Vector alkaline phophatase substrate Blue III: one substrate for brightfield histochemistry and high-resolution fluorescence imaging by confocal laser scanning microscopy

OBJECTIVE: To compare the intraocular pressure (IOP)-reducing effect of the fixed combinations of timolol 0.5% and latanoprost 0.001% or 0.005% after 4 weeks' treatment. DESIGN: Following a 1-week run-in period on timolol 0.5% once daily, 139 patients were randomized to once-daily treatment with a fixed combination of timolol 0.5% and latanoprost 0.001% (comb. 10) or latanoprost 0.005% (comp. 50) or to the individual monotherapies. The IOP was measured at inclusion and at 8 a.m., noon and 4 p.m. on days 1, 7 and 28. RESULTS: Comb. 10, comb. 50, latanoprost and timolol reduced IOP by 3.7, 6.1, 4.9 and 2.1 mmHg, respectively, from a baseline mean diurnal IOP (+/- SEM) of 24.8 +/- 0.5, 24.1 +/- 0.4, 25.2 +/- 1.2 and 24.8 +/- 0.9 mmHg, respectively. The difference in IOP reduction was significant between comb. 50 and comb. 10 (P < 0.001), latanoprost (P = 0.046) and timolol (P < 0.001) in favor of comb. 50. There was also a significant difference between latanoprost and timolol (P = 0.007), in favor of latanoprost. All treatments were generally well tolerated. CONCLUSION: This study indicates that a fixed combination of latanoprost 0.005% and timolol 0.5% could be useful in the treatment of glaucoma.     

Seroneutralization of porcine reproductive and respiratory syndrome virus correlates with antibody response to the GP5 major envelope glycoprotein

PURPOSE: To compare the long-term efficacy and safety of brimonidine 0.2% twice daily with timolol 0.5% twice daily in patients with glaucoma or ocular hypertension. METHODS: Of the 926 patients enrolled in the study, 837 met the protocol entry criteria and received either brimonidine 0.2% twice daily (n = 466) or timolol 0.5% (n = 371) twice daily in each eye for 1 year. RESULTS: Brimonidine and timolol significantly reduced mean intraocular pressure (P < .001) from baseline levels at every scheduled follow-up visit, both at hour 2 (peak) and hour 12 (trough). At weeks 1 and 2 and months 3 and 12, significantly greater mean decreases in intraocular pressure (P < .040) at peak were observed in patients treated with brimonidine than those treated with timolol. The mean intraocular pressure decrease at trough was significantly greater for timolol than for brimonidine at each follow-up visit (P < .001). With the exception of ocular allergy (in 11.5% of patients using brimonidine and less than 1% using timolol), fewer than 3% of patients in either treatment group withdrew from the study prematurely as a result of a specific adverse event. Patients receiving timolol experienced significant decreases in heart rate (P < .001) from baseline at all follow-up visits. No significant changes in heart rate were seen in patients treated with brimonidine. Neither medication produced clinically significant changes in blood pressure. CONCLUSION: Brimonidine is safe and effective in the long-term lowering of intraocular pressure in patients with glaucoma or ocular hypertension, with efficacy comparable to that of timolol but without a notable negative chronotropic effect on the heart.     

Characteristics of histamine-induced leukocyte rolling in the undisturbed microcirculation of the rat mesentery

