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Midodrine is an antihypotensive agent used primarily in the adult population for orthostatic hypotension and reflex syncope, postural orthostatic tachycardia syndrome (POTS), and hemodialysis-induced hypotension. Limited information about midodrine ingestion and overdose exists in children with only a single case series reported in the literature. Varying presentations of midodrine ingestion in children have not been shown to be acutely life-threatening in doses up to 50 mg. We present a case of a 12-year-old who intentionally ingested 100 mg of midodrine and presented with a hypertensive emergency and seizure activity. This is the largest reported dose ingested in a child. The patient was observed and treated with a nicardipine infusion in the pediatric intensive care unit (PICU). Prompt identification and treatment of symptoms contributed to a favorable outcome with no neurologic deficits and complete recovery from an intentional ingestion of midodrine. Mechanism, duration of action, and management of midodrine ingestion including treatment for a hypertensive emergency in children are discussed. Commonly used pharmacologic agents to treat hypertension are reviewed. This case report of a significant ingestion of midodrine reviews management of hypertensive emergencies and provides information and guidance to healthcare professionals unfamiliar with this medication and its potentially fatal effects.

In an attempt to synthesize 4-thia-6-azatricyclo[5.3.1.13,9]dodecan-5-imine as putative antihypotensive agent with prolonged effect, a reaction of 1-[(1RS,3SR,5SR)-bicyclo[3.3.1]non-6-en-3-yl]-3-tert-butylthiourea in the presence of bromine was undertaken. The intramolecular cyclization however was accompanied by precursive oxidation of thiourea to urea fragment and proceeded via nitrogen atom yielding the bridged tricyclic urea derivative as determined by X-ray analysis and liquid chromatography–mass spectrometry technique. The compounds obtained in the present study belong to a novel and unusual structural type of bridged tricyclic ureas.

The use of norepinephrine for maintaining blood pressure (BP) during spinal anesthesia for cesarean delivery has been described recently. However, its administration by titrated manually controlled infusion in this context has not been evaluated.In a double-blinded, randomized controlled trial, 110 healthy women having spinal anesthesia for elective cesarean delivery were randomly allocated to 1 of 2 groups. In group 1, patients received an infusion of 5 µg/mL norepinephrine that was started at 30 mL/h (2.5 µg/min) immediately after intrathecal injection and then manually adjusted within the range 0-60 mL/h (0-5 µg/min), according to values of systolic BP measured noninvasively at 1-minute intervals until delivery, with the objective of maintaining values near baseline. In group 2, no prophylactic vasopressor was given, and a bolus of 1 mL norepinephrine 5 µg/mL (5 µg) was given whenever systolic BP decreased to80% of the baseline value. The study protocol was continued until delivery. The primary outcomes of the study were the incidence of hypotension and the overall stability of systolic BP control versus baseline compared using performance error calculations. In addition, the incidence and timing of hypotension were further compared using survival analysis.Three patients were excluded from the analysis. Nine patients (17%) in group 1 had 1 or more episodes of hypotension versus 35 (66%) in group 2 (P.001). Performance error calculations showed that on average, systolic BP was maintained closer to baseline (P.001) in group 1. Survival curve analysis showed a significant difference between groups (log-rank test P.001). Four patients in each group had a recorded heart rate60 beats/min (P = .98). Despite a much greater rate of administration of norepinephrine in group 1 (median, 61.0 [interquartile range, 47.0-72.5] µg) versus group 2 (5.0 [0-18.1] µg) (P.001), there was no difference in neonatal outcome as assessed by Apgar scores and umbilical cord blood gas analysis.In patients having spinal anesthesia for elective cesarean delivery, a manually titrated infusion of 5 µg/mL of norepinephrine was effective for maintaining BP and decreasing the incidence of hypotension, with no detectable detrimental effect on neonatal outcome. Further investigation of the use of dilute norepinephrine infusions for routine use in obstetric patients is suggested.

Ethnopharmacological relevance To study Rosmarinus officinalis (Rosemary) essential oil effect on primary hypotension and its influence on both physical and psychological aspects responsible for health-related quality of life (HRQOL) of patients. Methodology Thirty-two patients with diagnosed hypotension were recruited between March 2007 and September 2008 for a prospective study for 72 weeks in a Spanish pharmacy. Clinical evaluation was carried out through the control of systolic and diastolic blood pressure levels (SBP and DBP, respectively) according to the International Standards from the American Society of Hypertension. HRQOL data were recorded within the SF-36 Health Survey ® questionnaire throughout the study. Statistical methods were used as the essential tools to evaluate the effectiveness of Rosemary essential oil and to assess the relationship between the two quantitative variables (SBP and DBP) and scores from physical and mental summary components (PSC and MSC) obtained from the SF-36 Health Survey. Results Both blood pressure variables of SBP and DBP reflect the clinically significant antihypotensive effect of Rosemary essential oil that was maintained throughout the treatment period. After validation of the use of the questionnaire (Cronbach's alpha coefficient>0.82), statistically significant differences have been found between pre-treatment and post-treatment values of PSC and MSC, which indicate an improvement in these parameters that is directly related to the variation in blood pressure values. Conclusions The increase achieved in blood pressure values after administration of Rosemary essential oil is clinically significant. The results obtained from this prospective clinical trial prove the effectiveness of statistical methodology as a new approach to explain the antihypotensive effect of rosemary essential oil and its relationship with the improvement in patients' quality of life.

BACKGROUND AND PURPOSE The consequences of compensatory responses to balloon catheter injury in rat carotid artery, on phenylephrine-induced relaxation and contraction in the contralateral carotid artery were studied. EXPERIMENTAL APPROACH Relaxation and contraction concentration–response curves for phenylephrine were obtained for contralateral carotid arteries in the presence of indomethacin (COX inhibitor), SC560 (COX-1 inhibitor), SC236 (COX-2 inhibitor) or 4-hydroxytetramethyl-L-piperidine-1-oxyl (tempol; superoxide dismutase mimetic). Reactive oxygen species were measured in carotid artery endothelial cells fluorimetrically with dihydroethidium. KEY RESULTS Phenylephrine-induced relaxation was abolished in contralateral carotid arteries from operated rats (Emax= 0.01 ± 0.004 g) in relation to control (Emax= 0.18 ± 0.005 g). Phenylephrine-induced contractions were increased in contralateral arteries (Emax= 0.54 ± 0.009 g) in relation to control (Emax= 0.38 ± 0.014 g). SC236 restored phenylephrine-induced relaxation (Emax= 0.17 ± 0.004 g) and contraction (Emax= 0.34 ± 0.018 g) in contralateral arteries. Tempol restored phenylephrine-induced relaxation (Emax= 0.19 ± 0.012 g) and contraction (Emax= 0.42 ± 0.014 g) in contralateral arteries, while apocynin did not alter either relaxation (Emax= 0.01 ± 0.004 g) or contraction (Emax= 0.54 ± 0.009 g). Dihydroethidium fluorescence was increased in contralateral samples (18 882 ± 435 U) in relation to control (10 455 ± 303 U). SC236 reduced the fluorescence in contralateral samples (8250 ± 365 U). CONCLUSIONS AND IMPLICATIONS Balloon catheter injury abolished phenylephrine-induced relaxation and increased phenylephrine-induced contraction in contralateral carotid arteries, through O2- derived from COX-2.

Summary This study compared the effects of intravenous infusions of phenylephrine and mephentermine on the prevention of maternal hypotension and neonatal outcome in patients receiving spinal anaesthesia for caesarean section. Sixty ASA 1-2 patients with term, uncomplicated singleton pregnancy undergoing caesarean section under spinal anaesthesia were randomly divided into two groups of 30 each, to receive a prophylactic intravenous infusion of either phenylephrine or mephentermine. The incidence of hypotension was statistically similar in the two groups. However, in patients receiving phenylephrine, 7 (23%) developed bradycardia and 6 (20%), reactive hypertension. Neonatal outcome, in terms of Apgar scores and umbilical artery pH, was similar in both the groups. To conclude, phenylephrine and mephentermine infusions are equally effective in preventing post spinal hypotension in patients undergoing caesarean section and are associated with a similar neonatal outcome.

