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

BACKGROUND: α-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. METHODS: Eighty 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. RESULTS: The 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. CONCLUSIONS: Under 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 REGISTRATION: Chinese 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.

BACKGROUND: Acute 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. METHODS: After 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. RESULTS: Significant 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. CONCLUSION: Compared 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 REGISTRATION: Trial registration: Chinese Clinical Trial Registry, ChiCTR1900020536, registered 7 January, 2019.

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).

Comparison of the treatment effects of methoxamine and combining methoxamine with atropine infusion to maintain blood pressure during spinal anesthesia for cesarean delivery: a double blind randomized trial.

OBJECTIVE: Hypotension is a common complication of spinal anesthesia for cesarean delivery. Atropine is a vagus nerve blocker that can antagonize vagus excitation to mitigate the reflex bradycardia. We aimed to assess the effect of methoxamine-atropine therapy in treating spinal anesthesia hypotension for cesarean section. PATIENTS AND METHODS: This is a double-blind randomized controlled study. Women under spinal anesthesia for elective caesarean delivery received boluses of methoxamine 2 mg alone (Group M, n = 40), or with addition of atropine 0.1 mg (Group MA1, n = 40), atropine 0.2 mg (Group MA2, n = 40) or atropine 0.3 mg (Group MA3, n = 40) upon a maternal systolic pressure ≤ 80% of baseline. The primary endpoint was systolic blood pressure and the secondary endpoints were maternal heart rates, instant neonatal heart rates, umbilical artery pH and umbilical artery base excess. RESULTS: Changes in systolic blood pressure were similar among the four groups. The incidences of bradycardia in groups M and MA1 were significantly higher than those in group MA2 and MA3. The fetal heart rates after delivery in groups MA2 and MA3 were higher than those in group M and MA1 but within the normal range. The acid-base status had no difference in the four groups. CONCLUSIONS: Methoxamine-atropine combination has a similar efficacy to methoxamine alone but has an increased hemodynamic stability and a less adverse effect occurrence.

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

BACKGROUND: Hemodynamic 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 AND METHODS: This 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). RESULTS: At 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. CONCLUSIONS: Continuous intravenous infusion of 2 µg/kg/min methoxamine is safe and effective in maintaining hemodynamic stability in elderly patients undergoing total hip arthroplasty.

A randomised, controlled, crossover study to investigate the safety and response of 1R,2S-methoxamine hydrochloride (NRL001) on anal function in healthy volunteers.

AIMS: This study aimed to assess the dose and volume effects of suppository preparations and safety of NRL001 (one of four possible stereoisomers of methoxamine hydrochloride) on anal sphincter tone using rectal suppositories in healthy adult volunteers. METHODS: This was a Phase I, single-centre, randomised, double-blind, three-way crossover study during which subjects received three single doses of 1 g rectal suppositories (containing 5 or 10 mg NRL001 or matching placebo) or 2 g rectal suppositories (containing 10 or 15 mg NRL001 or matching placebo) on three separate dosing days. The outcome measures were mean anal resting pressure (MARP) variables (monitored continuously for 20-30 min before and up to 6 h after dosing), pharmacokinetics (PK) and safety assessments. RESULTS: Twenty-six subjects were dosed with study medication. Two subjects were withdrawn prematurely and were not included in the main analysis. There was a dose-dependent increase in anal sphincter tone (MARP) when comparing the 5 and 10 mg doses of NRL001; however, the 15 mg dose did not have a significantly greater effect than the 10 mg dose. Suppository size (1 or 2 g) did not appear to have an effect on sphincter tone. There was no evidence against dose proportionality for the PK variables, but the mean maximum plasma concentration (Cmax ) for the 1 g suppository group was higher than for the 2 g group. Twenty-one adverse events were reported in 8 (30.8%) subjects. A dose dependent decrease in heart rate was noted; however, there were no adverse events reported that were related to this reduction in heart rate. CONCLUSIONS: The increase in anal sphincter tone supports the potential therapeutic use of NRL001 in treating faecal incontinence, with further studies in patients required. NRL001 was well tolerated in single doses of up to 15 mg.