PURPOSE: To determine the efficacy and safety of latanoprost treatment for 1 year in glaucoma patients, and to evaluate the effects of switching from timolol to latanoprost therapy. METHODS: Latanoprost 0.005% was topically applied once daily without masking for 6 months in 223 patients with elevated intraocular pressure after previous treatment with latanoprost once daily or 0.5% timolol twice daily for 6 months in a multicenter, randomized, double-masked, parallel group study. RESULTS: Compared with baseline values before treatment, a significant (P < .0001) diurnal reduction in intraocular pressure of 6 to 8 mm Hg was maintained with minimal fluctuation for the duration of treatment. When treatment was switched from timolol to latanoprost, intraocular pressure was reduced by 1.5 +/- 0.3 mm Hg (mean +/- SEM; 8% change in intraocular pressure; 31% of the intraocular pressure reduction produced by timolol; P < .001) compared with the change in intraocular pressure in patients remaining on latanoprost therapy. Of the patients initially enrolled, 95% successfully completed treatment. There was a slight overall increase in conjunctival hyperemia in patients who switched from timolol to latanoprost, but no change in those who continued latanoprost. The timolol-induced reduction of resting heart rate returned to baseline levels after switching to latanoprost. Of the 247 patients treated with latanoprost during the masked and/or open-label studies, 12 (5%) demonstrated a definite (n = 4) or possible (n = 8) increase in iris pigmentation. CONCLUSIONS: Latanoprost is a well-tolerated ocular hypotensive agent that appears to be more effective than timolol in reducing intraocular pressure. The increase in iris pigmentation appears to be harmless but requires further investigation.     

Expanding role of alpha adrenoceptor blockade in the treatment of benign prostatic hyperplasia

PURPOSE: To evaluate the efficacy and safety of timolol hemihydrate once daily versus timolol maleate gel forming solution once daily in patients with primary open-angle glaucoma or ocular hypertension. METHODS: We prospectively randomized patients with primary open-angle glaucoma or ocular hypertension to receive either timolol hemihydrate 0.5% solution or timolol maleate gel forming solution 0.5% every morning. The primary efficacy variable was the 8:00 AM trough intraocular pressure (IOP) 24 hours after administration. RESULTS: Three months after initiation of therapy, baseline IOP had decreased from 23.6 +/- 1.9 mmHg to 18.3 +/- 2.8 mmHg in the group taking timolol hemihydrate (n = 22) and from 23.7 +/- 2.2 mmHg to 18.4 +/- 3.1 mmHg in the group receiving timolol maleate gel (n = 21) at the 24-hour trough level. This was not a significant difference between groups at 3 months. Also, no difference was observed between groups in the 2-hour post instillation IOP. Visual acuity was decreased in the group receiving timolol maleate gel compared with those receiving timolol hemihydrate one minute after instillation of study medicine at month 3. Otherwise, ocular and systemic safety were similar between groups. No differences between groups in cardiac pulse or systolic and diastolic blood pressure were observed. CONCLUSION: Timolol hemihydrate 0.5% solution given once a day appears to be as efficacious and safe in decreasing IOP as timolol maleate gel 0.5% given once a day.     

Atypical beta-adrenoceptors in the rat isolated common carotid artery

1. The possible existence of atypical beta-adrenoceptors in vascular smooth muscle of the rat common carotid artery was examined in this study. 2. Isoprenaline produced concentration-dependent relaxation of noradrenaline (10(-7) M) precontracted ring segments of the carotid artery. The relaxation was not affected by endothelial denudation. 3. Propranolol (10(-8) M-3 x 10(-7) M) shifted the isoprenaline curve to the right without suppressing the maximum response. However, the slope (0.74) of the Schild plot was significantly (P < 0.05) less than 1. 4. Salbutamol (beta 2), CGP 12177 and BRL 37344 (beta 3) also concentration-dependently relaxed noradrenaline precontracted artery segments. These relaxations were not affected by propranolol (10(-7) M). Pretreatment of the artery segments with BRL 37344 did not desensitize the tissue to the relaxant effect of isoprenaline, CGP 12177 and salbutamol. 5. It is concluded that atypical beta-adrenoceptors exist in vascular smooth muscle of the common carotid artery.     

No evidence for dopamine-induced relaxation in isolated human mesenteric arterial strips from elderly patients

1. We investigate the effects of dopamine in isolated mesenteric artery from elderly patients. 2. Noradrenaline (10(-11) to 10(-4) M) and dopamine (2.7 x 10(-6) to 1.4 x 10(-3) M) induced a concentration-dependent contraction that was antagonized by prazosin. Fenoldopam (10(-8) to 10(-4) M) and clonidine (10(-9) to 10(-4) M) did not produce any contractile effects. 3. Potassium chloride (80 mM) produced a well-maintained plateau contraction and dopamine-induced contraction in these conditions, which was decreased by prazosin (10(-8) M). Neither fenoldopam nor isoprenaline (10(-10) to 10(-5) M) modified the well-maintained plateau. 4. Our results suggest that post-synaptic dopamine receptors are not present in this preparation but alpha1-adrenoceptors are present.     

