Measuring sexual harassment: development and validation of the Sexual Harassment Inventory

Recent studies have suggested that intravenous infusion of fenoldopam, a selective dopamine-1 receptor agonist, elevates intraocular pressure (IOP) in man. This study evaluated the effect of intravenous fenoldopam on IOP, aqueous humor outflow facility and gonioscopy in 12 healthy human subjects. Three doses (0.2, 0.5 and 1.0 microg/kg/min) were infused for 120 minutes in a double masked, placebo controlled, four-way crossover design. IOP was measured every 20 minutes in the supine position and every 40 minutes while sitting during the drug and placebo infusions. Tonography and gonioscopy were performed at baseline and after 120 minutes of infusion. Compared to placebo, IOP increased by 3.5 mm Hg (32%) for the lowest dose, 5.8 mm Hg (46%) for the intermediate dose, and 6.9 mm Hg (55%) for the highest dose (p<0.05 for all three doses). IOP returned to baseline within 30 minutes of stopping the infusion. The outflow facility decreased from baseline by 26% after 120 minutes of infusion for all drug doses. In contrast, outflow facility increased from baseline by 11% during placebo infusion. Compared to placebo, the fenoldopam induced changes in outflow were statistically significant (p<0.05). There was no change in the gonioscopic appearance of the anterior chamber angle during the infusion. This study shows that systemic administration of a selective dopamine-1 receptor agonist causes a significant dose-dependent increase in IOP that can be explained in part by diminished outflow facility. These results support a role for the dopamine-1 receptor in the modulation of IOP in general and suggest modulation of aqueous humor outflow by dopaminergic receptors.     

The effect of phacoemulsification on aqueous outflow facility

OBJECTIVE: Although control of intraocular pressure (IOP) after cataract extraction may be of critical importance, little is known regarding changes in facility of outflow in the early postoperative period. The effect of phacoemulsification and conjunctival peritomy size on the coefficient of aqueous outflow facility (C) and IOP was studied. DESIGN: Participants were assigned randomly to one of two treatment groups. PARTICIPANTS: Seventy-four patients with cataract and without evidence of glaucoma were studied. INTERVENTION: Patients were randomized to receive either single- or two-quadrant conjunctival peritomy and phacoemulsification. MAIN OUTCOME MEASURES: Tonometry and tonography were assessed before surgery and at 1 day, 1 week, 6 weeks, and 1 year after surgery by a masked observer. RESULTS: Fifty patients with a mean of 11.4 months' (range, 10-13 months) follow-up were analyzed. Patients with reduced preoperative facility of outflow (as defined by C < or = 0.28 microliter/min/mmHg) showed a significant improvement from a mean preoperative value of 0.24 +/- 0.04 microliter/min/mmHg to 0.41 +/- 0.22 microliter/min/mmHg at 1 year (P = 0.002, N = 19). Among all patients, there was no significant change between mean preoperative C and last follow-up (0.39 +/- 0.23 vs. 0.46 +/- 0.38 microliter/min/mmHg, not significant [ns], N = 50). Furthermore, there was no significant change between mean preoperative and final IOP (23.7 +/- 4.1 vs. 23.3 +/- 3.9 mmHg, ns, N = 50). There was a significant elevation of mean IOP on postoperative day 1 to 27 +/- 6.2 mmHg (P = 0.001, N = 50). Patients with IOP elevations greater than 8 mmHg on postoperative day 1 had significantly elevated IOP at 1 year compared to preoperative values (P = 0.02, N = 12). There were no significant differences detected regarding C or IOP between single- or two-quadrant peritomy groups. CONCLUSIONS: Outflow facility improves after phacoemulsification in patients with a reduced preoperative coefficient of aqueous outflow. Postoperative day 1 IOP is significantly elevated after phacoemulsification. Conjunctival peritomy size does not appear to play a role in aqueous outflow facility or IOP after surgery.     

