Infusion Of Methoxamine Research Articles

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.

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. Elderly patients undergoing spinal anesthesia. Administration of methoxamine prior to spinal anesthesia. 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. 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. 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.

The role of constant-speed pump infusion of methoxamine in lower limb tourniquet operation in patients with diabetes mellitus

The role of constant-speed pump infusion of methoxamine in lower limb tourniquet operation in patients with diabetes mellitus

A randomised dose-response study of prophylactic Methoxamine infusion for preventing spinal-induced hypotension during Cesarean delivery

Backgroundα-receptor agonists have been reported to be safe and effective for treating or preventing spinal-induced hypotension during cesarean delivery. As a pure α1 adrenergic agonist, methoxamine has potential advantages of reducing myocardial oxygen consumption and protecting the heart in obstetric patients compared to phenylephrine. The aim of this study was to determine the optimal prophylactic methoxamine infusion dose that would be effective for preventing spinal-induced hypotension in 50% (ED50) and 95% (ED95) of parturients.MethodsEighty parturients with a singleton pregnancy scheduled for elective cesarean delivery were randomly allocated to receive prophylactic methoxamine infusion at one of four different fixed-rates: 1 μg/kg/min (group M1), 2 μg/kg/min (group M2), 3 μg/kg/min (group M3), or 4 μg/kg/min (group M4). An adequate response was defined as absence of hypotension (maternal SBP < 80% of baseline or SBP < 90 mmHg). The values for ED50 and ED95 of prophylactic methoxamine infusion were determined by probit regression model. The outcomes of maternal hemodynamics and fetal status were compared among the groups.ResultsThe calculated ED50 and ED95 (95% confidence interval) of prophylactic methoxamine infusion dose were 2.178 (95% CI 1.564 to 2.680) μg/kg/min and 4.821 (95% CI 3.951 to 7.017) μg/kg/min, respectively. The incidence of hypotension decreased with increasing methoxamine infusion dose (15/20, 11/20, 7/20 and 2/20 in group M1, M2, M3 and M4 respectively, P < 0.001). 1-min Apgar scores and umbilical arterial PaO2 were lower but umbilical arterial PaCO2 was higher in Group M1. No difference was found in the other incidence of adverse effects and neonatal outcomes among groups.ConclusionsUnder the conditions of this study, when prophylactic methoxamine infusion was given at a fixed-rate based on body weight for preventing spinal-induced hypotension in obstetric patients, the values for ED50 and ED95 were 2.178 μg/kg/min and 4.821 μg/kg/min respectively.Clinical trial registrationChinese Clinical Trial Registry (ChiCTR), registry number of clinical trial: ChiCTR-1,800,018,988, date of registration: October 20, 2018.

Effect of continuous intraoperative infusion of methoxamine on renal function in elderly patients undergoing gastrointestinal tumor surgery: a randomized controlled trial

BackgroundAcute renal injury (AKI) caused by hypotension often occurs in elderly patients after gastrointestinal tumor surgery. Although vasoactive drugs can increase effective filtration pressure, they may increase renal vascular resistance and reduce renal blood flow. The effect of methoxamine on renal function is not clear.MethodsAfter obtaining written informed consent, 180 elderly patients undergoing elective gastrointestinal tumor surgery were randomly allocated into two groups: M group (continuous infusion of methoxamine at 2 μg/kg/min) and N group (continuous infusion of normal saline). The patients’ mean arterial pressure was maintained within 20% of baseline by a continuous infusion of methoxamine or normal saline. Maintenance fluid was kept at 5 mL/kg/h. According to Kidney disease improve global outcome (KDIGO) guidelines, creatinine was measured at 1, 2 and 7 days after operation, and urine volume at 6, 12 and 24 h after operation was measured to evaluate the occurrence of AKI. 162 patients were included in the final data analysis.ResultsSignificant differences in the incidence of postoperative Acute kidney injury (M group: 7.5%; N group: 18.3%; P < 0.05), the frequency of hypotension (M group: 1 [1–3]; N group: 3 [1–5]; P < 0.05), and the duration of intraoperative hypotension (M group: 2[0–10]; N group: 10 [5–16]; P < 0.05) were identified between the groups. Multivariate logistic regression analyses demonstrated that preoperative creatinine and the frequency of intraoperative hypotension were the common factors leading to the occurrence of postoperative AKI. The results of Cox multivariate analysis showed that age and AKI were independent risk factors for 30-day death.ConclusionCompared with the intraoperative continuous infusion of placebo and methoxamine, continuous infusion of 2 μg/kg/min methoxamine reduced the incidence of postoperative AKI and other clinical complications in elderly patients undergoing gastrointestinal surgery by raising blood pressure and improved the prognosis of patients.Trial registrationTrial registration: Chinese Clinical Trial Registry, ChiCTR1900020536, registered 7 January, 2019,