Muscarinic M2 receptor-mediated contraction in the guinea pig Taenia caeci: possible involvement of protein kinase C

Contraction of the guinea pig taenia caeci is mediated by muscarinic M3 receptors; however, they comprise only 30% of the muscarinic receptors present. This study investigated the role of the predominant M2 receptor population in contractions and possible second messengers involved after M3 receptors were selectively alkylated by 4-DAMP mustard [N-(2-chloroethyl)-4-piperidinyldiphenylacetate] (60 nM) in the presence of otenzepad (AF-DX 116; 1 microM). Concentration-response curves to oxotremorine-M (oxo-M) in the presence of histamine and isoprenaline were performed in the presence of otenzepad (1 and 3 microM), resulting in a mean apparent pK(B) of 6.49, indicative of an M2 response. As the taenia has intrinsic tone, precontraction with histamine was not necessary and, therefore, in some experiments only isoprenaline was included. In these studies, an M3 response to oxo-M was observed, as the mean apparent pK(B) for otenzepad was 5.89. To investigate protein kinase C (PKC) involvement in the M2 response following M3 inactivation, the inhibitor chelerythrine (1 microM) was included with histamine and isoprenaline in the absence and presence of otenzepad. The oxo-M concentration-response curve was shifted by otenzepad with an apparent pK(B) value of 6.05, a value significantly different from that seen in the absence of chelerythrine (P < 0.05). These results suggest that activation of PKC by a spasmogen such as histamine is necessary to see an M2 response following M3 receptor inactivation.     

Characterization of alpha-adrenoceptor subtype(s) mediating vasoconstriction in the perfused rabbit ovarian vascular bed

1. alpha 1-Adrenoceptor agonists, noradrenaline, phenylephrine, methoxamine, oxymetazoline and SDZ NVI 085 but not alpha 2-adrenoceptor agonists, UK 14304, tizanidine or clonidine evoked dose-dependent vasoconstriction of the isolated perfused rabbit ovarian vascular bed. The rank order of agonist potency was noradenaline > oxymetazoline > phenylephrine > SDZ NVI 085 > methoxamine. 2. Prazosin (10(-8) M - 10(-5) M) displaced agonist dose-response curves to the right. The pA2/pKB values ranged between 7.27 and 7.66 against noradrenaline, phenylephrine, methoxamine and SDZ NVI 085 and were not significantly different from each other. Prazosin was however significantly less potent against oxymetazoline (pA2 6.38). Yohimbine (10(-6) M - 10(-5) M) was not very effective against any of the agonists. 3. WB 4101 (10(-8) M - 10(-5) M) displaced agonist dose-response curves to the right. The pA2/ pKB values ranged between 7.08 and 7.93 against noradrenaline, phenylephrine, methoxamine and SDZ NVI 085. WB 4101 was significantly less potent against oxymetazoline (pKB 6.85). 4. SZL-49 (5 x 10(-6) M) but not chloroethylclonidine (3 x 10(-5) M) significantly reduced vasoconstrictor responses to all the agonists. 5. Electrical field stimulation of the ovarian bed produced frequency-dependent vasoconstrictor effects which were abolished by 6-OHDA. The responses were also antagonized in a concentration-dependent by prazosin (10(-7) M - 10(-5) M) and WB 4101 (3 x 10(-8) M - 3 x 10(-7) M). Yohimbine reduced the response to electrical stimulation by 20% at 10(-5) M. The vasoconstrictor effect was also inhibited by SZL-49 but not by chloroethylclonidine. 6. These results would suggest that the vasoconstrictor responses of the ovarian vascular bed to adrenergic agonists and to electrical stimulation are mediated via the alpha 1A-adrenoceptor subtype.     