This is a study evaluating the efficacy of Ankaferd Blood Stopper (ABS) as a hemostatic agent compared to hemostasis by phenylephrine in patients with anterior epistaxis. The study design is a prospective, randomized, controlled, nonblinded, clinical trial. In total, 49 patients were randomly seperated to receive hemostasis technique by means of either ABS wet tampon or phenylephrine impregnated gauze tampon for anterior epistaxis control. Patients were crossed over to the other technique after two unsuccessful attempts of the first technique. Measured outcomes such as number of applications, relationship of number of applications with bleeding intensity (1 = stains on napkin, 2 = soaked napkin, 3 = bowl needed), patient discomfort during hemostasis (0 = none, 9 = unbearable), and complications were assessed. Additional data were recorded for rebleeding within 7 days. 24 of the 49 patients were assigned to the new ABS group (group I) and remaining 25 were included in the standard phenylephrine group (group II). ABS was more effective than phenylephrine at control of anterior epistaxis (79.2 vs. 64%, p < 0.05). For the patients who crossed over from phenylephrine to ABS, 44.4% achieved hemostasis by ABS. ABS successfully treated all bleeding intensity 1 and 2 patients with one application (5 min). ABS patients experienced fewer rebleeding rates within 7 days compared to phenylephrine patients (8.3 vs. 20%, p < 0.05). The patients for which ABS was applied, significant differences in effective control of anterior epistaxis were observed compared to phenylephrine. ABS is effective, safe, quick, and easy alternative to the phenylephrine in patients with anterior epistaxis.

We assume that phenylephrine produces late pharmacological preconditioning through the opening of the mitochondrial KATP channels. To test this hypothesis, rat hearts were isolated and perfused with Krebs buffer solution by Langendorff method and subjected to 30 min regional ischemia followed by 60 min of reperfusion. In this study, phenylephrine as a selective alpha1-adrenoceptor agonist and 5HD (5-hydroxydecanoate) as a putatively specific blocker of the mitochondrial KATP channels were used. Rats were randomly divided into six groups (n=6): (I) Control: surgical procedure was performed with no ischemia/reperfusion, (II) ischemia/reperfusion: hearts underwent regional ischemia/reperfusion, (III) phenylephrine-early preconditioning: phenylephrine (50 microM) was perfused for 5 min prior to ischemia/reperfusion, (IV) phenylephrine-late preconditioning: rats were treated with phenylephrine (10 mg/kg, i.p) 24h prior to ischemia/reperfusion, (V) 5HD-phenylephrine early preconditioning-: 5HD (100 microM) was perfused for 5 min prior to phenylephrine as seen in group III, (VI) Phenylephrine late preconditioning-5HD: 5HD (100 microM) was perfused for 5 min prior to ischemia/reperfusion as seen in group IV and (VII) 5HD- ischemia/reperfusion: 5HD (100 microM) was perfused for 5 min prior to ischemia/reperfusion. Compared to ischemia/reperfusion group, phenylephrine in early and late phases decreased myocardial infarct size (% of ischemia zone), reduced CK-MB (Creatine Kinase-MB) release in the coronary effluent and improved cardiac function. Pretreatment with 5HD abolished phenylephrine-induced cardioprotection in early and late phases. It is concluded that phenylephrine-induced late cardioprotection was abolished by administration of 5HD in the isolated rat hearts.

Hypotension frequently complicates spinal anesthesia for cesarean delivery, and vasopressors are the mainstay for treatment. The most effective dose of phenylephrine for the treatment of spinal anesthesia-induced hypotension has not been estimated.Healthy nonlaboring women undergoing a cesarean delivery were recruited. All women received spinal anesthesia using hyperbaric bupivacaine 12 mg with fentanyl and morphine. Each subject received an i.v. crystalloid fluid bolus before and at the time of initiation of spinal anesthesia (preload and coload). An up-down sequential allocation method using the biased-coin design was used to estimate the 90% effective dose (ED(90)) of phenylephrine. The assigned phenylephrine dose was based on the response of the preceding subject. If the systolic blood pressure (SBP) decreased20% of baseline (i.e., SBP 20%) or to an SBP90 mm Hg, the assigned dose of phenylephrine was administered. If the SBP returned to within 20% of baseline oror = 90 mm Hg within 1 min, this was considered a success, otherwise it was a failure. The initial dose of phenylephrine was 100 microg. The ED(90) with 95% confidence intervals (CIs) was calculated using the maximum likelihood estimation and Firth logistic regression.Sixty-nine subjects were screened to participate, of whom 66 subjects consented. Forty-five of the enrolled subjects experienced spinal anesthesia-induced hypotension and received a blinded dose of phenylephrine. Those subjects who developed hypotension received doses of phenylephrine between 80 and 180 microg. No subjects experienced hypertension. Determined with the maximum likelihood estimation method, the ED(90) of phenylephrine was 147 microg (95% CI, 98-222 microg). With Firth regression, the probability of a successful response at 150 microg is 90.5% (95% CI, 66.0%-99.0%).In this study, we estimated that the ED(90) of phenylephrine required to treat spinal anesthesia-induced hypotension in cesarean delivery is approximately 150 microg.

Since it is unclear whether and how propofol affects the alpha(1)-mediated inotropic response, we used a pharmacokinetic-pharmacodynamic modeling approach in isolated rat hearts to analyze the effect of propofol on receptor binding and signal transduction. In Langendorff rat hearts perfused with buffer containing 12.3 microM phenylephrine, 1.27 nmol doses of [(3)H]-prazosin were infused (over 1 min), in the absence and presence of propofol (28 microM). Simultaneous analysis of prazosin outflow concentration and inotropic response (left ventricular developed pressure) using an agonist-antagonist interaction model allowed to estimate receptor affinity, as well as the parameters of the operational model of agonism. Propofol significantly (P

Background: Our previous study in a swine polytrauma model suggested that equieffective systemic pressor doses of arginine vasopressin (AVP) versus phenylephrine (PE) have differential effects on the systemic and cerebral microcirculation. The purpose of this study was to directly observe the effects of AVP versus PE on inflammatory changes evoked by tumor necrosis factor alpha (TNF) in the skeletal muscle microcirculation. Methods: Seventy-five male rats (180-250 g) were anesthetized with isoforane, intubated and mechanically ventilated with 100% oxygen. The cremaster muscle microcirculation was prepared for intravital video microscopy while being suffused with a heated hetastarch-electrolyte solution. Fluorescein isothiocyanate-labeled albumin (100 mg/kg) was administered intravenously (i.v.) before one of five protocols. In series 1 (n = 20), either AVP (0.2 U/mL) or its vehicle was added to the suffusate for 10 minutes, washed out for 30 minutes, then TNF was suffused (5 ng/mL) for 30 minutes. In series 2 (n = 16), the protocol was similar, except AVP (0.2 U/mL) or an equieffective dose of PE (0.04 mg/mL) was administered i.v. (4.5 mL/h) for 15 minutes before, during, and 45 minutes after TNF suffusion. In series 3 (n = 12), the protocol was similar to series 2, except venous hemorrhage preceded i.v. AVP or PE. In series 4 (n = 15), the protocol was similar to series 3, except an AVP antagonist (vaprisol, 1 mg/kg i.v.) or its vehicle was administered after hemorrhage. In the control series (n = 13), inflammation was evaluated either with a different suffusate (lactated Ringers instead of hetastarch solution), different antigen (histamine instead of TNF), or hemorrhage with no antigen. Results: In series 1, the TNF-evoked increase in leukocyte infiltration (i.e., rolling), leukocyte activation (i.e., sticking), and macromolecular permeability (i.e., albumin extravasation) were attenuated with topical AVP versus vehicle (both p < 0.05), with no effect on venular blood flow (which determines sheer stress). In series 2, the TNF-evoked increase in infiltration, activation, and permeability were all attenuated, and arteriolar blood flow (which determines perfused capillary surface area and hydrostatic pressure) was reduced with i.v. AVP versus i.v. PE (all p < 0.05). In series 3, after hemorrhage to mean arterial pressure

SUMMARY In a randomised, double-blinded study, we compared boluses of phenylephrine 100 microg with ephedrine 10 mg for treating hypotension (systolic blood pressure < 100 mmHg) in 204 patients having non-elective Caesarean section under spinal anaesthesia. Umbilical arterial (UA) and venous (UV) pH and base excess were similar between groups. In the ephedrine group, UA lactate concentration was higher (median 2.6 [interquartile range 2.3-3.3] vs 2.4 [1.9-3.0] mmolxl(-1), p = 0.002) and UV lactate concentration was higher (2.5 [2.2-3.2] vs 2.3 [1.9-2.8] mmolxl(-1), p = 0.016) and more patients had nausea or vomiting (12.7% vs 3.9%, p = 0.02). Clinical neonatal outcome was similar. Of the protocol-compliant patients (n = 148), UA Po(2) and UV Po(2) were lower in the phenylephrine group although oxygen content was similar. We conclude that phenylephrine and ephedrine are both suitable vasopressors for use in non-elective Caesarean sections.