Cardiovascular Responses to 5-hydroxytryptamine in Methimazole-induced Hypothyroid Pithed Rats

Patients suffering from hypothyroidism tend to develop diastolic hypertension. 5-Hydroxytryptamine (5-HT) is an amine that contributes to the maintenance of the blood pressure through central and peripheral 5-HT receptors. Curiously, the hypothyroidism alters the density of the 5-HT receptors in rodent brains. Analyze the effect of the methimazole-induced hypothyroidism on the peripheral cardiovascular responses elicited by 5-HT. The vasopressor and tachycardic responses to 5-HT (3-300μg/kg), and the vasodepressor responses to 5-HT, 5-carboxamidotryptamine (5-CT, 0.001-0.1μg/kg), isoprenaline (0.03-1μg/kg) and acetylcholine (ACh, 0.03-3μg/kg), during an infusion of methoxamine, were determined in pithed hypothyroid rats. The tachycardic and vasopressor responses to 5-HT and the vasodepressor responses to 5-CT and ACh remained unaffected, the vasodepressor response to 5-HT reduced, and the vasodepressor response to isoprenaline enhanced and reduced at the lowest and highest dose, respectively. These results suggest that hypothyroidism impairs the vasodepressor response to 5-HT, which could contribute to hypothyroidism-induced hypertension.

Augmentation index in the assessment of wave reflections and systolic loading

BackgroundAugmentation 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. Methods42 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. ResultsPrincipal 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. ConclusionAIx is a reasonable clinical trend indicator, albeit not an accurate surrogate measure of the amount of wave reflections.

Functional Characterization of the Prejunctional Receptors Mediating the Inhibition by Ergotamine of the Rat Perivascular Sensory Peptidergic Drive

Calcitonin gene-related peptide (α-CGRP) released from perivascular sensory nerves induces decreases in diastolic blood pressure (DBP). Experimentally, this can be shown by spinal thoracic (T9-T12) electrical stimulation of these afferent fibers. Because ergotamine inhibits these neurogenic vascular responses and displays affinity for monoaminergic receptors that inhibit neurotransmitter release, we investigated whether this ergotamine-induced inhibition results from activation of serotonin 5-HT1B/1D, dopamine D2-like, and α2-adrenergic receptors. Wistar rats were pithed and, under autonomic ganglion blockade, received intravenous infusions of methoxamine followed by ergotamine (0.1-3.1 μg kg-1 min-1). Thoracic T9-T12 electrical stimulation or an intravenous bolus of α-CGRP resulted in decreases in DBP. Ergotamine inhibited the electrically induced, but not α-CGRP-induced, responses. The vasodilator sensory inhibition by 3.1 μg of ergotamine kg-1 min-1 was resistant to simultaneous blockade of 5-HT1B/1D, D2-like, and α2-adrenergic receptors upon addition of antagonists GR127935, haloperidol, and rauwolscine. Moreover, the inhibition by 0.31 μg of ergotamine kg-1 min-1 was unaltered by GR127935 and haloperidol, partly blocked by GR127935 and rauwolscine or rauwolscine and haloperidol, and abolished by GR127935, haloperidol, and rauwolscine. These findings imply that prejunctional 5-HT1B/1D, D2-like, and α2-adrenergic receptors mediate the sensory inhibition induced by 0.31 μg of ergotamine kg-1 min-1, whereas larger doses may involve other receptors. Thus, ergotamine's ability to inhibit the perivascular sensory peptidergic drive may result in facilitation of its systemic vasoconstrictor properties.