Rate of cerebrospinal fluid formation, resistance to reabsorption of cerebrospinal fluid, brain tissue water content, and electroencephalogram during desflurane anesthesia in dogs

Propofol decreases intraocular pressure (IOP) and the IOP response to laryngoscopy and intubation, but the mechanisms responsible for this effect have not been reported. The present study examined the effect of propofol on IOP, intraocular fluid formation and outflow facility, and intraocular compliance. Twenty-two white New Zealand rabbits were anesthetized with halothane (0.8%-1.0% inspired concentration) in nitrous oxide (2 L/min) and oxygen (1 L/min). Muscle paralysis was established with pancuronium, and the lungs were mechanically ventilated through a tracheal tube. Twelve rabbits examined under these conditions served as controls. In the treatment group (n = 10), 6 mg/kg propofol followed by 18 mg.kg-1 x h-1 propofol intravenously was added to halothane/nitrous oxide/oxygen anesthesia. In both groups, a series of intraocular infusions was made via a 30-gauge needle in the anterior chamber, and IOP, the rate of aqueous humor formation (Fa), and trabecular outflow facility (Ctr) were determined using conventional analysis. These same measures, as well as intraocular compliance, were determined using a new method of analysis adapted from the manometric technique for determining cerebrospinal fluid dynamics. IOP was 11.3 +/- 1.8 mm Hg (mean +/- SD) in halothane-anesthetized controls and decreased to 9.4 +/- 2.2 mm Hg when propofol was added to halothane anesthesia (P < 0.05). By conventional analysis, Fa was 2.82 +/- 0.94 microL/min and Ctr was 0.121 +/- 0.044 microL.min-1 x mm Hg-1 in controls. After addition of propofol, Fa decreased by 24% to 2.15 +/- 0.62 microL/min (P < 0.05) and Ctr decreased by 18% to 0.099 +/- 0.034 microL.min-1 x mm Hg-1 (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour intravenous infusion

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.     

Disinhibition of AVP release during noradrenaline and angiotensin II infusions in dogs by maintaining normotension with sodium nitroprusside

Noradrenaline (NA) and angiotensin II (A II) were infused intravenously in conscious dogs without (series I) and with (series II) additional infusions of sodium nitroprusside at doses re-establishing normal levels of mean arterial pressure (MAP). In series I, NA infusion (1.6 micrograms/min per kg for 30 min) initially elevated MAP by some 25 mm Hg and lowered heart rate by some 30 beats/min. Plasma concentrations of arginine vasopressin (AVP) remained constant, while those of A II and atrial natriuretic factor were slightly, but significantly, increased. Infusion of A II (10 or 20 ng/min per kg for 30 min) induced similar rises in MAP and slight reductions of heart rate and increased plasma AVP by 70% and atrial natriuretic factor by 60%. In series II, sodium nitroprusside (1-4 micrograms/min per kg) was added for 30 min to infusions of NE (1.6 micrograms/min per kg) and A II (20 ng/min per kg) in order to maintain MAP at its control level. This resulted in an 11-fold increase in plasma AVP during NA infusion and a 19-fold increase during A II infusion. Infusing sodium nitroprusside (4 micrograms/min per kg) alone lowered MAP to clearly hypotensive levels, but the resulting rises in plasma AVP were less than, rather than equal to, those seen at normotensive MAP levels during the combined infusions of sodium nitroprusside with A II or NA, respectively. It is concluded that both NA and A II exert strong stimulatory actions on AVP release which are, however, counteracted by inhibitory influences arising from the hypertensive effects of NA and A II.     

Effects of inhibition of the L-arginine/nitric oxide pathway on vasodilation caused by beta-adrenergic agonists in human forearm

BACKGROUND: We examined whether vasodilator responses to beta-agonists in human forearm vasculature are mediated in part through the nitric oxide pathway. METHODS AND RESULTS: We measured forearm blood flow responses to brachial artery infusions of beta-adrenergic agonists in healthy men. Salbutamol was more than 100 times as potent as dobutamine. Cumulative doses of salbutamol (0.3 to 3.5 nmol.min-1) did not cause tachyphylaxis to an identical repeated infusion after a 24-minute recovery period. Vasodilators were infused with this sequence during coinfusion of saline and NG-monomethyl-L-arginine (L-NMMA, 4 mumol.min-1), an inhibitor of nitric oxide synthase. L-NMMA coinfusion inhibited responses (area under the dose-response curve) to isoproterenol (0.01 to 0.1 nmol.min-1) by 59 +/- 7% (n = 5) and inhibited those to salbutamol (0.3 to 3.5 nmol.min-1) by 52 +/- 6% (n = 8). L-NMMA had no significant effect on vasodilator responses to nitroprusside (2.7 to 11.0 nmol.min-1, n = 8), verapamil (20 to 80 nmol.min-1, n = 8), or prostacyclin (0.08 to 0.24 nmol.min-1, n = 8). CONCLUSIONS: These results suggest that beta-adrenergic vasodilator responses in human forearm vasculature are mediated predominantly through beta 2-adrenergic receptors and are dependent on nitric oxide synthesis.     