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.

A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days.

AIMS: The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). METHODS: Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. RESULTS: Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. CONCLUSIONS: Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect.

Meta-analysis for cardiovascular effects of NRL001 after rectal application in healthy volunteers.

AIMS: NRL001 is a highly specific α1 -adrenoceptor agonist currently under evaluation for the treatment of faecal incontinence caused by a weak internal anal sphincter. The aim of this meta-analysis was to quantify the effect of NRL001 on cardiovascular parameters including heart rate, blood pressure and QT interval. METHODS: Data from the four Phase I healthy volunteer studies SUM (NCT00857467), SURD (NCT01099670), SUSD (NCT00850590) and SAGE (NCT01099683) were pooled and analyses were performed on individual subject data. Mixed effects regression analysis was used to determine the effect of NRL001 on heart rate, blood pressure and QT intervals. A multivariate statistical model was used to determine the effect of covariates on heart rate. RESULTS: Subjects given NRL001 experienced a dose related decrease in heart rate of up to 9.48 bpm compared with subjects in the placebo arms. No statistically significant evidence for a threshold effect was found. There was no clear evidence of dose effect of NRL001 on blood pressure. QT interval increased in all NRL001 subject as expected; QTC F also showed a statistically significant increase. However, QTC B was shortened with no significant treatment effect. CONCLUSIONS: NRL001 was found to have a dose-dependent effect on heart rate; however clinically-relevant bradycardia was not reported, indicating the decrease in heart rate was not of clinical significance. Furthermore, no clinically-significant drug effect on blood pressure or mean arterial pressure was observed. QT intervals were affected by changes in heart rate. However, trends were dependant on the correction factor used. No consistent QT effect was observed, but a thorough QTC study will be required to confirm the effects of rectally applied NRL001.

Evidence that chronic administration of 17ß-oestradiol decreases the vasopressor responses to adrenergic system stimulation in streptozotocin-diabetic female rats.

In vitro studies have indicated that 17ß-oestradiol exerts beneficial effects on the cardiovascular system by activating the nitric oxide pathway. However, these effects have not been demonstrated in vivo in the systemic vasculature of rats made diabetic through streptozotocin induction. Therefore, the goal of this study was to determine the effect of 17ß-oestradiol on vasopressor responses induced by sympathetic stimulation or i.v. injections of noradrenaline, methoxamine and B-HT 933 in sham-operated or ovariectomised, diabetic or non-diabetic female rats. Thus, rats were ovariectomised or sham-operated for this experiment. One week later, the animals were treated with streptozotocin (60mg/kg, i.p.) or its vehicle. Two weeks later, these rats were treated daily with 17ß-oestradiol (10µg/kg, s.c.) or its vehicle for five weeks. Next, under anaesthesia, the animals were pithed and prepared for blood pressure and heart rate measurements. 17ß-oestradiol failed to modify the vasopressor responses to (i) sympathetic stimulation, noradrenaline, methoxamine or B-HT 933 in sham-operated non-diabetic rats; (ii) sympathetic stimulation or B-HT 933 in sham-operated diabetic rats; (iii) noradrenaline or methoxamine in ovariectomised non-diabetic rats. In contrast, 17ß-oestradiol significantly decreased the vasopressor responses to (i) noradrenaline and methoxamine in sham-operated diabetic rats; (ii) sympathetic stimulation or B-HT 933 in ovariectomised non-diabetic rats; and (iii) sympathetic stimulation, noradrenaline, methoxamine or B-HT 933 in ovariectomised diabetic rats. These results suggest that chronic administration of 17ß-oestradiol decreases the vasopressor responses to adrenergic system stimulation in streptozotocin-induced diabetic rats. This report describes the first in vivo study reporting this effect of 17ß-oestradiol in diabetes.

Cholinergic basal forebrain structures are involved in the mediation of the arousal effect of noradrenaline.