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of \u03b12-adrenoceptors and 5-HT1 receptors

BackgroundDihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow.MethodsPithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure.ResultsDHE inhibited the vasodepressor responses to electrical stimulation (0.56–5.6 Hz), without affecting those to i.v. α-CGRP (0.1–1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-like; 310 μg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses.ConclusionDHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE’s vasoconstrictor properties resulting in an increased vascular resistance.

Pharmacological analysis of the inhibition produced by moxonidine and agmatine on the vasodepressor sensory CGRPergic outflow in pithed rats

Calcitonin gene-related peptide (CGRP) plays a role in several (patho)physiological functions, and modulation of its release is considered a therapeutic target. In this respect, electrical spinal (T9­-T12) stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. This study investigated the role of imidazoline I1 and I2 receptors in the inhibition by moxonidine and agmatine of these vasodepressor responses. Male Wistar pithed rats (pretreated i.v. with 25mg/kg gallamine and 2mg/kg⋅min hexamethonium) received i.v. continuous infusions of methoxamine (20μg/kg⋅min) followed by physiological saline (0.02ml/min), moxonidine (1, 3, 10 or 30μg/kg⋅min) or agmatine (1000 or 3000μg/kg⋅min). Under these conditions, electrical stimulation (0.56–5.6Hz; 50V; 2ms) of the spinal cord (T9-T12) produced frequency-dependent vasodepressor responses which were: (i) unchanged during saline infusion; and (ii) inhibited during the above infusions of moxonidine or agmatine. Moreover, using i.v. administrations, the inhibition by 3μg/kg⋅min moxonidine or 3000μg/kg⋅min agmatine (which failed to inhibit the vasodepressor responses by α-CGRP; 0.1–1µg/kg) was: (i) unaltered after saline (1ml/kg), rauwolscine (300μg/kg; α2-adrenoceptor antagonist) or BU224 (300μg/kg; imidazoline I2 receptor antagonist); and (ii) reversed after AGN 192403 (3000μg/kg; imidazoline I1 receptor antagonist). This reversion was relatively more pronounced after AGN 192403 plus rauwolscine. These blocking doses of antagonists lacked any effects on the electrically-induced vasodepressor responses. Therefore, the inhibition of the vasodepressor sensory CGRPergic outflow by moxonidine and agmatine is mainly mediated by prejunctional imidazoline I1 receptors on perivascular sensory nerves.

Dose-dependent effects of intravenous methoxamine infusion during hip-joint replacement surgery on postoperative cognitive dysfunction and blood TNF-\u03b1 level in elderly patients: a randomized controlled trial

BackgroundPostoperative 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.MethodsThis 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.ResultsThe 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.ConclusionsIntravenous 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 registrationChinese Clinical Trial Register (Unique identifier: ChiCTR-INR-15007607, retrospectively registered 18 Dec 2015).

Effects of endogenous nitric oxide on adrenergic nerve-mediated vasoconstriction and calcitonin gene-related peptide-containing nerve-mediated vasodilation in pithed rats

Vascular adrenergic nerves mainly regulate the tone of blood vessels. Calcitonin gene-related peptide-containing (CGRPergic) vasodilator nerves also participate in the regulation of vascular tone. Furthermore, there are nitric oxide (NO)-containing (nitrergic) nerves, which include NO in blood vessels as vasodilator nerves, but it remains unclear whether nitrergic nerves participate in vascular regulation. The present study investigated the role of nitrergic nerves in vascular responses to spinal cord stimulation (SCS) and vasoactive agents in pithed rats. Wistar rats were anesthetized and pithed, and vasopressor responses to SCS and injections of norepinephrine were observed. To evaluate vasorelaxant responses, the BP was increased by a continuous infusion of methoxamine with hexamethonium to block autonomic outflow. After the elevated BP stabilized, SCS and injections of acetylcholine (ACh), sodium nitroprusside (SNP), and CGRP were intravenously administered. We then evaluated the effects of the NO synthase (NOS) inhibitor, N-ω-nitro-L-arginine methylester hydrochloride (L-NAME), on these vascular responses. Pressor responses to SCS and norepinephrine in pithed rats were enhanced by L-NAME, while the combined infusion of L-NAME and L-arginine had no effect on these responses. L-NAME infusion significantly increased the release of norepinephrine evoked by SCS. In pithed rats with artificially increased BP and L-NAME infusion, depressor response to ACh (except for 0.05nmol/kg) was suppressed and SNP (only 2nmol/kg) was enhanced. However, depressor responses to SCS and CGRP were similar to control responses. The present results suggest endogenous NO regulates vascular tone through endothelium function and inhibition of adrenergic neurotransmission, but not through CGRPergic nerves.