Blockade of endogenous nitric oxide production results in moderate hypertension, reducing sympathetic activity and shortening bleeding time in healthy volunteers

BACKGROUND: Short-term infusion of NG-monomethyl-L-arginine (L-NMMA) reversibly inhibits endogenous nitric oxide (NO) production in humans. We studied responses to more long-lasting (60 min) infusions, at doses high enough to cause effective inhibition of endogenous NO. METHODS: Eight healthy volunteers had catheters (pulmonary, arterial and venous) placed. Measurements included hemodynamics, endogenous NO levels in nasal air, bleeding time, and cyclic guanosine monophosphate (cGMP) and catecholamines in plasma. L-NMMA was infused at 0.3 mg.kg-1.min-1 during 30 min, followed by 0.15 (n = 6) or 0.3 (n = 2) mg.kg-1.min-1 during 30 min. RESULTS: L-NMMA significantly elevated mean arterial pressure by 12 +/- 3%, due to an increase in systemic vascular resistance. Cardiac output decreased by 23 +/- 3%, due to a decrease in stroke volume. Pulmonary vascular resistance (P < 0.05) increased, but mean pulmonary arterial pressure was stable. Forearm vascular resistance (P < 0.05) decreased. Bleeding time was shortened by 31 +/- 4% (P < 0.01). L-NMMA infusion reduced NO concentrations in nasal air by 64 +/- 2% (P < 0.01). Arterial pressure remained elevated and nasal NO remained depressed 90 min after the infusion, whereas most other responses were reversed at that time. Plasma cGMP showed only minor changes. Plasma norepinephrine decreased, suggesting reflexogenic inhibition of sympathetic activity, whereas epinephrine levels were low and stable throughout the experiment. CONCLUSION: Dosage of (13.5 mg.kg-1 in 60 min) L-NMMA infusion in humans was well tolerated. Pronounced and long-lasting inhibition of endogenous NO production, as evidenced by measurements in nasal air, resulted in unevenly distributed vasoconstriction, a transient decrease in cardiac output, and reflexogenic sympathetic withdrawal. Furthermore, bleeding time was shortened, suggesting platelet activation.     

Agonist-induced desensitization of adenylyl cyclase activity mediated by 5-hydroxytryptamine7 receptors in rat frontocortical astrocytes

A reward-relevant relationship between dopamine projection regions of the ventral tegmental area (VTA) was investigated through the use of brain stimulation reward (BSR) thresholds. Using a rate-free method, changes in VTA BSR thresholds were determined after intracranial injections of the dopamine D1 antagonist, SCH 23390 into the prefrontal cortex (PFC), or the nucleus accumbens (NAcc). Reward thresholds assessed immediately after the infusion of SCH 23390 into the NAcc (0.5 microgram/0.5 microliter/side) were significantly higher than those assessed just after saline infusions, indicating a drug-induced attenuation of the rewarding effects of the brain stimulation. The effects of this dose subsided when tested 24 h later. Conversely, intra-PFC infusions of SCH 23390 at the same dose (0.5 microgram/0.5 microliter/side) resulted in lowered BSR thresholds when rats were tested immediately after infusion. In addition, animals tested 24 h after receiving the lowest dose (0.125 microgram/0.5 microliter/side) demonstrated a robust delayed threshold-lowering effect. These immediate and delayed effects of the intra-PFC dopamine antagonist demonstrate a facilitation of VTA BSR and are consistent with the view that PFC dopamine serves a modulatory role over important reward elements within the NAcc. The deferred effects of intra-prefrontal cortex DA receptor blockade on brain stimulation reward thresholds may reflect adaptive responses of subcortical structures to changes in PFC dopamine neurotransmission. It has been suggested that neural adjustments of this type may underlie long term changes in central nervous system functioning brought about by disease, drug use or behavioral conditioning.     