BACKGROUND: Phenylephrine and ephedrine are both used to maintain arterial blood pressure during spinal anesthesia for cesarean delivery. Usually, either drug is given alone but several previous studies have described combining the drugs. However, the effect of varying the proportion of vasopressors in such combinations has not been reported. METHODS: One-hundred-twenty-five parturients having spinal anesthesia for elective cesarean delivery were randomized to receive an IV infusion of phenylephrine and ephedrine combined in one of five different concentration ratios. Assuming phenylephrine 100 g to be approximately equipotent to ephedrine 8 mg, the groups contained the proportional potency equivalent of 100%, 75%, 50%, 25% or 0% of phenylephrine and 0%, 25%, 50%, 75% or 100%, respectively, of ephedrine. The infusions were adjusted to maintain systolic blood pressure (SBP) near baseline until uterine incision. Hemodynamic changes and umbilical cord blood gases were compared. RESULTS: As the proportion of phenylephrine decreased and proportion of ephedrine increased among the groups, the following significant trends were detected: the incidences of hypotension and nausea/vomiting increased, the median magnitude of deviations of SBP above or below baseline and the bias for SBP to be above baseline increased, maternal heart rate was faster, fetal pH and base excess decreased, umbilical arterial oxygen content decreased and umbilical venous Po2 increased. CONCLUSIONS: When varying combinations of phenylephrine and ephedrine were given by infusion to maintain arterial blood pressure during spinal anesthesia for cesarean delivery, as the proportion of phenylephrine decreased and the proportion of ephedrine increased, hemodynamic control was reduced and fetal acid-base status was less favorable. Combinations of phenylephrine and ephedrine appear to have no advantage compared with phenylephrine alone when administered by infusion for the prevention of hypotension associated with spinal anesthesia for cesarean delivery. (Anesth Analg 2008;107:1295‐1302)

We describe the novel use of a closed-loop feedback computer-controlled infusion of phenylephrine for maintaining blood pressure in 53 patients having spinal anaesthesia for elective caesarean section. A simple on-off algorithm was used that activated an intravenous phenylephrine infusion at 100 microg.min(-1) when systolic blood pressure was less than or equal to baseline and stopped the infusion when systolic blood pressure exceeded baseline. Up to uterine incision, 94.6% of all systolic blood pressure measurements were within the range (baseline +/- 20%). Seven patients (13.2%) had one or more episodes of hypotension (systolic blood pressure 120% of baseline). No patient had nausea or vomiting and in no case was umbilical arterial blood pH < 7.2. Calculated system performance parameters were comparable with those of previously published closed-loop systems and provide a reference for the potential development and comparison of more advanced algorithms.

Patients with hypertension have a blunted sensitivity of baroreflex control of heart period. In these patients, baroreflex sensitivity is positively related to heart rate variability and inversely related to blood pressure variability. We hypothesized that this relationship would also be evident in healthy normotensive subjects and that individuals with higher baroreflex sensitivity would have lower ambulatory 24-hour blood pressure. Twenty-four-hour ambulatory blood pressure and heart rate were recorded in 50 healthy, normotensive, nonobese individuals (31 women and 19 men). The baroreflex was assessed using sequential bolus administration of sodium nitroprusside and phenylephrine, and baroreflex sensitivity was calculated as the slope of the relation between systolic blood pressure and R-R interval during the resulting blood pressure transients. Baroreflex sensitivity was inversely correlated to 24-hour average mean arterial pressure ( R =0.49; P R =0.33; P =0.02). In contrast, no relationship was found between baroreflex sensitivity and 24-hour heart rate or blood pressure variabilities. We conclude that the relationship between baroreflex sensitivity and daytime heart rate variability was similar to that reported previously in hypertensive subjects. Furthermore, the inverse relation between baroreflex sensitivity and mean arterial pressure supports the idea that the baroreflex may exert longer-term effects on blood pressure than thought previously.

The effects of exercise training on baroreflex control of sympathetic nerve activity in human hypertension are unknown. We hypothesized that exercise training would improve baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate (HR) in patients with hypertension and that exercise training would reduce MSNA and blood pressure (BP) in hypertensive patients. Twenty never-treated hypertensive patients were randomly divided into 2 groups: exercise-trained (n=11; age: 46±2 years) and untrained (n=9; age: 42±2 years) patients. An age-matched normotensive exercise-trained group (n=12; age: 42±2 years) was also studied. Baroreflex control of MSNA (microneurography) and HR (ECG) was assessed by stepwise intravenous infusions of phenylephrine and sodium nitroprusside and analyzed by linear regression. BP was monitored on a beat-to-beat basis. Exercise training consisted of three 60-minute exercise sessions per week for 4 months. Under baseline conditions (before training), BP and MSNA were similar between hypertensive groups but significantly increased when compared with the normotensive group. Baroreflex control of MSNA and HR was similar between hypertensive groups but significantly decreased when compared with the normotensive group. In hypertensive patients, exercise training significantly reduced BP ( P P P P P P

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.

We previously found rostral spread of spinal plain levobupivacaine to be less with prophylactic i.v. phenylephrine than with ephedrine during Caesarean delivery. This study investigated whether rostral spread of spinal hyperbaric bupivacaine is also less with phenylephrine than with ephedrine.The study was randomized and double blind. It compared phenylephrine 100 microg ml-1 (phenylephrine group, n=27), and ephedrine 4.5 mg ml-1 (ephedrine group, n=27), given by infusion during spinal anaesthesia for Caesarean delivery. Block height was assessed to cold and light touch sensation at 15, 30, 60, and 90-min after the spinal injection of 2.8 ml of hyperbaric 0.5% w/v bupivacaine, combined with 0.4 ml diamorphine (1 mg ml-1). Umbilical blood gas values were monitored during the study.Block height was similar for both groups at all of the assessment times. Umbilical artery pH was higher with phenylephrine [median 7.32 (IQR 7.28-7.34)] than with ephedrine [7.20 (7.10-7.28)] (P0.0001). There was a strong negative correlation between umbilical artery pH and spinal-delivery interval, but only with ephedrine: phenylephrine group, r2=0.09 (P=0.17), and ephedrine group, r2=0.53 (P0.0001). Five-minute Apgar scores were higher with phenylephrine [10 (9-10)] than ephedrine [9 (9-9)] (P=0.009).In contrast to its effect on spinal plain levobupivacaine, we did not find rostral spread of spinal hyperbaric bupivacaine to be less with prophylactic phenylephrine than with ephedrine. We observed an unexpectedly high incidence of fetal acidosis with ephedrine and found evidence that longer spinal-delivery intervals increase the risk of fetal acidosis developing with ephedrine, but not phenylephrine.

Impaired endothelial-derived NO (eNO) is invoked in the development of many pathological conditions. Systemic inhibition of NO synthesis, used to assess the importance of NO to blood pressure (BP) regulation, increases BP by ≈15 mm Hg. This approach underestimates the importance of eNO, because BP is restrained by baroreflex mechanisms and does not account for a role of neurally derived NO. To overcome these limitations, we induced complete autonomic blockade with trimethaphan in 17 normotensive healthy control subjects to eliminate baroreflex mechanisms and contribution of neurally derived NO. Under these conditions, the increase in BP reflects mostly blockade of tonic eNO. N G -Monomethyl- l -arginine (250 μg/kg per minute IV) increased mean BP by 6±3.7 mm Hg (from 77 to 82 mm Hg) in intact subjects and by 21±8.4 mm Hg (from 75 to 96 mm Hg) during autonomic blockade. We did not find a significant contribution of neurally derived NO to BP regulation after accounting for baroreflex buffering. To further validate this approach, we compared the effect of NOS inhibition during autonomic blockade in 10 normotensive individuals with that of 6 normotensive smokers known to have endothelial dysfunction but who were otherwise normal. As expected, normotensive smokers showed a significantly lower increase in systolic BP during selective eNO blockade (11±4.5 versus 30±2.3 mm Hg in normotensive individuals; P

1 Inhibition of the Na+–K+–2Cl− cotransporter (NKCC1) with bumetanide reduced contractile responses to phenylephrine (PE) in male rat aortas (129±4% of 60 mM KCl-induced contraction control vs 108±7% bumetanide; PE 10−5 M; P

Background and Aim: Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamic circulation in cirrhosis. Animal models of cirrhosis and portal vein ligation have helped in our understanding of portal hypertension. The etiopathogenesis of non-cirrhotic portal fibrosis (NCPF), a common cause of portal hypertension, is still poorly understood. The aim of this study was to investigate the pathophysiology of NCPF in a rabbit model. Methods: An indwelling cannula was inserted into the gastrosplenic vein of rabbits. Animals were randomly injected with saline (Group I, n = 13) or lipopolysaccharide (Group II, n = 13) from heat killed Escherichia coli at 0, 1, 2, 7, 14 and 28 days. Portal pressure was measured at 3 months and vasoresponsiveness studied in isolated aortic rings in intact and in endothelium-denuded tissues from both groups. Results: In all group II compared with group I animals, the splenic weight (0.89 ± 0.16 vs 0.62 ± 0.1 g, P