Effect of beta-adrenergic agonists on paracellular width and fluid flow across outflow pathway cells

PURPOSE: To determine whether the adrenergic agonists epinephrine and isoproterenol regulate fluid flow across endothelial cells cultured from the human aqueous outflow pathway and to evaluate associated cellular mechanisms. METHODS: Confluent monolayers of human trabecular meshwork (TM) or Schlemm's canal endothelial (SCE) cells were grown on porous filter supports. The monolayers were perfused with media while fluid flow, expressed as hydraulic conductivity (HC = microl/min/mm Hg/cm2), was continuously measured in preparations treated with isoproterenol, epinephrine, or control medium. Morphometric ultrastructural methods were used to measure the area occupied by the intercellular space and by each cell. RESULTS: SCE cells and TM cells exposed to isoproterenol or epinephrine responded with an increase in transendothelial fluid flow. Dose-response curves for both adrenergic agonists showed that HC increased linearly as a function of the log of the isoproterenol and epinephrine concentration. At 10(-4) M isoproterenol, the HC increased threefold, and threshold conditions were reached at 10(-9) M. The increase in HC was apparent after isoproterenol had been applied for 1 hour, reached a peak in 3 to 4 hours, and declined gradually to return to baseline conditions in 10 to 12 hours. Morphometric analyses showed that the area occupied by the intercellular space increased fourfold when isoproterenol was used at 10(-4) M, whereas the cell area decreased as a function of the concentration of adrenergic agonist. Epinephrine's effects on HC and cell morphology were blocked by pretreatment with equimolar concentrations of the nonselective beta-blocker, timolol. CONCLUSIONS: Epinephrine and isoproterenol increase flow through the paracellular pathway of SCE and TM cells through a beta-receptor mediated response that widens the intercellular space and reduces cell area. These findings support the hypothesis that epinephrine decreases the intraocular pressure in glaucoma therapy by promoting fluid flow across the SCE and TM cells lining tissues of the major aqueous outflow pathway.     

The effects of unoprostone isopropyl 0.12% and timolol maleate 0.5% on diurnal intraocular pressure

PURPOSE: To compare the effect of unoprostone isopropyl 0.12% to that of timolol maleate 0.5% solution given twice daily on the diurnal curve of intraocular pressure (IOP) in patients with primary open-angle glaucoma or ocular hypertension. METHODS: In this investigator-masked, single-center, parallel-group comparison, 36 patients with primary open-angle glaucoma or ocular hypertension were randomized in a 2:1 ratio to receive either unoprostone isopropyl 0.12% or placebo/timolol maleate 0.5% solution, respectively. A placebo-controlled diurnal curve on day 0 and active-controlled diurnal curves at weeks 2 and 4 were performed at 0, 2, 4, 6, 8, 10, 12, and 24 hours. At week 2, administration of unoprostone isopropyl twice daily was compared with administration of timolol maleate twice daily. At week 4, administration of unoprostone isopropyl three times daily was compared with administration of timolol maleate twice daily. RESULTS: At the 24-hour 8:00 AM trough at week 2, administration of unoprostone isopropyl twice daily decreased IOP from 23.4 +/- 2.0 mmHg at baseline to 19.3 +/- 4.4 mmHg, and timolol maleate reduced IOP from 24.4 +/- 2.6 mmHg to 17.5 +/- 2.9 mmHg. At the 8:00 AM trough at week 4, unoprostone isopropyl given three times daily produced an IOP of 19.6 +/- 3.3 mmHg and timolol maleate resulted in an IOP of 19.4 +/- 3.0 mmHg. No statistical differences between groups were observed at any time point during either diurnal curve. Safety was similar in the two treatment groups, with no differences between groups in conjunctival hyperemia, anterior segment inflammation, or iris color change. CONCLUSION: Results of this short-term pilot trial indicate that unoprostone isopropyl may be safe and effective in reducing IOP from baseline when given twice or three times daily.     