Immediate post renal transplant period and hypertension: concordance between clinic and ambulatory blood pressure

Background: Markedly increased pulse wave velocity (PWV) with aging has been reported in numerous studies. Arterial wave reflection (WR) timing based on of the Augmentation Index (AI) framework does not change appreciably, despite increased PWV. The cause for this apparent discordance has not been established. Although a distal shift of reflecting sites has been proposed, this proposition has been exclusively based on the timing of the inflection point, which is a very limited approach. We hypothesize that AI is not capable of detecting early-systolic effects of reflection, particularly when PWV is high, leading to an apparent reflection-free period in early ejection. Methods: Simultaneous aortic pressure and flow were measured in anesthetized, open-chest dogs (n1⁄45). Intravenous infusion of methoxamine (MTX) and nitroprusside (NTP) were used to increase and decrease WRs, respectively. A coupled left ventricle-arterial system model was used to alter reflection magnitude and timing. Effects of reflection in early-systole were assessed with a systolic pressure-flow ratio (SPFR). Results: SPFR in the case of NTP remained close to aortic characteristic impedance (Zc) [horizontal dashed line] up until peak flow (Fig.1A). In control and MTX, SPFR grew increasingly divergent from Zc before peak flow (Fig.1B-C). Even when an inflection point is observed on the pressure waveform (Fig.1D, inset), SPFR diverges from Zc before the inflection, indicative of early-systole WRs. Modeling studies confirmed the dog experiments in a noise-free environment; only when wave reflections are substantially delayed and/or minimal does SPFR equal Zc in earlysystole. Divergence from this relation is due to WRs. Conclusion:WRs can alter pressure-flow relations in early-systole, prior to time of peak flow and the inflection point on the pressure waveform. Since AI is blind to early-systolic WRs, it should not be used to assess WR timing, especially when PWV is high. This is a particularly important limitation of AI to recognize when studying older subjects as well as those with hypertension in which PWV is elevated. When an appropriate method is used to gauge WR magnitude and timing in earlysystole, elevated PWV is indeed associated with earlier effects of reflections.

Simultaneous activation of the α1A-, α1B- and α1D-adrenoceptor subtypes in the nucleus accumbens reduces accumbal dopamine efflux in freely moving rats.

Intra-accumbal infusion of the α1-adrenergic agonist methoxamine, which has comparable affinity for α1A-, α1B- and α1D-adrenoceptor subtypes, fails to alter noradrenaline efflux but reduces dopamine efflux in the nucleus accumbens of rats. In-vivo microdialysis experiments were carried out to analyse the putative contribution of α1A-, α1B- and α1D-adrenoceptor subtypes to the methoxamine-induced decrease in accumbal dopamine efflux in freely moving rats. The drugs used were dissolved in the infusion medium and administered locally through a dialysis membrane. Intra-accumbal infusions of the α1A-adrenoceptor antagonist 5-methylurapidil (6 pmol), the α1B-adrenoceptor antagonist cyclazosin (0.6 and 6 pmol) and the α1D-adrenoceptor antagonist BMY 7378 (0.6 pmol) did not alter accumbal efflux of noradrenaline or dopamine: pretreatment with each of these α1-adrenoceptor subtype-selective antagonists counteracted the methoxamine (24 pmol)-induced decrease in accumbal dopamine efflux. Doses indicated are the total amount of drug administered over a 60-min infusion period. These results clearly suggest that the α1A-, α1B- and α1D-adrenoceptor subtypes in the nucleus accumbens mediate the α1-adrenergic agonist methoxamine-induced decrease in accumbal dopamine efflux. The present study also provides in-vivo neurochemical evidence indicating that concomitant, but not separate, activation of the α1A-, α1B- and α1D-adrenoceptors in the nucleus accumbens is required for α1-adrenergic inhibition of accumbal dopaminergic activity.