Background Plasma volume expansion is often performed during adrenergic therapy in the intensive care unit, but little is known about their combined effects. Materials and methods The influence of three adrenergic drugs (50 μg/kg/min of dopamine, 0.1 μg/kg/min of isoprenaline, or 3 μg/kg/min of phenylephrine) on the relationship between plasma dilution (an index of volume expansion) and the central hemodynamic responses to volume loading with 24 ml/kg of 0.9% saline were evaluated in 6 adult sheep. Kinetic analysis was also applied to the data on plasma dilution and the urinary excretion measured during and after volume loading. Results The adrenergic agents markedly changed the baseline values for all hemodynamic parameters. The kinetic analysis showed that phenylephrine, which is an alpha-adrenergic receptor agonist, promoted renal excretion of infused fluid at the expense of fluid distribution to the periphery ( P versus controls). Isoprenaline, which stimulates adrenergic beta-receptors, had the opposite effect. During volume expansion, cardiac atrial pressures increased by 25 to 90%, cardiac output by 13–80% and the arterial pressures by 2 to 22%. Plasma dilution during and after volume loading correlated, in a linear fashion, with these hemodynamic responses. The correlations were strong ( r > 0.80) in the control and phenylephrine groups, but weaker in the dopamine and isoprenaline groups. Dopamine was associated with the most variable hemodynamic responses overall. Conclusions Adrenergic drugs altered the hemodynamics at baseline (direct effects), changed the distribution and elimination of infused 0.9% saline (indirect effects) and, finally, modified most hemodynamic responses to plasma dilution (interaction effects).

To evaluate the potential differential effects of norepinephrine, an alpha1-, beta1-, and beta2-receptor agonist, to the alpha1-agonist phenylephrine on jejunal mucosal perfusion, gastric-arterial PCO2 gradient, and the global splanchnic oxygen demand-supply relationship after cardiac surgery.A randomized, prospective, interventional crossover study.A university cardiothoracic intensive care unit.Ten patients were studied during propofol sedation and mechanical ventilation after uncomplicated coronary artery bypass surgery.Each patient received randomly and sequentially norepinephrine (0.052+/-0.009 microg/kg/min) and phenylephrine (0.50+/-0.22 microg/kg/min) to increase mean arterial blood pressure by 30%.Data on jejunal mucosal perfusion, jejunal mucosal hematocrit, and red blood cell velocity (laser Doppler flowmetry) as well as gastric-arterial Pco2 gradient (tonometry) and splanchnic oxygen extraction were obtained before (control) and during a 30-min drug infusion period after the target mean arterial blood pressure was reached. The procedure was sequentially repeated for the second vasopressor. Both drugs induced a 40-46% increase in systemic vascular resistance with no change in cardiac index. Neither jejunal mucosal perfusion, jejunal mucosal hematocrit, red blood cell velocity, nor gastric-arterial Pco2 gradient was affected by any of the vasopressors. Splanchnic oxygen extraction increased from 38.2% to 43.1% (p.001) with norepinephrine and from 39.3% to 47.5% (p.001) with phenylephrine. This increase was significantly more pronounced with phenylephrine compared with norepinephrine (p.05). Mixed venous-hepatic vein oxygen saturation gradient increased with both drugs (p.01), and the increase was more pronounced with phenylephrine (p.05). Splanchnic lactate extraction was not significantly affected by any of the vasopressors.Phenylephrine induced a more pronounced global alpha1-mediated splanchnic vasoconstriction compared with norepinephrine. Neither of the vasoconstrictors impaired perfusion of the gastrointestinal mucosa in postcardiac surgery patients. The lack of norepinephrine-induced, alpha1-mediated impairment of gastrointestinal perfusion is not explained by a beta2-mediated counteractive vasodilation but instead by possible mucosal autoregulatory escape.

In this work, we analyzed the interaction of nitric oxide (NO) with some of the mechanisms known to regulate intracellular calcium levels in order to gain insight into the mechanisms responsible for the reduced vascular pressor response to vasoconstrictors observed in an experimental model of liver cirrhosis. Specifically, we hypothesized that the entry of calcium through capacitative channels is defective in this model. The experiments were performed with isolated, Krebs-perfused and de-endothelialized mesenteric arterial bed of rats with bile duct ligation (4 weeks) and their controls. Pretreatment with thapsigargin to inhibit calcium uptake into sarcoplasmic reticulum potentiated the pressor responses to methoxamine, but the response of the cirrhotic vessels was significantly lower than that of the controls. Under the same conditions, perfusion of the mesenteries with zero calcium-Krebs resulted in lower pressor responses to methoxamine, especially in the mesenteries of the bile duct-ligated rats. To specifically analyze the entry of calcium through store-operated calcium channels, the pressor response to the addition of calcium was studied in mesenteries perfused with zero calcium-Krebs and in the presence of thapsigargin. Again, the response of the cirrhotic mesenteric beds was significantly lower than that of the control vessels. Under all these experimental conditions, the differences between control and cirrhotic responses were abolished by pretreatment with the NO synthesis inhibitor N w -nitro- l -arginine (NNA). These results indicate that, in the mesenteric bed of bile duct-ligated rats, an excess of nitric oxide interferes with the release of calcium from thapsigargin-sensitive internal stores and also reduces the capacitative entry of calcium into vascular muscular cells induced by the depletion of calcium from internal stores. This mechanism may have an important role in the reduced pressor response observed in the mesenteric vascular bed in cirrhosis.

Background Many methods for preventing hypotension during spinal anesthesia for cesarean delivery have been investigated, but no single technique has proven to be effective and reliable. This randomized study studied the efficacy of combining simultaneous rapid crystalloid infusion (cohydration) with a high-dose phenylephrine infusion. Methods Nonlaboring patients scheduled to undergo elective cesarean delivery received an intravenous infusion of 100 mug/min phenylephrine that was started immediately after spinal injection and titrated to maintain systolic blood pressure near baseline values until uterine incision. In addition, patients received infusion of lactated Ringer's solution that was given either rapidly (group 1, n = 57) or at a minimal maintenance rate (group 0, n = 55). Maternal hemodynamic changes and neonatal condition were compared. Results Six patients were excluded from analysis. Only 1 of 53 patients (1.9% [95% confidence interval, 0.3-9.9%]) in group 1 experienced hypotension versus 15 of 53 patients (28.3% [95% confidence interval, 18.0-41.6%]) in group 0 (P = 0.0001). Compared with group 0, patients in group 1 had greater values for the following: serial measurements of systolic blood pressure (P = 0.02), minimum recorded systolic blood pressure (P = 0.0002), and minimum recorded heart rate (P = 0.013). Total phenylephrine consumption was smaller in group 1 compared with group 0 (P = 0.008). Neonatal outcome and maternal side effects were similar between groups. Conclusions Combination of a high-dose phenylephrine infusion and rapid crystalloid cohydration is the first technique to be described that is effective for preventing hypotension during spinal anesthesia for cesarean delivery.

Mean arterial pressure (MAP) increases after birth, however, the mechanisms remain unclear. Systemic angiotensin II (ANG II) infusions increase MAP in newborn sheep, but the direct effects of ANG II on peripheral vascular resistance (PVR) are minimal. Thus, its systemic pressor effects may reflect release of other pressor agents, e.g. α-agonists and/or AVP, suggesting they contribute to postnatal regulation of MAP and PVR. To address this, we performed studies in conscious sheep at 7–14, 15–21, and 22–35 d postnatal, infusing phenylephrine (PE) or AVP systemically or intra-arterially into the hindlimb while measuring MAP, heart rate (HR), and femoral blood flow (FmBF). Basal MAP and FmBF rose, whereas HR and femoral vascular resistance (FmVR) fell (p ≤ 0.03) during the first month postnatal. Although systemic PE and AVP dose dependently increased MAP and FmVR and decreased FmBF and HR (p < 0.001, ANOVA) at all ages, responses were not age dependent. Notably, increases in FmVR exceeded increases in MAP, and responses to PE appeared to exceed AVP (p < 0.05). Hindlimb infusions of both agents decreased FmBF and increased FmVR dose dependently (p < 0.001, ANOVA) at all ages without altering MAP or HR. These responses also were not age dependent. Unlike ANG II, PE and AVP directly increase PVR in newborn sheep. Moreover, FmVR increases more than MAP at all doses, suggesting these agonists may contribute to postnatal MAP regulation and could mediate the effects of systemic ANG II on postnatal MAP.