Chronotropic effects of optical isomers of ephedrine and methylephedrine in the isolated rat right atria and in vitro assessment of direct and indirect actions on beta 1-adrenoceptors

Effects of optical isomers of ephedrine (EPH) and methylephedrine (MEP) on the spontaneous beating rate of isolated right atrium of normal and reserpinized rat were investigated to assess direct and indirect actions on beta 1-adrenoceptors. l-EPH (3 x 10(-7) - 3 x 10(-5) M) and d-EPH (10(-6) - 10(-4) M) markedly increased beating rate of rat right atrium. l-MEP (10(-5) - 3 x 10(-4) M) showed slight increase in heart rate. The potency of positive chronotropic effect is l-EPH > d-EPH "l-MEP. l-EPH was about 3 times as potent as d-EPH. In addition, d-MEP (3 x 10(-5) - 3 x 10(-4) M) caused a decrease in heart rate. Positive chronotropic effects of EPH isomers and l-MEP were attenuated by pretreatment with atenolol ( a selective beta 1-adrenoceptor antagonist) or reserpine treatment (8 mg/kg, s.c.). In reserpinized atria, the maximal increase by d-EPH was quite small, and l-MEP decreased heart rate. On the other hand, d-MEP, at 3 x 10(-4) M, did not show antagonist activity against the positive chronotropic effect of isoprenaline (10(-10) - 10(-5) M). These results suggest that l-EPH, d-EPH and l-MEP have beta 1-adrenoceptor agonist activity, while d-MEP is suggested to have only low or no affinity for beta 1-adrenoceptors. The relatively weak activity of l-MEP is believed to be mainly mediated by released noradrenaline. It is also suggested that d-EPH has very potent noradrenaline-releasing activity.     

Sweat gland carcinoma of the foot: a review and patient report

PURPOSE: To determine the accuracy of applanation tonometry in patients with corneas thinned by photorefractive keratectomy, and to correlate corneal changes with tonometric readings. METHODS: The intraocular pressure was measured with Goldmann applanation tonometry in 87 patients who underwent photorefractive keratectomy before and 1, 6 and 12 months after treatment. The treatments ranged from -1.5 to -14 diopters (mean=-7.6+/-4.1 diopters) and the fellow eyes were used as controls. RESULTS: In the treated eyes the intraocular pressure before surgery ranged from 11 to 26 mmHg (mean=17.7+/-2.8 mmHg). One month after surgery it ranged from 5 to 22 mmHg (mean=11.9+/-2.7 mmHg) with a significant underestimation (P=1x10(-33)). Six months after surgery it ranged from 6 to 22 mmHg (mean=12+/-3 mmHg) with a significant underestimation (P=5x10(-30)). Twelve months after surgery it ranged from 8 to 22 mmHg (mean=12.7+/-2.7 mmHg) with a significant underestimation (P=5x10(-31)). CONCLUSIONS: A correcting factor should be applied when using applanation tonometry to measure intraocular pressure in patients who have undergone PRK.     

The interaction of McN-A-343 with muscarine receptors in cardiac and smooth muscle

The interaction of the muscarine receptor partial agonist (4-m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) was investigated at muscarine receptors in the atria and taenia caeci of the guinea-pig to compare its interaction at the muscarine M2 receptor in the two tissues. In the smooth muscle, the muscarine M3 receptor subtype is responsible for the contractile response but the major subtype detected in binding or antibody experiments is the M2 subtype. In guinea pig atria the dissociation constant of McN-A-343 at muscarine receptors was 15.2 microM determined in functional experiments on left atria in McEwen's solution or 14.8 microM in binding experiments with [3H]-(-)-quinuclidinyl benzilate ([3H]QNB) in the same medium containing 5'-guanylylimododiphosphate (50 microM). In the taenia caeci, the dissociation constant estimated for McN-A-343 at the M3 receptor from functional experiments based on the contractile response to the agonist in McEwen's solution was 4.6 microM. This value was similar to the dissociation constant (6.2 microM) estimated from binding studies versus [3H]QNB conducted in the same medium although studies with 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepine 6-one (AF-DX 116) versus [3H]-(-)-N-methylscopolamine suggested that 70% of the receptors were the M2 subtype. The presence of the M2 subtype in the taenia caeci was also confirmed by the ability of oxotremorine to inhibit the increase in cAMP produced by isoprenaline (10 microM) since apparent pKB values for AF-DX 116 and hexahydrosiladiphenidol were 6.95 and 6.75, respectively. McN-A-343 (100 microM) failed to inhibit the response to isoprenaline and did not antagonize the inhibitory response to oxotremorine. It is concluded that the apparent affinity of McN-A-343 for muscarine M2 receptors in the atria and the taenia caeci differs and a number of explanations are discussed.     