Role of 5-HT7 receptors in the inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats

The role of calcitonin gene-related peptide (CGRP) in the modulation of vascular tone has been widely documented. Indeed, electrical stimulation of the perivascular sensory outflow in pithed rats induces vasodepressor responses by activation of CGRP receptors. This study investigated the role of 5-HT7 receptors in the inhibition of the rat vasodepressor sensory outflow. Male Wistar pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by physiological saline or AS-19 (a 5-HT7 receptor agonist). Then, electrical stimulation of the spinal cord resulted in frequency-dependent decreases in DBP. The infusions of AS-19, as compared to those of saline, inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i.v. bolus injections of exogenous α-CGRP. This inhibition by AS-19 was abolished by the antagonists pimozide (5-HT7) or sulfisoxazole (ETA), but not by indomethacin (COX1/2) or losartan (AT1), at doses that did not affect per se the electrically-induced vasodepressor responses. Interestingly, glibenclamide (an ATP-dependent K+ channel blocker) attenuated these vasodepressor responses. The present results suggest that AS-19-induced inhibition of the rat vasodepressor sensory CGRPergic outflow is mainly mediated by 5-HT7 receptors via endothelin release, with the possible involvement of ATP-dependent K+ channels.

Effects of continuous intravenous infusion of methoxamine on the intraoperative hemodynamics of elderly patients undergoing total hip arthroplasty.

BackgroundHemodynamic disturbances are common during continuous epidural anesthesia in elderly patients undergoing total hip arthroplasty. This study aimed to investigate the effects of methoxamine on the intraoperative hemodynamics in elderly patients undergoing total hip arthroplasty under epidural anesthesia.Material/MethodsThis prospective study included 150 elderly patients undergoing elective total hip arthroplasty under epidural anesthesia. Patients were randomly assigned into 5 groups (n=30 per group): a control group receiving saline (Group C), a dopamine group receiving 7 μg/kg/min dopamine (Group D), and methoxamine groups receiving 1, 2, or 3 μg/kg/min methoxamine (Groups M1, M2, and M3, respectively). Hemodynamic parameters were assessed 10 min before anesthesia (T1); 10 min (T2), 20 min, (T3), 30 min (T4), and 60 min (T5) after anesthesia; and at the conclusion of surgery (T6).ResultsAt T2–T6, the mean arterial pressure, central venous pressure, cardiac output, stroke volume, stroke volume ratio, and pulmonary vascular resistance were higher in Groups D, M2, and M3 compared to Group C (p<0.05). Compared to Group D, the heart rate and rate pressure product were significantly lower in Groups M1–M3. Infusion volume, ephedrine dose, and postoperative 24-h urine volume were significantly lower and intraoperative urine volume was significantly greater in Groups D, M2, and M3 compared with Group C. Hypertension occurred more frequently in Group M3 than in any other group.ConclusionsContinuous intravenous infusion of 2 μg/kg/min methoxamine is safe and effective in maintaining hemodynamic stability in elderly patients undergoing total hip arthroplasty.

The Role of Pre-junctional D2-like Receptors Mediating Quinpirole-Induced Inhibition of the Vasodepressor Sensory CGRPergic Out-flow in Pithed Rats

