. AZD1305) and the beat-by-beat QT interval variability (quantified as the short-term variability, STV) changed from 2 +/- 0.8 to 2 +/- 0.3 ms (NS) and from 2 +/- 0.2 to 12 +/- 1.1 ms (P < 0.001), respectively. Following dofetilide-induced TdP, 6 rabbits each were injected with saline or AZD1305. In contrast to saline, AZD1305 abbreviated the QT interval (from 275 +/- 25 to 216 +/- 9 ms, P < 0.05), reduced the STV to 1 +/- 0.1 ms (P < 0.001) and suppressed TdP in all 6 rabbits (P < 0.01 vs. saline). In conclusion, AZD1305 can be characterised as a combined ion channel blocker that delays repolarization without increasing beat-by-beat variability of repolarization (BVR) or inducing TdP whereas selective IKr blockade by dofetilide prolongs the QT interval and eventually increases BVR resulting in TdP.

Intra-anal application of L-erythro methoxamine gel increases anal resting pressure in patients with incontinence.

BACKGROUND: This study examined the effects of a single dose of intra-anal L-erythro methoxamine on mean anal resting pressure (MARP) and cardiovascular variables in patients with faecal incontinence. METHODS: Patients had anorectal physiology tests and ultrasonography before participating. Six patients received 0.3 and 1 per cent gels on separate days, two patients received 0.3 per cent gel, and two patients received 1 per cent gel. MARP, blood pressure, pulse rate and plasma drug concentrations were measured for 6 h after application. RESULTS: Intra-anal 0.3 per cent gel caused a rapid, significant rise in MARP lasting 2 h (P = 0.036). In four of these patients, the response was sufficient to increase MARP to within the normal range at 2 h. Application of 1 per cent gel caused a significant rise in MARP for 4 h after application (P = 0.028). There was a significant decrease in pulse at 2 and 1 h respectively after application of 0.3 and 1 per cent gels. CONCLUSION: Intra-anal application of L-erythro methoxamine can be used to increase MARP in patients with faecal incontinence. Application of 1 per cent L-erythro methoxamine gel produced a rapid, sustained rise in MARP, which raises the possibility of therapeutic application.

Successful treatment of retrograde ejaculation with the alpha1-adrenergic agonist methoxamine: case study.

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.

Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, double-blind crossover study.

The aim of the study was to evaluate the potential role for a selective alpha1-adrenoceptor agonist in the treatment of urinary stress incontinence. A randomised, double-blind, placebo-controlled, crossover study design was employed. Half log incremental doses of intravenous methoxamine or placebo (saline) were administered to a group of women with genuine stress incontinence while measuring maximum urethral pressure (MUP), blood pressure, heart rate, and symptomatic side effects. Methoxamine evoked non-significant increases in MUP and diastolic blood pressure but caused a significant rise in systolic blood pressure and significant fall in heart rate at maximum dosage. Systemic side effects including piloerection, headache, and cold extremities were experienced in all subjects. The results indicate that the clinical usefulness of direct, peripherally acting sub-type-selective alpha1-adrenoceptor agonists in the medical treatment of stress incontinence may be limited by associated piloerection and cardiovascular side effects.

Use of vasopressors to raise cerebral perfusion pressure in head injured patients.

Cerebral ischemia due to low cerebral perfusion pressure (CPP) is the most important secondary effect of severe head injury. There is consensus regarding the maintenance of this pressure at levels above 70 mm Hg. One way to elevate CPP is by increasing mean arterial pressure (MAP). In this study, the authors attain this target by using adrenergic vasopressors investigating the effectiveness of dopamine, noradrenaline and methoxamine in 16 severe head injured patients. The results were: a) the increase of MAP effectively increased CPP without changes in intracranial pressure (ICP) and cerebral extraction of oxygen (CEO2); b) noradrenaline at a dose of 0.5 mg to 5 mg/h was effective and safe and might be considered the drug of choice; c) dopamine was not as effective at a high dose of 10 to 42.5 micrograms/kg/min; d) methoxamine given as a bolus was an effective way to control sudden decreases in MAP. It made the patients more responsive to dopamine. No important undesirable reactions occurred during the study.

Porcine hepatic response to sepsis and its amplification by an adrenergic receptor alpha1 agonist and a beta2 antagonist.

1. We investigated the effect of adrenergic receptor stimulation or inhibition on the hepatic ultrastructural changes in a porcine faecal peritonitis model of multi-organ failure. We infused either the alpha1 adrenergic receptor agonist methoxamine or the beta2 adrenergic receptor antagonist ICI 118551 during 8 h of the study.2. Anaesthetized pigs (25-30 kg) were divided into four non-septic groups (control, non-septic, non-septic methoxamine and non-septic ICI 118551) and three septic groups (septic, septic methoxamine and septic ICI 118551).3. Changes in hepatic ultrastructure were measured by morphometric analysis. The septic group was significantly worse than all the non-septic groups. Septic methoxamine and septic ICI 118551 were significantly worse than the septic group.4. Septic methoxamine and septic ICI 118551 had a significantly increased perisinusoidal space; septic methoxamine had significant hepatocyte vacuolation.5. Hepatic ultrastructural changes were independent of hepatic blood flow.6. Septic methoxamine had significant myocardial depression.7. The alpha1 adrenergic receptor agonist methoxamine or the beta2 antagonist ICI 118551 both amplified the hepatic injury normally found during sepsis in our porcine model.8. These findings suggest that during sepsis a protective endogenous beta2 adrenergic receptor-mediated anti-inflammatory response is activated via cell membrane transduction to stimulate the trimeric G-protein complex Gs and activate the second cell messenger cAMP.9. In addition, it is likely that alpha1 adrenergic receptor agonists amplify the inflammatory response by stimulating the cell-surface receptor-linked trimeric G-protein complex to activate Gq and the second cell messenger phospholipase C.