Angiotensin-(1-7) and the rat aorta: modulation by the endothelium

Peptide metabolites of angiotensin I and II are active components of the renin-angiotensin system. One such peptide is angiotensin-(1-7), which has been shown to be present in various tissues and has properties distinct from those of angiotensin II. We examined the effects of angiotensin-(1-7) on endothelium-intact and denuded rat aorta. Second, we evaluated whether an interaction occurred between angiotensin-(1-7) and angiotensin peptides, as well as noradrenaline. Finally, we addressed whether the responses to angiotensin-(1-7) were mediated by an AT1 receptor. Angiotensin-(1-7) produced concentration-dependent relaxations of the rat aorta that were significantly greater in endothelium-intact preparations (81.1 +/- 18.9% and 29.6 +/- 2.9% for intact and denuded, respectively). Angiotensin-(1-7) inhibited responses generated to angiotensin I, II, III, and noradrenaline. In endothelium-denuded preparations, angiotensin-(1-7) produced a rightward shift of the concentration-effect curves to angiotensin II and noradrenaline. In addition, the inhibition against angiotensin I and II was significantly greater in endothelium-intact preparations [mean median inhibitory concentration (IC50) values for endothelium-intact preparations, 1.25 x 10(-9) M and 1.57 x 10(-9) M for angiotensin I and II, respectively; and for endothelium-denuded preparations, 1.77 x 10(-8) M and 1.17 x 10(-8) M for angiotensin I and II, respectively). Losartan did not affect relaxations in endothelium-intact preparations but caused a significant potentiation of the relaxation by angiotensin-(1-7) in denuded preparations. We conclude that angiotensin-(1-7) is a component of the renin-angiotensin system that acts to modulate the pressor effects of angiotensin II and noradrenaline.     

Influence of a selective guanylate cyclase inhibitor, and of the contraction level, on nitrergic relaxations in the gastric fundus

1. The influence of the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) on non-adrenergic non-cholinergic (NANC) relaxations and the possible role of a nerve-derived hyperpolarizing factor in NANC relaxation were investigated in the rat gastric fundus. 2. ODQ (10(-6) and 10(-5) M) concentration-dependently inhibited the short-lasting relaxations by NO (2 x 10(-6) M-10(-4) M) administered as a bolus without influencing the relaxation by 3 x 10(-8) M isoprenaline. The relaxation by an infusion of NO was reduced to the same extent by 10(-6) and 10(-5) M ODQ. 3. The electrically induced short-lasting and sustained relaxations (40 V, 1 ms, 0.5-16 Hz, 10 s trains at 2 min interval or cumulative increase in the frequency every 2 min) in NANC conditions were inhibited to a similar extent by 10(-6) and 10(-5) M ODQ, and by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 3 x 10(-4) M). 4. ODQ (10(-6) M) and L-NAME (3 x 10(-4) M), administered after 5, 10 or 20 min of long-term stimulation, reversed the relaxation to a similar extent (approximately 50% at 2 Hz and 20% at 8 Hz). 5. When the tissues were contracted to 40% of maximum by adapting the concentration of prostaglandin F2alpha (PGF2alpha), the inhibitory effect of 3 x 10(-4) M L-NAME on relaxations induced by train and cumulative stimulation was the same as when tissues were contracted with 3 x 10(-7) M PGF2alpha. 6. The findings of this study illustrate that the relaxation by exogenous and endogenous NO in the rat gastric fundus is due to activation of soluble guanylate cyclase. During long-term electrical stimulation, the partial contribution of NO to NANC relaxation is maintained but it is small at higher frequencies of stimulation. Evidence for the contribution of a nerve-derived hyperpolarizing factor to NANC relaxation was not obtained.     