Gender has been reported to influence baroreflex heart rate regulation and baroreflex blood pressure buffering. We tested the hypothesis that gender influences baroreflex regulation of heart rate and sympathetic vasomotor tone. We recruited 32 normal-weight healthy subjects (17 men and 15 women). ECGs for heart rate, brachial and finger blood pressure, and muscle sympathetic nerve activity (MSNA) were measured. Baroreflex heart rate and MSNA regulation were assessed using incremental phenylephrine and nitroprusside infusions. Baseline blood pressure was similar in men and women. MSNA was 21±2.5 bursts/min in women and 19±2.8 bursts/min in men (NS). The gain of the baroreflex MSNA curves was similar in women and men (−1.9±0.2 bursts/min per mm Hg in men and −2.0±0.3 bursts/min per mm Hg in women). Baroreflex gain for heart rate regulation was 17±3.2 ms/mm Hg in women and 19±1.9 ms/mm Hg in men (NS). We conclude that baroreflex gains for heart rate and sympathetic MSNA regulation are similar in women and men. However, the probability for congruence between men and women in terms of the MSNA baroreflex curves was 0.06% for burst rate, 0.4% for burst incidence, and 0.01% for burst area. In women, the MSNA baroreflex curve may be shifted to slightly lower blood pressure such that at a given blood pressure MSNA tends to be lower.

To compare the effects of norepinephrine and metaraminol on hemodynamics in septic shock patients.Open-label, controlled clinical trial in the general intensive care unit of a university-affiliated hospital.Ten consecutive septic shock patients receiving norepinephrine to maintain the mean arterial pressure higher than 65 mmHg.Patients were monitored with pulmonary artery catheter and indirect calorimetry. At the baseline hemodynamic variables were obtained during norepinephrine infusion. Subsequently norepinephrine was replaced by metaraminol infusion in a dose sufficient to keep mean arterial pressure constant. After 20 min of stable arterial pressure a new set of measurement was repeated.Mean arterial pressure did not differ significantly with norepinephrine or metaraminol; there was no relationship between the norepinephrine and metaraminol doses. Replacement norepinephrine with metaraminol did not modify hemodynamic variables; in particular there were no changes in heart rate, stroke volume index, pulmonary artery occlusion pressure, or oxygen consumption index.This study shows that metaraminol increases arterial pressure as does norepinephrine in septic shock patients. Despite similar effects of norepinephrine and metaraminol, there was no relationship between the dose of the two drugs.

We compared renal interlobar arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in terms of cytochrome P450 (CYP) 4A and CYP2E1 protein expression; levels of 20-HETE, 19-HETE, and 18-HETE; and responsiveness to phenylephrine in the absence and presence of N- methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 μmol/L), a CYP4A inhibitor. Relative to data in WKY, arteries of SHR exhibited diminished ( P max was similar in both strains, but SHR vessels were more sensitive as denoted by the lower ( P 50 (0.28±0.07 versus 0.71±0.12 μmol/L). DDMS decreased 20-HETE and, to a lesser extent, 19-HETE, while increasing ( P 50 for phenylephrine by 475% and 54% in vessels of SHR and WKY, respectively. The desensitizing effect of DDMS was reversed by 20-HETE. Notably, the minimal concentration of 20-HETE that decreased the EC 50 for phenylephrine in DDMS-treated vessels was smaller in SHR (0.1 μmol/L) than WKY (10 μmol/L), and the sensitizing effect of 20-HETE was blunted ( P

This study compared the effects of intravenous infusions of ephedrine and mephentermine for maintenance of maternal arterial pressure and neonatal outcome in pregnant women receiving subarachnoid block for lower segment Caesarean section. Sixty patients who developed hypotension following subarachnoid block for Caesarean section were randomly divided into two groups of 30 each to receive an intravenous infusion of ephedrine or mephentermine. Hypotension was defined as a decrease in systolic blood pressure of > or = 20% from the baseline value or an absolute value of

Adverse systemic reactions such as cardiovascular effects may occur following topical ocular application of phenylephrine. We report the case of a 49-year-old woman who, following topical application of phenylephrine eyedrops, experienced hypertension with electrocardiographic modifications and a rise in cardiac troponin Ic.

1. The effects of balloon injury on the reactivity of ipsilateral and contralateral carotid arteries were compared to those observed in arteries from intact animals (control arteries). 2. Carotid arteries were obtained from Wistar rats 2, 4, 7, 15, 30 or 45 days after injury and mounted in an isolated organ bath. Reactivity to angiotensin II (Ang II), phenylephrine (Phe) and bradykinin (BK) was studied. Curves were constructed in the absence or presence of endothelium or after incubation with 10 microm indomethacin, 500 microm valeryl salicylate or 0.1 microm celecoxib. 3. Phe, Ang II and BK maximum effects (Emax) were decreased in ipsilateral arteries when compared to control arteries. No differences were observed among pD2 or Hill coefficient. 4. Emax to Phe (4 and 7 days) and to Ang II (15 and 30 days) increased in the contralateral artery. In addition, Phe or Ang II reactivity was not significantly different in aorta rings from control or carotid-injured animals. 5. The increased responsiveness of contralateral artery was not due to changes in carotid blood flow or resting membrane potential. The endothelium-dependent inhibitory component is not present in the contraction of contralateral arteries and it is not related to superoxide anion production. 6. Indomethacin decreased contralateral artery responsiveness to Phe and Ang II. Valeryl salicylate reduced the Ang II response in contralateral and control arteries. Celecoxib decreased the Phe Emax of contralateral artery. 7. In conclusion, decreased endothelium-derived factors and increased prostanoids appear to be responsible for the increased reactivity of contralateral arteries after injury.

Many of the actions of angiotensin II (Ang II) are mediated by angiotensin type 1 receptors (AT 1 ), of which there are 2 pharmacologically indistinguishable subtypes (AT 1A and AT 1B ). The purpose of this study was to evaluate the effect of an AT 1A homozygous deletion (AT 1A −/− ) on vascular reactivity. AT 1A −/− mice and control littermates (AT 1A +/+ ) were infused with vehicle (saline) or Ang II (1000 ng · kg −1 · min −1 ) for 7 days by osmotic pumps. Systolic pressure was increased in AT 1A +/+ mice (Δ45±8 mm Hg, P 1A −/− mice (Δ5±3 mm Hg, P >0.13) on day 7. The carotid artery response to the vasodilators acetylcholine (ACh), nitroprusside, and papaverine and to the vasoconstrictors phenylephrine, U46619, 5-hydroxytryptamine (5-HT), and KCl were not different between vehicle-infused AT 1A +/+ and AT 1A −/− animals. Carotid relaxation to ACh was impaired and contraction to 5-HT was increased in Ang II–infused AT 1A +/+ mice. Ang II did not affect carotid responses in AT 1A −/− mice. Superoxide, measured by lucigenin (5 μmol/L), and hydroethidine staining were not different between AT 1A +/+ and AT 1A −/− mice after vehicle or Ang II infusion, suggesting that it was not contributing to the altered ACh and 5-HT responses. The Rho-kinase inhibitor Y-27632 (1 μmol/L) attenuated the 5-HT response in both vehicle- and Ang II–infused AT 1A +/+ mice. Moreover, concentration-dependent relaxation to Y-27632 and RhoA protein expression were not different in vehicle- or Ang II–infused AT 1A +/+ . These data demonstrate that the AT 1A receptor is required for Ang II–induced changes in carotid artery function.

Phosphatidylinositol 3-kinase (PI3K) has been implicated in low extracellular Mg 2+ concentration ( [Mg 2+ ] e )–induced aortic contraction, and Mg 2+ deficiency has been associated with hypertension. Moreover, arterial PI3K activity is increased in hypertensive deoxycorticosterone (DOCA)-salt rats. We hypothesized that low [Mg 2+ ] e activates PI3K, eliciting enhanced vascular contraction, PI3K activity, and norepinephrine (NE)-induced contraction. Spontaneous tone was monitored in endothelium-denuded aortic strips from sham and DOCA-salt rats exposed to low Mg 2+ (0.15 mmol/L), high Mg 2+ (4.8 mmol/L), or normal (1.17 mmol/L) physiologic salt solution (PSS) in isolated tissue baths. LY294002 (20 μmol/L), a PI3K inhibitor, or vehicle was added (30 minutes), followed by NE (10 −9 to 3 x10 −-5 mol/L). Low [Mg 2+ ] e significantly enhanced tone in aortas from DOCA-salt and sham rats compared with normal PSS (DOCA-salt low [Mg 2+ ] e , +51.5 +7.0 vs DOCA-salt normal PSS, +7.1 +1.4 % of initial phenylephrine [PE] contraction). LY294002 and incubation with high Mg 2+ PSS decreased tone in aortas from DOCA-salt rats (low [Mg 2+ ] e LY294002, −-87.5 +8.8; normal PSS LY294002, −81.7 +13.7; and high [Mg 2+ ] e , −31.2 +10.8 % of initial PE contraction). Low [Mg 2+ ] e leftward-shifted NE-induced aortic contractions in sham and thus matched the shift observed with DOCA (−log EC 50 mol/L: sham PSS, −7.7 +0.1; DOCA-salt PSS, −8.2 +0.1; sham low [Mg 2+ ] e , −8.2 +0.1; and DOCA-salt low [Mg 2+ ] e , −8.1 +0.1). Moreover, this shift was inhibited by LY294002. In conclusion, low [Mg 2+ ] e might activate PI3K, leading to enhanced tone and agonist-induced contraction observed in aortas from DOCA-salt hypertensive rats.