Cholinergic basal forebrain structures are implicated in cortical arousal and regulation of the sleep-wake cycle. Cholinergic neurones are innervated by noradrenergic terminals, noradrenaline excites them via alpha-1 receptors and microinjection of noradrenaline into the basal forebrain enhances wakefulness. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing effects of noradrenaline. To elucidate the roles of cholinergic basal forebrain structures we administered methoxamine, an alpha-1-adrenergic agonist into the basal forebrain, in intact animals and again after selective destruction of the basal forebrain cholinergic cells by 192 IgG-saporin. In eight male Han-Wistar rats implanted with electroencephalogram/electromyogram electrodes, a microdialysis probe targeted into the basal forebrain was perfused with artificial cerebrospinal fluid for 6 h on a baseline day, and with cerebrospinal fluid in the first and with methoxamine in the second 3-h period of the subsequent day. The sleep-wake activity was recorded for 24 h on both days. Saporin was then injected into the basal forebrain and 2 weeks later the same experimental schedule (with cerebrospinal fluid and methoxamine) was repeated. In the intact animals, methoxamine exhibited a robust arousing effect and non-rapid eye movement (NREM) and REM sleep was suppressed. Lesioning of the basal forebrain cholinergic neurones abolished almost completely the NREM sleep-suppressing effect of methoxamine, whereas the REM sleep-suppressing effect remained intact. Thus, the basal forebrain cholinergic neurones mediate, at least in part, cortical arousal and non-REM sleep-suppression, but they are not involved in the REM sleep-suppressing effects of noradrenaline.

Extra forces evoked during electrical stimulation of the muscle or its nerve are generated and modulated by a length-dependent intrinsic property of muscle in humans and cats.

Extra forces or torques are defined as forces or torques that are larger than would be expected from the input or stimuli, which can be mediated by properties intrinsic to motoneurons and/or to the muscle. The purpose of this study was to determine whether extra forces/torques evoked during electrical stimulation of the muscle or its nerve with variable frequency stimulation are modulated by muscle length/joint angle. A secondary aim was to determine whether extra forces/torques are generated by an intrinsic neuronal or muscle property. Experiments were conducted in 14 able-bodied human subjects and in eight adult decerebrate cats. Torque and force were measured in human and cat experiments, respectively. Extra forces/torques were evoked by stimulating muscles with surface electrodes (human experiments) or by stimulating the nerve with cuff electrodes (cat experiments). In humans and cats, extra forces/torques were larger at short muscle lengths, indicating that a similar regulatory mechanism is involved. In decerebrate cats, extra forces and length-dependent modulation were unaffected by intrathecal methoxamine injections, despite evidence of increased spinal excitability, and by transecting the sciatic nerve proximal to the nerve stimulations. Anesthetic nerve block experiments in two human subjects also failed to abolish extra torques and the length-dependent modulation. Therefore, these data indicate that extra forces/torques evoked during electrical stimulation of the muscle or nerve are muscle length-dependent and primarily mediated by an intrinsic muscle property.

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.

Arterial blood pressure and aortic responses in obese, age-grouped Zucker rats.

Endothelial dysfunction is one of the many proposed mechanisms of hypertension and it may justify, at least in part, the increased blood pressure of hypertensive subjects. Nevertheless, the exact mechanisms involved in the hypertensive condition of obese Zucker rats are unclear. In this study, we measured the arterial blood pressure (tail cuff method) of four groups of seven, female, obese Zucker rats each. The rats of groups 1-4 were 9-12, 15-18, 21-24 and 27-30 weeks old respectively. We also evaluated the responses of aortic rings to KCl, methoxamine and acetylcholine, in these animals. Aortic rings were successively exposed to 80 mM KCl and to methoxamine (10(-8)-10(-5) M). The endothelium-dependent relaxation to acetylcholine (10(-9)-10(-5) M) was also established in the methoxamine-precontracted tissue (precontraction close to 80% of the maximum effect of methoxamine). A clear increase in the arterial blood pressure was observed when the age of these animals increased. The contractile responses to KCl and methoxamine were lower in the aortic rings of rats with increased arterial blood pressure. The response to acetylcholine was lower in the rings from 15-18, 21-24 and 27-30 weeks old rats, than in the younger groups. In conclusion, obese Zucker rats develop hypertension and endothelial dysfunction. Nevertheless, the arterial contractions elicited by depolarization or by α(1)-adrenoceptor stimulation decrease in aged, obese Zucker rats.