Determination of penicillamine or tiopronin in pharmaceutical preparations by flow injection analysis

Two flow injection analysis (FIA) methods, using spectrophotometric detection, are proposed for the determination of penicillamine or tiopronin [N-(2-mercaptopropionylglycine)]. The procedures are based on the formation of yellow complexes between these thiol-containing drugs and Pd(II), in a 1 M or 0.25 M HCl medium, respectively. With peak height as a quantitative parameter, penicillamine is determined over the range 1.0 x 10(-5)-7.0 x 10(-4) M; for tiopronin the range is 1.0 x 10(-5)-6.0 x 10(-4) M. The methods have been applied to the routine determination of the drugs in pharmaceutical preparations.     

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)     

Exogenous NPY modulation of cardiac autonomic reflexes and its pressor effect in the conscious rabbit

1. Neuropeptide Y (NPY) may inhibit sympathetic and vagal transmission via presynaptic Y2 receptors and cause vasoconstriction via postsynaptic Y1 receptors. We examined the effects of NPY and related peptides on cardiovascular parameters and autonomic reflexes in the conscious rabbit. Further, the postjunctional effects of NPY and related peptides were assessed on acetylcholine (ACh) and isoprenaline agonist dose-chronotropic response curves. 2. In conscious rabbits the cardiac baroreceptor-heart rate reflex (baroreflex), Bezold-Jarisch like and nasopharyngeal reflexes were assessed in control, propranolol-treated or methscopolamine-treated (baroreflex only) groups, before and 30 min after i.v. administration of NPY (10 microg kg[-1] + 5 microg kg[-1] min[-1]) or vehicle (saline, 10 ml h[-1]). The effects of equivalent pressor doses of [Leu31, Pro34]NPY or methoxamine on the baroreflex were also examined. In separate animals, dose-heart rate (HR) response curves to isoprenaline or ACh were constructed before and 15 min after administration of NPY, [Leu31,Pro34]NPY (ACh only) or [Leu31,Pro34]NpY + sodium nitroprusside (ACh only). 3. Administration of NPY-receptor agonists caused sustained bradycardia (in the absence of methscopolamine) and rightward shifts of the barocurves in all 3 groups. The range of sympathetically-mediated tachycardia was significantly decreased by NPY or [Leu31,Pro34]NPY in the methscopolamine-treated group. However, these changes in the baroreflex were no different from those elicted by equipressor doses of methoxamine. There was no vagal inhibition by any NPY-receptor agonist in all three autonomic reflexes examined. ACh or isoprenaline dose-HR response curves were not affected by NPY peptide administration. 4. We conclude that in the conscious rabbit, at a single dose that elicits a significant pressor response, exogenous NPY has no direct effect on modulation of cardiac and autonomic reflexes. Non-specific effects of exogenous NPY on the baroreflex may be fully explained by its pressor action. There was no effect of NPY on postjunctional ACh or isoprenaline agonist dose-response curves. Therefore, it is unlikely that endogenous NPY has a functional role in directly modulating cardiac autonomic neurotransmission in the rabbit.     

The fetoplacental pressor effects of low-dose acetylsalicylic acid and angiotensin II in the ex vivo cotyledon model