Calcitonin gene-related peptide (CGRP) released from perivascular sensory nerves plays a role in the regulation of vascular tone. Indeed, electrical stimulation of the perivascular sensory out-flow in pithed rats produces vasodepressor responses, which are mainly mediated by CGRP release. This study investigated the potential role of dopamine D1 -like and D2 -like receptors in the inhibition of these vasodepressor responses. For this purpose, male Wistar pithed rats (pre-treated i.v. with 25 mg/kg gallamine and 2 mg/kg min. hexamethonium) received i.v. continuous infusions of methoxamine (20 μg/kg min.) followed by physiological saline (0.02 ml/min.), the D1 -like receptor agonist SKF-38393 (0.1-1 μg/kg min.) or the D2 -like receptor agonist quinpirole (0.03-10 μg/kg min.). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the thoracic spinal cord (T9 -T12 ) resulted in frequency-dependent vasodepressor responses which were (i) unchanged during the infusions of saline or SKF-38393 and (ii) inhibited during the infusions of quinpirole (except at 0.03 μg/kg min.). Moreover, the inhibition induced by 0.1 μg/kg min. quinpirole (which failed to inhibit the vasodepressor responses elicited by i.v. bolus injections of exogenous α-CGRP; 0.1-1 μg/kg) was (i) unaltered after i.v. treatment with 1 ml/kg of either saline or 5% ascorbic acid and (ii) abolished after 300 μg/kg (i.v.) of the D2 -like receptor antagonists haloperidol or raclopride. These doses of antagonists (enough to completely block D2 -like receptors) essentially failed to modify per se the electrically induced vasodepressor responses. In conclusion, our results suggest that quinpirole-induced inhibition of the vasodepressor sensory CGRPergic out-flow is mainly mediated by pre-junctional D2 -like receptors.

The α1-, but not α2-, adrenoceptor in the nucleus accumbens plays an inhibitory role upon the accumbal noradrenaline and dopamine efflux of freely moving rats

In vivo microdialysis was used to analyse the role of the α1- and α2-adrenoceptor subtypes in the regulation of noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats. Intra-accumbal infusion of α1-adrenoceptor agonist methoxamine (24pmol) failed to alter the noradrenaline efflux, but decreased the dopamine efflux. The intra-accumbal infusion of α1-adrenoceptor antagonist prazosin (6, 600 and 6000pmol) produced a dose-related increase and decrease of the noradrenaline and dopamine efflux, respectively. An ineffective dose of prazosin (6pmol) counteracted the methoxamine (24pmol)-induced decrease of dopamine efflux. The prazosin (6000pmol)-induced increase of noradrenaline efflux, but not the decrease of dopamine efflux, was suppressed by the co-administration of an ineffective dose of methoxamine (0.024pmol). Neither the α2-adrenoceptor agonist clonidine (300pmol) and UK 14,304 (300pmol) nor the α2-adrenoceptor antagonist RX 821002 (0.6, 3, 600 and 6000pmol) significantly affected the accumbal noradrenaline and dopamine efflux. The doses mentioned are the total amount of drug over the 60-min infusion period. The present results show that (1) accumbal α1-adrenoceptors which are presynaptically located on noradrenergic nerve terminals inhibit the accumbal noradrenaline efflux, increasing thereby the accumbal dopamine efflux, (2) accumbal α1-adrenoceptors which are postsynaptically located on dopaminergic nerve terminals inhibit the accumbal dopamine efflux, and (3) accumbal α2-adrenoceptors play no major role in the regulation of accumbal efflux of noradrenaline and dopamine.

The 5-HT 1 receptors inhibiting the rat vasodepressor sensory CGRPergic outflow: Further involvement of 5-HT 1F, but not 5-HT 1A or 5-HT 1D, subtypes

We have previously shown that 5-HT 1B receptors inhibit prejunctionally the rat vasodepressor CGRPergic sensory outflow. Since 5-HT 1 receptors comprise 5-HT 1A, 5-HT 1B, 5-HT 1D and 5-HT 1F functional subtypes, this study has further investigated the role of 5-HT 1A, 5-HT 1D and 5-HT 1F receptor subtypes in the inhibition of the above vasodepressor sensory outflow. Pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by 5-HT 1 receptor agonists. Then electrical spinal stimulation (T 9–T 12) or i.v. bolus injections of exogenous α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The electrically-induced vasodepressor responses remained unchanged during infusions of the 5-HT 1A receptor agonists 8-OH-DPAT and NN-DP-5-CT. In contrast, these responses were inhibited by the agonists sumatriptan (5-HT 1A/1B/1D/1F), indorenate (5-HT 1A), PNU-142633 (5-HT 1D) or LY344864 (5-HT 1F), which did not affect the vasodepressor responses to exogenous CGRP (implying a prejunctional sensory-inhibition). When analysing the effects of antagonists: (i) 310 μg/kg (but not 100 μg/kg) GR127935 (5-HT 1A/1B/1D/1F) abolished the inhibition to sumatriptan, indorenate, PNU-142633 or LY344864; (ii) 310 μg/kg SB224289 (5-HT 1B) or BRL15572 (5-HT 1D) failed to block the inhibition to sumatriptan or PNU-142633, whereas SB224289 + BRL15572 partly blocked the inhibition to sumatriptan; and (iii) 10 μg/kg WAY100635 (5-HT 1A) failed to block the inhibition to indorenate. These results suggest that 5-HT 1F, but not 5-HT 1A or 5-HT 1D, receptor subtypes inhibit the vasodepressor sensory CGRPergic outflow although, admittedly, no selective 5-HT 1F receptor agonist is available yet. The pharmacological profile of these receptors resembles that shown in rat dorsal root ganglia by molecular biology techniques.