NaCl-preferring NZB/B1NJ mice and NaCl-avoiding CBA/J mice have similar amiloride inhibition of chorda tympani responses to NaCl

After intracameral injection calcitonin gene-related peptide has been demonstrated to break the blood aqueous barrier and increase intraocular pressure in rabbits. However in cats, calcitonin gene-related peptide decreases intraocular pressure by increasing the outflow facility of aqueous humor. In the present study, the effect of intracameral injection of calcitonin gene-related peptide on the outflow facility in rabbits has been investigated and the intraocular pressure and outflow facility were measured following intravitreal administration of calcitonin gene-related peptide. The results demonstrate that in spite of the apparent pseudofacility component caused by a breakdown of the blood aqueous barrier also the true trabecular outflow is probably increased in the rabbit eye after intracameral injection of calcitonin gene-related peptide. The intravitreal administration of calcitonin gene-related peptide leaves the blood aqueous barrier intact and causes an increase in the outflow facility of aqueous humor with a concomitant long-lasting decrease in intraocular pressure.     

Effects of angiotensin II and its blockers Sar1-Ile8-angiotensin II and DuP 753 on drinking in ducks in relation to properties of subfornical organ neurons

Properties of systemically applied angiotensin II in stimulating water intake of normally hydrated ducks were studied and the results compared with properties of angiotensin II-responsive neurons of the subfornical organ which are considered as targets for circulating angiotensin II acting as a dipsogen. Following intravenous infusion of hypertonic saline (2000 mosmol.kg-1 at 0.3 ml.min-1 for 1 h), intravenous infusion of 0.3 ml.min-1 isotonic saline with angiotensin II (200 ng.min-1), starting 1 h later, stimulated drinking in each case at an angiotensin II plasma level of about 1400 pg.ml-1. Without hypertonic priming, the same angiotensin II infusion did not stimulate drinking in each experiment; however, if effective, repeated infusions of ANGII induced stable dipsogenic responses. Angiotensin II infusions did not alter plasma levels of antidiuretic hormone. Sar1-Ile8-angiotensin II, a non-selective angiotensin II antagonist, acted weakly as a partial agonist when infused at a dose 200-fold higher than angiotensin II and effectively blocked the dipsogenic action of angiotensin II; this corresponds to the inhibition of angiotensin II-induced excitation by Sar1-Ile8-angiotensin II observed in duck subfornical organ neurons. DuP 753 (losartan), an angiotensin II antagonist specifically blocking AT1 receptors in mammals, had equivocal effects on angiotensin II-induced drinking in ducks at rates 50- and 200-fold higher than angiotensin II, which corresponds to the weak inhibitory action of this compound on angiotensin II-induced neuronal excitation in the duck SFO. Blood pressure was only marginally elevated by the applied angiotensin II dose and Sar1-Ile8-angiotensin II had no effect.     

Increased pressor function of central vasopressinergic system in hypertensive renin transgenic rats

OBJECTIVE: Renin transgenic hypertensive rats [TGR(mRen2)27] have increased contents of angiotensin II and arginine vasopressin (AVP) in the cardiovascular brain regions. The aim of the present study was to evaluate the effects of centrally released AVP on the regulation of baseline blood pressure in TGR(mRen2)27 rats and to determine the interaction between AVP and angiotensin II in the central control of blood pressure in this model of hypertension. DESIGN: Three basic series of experiments were performed on 20 TGR(mRen2)27 and 20 Hannover Sprague-Dawley conscious rats, chronically instrumented with lateral cerebral ventricle (LCV) cannulae and femoral artery catheters. In series 1, blood pressure and heart rate were recorded during an LCV infusion of artificial cerebrospinal fluid before and after LCV administration of angiotensin II. In series 2, the effects of an LCV administration of angiotensin 11 (100 ng) on mean arterial pressure and the heart rate were determined during LCV infusion of a selective AVP receptor (V1) antagonist [1-(1-mercapto-4-methylcyclohexaneacetic acid)-8-arginine vasopressin (MeCAAVP) and d(CH2)5[Tyr(Me)2,Ala-NH2(9)]AVP] or a selective angiotensin II type 1 (AT1) receptor antagonist (losartan) or both. In series 3, mean arterial pressure and the heart rate were determined after an LCV injection of either AVP (10 ng) or AVP together with angiotensin II. RESULTS: The LCV infusions of antagonists to V1 and AT1 receptors caused significant comparable decreases in baseline MAP in TGR(mRen2)27 but not in Sprague-Dawley rats. Angiotensin II elicited significant pressor responses, both in TGR(mRen2)27 and in Sprague-Dawley rats. Blockade of V1 receptors significantly reduced the duration and the maximum amplitude of the central pressor response to angiotensin II in TGR(mRen2)27 rats, whereas in Sprague-Dawley rats the maximum pressor effect was not significantly altered. In both strains, the pressor response to angiotensin II was abolished by blockade of AT1 receptors. CONCLUSIONS: The results indicate that the elevated blood pressure in TGR(mRen2)27 rats is partly caused by increased function of the brain angiotensinergic AT1 and vasopressinergic V1 systems. Centrally released AVP is involved in mediation of the pressor effect exerted by centrally applied angiotensin II in TGR(mRen2)27 rats.     