OBJECTIVE: Our purpose was to investigate perfusion pressure changes ex vivo induced by angiotensin II on fetoplacental vasculature pretreated with low-dose acetylsalicylic acid. STUDY DESIGN: Two cotyledons from each of 12 placentas were perfused. The intervillous space of one cotyledon was infused with acetylsalicylic acid (5 x 10(-5) mol/L) similar to the serum concentration of women receiving daily low-dose aspirin therapy (60 to 81 mg). The control cotyledon was infused with an equivalent amount of normal saline solution. Two doses of angiotensin II, 1 x 10(-11.5) and 1 x 10(-10) moles, were injected as boluses into the chorionic arteries of each cotyledon. A 3 x 10(-7) mole dose of angiotensin II was also injected into the intervillous space. Statistical analysis was performed with analysis of variance, and results are expressed as mean pressure change in millimeters of mercury +/- SEM. RESULTS: Perfusion pressure response did not vary between cotyledons pretreated with acetylsalicylic acid and control cotyledons when 3 x 10(-7) moles of angiotensin II was injected into the intervillous space (8.0 +/- 1.9 mm Hg vs 9.8 +/- 1.6 mm Hg, p = 0.59). There were no differences between cotyledons in pressure response to 1 x 10(-11.5) moles of angiotensin II injected into the fetal circuit (5.9 +/- 0.8 mm Hg vs 6.7 +/- 0.9 mm Hg, p = 0.51). However, in the cotyledons pretreated with acetylsalicylic acid there was a decrease in the pressor response to 1 x 10(-10) moles of angiotensin II (14.1 +/- 1.4 mm Hg vs 21.5 +/- 3.3 mm Hg, p = 0.05). CONCLUSIONS: Low-dose aspirin infused into the intervillous space decreases vasoconstriction elicited by angiotensin II in the fetoplacental compartment. This suggests that maternal low-dose aspirin therapy has effects in the fetoplacental circulation in addition to its effects in the maternal circulation.     

Preservation of vascular function in rat mesenteric resistance arteries following cold storage, studied by small vessel myography

1. The use of isolated blood vessels to investigate the physiological and pharmacological control of the vasculature is limited by the requirement to use freshly isolated vessels. Hence, the aim of this study was to determine whether vascular smooth muscle and endothelial cell function could be preserved in resistance arteries by storing them in physiological salt solution (PSS) at 4 degrees C. 2. Third order mesenteric resistance arteries (mean internal diameter 237+/-6 microm) were dissected from the mesenteric bed of male Cob-Wistar rats. The vessel segments were mounted in a small vessel myograph for measurement of isometric tension, and equilibrated at their optimum resting force. Contractile responses to noradrenaline (NA; 1 x 10(-9) - 3 x 10(-5) M), phenylephrine (PE, 1 x 10(-9)-3 x 10(-5) M), potassium chloride (KCI; 2.5-140 mM) and endothelin (ET-1, 1 x 10(-11)-3 x 10(-7) M) and relaxant responses to acetylcholine (ACh; 1 x 10(-9) - 3 x 10(-5) M) and 3-morpholinosydnonimine (SIN-1; 1 x 10(-9) - 1 x 10(-4) M) were obtained in arteries, immediately after dissection (day 0) and following one to four days storage (day 1-day 4). 3. All arteries produced concentration-dependent contractions in response to each of the vasoconstrictors. There were no significant differences in the magnitude or sensitivity (pD2) of the vasoconstrictor responses between fresh and stored vessels. 4. Arteries precontracted with NA to approximately 80% of the maximum response, relaxed in a concentration-dependent manner in response to ACh and SIN-1. Vessel storage for up to three days resulted in no change in response to ACh or SIN-1. 5. Vessels analysed after four days of storage demonstrated a significant increase in sensitivity to ACh and SIN-1 (-logIC50 (M) values; ACh; day 0, 7.46+/-0.13 vs day 4, 7.97+/-0.11, P<0.01 and SIN-1; day 0, 4.87+/-0.10 vs day 4, 5.52+/-0.08, P<0.01). There was also a significant increase in the maximum relaxant response to ACh after four days of storage (% relaxation; day 0, 92.65+/-2.84 vs day 4, 100.36+/-0.36, P<0.05). 6. These results demonstrate that small resistance arteries remain viable if stored in PSS at 4 degrees C for up to four days, with no loss in endothelial cell function. The altered sensitivity to the vasodilators on day 4 suggests that vessels should only be stored for up to three days following dissection for analysis of functional responses.