The relations among hypertensive response, oxidative stress, and mitogen-activated protein kinase (MAPK) in cardiovascular tissues have not been fully established. We investigated the involvement of reactive oxygen species on changes in the hemodynamics and cardiovascular MAPKs activities induced by acutely administered angiotensin II (Ang II) in conscious normotensive rats with or without treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol). Intravenous infusion of a pressor dose of Ang II rapidly increased mean arterial blood pressure (MBP) by 53±5 mm Hg. After a 30-minute treatment with Ang II, phosphorylated MAPKs (ERK1/2, JNK, p38) as well as thiobarbital reactive substances (T-BARS) were increased in the aorta and cardiac left ventricle. Tempol had no significant effect on the elevation of MBP elicited by Ang II; however, it dose-dependently suppressed the augmented phosphorylation of cardiovascular MAPKs and increased T-BARS levels in plasma and tissues induced by Ang II. An acutely administered pressor dose of phenylephrine, an α-adrenoceptor agonist, also showed tempol-sensitive cardiovascular MAPK activation and tempol-insensitive blood pressure elevation. These in vivo data indicate that acute administration of Ang II or phenylephrine provoked an increase in oxidative stress in the cardiovascular tissues leading to the activation of MAPKs, whether it was mediated by pressure overload or the direct action of these vasoconstrictors, and that oxidative stress might not have a major contribution to the acute hypertensive responses elicited by the vasoconstrictors.

Constriction of the penile vasculature prevents erection and is largely mediated by physiological agonists. We hypothesized that protein kinase C (PKC) may act as a regulator of penile vascular tone. Studies were designed to identify PKC isoforms present and to investigate their roles in phenylephrine-induced muscle contraction in the isolated rat corpora cavernosa. We demonstrated the presence of PKCalpha, beta, gamma, epsilon, delta, eta, and iota in rat corpora cavernosa and a subcellular distribution, which favored a membrane association for PKCalpha, beta, delta, and iota. Phenylephrine (3 microM) generated an active stress of 9.6 +/- 1.5 mN/mm2 and was associated with a significant increase of PKCalpha and PKCiota immunoreactivity in the particulate fraction. The amount of PKCalpha and PKCiota in the particulate fraction rose by 36 +/- 4.4 and 51 +/- 2.2% with phenylephrine stimulation. Furthermore, the phenylephrine concentration-response curve was potentiated in the presence of phorbol 12-myristate13-acetate (PMA) (0.1 microM), a PKC activator (EC50: phenylephrine 1.0 +/- 0.8 microM vs phenylephrine + PMA 0.3 +/- 0.1 microM) and inhibited in the presence of chelerythrine chloride (30 microM), a PKC inhibitor (EC50: phenylephrine 1.0 +/- 0.8 microM vs phenylephrine + chelerythrine chloride 5.7 +/- 2.4 microM). Based on these results, we suggest a potential role for PKCalpha and PKCiota in phenylephrine-induced smooth muscle tone of the rat cavernosum.

Although it has been reported that the increase in blood pressure improves arterial oxygen saturation (SaO2) in children with tetralogy of Fallot, no prospective study has demonstrated that an increase in blood pressure induces an increase in pulmonary blood flow in these patients. The purpose of this study was to see whether a phenylephrine-induced increase in systemic blood pressure increased pulmonary blood flow, resulting in improved arterial oxygenation in tetralogy of Fallot. In 14 consecutive children with tetralogy of Fallot (2–32 months old), transesophageal pulsed Doppler signals of left upper pulmonary venous flow (PVF) velocity were recorded before and four minutes after 10/μg · kg−1 of phenylephrine iv. Simultaneously, arterial blood gas analysis and hemodynamic measurements were performed. The minute distance (MD) was calculated as the product of the heart rate and the sum of time-velocity integrals of PVF. Phenylephrine iv increased mean arterial blood pressure from 54 ± 8 mmHg to 73 ± 10 mmHg. This phenylephrineinduced hypertension significantly increased SaO2 and MD (92.0 ± 7.5 vs 95.0 ± 5.0% and 1318 ± 344 vs 1533 ± 425 cm · min−1, respectively). There was a significant correlation (r = 0.72) between the change in MD and the change in SaO2. Our results suggest that the phenylephrine-induced increase in systemic blood pressure produces an increase in pulmonary blood flow in tetralogy of Fallot. Our results further suggest that this increase in pulmonary blood flow is involved in the mechanism of phenylephrine-induced improvement of arterial oxygenation in tetralogy of Fallot.

(1) Septic shock represents an important risk factor for patients critically ill. This pathology has been largely demonstrated to be a result of a myriad of events. Glucocorticoids represent the main pharmacological therapy used in this pathology. (2) Previously we showed that ATP-sensitive potassium (KATP) channels are involved in delayed vascular hyporeactivity in rats (24 h after Escherichia coli lipopolysaccharide (LPS) injection). In LPS-treated rats, we observed a significant hyporeactivity to phenylephrine (PE) that was reverted by glybenclamide (GLB), and a significant increase in cromakalim (CRK)-induced hypotension. (3) We evaluated the effect of dexamethasone (DEX 8 mg kg-1 i.p.) whether on hyporeactivity to PE or on hyperreactivity to CRK administration, in vivo, in a model of LPS (8 x 106 U kg-1 i.p.)-induced endotoxemia in urethane-anaesthetised rats. (4) DEX treatment significantly reduced, in a time-dependent manner, the increased hypotensive effect induced by CRK in LPS-treated rats. This effect was significantly (P

Background Preservation of vascular tissue plays a crucial role in the success of organ transplantation. We investigated and compared the performance of 4 preservation solutions at preserving vascular tissue over 24, 48, and 72 h under hypothermic conditions. Materials and methods Rat aortic segments were stored in University of Wisconsin (UW), Modified University of Wisconsin (mUW), EuroCollins (EC), and Bretschneider Histidine-tryptophan-ketoglutarate (HTK) solutions at 4°C for 24, 48, and 72 h. Functional assessment was performed by measuring smooth muscle cell contraction and endothelium-dependent relaxation after stimulation with phenylephrine and acetylcholine, respectively, in an organ bath. Results UW and EC solutions were superior to the other solutions for endothelial cell preservation and were not statistically different from each other at any time ( P i.e. , contractile) preservation was best achieved with UW solution for up to 72 h. HTK appeared to function well at 24 h, but at 48 and 72 h, there was a major decline in contractile response and relaxation. Conclusion UW solution appears to be superior for the preservation of the functional integrity of vascular tissue stored under hypothermic conditions up to 72 h.

The human saphenous vein (HSV) is the most widely used graft in coronary artery revascularization procedures and is susceptible to spasm perioperatively. The aim of this study is to elucidate the mechanism(s) of agonist-induced excitation-contraction coupling in this vessel. Isometric contraction experiments were combined with in situ smooth muscle intracellular Ca2+ concentration ([Ca2+]i) imaging by confocal microscopy of intact undistended HSV segments during activation with phenylephrine (PE; 50 μM). Stimulation with PE produced a sustained contraction. Preincubation with 5 μM nifedipine, a blocker of the L-type voltage-operated Ca2+ channel, or 50 μM SKF-96365, a blocker of both the voltage- and receptor-operated channels, reduced force generation by 25–30%. Ca2+ imaging revealed that PE elicited only a transient rise in [Ca2+]i, suggesting that Ca2+plays only a minor role. However, a requirement for basal Ca2+ levels was demonstrated when PE contractions could not be maintained in Ca2+-free medium. In light of the transient Ca2+ response, it appears that signals other than Ca2+ must maintain the tonic contraction elicited by PE, such as those that sensitize the myofilaments to Ca2+. Application of HA-1077 (a Rho kinase inhibitor) at the peak of the contraction completely abolished the plateau phase of the response, whereas application of genistein (a tyrosine kinase inhibitor) reduced this phase by ∼50%. The foregoing results suggest that, whereas the transient Ca2+ signal can contribute to the development of force, maintenance of the plateau phase of the PE contraction in the HSV is the result of myofilament Ca2+ sensitization by Rho kinase and tyrosine phosphorylation. The elucidation of the mechanisms of excitation-contraction coupling in the HSV may be useful for the development of therapeutic strategies for the alleviation of vein graft spasm.