Regulation of lung liquid secretion in immature fetal sheep: hormonal interaction

The present studies were designed to test the hypothesis that arginine vasopressin (AVP) can interact with hydrocortisone and 3,5,3'-triiodothyronine (T3) to induce maturation of lung liquid reabsorptive processes in fetal sheep < 130 days gestation. Lung liquid production rates were measured in chronically catheterized thyroidectomized fetal sheep during eight different experimental treatments. Each experiment consisted of a 2-h control period followed by a 5-h treatment period. Net secretion or reabsorption of lung liquid was measured by using impermeant marker dilution techniques. AVP alone (50 mU/kg bolus plus 5.0 mU.kg-1.min-1 i.v. infusion) does not alter lung liquid secretion in fetal sheep 125 +/- 0.72 (SE) days gestation. In contrast, AVP (same dose as above) with T3 (30 micrograms) and hydrocortisone (6.94 mg/min) depressed lung liquid secretion and caused reabsorption of fluid. T3 alone, T3 and hydrocortisone, T3 and AVP, hydrocortisone alone, hydrocortisone and AVP, and saline did not result in net lung liquid reabsorption over a 5-h treatment period. These investigations demonstrate that AVP, T3, and hydrocortisone interact to cause lung liquid reabsorption in immature fetal lungs.     

Assessment of the role of the renin-angiotensin system in cardiac contractility utilizing the renin inhibitor remikiren

1. The role of the renin-angiotensin system in the regulation of myocardial contractility is still debated. In order to investigate whether renin inhibition affects myocardial contractility and whether this action depends on intracardiac rather than circulating angiotensin II, the regional myocardial effects of systemic (i.v.) and intracoronary (i.c.) infusions of the renin inhibitor remikiren, were compared and related to the effects on systemic haemodynamics and circulating angiotensin II in open-chest anaesthetized pigs (25-30 kg). The specificity of the remikiren-induced effects was tested (1) by studying its i.c. effects after administration of the AT1-receptor antagonist L-158,809 and (2) by measuring its effects on contractile force of porcine isolated cardiac trabeculae. 2. Consecutive 10 min i.v. infusions of remikiren were given at 2, 5, 10 and 20 mg min-1. Mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), systemic vascular resistance (SVR), myocardial oxygen consumption (MVO2) and left ventricular (LV) dP/dtmax were not affected by remikiren at 2 and 5 mg min-1, and were lowered at higher doses. At the highest dose, MAP decreased by 48%, CO by 13%, HR by 14%, SVR by 40%, MVO2 by 28% and LV dp/dtmax by 52% (mean values; P < 0.05 for difference from baseline, n = 5). The decrease in MVO2 was accompanied by a decrease in myocardial work (MAP x CO), but the larger decline in work (55% vs. 28%; P < 0.05) implies a reduced myocardial efficiency ((MAP x CO)/MVO2). 3. Consecutive 10 min i.c. infusions of remikiren were given at 0.2, 0.5, 1, 2, 5 and 10 mg min-1. MAP, CO, MVO2 and LV dP/dtmax were not affected by remikiren at 0.2, 0.5 and 1 mg min-1, and were reduced at higher doses. At the highest dose, MAP decreased by 31%, CO by 26%, MVO2 by 46% and LV dP/dtmax by 43% (mean values; P < 0.05 for difference from baseline, n = 6). HR and SVR did not change at any dose. 4. Thirty minutes after a 10 min i.v. infusion of the AT1 receptor antagonist, L-158,809 at 1 mg min-1, consecutive 10 min i.c. infusions (n = 5) of remikiren at 2, 5 and 10 mg min-1 no longer affected CO and MVO2, and decreased LV dP/dtmax by maximally 27% (P < 0.05) and MAP by 14% (P < 0.05), which was less than without AT1-receptor blockade (P < 0.05). HR and SVR remained unaffected. 5. Plasma renin activity and angiotensin I and II were reduced to levels at or below the detection limit at doses of remikiren that were not high enough to affect systemic haemodynamics or regional myocardial function, both after i.v. and i.c. infusion. 6. Remikiren (10(-10) to 10(-4) M) did not affect contractile force of porcine isolated cardiac trabeculae precontracted with noradrenaline. In trabeculae that were not precontracted no decrease in baseline contractility was observed with remikiren in concentrations up to 10(-5) M, whereas at 10(-4) M baseline contractility decreased by 19% (P < 0.05). 7. Results show that with remikiren i.v., at the doses we used, blood pressure was lowered primarily by vasodilation and with remikiren i.c. by cardiac depression. The blood levels of remikiren required for its vasodilator action are lower than the levels affecting cardiac contractile function. A decrease in circulating angiotensin II does not appear to be the sole explanation for these haemodynamic responses. Data support the contention that myocardial contractility is increased by renin-dependent angiotensin II formation in the heart.     