Pulse Pressure, Arterial Compliance and Wave Reflection Under Differential Vasoactive and Mechanical Loading

Similar pulse pressure increases and flow reductions have been reported by many investigators, despite dissimilar forms of arterial loading applied. Increased vascular load is most commonly observed due to mechanical and vasoactive interventions. The present study intended to differentiate the hemodynamic contributions of these two forms of arterial loading at closely matched blood pressure levels. To accomplish this, proximal aortic characteristic impedance (Z(o)), total arterial compliance (C), peripheral vascular resistance (R(s)) and time-domain resolved forward (P(f)) and reflected (P(r)) waves were obtained in six anesthetized, thoracotomized and ventilated dogs. Acute loading was accomplished by brief descending thoracic aorta (DTA) occlusion or by intravenous bolus infusion of methoxamine (MTX:5 mg/ml) Systolic pressure increases were matched to a similar extent. Results showed that pulse pressures were drastically increased, reflecting large increases in wave reflections and decreases in arterial compliances. Changes in Z(o), R(s) and C were quantitatively different between the two forms of loading. DTA occlusion primarily increased Z(o) and R(s) with a concurrently large reduction in C. MTX infusion significantly increased small vessel R(s) to the same extent as DTA occlusion, but with a slight decrease in C secondary to an increase in pressure, with Z(o) unchanged. Examination of dynamic loading showed similar increases in reflection coefficients, but P(f) and P(r) were qualitatively different. We conclude that vasoactive methoxamine infusion provides primarily an increased resistive load, while mechanical DTA occlusion provides an increased complex load to the left ventricle. These loads also occur earlier and variably during ventricular ejection.

Activation of 5-HT1B receptors inhibits the vasodepressor sensory CGRPergic outflow in pithed rats

The importance of calcitonin gene-related peptide (CGRP) in the regulation of vascular tone has been widely documented. Indeed, stimulation of the perivascular sensory outflow in pithed rats results in vasodepressor responses, which are mediated by CGRP release. These vasodepressor responses are inhibited by clonidine via prejunctional alpha(2A/2C)-adrenoceptors, but no study has yet reported the role of prejunctional 5-hydroxytryptamine (5-HT) receptors in this experimental model. Since activation of prejunctional 5-HT(1) receptors results in inhibition of neurotransmitter release, this study sets out to investigate as an initial approach the role of 5-HT(1B) receptors in the inhibition of the vasodepressor sensory outflow in pithed rats. Male Wistar pithed rats were pretreated with hexamethonium (2mg/kg.min) followed by i.v. continuous infusions of methoxamine (20 microg/kg min), and then by saline (0.02 ml/min) or CP-93,129 (a rodent 5-HT(1B) receptor agonist; 0.1, 1 and 10 microg/kg min). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T(9)-T(12)) resulted in frequency-dependent decreases in diastolic blood pressure. The infusions of CP-93,129, as compared to those of saline, inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i.v. bolus injections of exogenous alpha-CGRP (0.1, 0.18, 0.31, 0.56 and 1 microg/kg). This inhibition by CP-93,129 was abolished by the antagonists GR127935 (5-HT(1B/1D)) or SB224289 (5-HT(1B)), but not by BRL15572 (5-HT(1D)). The above results suggest that CP-93,129-induced inhibition of the vasodepressor (perivascular) sensory outflow in pithed rats is mainly mediated by activation of prejunctional 5-HT(1B) receptors.