In a double-blinded, placebo-controlled, randomized study, we evaluated the effect of prophylactic IM phenylephrine at doses of 1.5 and 3 mg on hyperbaric tetracaine spinal anesthesia-induced hypotension in 90 normotensive and hypertensive patients aged65 yr undergoing surgery for hip fracture. Thirty normotensive patients received 1.5 or 3 mg of phenylephrine IM (N/P-1.5 and N/P-3.0 groups; n = 15 in each), whereas controls received saline (N/C group; n = 15), and 45 hypertensive patients were treated in a similar manner (H/P-1.5, H/P-3.0, and H/C groups; n = 15 in each). All groups had a peak sensory block height of T9, with a range of T8 to T10. The incidence of hypotension (25% decrease in mean arterial blood pressure [MAP] from baseline) was significantly lower in the patients who received phenylephrine 1.5 or 3 mg than in the controls, both in the normotensive and hypertensive groups (P0.01). The N/P-3.0 and N/P-1.5 groups and the H/P-3.0 group had significantly lower percentage reductions in MAP (P0.05) and required significantly smaller doses of rescue IV ephedrine (P0.05) than did the N/C group or the H/C group. The H/P-1.5 group also required significantly less rescue IV ephedrine (P0.05), although it was not sufficient to significantly attenuate the percentage decrease in MAP compared with that in the H/C group. Bradycardia (heart rate50 bpm) as an adverse effect after IM administration of phenylephrine was not observed in any of the groups. Hypertension (MAP20% increase from baseline) after medication occurred in the N/P-3.0 and H/P-3.0 groups, but not in the N/P-1.5 and H/P-1.5 groups. We conclude that prophylactic IM injection of 1.5 mg of phenylephrine is a safe (defined as the inhibition of bradycardia and hypertension) and effective means of reducing the incidence of hypotension associated with spinal anesthesia in normotensive and hypertensive elderly patients.We evaluated the efficacy and safety of small-dose IM phenylephrine for prophylaxis against spinal anesthesia-induced hypotension in normotensive and hypertensive elderly patients. Phenylephrine 1.5 mg IM was effective for reducing the incidence of hypotension and avoided adverse effects.

In conscious, freely-moving, male, Sprague-Dawley rats, the regional haemodynamic responses to the synthetic cannabinoids, WIN-55212-2 and HU 210, were compared. The possible involvement of cannabinoid, CB1-receptors, or β2-adrenoceptors in the responses to WIN-55212-2 and HU 210 were investigated using the CB1-receptor antagonist, AM 251, or the β2-adrenoceptor antagonist, ICI 118551, respectively. Both WIN-55212-2 (150 μg kg−1) and HU 210 (100 μg kg−1) had pressor, renal, and mesenteric vasoconstrictor and hindquarters vasodilator actions, although the effects of HU 210 were much more sustained than those of WIN-55212-2. Lower doses of the cannabinoids (WIN-55212-2, 50 μg kg−1, HU 210, 10 μg kg−1) had less consistent actions. All the significant cardiovascular effects of WIN-55212-2 and HU 210 were antagonized by pretreatment with AM 251 (3 mg kg−1). Furthermore, pretreatment with the β2-adrenoceptor antagonist, ICI 118551, inhibited the hindquarters vasodilator effects of WIN-55212-2 and of HU 210. On the basis of the present findings, and our earlier work, it is suggested that, in conscious rats, the pressor and vasoconstrictor effects of HU 210 and WIN-55212-2 involve cannabinoid-receptor-mediated increases in sympathetic activity. The accompanying hindquarters vasodilator actions of these agonists are cannabinoid receptor-mediated and appear to involve β2-adrenoceptors. Keywords: Cannabinoids, HU 210, WIN-55212-2, haemodynamics Introduction Previously (Gardiner et al., 2001), we have drawn attention to the complexity of the cardiovascular effects of cannabinoids as described in the literature, and have suggested that this might reflect variations in experimental conditions. Considering the in vivo studies, it appears that the state of anaesthesia influences the cardiovascular response to synthetic cannabinoids, since we have recently reported that WIN-55212-2, which has been shown to have marked hypotensive effects in anaesthetized rats (Lake et al., 1997), has dose-dependent pressor and renal and mesenteric vasoconstrictor effects in conscious rats, with hindquarters vasodilator actions being seen only with the higher doses of the cannabinoid (Gardiner et al., 2001). In our previous study, we made no formal assessment of the involvement of cannabinoid receptors in the vasoconstrictor or vasodilator responses to WIN-55212-2. Thus, the first aim of the present study was to determine the effects of the cannabinoid, CB1-receptor antagonist, AM 251 (Gatley et al., 1996, 1997) on the cardiovascular responses to WIN-55212-2 in conscious rats. We considered this an important experiment since, unlike SR 141716A, AM 251 is commercially available and yet there are no published in vivo data on the cardiovascular effects of AM 251, either on baseline haemodynamic status, or on responses to cannabinoids. In addition, since we (Gardiner et al., 2001) have hypothesized that the hindquarters vasodilator action of WIN-55212-2 could be mediated by β2-adrenoceptors, our second aim was to assess the effects of the β2-adrenoceptor antagonist, ICI 118551 (Bilski et al., 1983), on responses to WIN-55212-2. In anaesthetized rats, other cannabinoid agonists, such as HU 210, which differ structurally from WIN-55212-2 (for review see Pertwee, 1997), have also been reported to cause CB1-receptor-mediated hypotension, and this has been taken as a sign of vasodilatation (e.g., Lake et al., 1997). However, it is clear from our studies with WIN-55212-2, that it is only by monitoring regional haemodynamics that one can get a proper picture of the processes underlying any effects substances, such as cannabinoids, have on systemic arterial blood pressure. Very recently, some work has been published which indicates a complex regional haemodynamic profile associated with administration of HU 210 in urethane-anaesthetized rats (Wagner et al., 2001). However, because of the technique they used, Wagner et al. (2001) were restricted to making measurements at a single point in time following HU 210 administration. We know of only one report of the cardiovascular effects of HU 210 in conscious rats (Vidrio et al., 1996), and in that study, the cannabinoid was administered i.p., and measurements were restricted to blood pressure and heart rate, monitored indirectly. Therefore, the final aim of the present study was to make continuous measurements of the regional haemodynamic effects of HU 210 in conscious rats, to ascertain whether or not they resembled those of WIN-55212-2, and to determine the effects of cannabinoid receptor antagonism (with AM 251), or β2-adrenoceptor antagonism (with ICI 118551), thereupon. Some of the results have been presented to the British Pharmacological Society (Gardiner et al., 2002a,2002b).

Hypertension development, phenylephrine-induced contraction and Na(+),K(+)-ATPase functional activity and protein expression in aorta (AO), tail (TA) and superior mesenteric (SMA) arteries from ouabain- (25 microg day(-1), s.c., 5 weeks) and vehicle-treated rats were evaluated. Ouabain treatment increased systolic blood pressure (127+/-1 vs 160+/-2 mmHg, n=24, 35; P 0.05) and smaller in TA (dAUC: 62.1+/-5.5 vs 41.4+/-8.2%, n=12, 13; P

The ability of glycopyrronium to reduce the severity of hypotension following subarachnoid block in parturients with a relative bradycardia was evaluated in a double-blind randomised controlled study. Women with a resting heart rate of < or = 80 beat x min(-1) presenting for elective Caesarean section were randomly allocated to receive either glycopyrronium 2 microg x kg(-1) or normal saline intravenously once positioned for combined spinal-epidural anaesthesia. Following spinal injection of 2.6 ml hyperbaric bupivacaine 0.5% and fentanyl 15 microg, women randomly allocated to the saline group were given 6 mg ephedrine so that all parturients received some prophylaxis against hypotension other than the fluid preload. Further ephedrine and fluid boluses were administered if mean arterial pressure fell 20% or more from resting values. Using a sequential analysis technique, analysis after the first 20 subjects indicated the study should be stopped, with no difference in ephedrine requirements or hypotension between the groups. We conclude that pretreatment with glycopyrronium 2 microg x kg(-1) is no more effective than 6 mg ephedrine in preventing hypotension following subarachnoid block in parturients with relatively low resting heart rates.