Epilepsy in patients with multiple sclerosis: radiological-clinical correlations

This study was performed to determine whether the stimulatory effect of plasma angiotensin II (ANG II) on arginine vasopressin (AVP) and oxytocin (OT) secretion in humans is mediated by AT1 subtype receptors. For this purpose, the effects of the AT1 receptor antagonist losartan (50 mg orally) or a placebo on the AVP and OT responses to ANG II (intravenous infusion for 60 minutes of successively increasing doses of 4, 8, and 16 ng/kg min; each dose for 20 minutes) administration were evaluated in seven normal men. In additional experiments, the same subjects were tested with losartan (50 mg orally) alone or placebo alone. Neither losartan nor placebo given alone modified the basal levels of AVP and OT. ANG II infusion induced significant increments in both serum AVP and OT levels (mean peaks were 1.55 and 1.41 times higher than baseline, respectively). Both hormonal responses to ANG II were completely abolished by pretreatment with losartan. These data provide evidence of AT1 receptor involvement in mediation of the ANG II-stimulating effect on AVP and OT secretion.     

Prolonged mivacurium infusion in young and elderly adults

PURPOSE: This study was designed to evaluate pharmacodynamically and pharmacokinetically if the cis-cis isomer of mivacurium contributed to neuromuscular block during prolonged infusions lasting more than four hours in young adult and elderly (> 60 yr) patients. METHODS: The mechanomyogramic neuromuscular response of the adductor pollicis was recorded in 32 adults 18-59 yr. and 19 elderly (> 60 yr.) patients during N2O:O2:opioid anaesthesia. The mivacurium infusion rate was adjusted to maintain single twitch depression at 95 +/- 4% of control. Blood samples were taken every 30 min to determine the plasma concentration of cis-cis isomer of mivacurium. At the end of the surgical procedure, patients were allowed to recover spontaneously to at least 25% of control twitch response. RESULTS: The mean mivacurium infusion requirement to maintain 97 +/- 1 (mean +/- SD)% depression of the twitch response was 6.0 +/- 0.4 micrograms.kg-1.min-1 in young adults, and 4.3 +/- 0.3 micrograms.kg-1.min-1 in elderly patients (P < 0.001). The infusion requirement in patients with low plasma cholinesterase activity was the lowest 2.4 +/- 1.2 micrograms.kg-1.min-1. Plasma cis-cis isomer concentrations reached peak levels within one-two hours and remained relatively constant throughout the duration of infusion even in patients with low cholinesterase activity. There was no relationship between duration of infusion, plasma concentrations of cis-cis isomer and the early recovery indices of mivacurium (up to 25%). Neuromuscular transmission recovered adequately with or without antagonism in all patients. CONCLUSION: When the mivacurium infusion was titrated to maintain 95 +/- 4% twitch depression, the plasma concentration of the cis-cis isomer did not increase during prolonged infusions (four hours) and neuromuscular transmission recovers satisfactorily.     

Sensitization and conditioning of feeding following multiple morphine microinjections into the nucleus accumbens

The effects of repeated morphine infusions (10 micrograms/0.5 microliter) into the nucleus accumbens on feeding were studied in sated rats. As shown previously, intra-accumbens morphine infusions induced a large increase in food intake. After undergoing repeated morphine treatment, animals consumed significant quantities of food in response to a saline or sham injection, compared to their pre-morphine baseline. This conditioned feeding was present up to 18 days after the final drug infusion. Additionally, repeated morphine administration caused a progressive sensitization of feeding; the final morphine infusion elicited nearly double the amount of food intake as the first. Multiple saline infusions had no behavioral effects. Repeated stimulation of opiate receptors may enhance associative mechanisms such that previously neutral environmental stimuli acquire the ability to elicit feeding. Abnormal activation of this system may be a possible neural substrate for compulsive feeding and bulimia.     