Comparison of the effects of clonidine on tyramine- and methoxamine-evoked mydriasis in man.

1. It has been reported previously that clonidine can potentiate tyramine-evoked mydriasis on the pain-free side of cluster headache patients. We examined whether a single oral dose of clonidine (200 micrograms) can also potentiate tyramine-evoked mydriasis in healthy subjects, using mydriasis to methoxamine, a directly acting sympathomimetic amine, as a control. 2. Eight healthy male volunteers participated in four weekly sessions. In the first two sessions (Experiment 1) the effect of clonidine or placebo on the mydriasis to tyramine hydrochloride eyedrops (75 mM; 2 x 10 microliters), and in the last two sessions (Experiment 2) the effect of clonidine or placebo on the mydriasis to methoxamine hydrochloride eyedrops (20 mM; 2 x 10 microliters) was examined. In both experiments subjects were allocated to drugs and sessions according to a double-blind balanced design. In both experiments, pupil diameter of both the treated and the untreated eyes was recorded in standard ambient light and in the dark, before, and 2 h after clonidine/placebo, via binocular infrared television pupillometry. Salivation (dental roll technique), systolic and diastolic blood pressure (sitting), heart rate, and self-ratings of mood and feelings (visual analogue scales), were also measured before, and 2 h after the ingestion of clonidine or placebo. 3. Both tyramine and methoxamine produced a significant mydriasis, which was more prominent in the light condition (change in resting pupil size; mm +/- s.e.mean: tyramine/light 1.05 +/- 0.28; tyramine/dark: 0.73 +/- 0.15; methoxamine/light: 1.65 +/- 0.28; methoxamine/dark: 0.85 +/- 0.15). Clonidine produced a significant miosis in the untreated eye which was more prominent in the light condition (change in resting pupil size; mm +/- s.e.mean: Experiment 1, light: -1.34 +/- 0.19; Experiment 1, dark: -0.46 +/- 0.1; Experiment 2, light -0.97 +/- 0.18; Experiment 2, dark: -0.29 +/- 0.17). Clonidine had no significant effect on either tyramine- or methoxamine-evoked mydriasis. 4. In agreement with previous reports, clonidine significantly reduced salivation (g, mean +/- s.e.mean; Experiment 1: -0.84 +/- 0.22; Experiment 2: -0.55 +/- 0.11), systolic blood pressure (mm Hg; Experiment 1: -17.5 +/- 3.76; Experiment 2: -23.38 +/- 4.67), diastolic blood pressure (mm Hg; Experiment 2: -12.38 +/- 2.05), alertness (mm; Experiment 2: -24.19 +/- 5.40), and anxiety (mm; Experiment 1: -13.82 +/- 4.60), indicating the presence of pharmacodynamically effective tissue levels of the drug. 5. These results show that a single oral dose (200 micrograms) of clonidine causes significant miosis in human subjects, and fails to potentiate tyramine-evoked mydriasis. This indicates that the pupil on the asymptomatic side of cluster headache patients is affected differently from the pupils of healthy volunteers by tyramine and/or clonidine.

Coronary artery spasm with ventricular tachycardia after administration of methoxamine during cervical epidural anesthesia--a case report.

Coronary artery spasm occurred during thoracotomy under cervical epidural anesthesia in a 60-year-old male patient who had no prior history of myocardial ischemia. It is most likely that the administration of methoxamine induced the spasm. Hypotension and venodilatation induced by the epidural anesthesia and increased vagal tone might also contribute to the spasm.

Influence of tachycardia and arterial hypertension on infarct size in the pig.

To investigate the clinically important but controversial question of how hypertension during coronary occlusion affects infarct size 24 pigs underwent 1 h occlusion of the mid left anterior descending coronary artery and 24 h reperfusion and were randomised to one of three treatment groups. In group 1 blood pressure was increased during the occlusion period by an infusion of methoxamine; in group 2 tachycardia was induced by atrial pacing; and in group 3 no intervention was performed. The area at risk and infarct size were quantified by digital planimetry of slices of myocardium previously marked with fluorescein and with triphenyl-tetrazolium. Methoxamine maintained mean aortic blood pressure at 117 (SEM8) mmHg during occlusion, whereas the values were 80(6) mmHg in group 2 and 67(9) mmHg in group 3. Pacing increased heart rate to 146(1) beats.min-1 in group 2; it was 103(5) in group 1 and 99(8) in group 3. The pressure-rate product achieved was similar in groups 1 and 2 and significantly higher than in group 3. The pathological studies showed infarct size to be moderately but significantly larger in group 1 (14[3.5]% of the left ventricle) and similar in groups 2 (10.5[3.9]%) and 3 (10.1[2.2]%). The ratio of infarct size to area at risk was also significantly higher (0.743[0.057]) in group 1 with no differences between group 2 (0.604[0.055]) and group 3 (0.613[0.027]). At similar pressure-rate product, infarct size was thus greater with hypertension but not with pacing alone, showing a deleterious effect of increasing blood pressure in this experimental model with negligible collateral blood flow.