In this study the effect of phenylephrine and norepinephrine for the treatment of systemic hypotension were evaluated in patients with chronic pulmonary hypertension. When systemic hypotension (systolic arterial pressure

Abstract — — The mouse is the most used animal for studying the genetic basis of cardiovascular diseases. However, the mechanisms of regulation of cardiovascular function in this animal are not yet well understood. The goal of this study was to evaluate the baroreflex, the Bezold-Jarisch cardiopulmonary reflex (BJR), and the chemoreflex in mice with hypertension induced by inhibition of NO using Nω -nitro- l -arginine-methyl ester (L-NAME). Basal mean arterial pressure (MAP) measured under anesthesia (urethane, 1 mg/g IP) was significantly higher in L-NAME (400 μg/g IP for 7 days)–treated (HT) mice (n=7) compared with vehicle-treated (NT; n=10) animals (126±9 versus 79±2 mm Hg) without differences in heart rate (HR). Baroreflex sensitivity, evaluated using phenylephrine (1 μg/g IV) was enhanced in HT mice compared with NT mice (−9.8±1.4 versus −4.9±0.5 bpm/mm Hg). The BJR, induced by phenylbiguanide (40 ng/g IV), was significantly attenuated in HT animals (MAP, −13±5%; HR, −39±6%) compared with NT animals (MAP, −38±5%; HR, −66±2%). The chemoreflex, induced by potassium cyanide (0.26 μg/g IV), was significantly attenuated in HT animals (MAP, +14±4%; HR, −8±2%) compared with NT animals (MAP, +29±4%; HR, −15±4%). As has been observed in rats, chronic inhibition of NO synthase in mice results in arterial hypertension. Enhancement of baroreflex sensitivity and attenuation of BJR and chemoreflex seem to be mainly caused by inhibition of NO synthesis because individual analyses did not show positive correlation between changes in these reflexes and MAP levels in the HT group.

Pre-emptive intramuscular (i.m.) vasopressors were evaluated in 108 patients undergoing elective Caesarean section under spinal anaesthesia, assigned to four groups in a randomized, double-blind, placebo-controlled study. Group 1 received pre-emptive phenylephrine 4 mg i.m., group 2 received phenylephrine 2 mg i.m., group 3 received ephedrine 45 mg i.m., while controls received an i.m. injection of saline, all given immediately after induction of spinal anaesthesia. Hypotension was defined as a 25% decrease in mean arterial pressure (MAP). Rescue intravenous (i.v.) boluses of ephedrine were given if the patient was hypotensive or reported nausea, vomiting or dizziness. The incidence of hypotension was 33% in the phenylephrine 4 mg group compared with 70% in the control and phenylephrine 2 mg groups (P=0.03), and 48% in the ephedrine 45 mg group. The phenylephrine 4 mg and ephedrine 45 mg groups had a significantly lower percentage reduction in MAP (-21 (SD 14)% and -22 (14)%) compared with controls (-32 (18)%, P=0.04). They also had a lower total dose of rescue i.v. ephedrine (15.7 (15.7) mg and 15.8 (15.6) mg) compared with controls (28.8 (20.6) mg, P=0.02). We conclude that pre-emptive i.m. phenylephrine 4 mg and ephedrine 45 mg reduce the severity of hypotension and the total dose of rescue i.v. ephedrine during spinal anaesthesia for Caesarean section.

The present study examined whether alterations in the cardiac baroreceptor reflex in hypertension may be a function of constitutional differences associated with gender and age. These hypotheses were tested using a cross-sectional design that compared 20 normotensive and 21 hypertensive men and women of varying age for differences in baroreceptor reflex sensitivity and response latency for heart rate, obtained using a modified bolus phenylephrine (Oxford) method. Relative to their respective normotensive controls, baroreceptor reflex sensitivity was reduced in hypertensive men, but not in hypertensive women. Among normotensive subjects, men had greater baroreceptor reflex sensitivity than women. Independent from the effects associated with differences in blood pressure, age was not a significant predictor of reduction in baroreceptor reflex sensitivity. However, a combination of high blood pressure and older age was associated with a significant increase in baroreceptor reflex response time. In summary, gender and aging interacted with hypertension to alter two different aspects of the baroreceptor reflex. These results provide a preliminary indication that a decline in arterial baroreflex sensitivity may be more specific to hypertension in men than in women. Prolongation in baroreflex response latency in older hypertensive subjects also suggested that aging and hypertension may have a synergistic effect on cardiac parasympathetic function.

Abstract —Intercellular adhesion molecule-1 (ICAM-1), part of an immunoglobulin-like superfamily of adhesion molecules, is involved in several cardiovascular diseases. We investigated whether in vivo angiotensin II (Ang II) increases ICAM-1 in rats. Sprague-Dawley rats were infused with vehicle or Ang II (750 μg · kg −1 · d −1 SC) for 7 days. The contribution of Ang II receptors to ICAM-1 expression was investigated with a nonpeptide Ang II type 1 (AT 1 ) receptor antagonist losartan (30 mg · kg −1 · d −1 in drinking water). Systolic blood pressure was elevated in Ang II–treated animals compared with sham-treated controls, and losartan blocked this increase. Tumor necrosis factor (TNF)-α (5 μg/kg IP bolus), a prototype inducer of ICAM-1, was administered as a positive control for ICAM-1 expression. After treatment, hearts were frozen in liquid nitrogen; homogenates were subjected to SDS-PAGE and immunoblotted with an anti-rat ICAM-1 monoclonal antibody. We detected a predominantly high-molecular-weight band in homogenates from non–TNF-α–treated rats, which was enhanced by 80±5% in TNF-α–treated rats. This band measured ≈200 kDa, which is the molecular weight of ICAM-1 in its native dimer form. The same band was detected in homogenates from sham and Ang II–treated rats, with the latter showing a 150±10% increase in ICAM-1 versus sham controls. Immunoprecipitation of rat heart homogenates with anti-rat ICAM-1 antibody resulted in a dominant band of the same molecular weight as samples not treated with antibody. Losartan prevented enhanced expression of ICAM-1 in the presence of Ang II but had no effect on basal ICAM-1 expression. Phenylephrine, an α-agonist (3 mg · kg −1 · d −1 ), was infused for 1 week but had no effect on ICAM-1 expression, even though systolic blood pressure was elevated to the same level as in rats treated with Ang II. Thus, heart ICAM-1 expression is enhanced via AT 1 receptor activation independent of hypertension. Ang II–induced ICAM-1 expression was time and dose dependent, with maximal expression occurring within 5 to 7 days at 100 to 750 μg/kg Ang II. Immunohistochemical staining demonstrated markedly increased ICAM-1 levels in the perivascular area in Ang II–infused rats. Monocyte/macrophage accumulation was significantly greater in Ang II–treated rat hearts than in sham-treated hearts (10±1; P

The mechanisms that mediate hyporesponsiveness to vasoconstrictors in liver cirrhosis are not completely established. In the present study we have explored the role of NO and potassium channels by studying the pressor response to methoxamine in rats with carbon tetrachloride-induced cirrhosis with ascites. Experiments were performed in the isolated and perfused mesenteric arterial bed of control rats and of cirrhotic rats with ascites. Pressor responses to methoxamine, an α-adrenergic agonist, were analysed under basal conditions, after inhibition of guanylate cyclase with Methylene Blue (MB; 10 µM), after inhibition of NO synthesis with NG-nitro-L-arginine (L-NNA; 100 µM) and after blockade of potassium channels with tetraethylammonium (TEA; 3 mM). Compared with those from controls, preparations from cirrhotic rats showed a lower pressor response to methoxamine (maximum: controls, 114.4±6.8 mmHg; cirrhotic rats, 74.7±7.3 mmHg). Pretreatment with MB or L-NNA increased the responses in both groups, but without correcting the lower than normal response of the cirrhotic rats. Pretreatment with TEA alone did not modify the responses as compared with the untreated groups. Pretreatment with TEA plus MB or TEA plus L-NNA also potentiated the responses, and the responses of the cirrhotic animals were greater than those of the groups treated with MB or L-NNA alone. However, no treatment completely normalized the lower response of the mesenteries from cirrhotic animals, suggesting that factors other than NO and potassium channels also participate, although to a lesser degree, in the lower pressor response of the mesenteric arterial bed of animals with cirrhosis. These results confirm that NO and potassium channels are important mediators of the lower vascular pressor response of the mesenteric bed of cirrhotic rats with ascites. This effect seems to be mediated by the NO-dependent formation of cGMP and by the NO-dependent and -independent activation of potassium channels.