Hormonal and metabolic effects of paraventricular hypothalamic administration of neuropeptide Y during rest and feeding

To investigate the role of neuropeptide Y (NPY) in the paraventricular nucleus of the hypothalamus (PVN) in the regulation of autonomic outflow, hormonal (plasma insulin and catecholamines), metabolic (blood glucose and plasma free fatty acids) and cardiovascular (heart rate and main arterial pressure) indices were measured before, during, and after bilateral infusion of NPY (1.0, 0.2, 0.04 micrograms in 1 microliter synthetic CSF) into the PVN of conscious resting rats. Administration of the highest dose (1.0 microgram/microliter) caused bradycardia and reduced circulating norepinephrine levels without effecting circulating fuels, insulin or epinephrine. In a second experiment, feeding-induced changes in hormonal and metabolic indices were assessed after NPY administration (1.0 microgram/microliter) into the PVN. During and after feeding, NPY enhanced the feeding-induced insulin response (P < 0.01) and attenuated the feeding-induced norepinephrine response (P < 0.05). The results of the present study suggest that stimulation of NPY receptors in the PVN decreases sympathetic activity and increases parasympathetic activity in resting conditions, and that these effects are potentiated during feeding.     

Audit of regional screening guidelines for vestibular schwannoma

PURPOSE: To evaluate the cerebral oxygenation effects of hypotension induced by prostaglandin E1 (PGE1) during fentanyl-oxygen anaesthesia. METHODS: Ten patients who underwent elective cardiac surgery received infusion of PGE1. After measuring the baseline arterial, mixed venous and internal jugular vein blood gases, systemic haemodynamics, and regional cerebral oxygen saturation (rSO2) estimated by INVOS 3100R, PGE1 was continuously infused at 0.25-0.65 microgram.kg-1.min-1 (mean dosage: 410 +/- 41.4 mg.kg-1.min-1) intravenously. Ten, 20 and 30 minutes after the start of drug infusions, blood gases described above were obtained simultaneously with the measurement of systemic haemodynamics and rSO2. Thirty minutes from the start of drug infusions, administration of PGE1 was stopped. The same parameters were measured again 10, 30 minutes after the stop of drug infusion. RESULTS: PGE1 decreased mean arterial pressure (MAP) to approximately 70% of the baseline value (P < 0.05). PGE1 increased mixed venous saturation, but in contrast did not affect internal jugular pressure, internal jugular oxygen saturation and rSO2. CONCLUSIONS: These results suggest that PGE1 is a suitable drug for induced hypotension because flow/metabolism coupling of brain and regional cerebral oxygenation were well maintained during hypotension.     

Differential effects of endotoxaemia on pressor and vasoconstrictor actions of angiotensin II and arginine vasopressin in conscious rats