A new approach to assessing the structural total peripheral resistance amplifier in renal (Page) hypertension in conscious rabbits.

BACKGROUND AND AIM: Structural changes in the large resistance vessels in hypertension amplify resistance responses in vitro, but their role in vivo has been controversial. To resolve this matter, we re-examined earlier data in Page hypertension. METHODS: Total peripheral resistance (TPR) and total peripheral conductance (TPC) responsiveness were compared in hypertensive and normotensive rabbits, 5 weeks after bilateral renal cellophane wrapping or sham operation. The rabbits were studied with effectors intact; during ganglionic blockade; during neurohumoral blockade (NHB). For each condition extended scaled dose (ScD)-TPC and TPR curves were derived from individual dose-response curves to two constrictors and two dilators. RESULTS: The ScD-response curves had two major nonlinearities: at high constrictor doses, due to functional (reversible) rarefaction (reduction in microcirculatory density); at high dilator doses, due to impaired autoregulation. The amplifier is best assessed during NHB over the intervening ScD range, by determining the TPR and TPC ratios from hypertensive and normotensive rabbits. Over this range the hypertensive: normotensive (H: N) ratio averaged 1.88 +/- 0.03 TPR units and was the same for constrictor and dilator responses, suggesting a structural basis; the resting H: N TPR ratio was also closely similar. At higher ScDs functional rarefaction developed initially at a greater rate in normotensive than in hypertensive rabbits. We conjecture that this was because some permanent rarefaction had already developed in hypertensive rabbits since the onset of hypertension. CONCLUSION: The systemic structural TPR amplifier is haemodynamically important in vivo and contributes to hypertension.

Nitric oxide and vascular remodeling modulate hepatic arterial vascular resistance in the isolated perfused cirrhotic rat liver.

BACKGROUND/AIMS: Hepatic arterial resistance is modulated by the hepatic arterioles but the role of NO and vascular remodeling in hepatic arterial resistance in cirrhosis is unknown. METHODS: Cirrhosis was induced by CCl(4) or BDL. Using a bivascular liver perfusion dose-responses curves to methoxamine were obtained from the hepatic artery in absence and presence of L-NMMA. Lumen-diameter, wall thickness and number of smooth muscle nuclei were quantitated in the arteries using image analysis. RESULTS: Hepatic arterial resistance and the response to methoxamine were lower in cirrhosis compared to controls (p< or = 0.04) and lower in BDL compared to CCl(4) (p< or = 0.01). L-NMMA increased the response to methoxamine in CCl(4) (p=0.002) and BDL (p=0.05) but corrected the response only in CCl(4) (p=n.s. vs. control). Wall thickness and the number of smooth muscle nuclei were significantly smaller in cirrhosis compared to controls (p<0.05) and the number of nuclei was also lower in BDL compared to CCl(4) (p=0.005). CONCLUSIONS: NO is the main modulator of hepatic arterial resistance in CCl(4) but not in BDL. Intrahepatic arterial remodeling is present in both cirrhotic models but is greater in BDL. This indicates a larger role of structural changes in the control of hepatic arterial resistance in BDL.

Evidence that some imidazoline derivatives inhibit peripherally the vasopressor sympathetic outflow in pithed rats.