1. Regional haemodynamic responses to arginine vasopressin (AVP; 0.5, 1.0, 5.0 pmol i.v.) and angiotensin II (AII; 5.0, 10.0, 50.0 pmol i.v.) were measured in conscious Long Evans rats at various times (0, 2, 6 and 24 h) during infusion of lipopolysaccharide (LPS, 150 microg kg(-1) h(-1), i.v., n=9) or saline (n=9). Additional experiments were performed in vasopressin-deficient (Brattleboro) rats infused with LPS (n=7) or saline (n=8) to determine whether or not, in the absence of circulating vasopressin, responses to the exogenous peptides differed from those in Long Evans rats. 2. In the Long Evans rats, during the 24 h infusion of LPS, there was a changing haemodynamic profile with renal vasodilatation from 2 h onwards, additional mesenteric vasodilatation at 6 h, and a modest hypotension (reduction in mean arterial blood pressure (MAP) from 103+/-1 to 98+/-2 mmHg) associated with renal and hindquarters vasodilatation at 24 h. 3. In the Brattleboro rats, the changes in regional haemodynamics during LPS infusion were more profound than in the Long Evans rats. At 2 h and 6 h, there was a marked fall in MAP (from 103+/-3 mmHg; to 65+/-3 mmHg at 2 h, and to 82+/-4 mmHg at 6 h) associated with vasodilatation in all three vascular beds. After 24 h infusion of LPS, the hypotension was less although still significant (from 103+/-3 mmHg; to 93+/-4 mmHg, a change of 10+/-4 mmHg), and there was renal and hindquarters vasodilatation, but mesenteric vasoconstriction. 4. During infusion of LPS, at each time point studied, and in both strains of rat, pressor responses to AII and AVP were reduced, but the changes were less marked at 6 h than at 2 h or 24 h. The reduced pressor responses were not accompanied by generalized reductions in the regional vasoconstrictor responses. Thus, in the Long Evans rats, the renal vasoconstrictor responses to both peptides were enhanced (at 6 h and 24 h for AVP; at all times for AII), whereas the mesenteric vasoconstrictor response to AVP was unchanged at 2 h, enhanced at 6 h and reduced at 24 h. The mesenteric vasoconstrictor response to AII was reduced at 2 h, normal at 6 h and reduced at 24 h. The small hindquarters vasoconstrictor responses to both peptides were reduced at 2 h and 6 h, but normal at 24 h. 5. In the Brattleboro rats, the renal vasoconstrictor responses to both peptides were reduced at 2 h and enhanced at 6 h and 24 h, whereas the mesenteric vasoconstrictor response to AVP was normal at 2 h and 6 h, and reduced at 24 h. The response to AII was reduced at 2 h, normal at 6 h and reduced again at 24 h. There were no reproducible hindquarters vasoconstrictions to AVP in the Brattleboro rats. The small hindquarters vasoconstrictor responses to AII were unchanged at 2 h and enhanced at 6 h and 24 h. 6. In isolated perfused mesenteric vascular beds, removed after 24 h of LPS infusion in vivo, there was an increase in the potency of AVP in both strains (Long Evans, ED50 saline: 56.9+/-15.0 pmol, ED50 LPS: 20.4+/-4.8 pmol, Brattleboro, ED50 saline: 38.6+/-4.2, ED50 LPS: 19.6+/-2.9 pmol), but no change in the responses to AII. 7. These findings indicate that a reduced pressor response to a vasoconstrictor challenge during LPS infusion is not necessarily associated with a reduced regional vasoconstriction. The data obtained in the Brattleboro rats indicate a potentially important role for vasopressin in maintaining haemodynamic status during LPS infusion in Long Evans rats. However, it is unlikely that the responses to exogenous AVP (or AII) are influenced by changes in the background level of endogenous vasopressin, since the patterns of change were similar in Long Evans and Brattleboro rats. 8. The results obtained in isolated perfused mesenteric vascular beds differed from those in vivo, possibly due to the conditions pertaining with in vitro perfusion.     

Unusual accumulation of glycogen in liver parenchymal cells in a patient with anorexia nervosa

Raised plasma concentrations of atrial natriuretic peptide (ANP) have been reported in patients with Type 1 (insulin dependent) diabetes mellitus (DM) who have poor glycaemic control and are associated with the presence of microalbuminuria. To test the hypothesis that elevations in plasma ANP concentration increase urinary albumin excretion in Type 1 DM, we have studied the effects of intravenous infusions of ANP in eight such subjects with established microalbuminuria. Blood glucose was maintained between 4 and 7 mmol l-1 in all subjects for the duration of studies; after euglycaemia had been established, a standard oral water load (20 ml kg-1 plus replacement of urinary losses) was given. Once steady state diuresis was attained, subjects received intravenous infusion of either placebo (0.9% saline), low dose (2.5 pmol kg-1 min-1) or high dose (5.0 pmol kg-1 kg min-1) ANP solution in a randomized, double-blind protocol. Infusion of ANP caused a dose-dependent increase in urinary albumin excretion rate (placebo, 11.3 (SD 8.9) to 8.7 (SD 6.8) micrograms min-1; low dose ANP, 12.4 (SD 9.9) to 26.5 (SD 27.5) micrograms min-1, p < 0.01; high dose ANP 10.3 (SD 7.3) to 36.6 (SD 28.5) micrograms min-1, p < 0.001, ANOVA). Only high dose ANP caused an increase in urine flow. Blood glucose remained unchanged in all studies. We conclude that intravenous infusions of ANP cause a dose-dependent increase in urinary albumin excretion rate in Type 1 DM subjects with microalbuminuria. These data support the hypothesis that ANP has albuminuric actions which may contribute to microalbuminuria in Type 1 DM.