Imidazoline derivatives (e.g. clonidine and moxonidine) and alpha(2)-adrenoceptor agonists (e.g. B-HT 933) have been shown to inhibit sympathetically-induced [(3)H]noradrenaline release in several isolated blood vessels. The present study has compared the potential capability of agonists at imidazoline I(1/2) receptors and/or alpha(1/2)-adrenoceptors to inhibit the sympathetically-induced vasopressor responses in pithed rats. For this purpose, male Wistar rats were pithed and prepared for measurement of diastolic blood pressure and heart rate. Then, the vasopressor responses induced by either selective electrical stimulation (2 ms, 60 V; 0.03, 0.1, 0.3, 1 and 3 Hz) of the vascular sympathetic outflow (T(7)-T(9)) or i.v. bolus injections of exogenous noradrenaline (0.03, 0.1, 0.3, 1 and 3 microg/kg) were determined before and during i.v. continuous infusions of the agonists B-HT 933 (alpha(2)), clonidine (alpha(2), I(1)), moxonidine (alpha(2), I(1)), cirazoline (alpha(1), I(2)), agmatine (putative endogenous ligand of imidazoline receptors) and methoxamine (alpha(1)), or equivalent volumes of physiological saline. Electrical sympathetic stimulation elicited frequency-dependent vasopressor responses which were significantly inhibited during the continuous infusions of B-HT 933, clonidine, moxonidine, cirazoline and agmatine, but not of physiological saline. Interestingly, the vasopressor responses to exogenous noradrenaline, which remained unaffected during the infusions of physiological saline, B-HT 933, moxonidine, cirazoline and agmatine, were significantly blocked during the infusions of clonidine or methoxamine. These results suggest that B-HT 933, moxonidine, cirazoline and agmatine induced a prejunctional inhibition of the vasopressor sympathetic outflow in pithed rats, whilst clonidine inhibited the vasopressor sympathetic outflow by both prejunctional and postjunctional mechanisms.

Noradrenergic control of arginine vasopressin release from the ewe hypothalamus in vitro: sensitivity to oestradiol.

The present study aims at ascertaining the influence of alpha(1)-adrenoreceptors on arginine vasopressin (AVP) release in vitro and determine whether E(2) modulates the alpha(1)-adrenoreceptor and AVP interaction. Ten minutes after ewe killing, sagittal midline hypothalamic slices (from the anterior preoptic area to the mediobasal hypothalamus with the median eminence, 2 mm thick, 2 per sheep) were dissected, placed in oxygenated minimum essential media-alpha (MEM-alpha) at 4 degrees C and within 2 h were singly perifused at 37 degrees C with oxygenated MEM-alpha (pH 7.4; flow rate 0.15 ml/min), either with or without E(2) (24 pg/ml). After 4 h equilibration, 10 min fractions were collected for 4 h interposed with 10 min exposure at 60 min to a specific alpha(1)-adrenoreceptor agonist or antagonist at various doses (0.1-10 mm). At the end of all perifusions, slices responded to KCl (100 mm) with AVP efflux (p < 0.05). Release of AVP was enhanced (p < 0.05) by the alpha(1)-adrenoreceptor agonist (methoxamine 10 mm; no E(2), n = 7 perifusion chambers: from 14.3 +/- 2.7 to 20.9 +/- 3.9, with E(2), n = 10: from 10.7 +/- 1.2 to 18.4 +/- 3.4 pg/ml) or the antagonist (thymoxamine 10 mm; no E(2), n = 5: from 9.5 +/- 3.1 to 30.4 +/- 6.0, with E(2), n = 10: from 10.8 +/- 0.9 to 39.1 +/- 6.3 pg/ml). With the agonist, the response occurred only at 80 min (p < 0.05) both in the presence and absence of E(2). Whereas, after the antagonist, values were higher (p < 0.05) throughout the post-treatment period (80-170 min) without E(2), but declined by 150 min in the presence of E(2). Furthermore, the response to the alpha(1)-adrenoreceptor antagonist was greater (p < 0.05; 90-140 min) than the agonist only in the presence of E(2). In conclusion, these results reveal direct alpha(1)-adrenoreceptor-mediated control of the hypothalamic AVP neuronal system which is modulated by E(2).

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.