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PubMed2002

Sildenafil reverses O2 constriction of the rabbit ductus arteriosus by inhibiting type 5 phosphodiesterase and activating BK(Ca) channels.

Oxygen constriction causes functional closure of the ductus arteriosus (DA) at birth. Although DA closure is crucial for postnatal adaptation, patency of the DA is critical for survival of newborns with duct-dependent cardiac malformations. In these cases, DA patency is achieved by i.v. infusion of prostaglandin E1, which, though effective, is often associated with complications. We hypothesized that sildenafil, a specific phosphodiesterase type 5 inhibitor, is an effective DA vasodilator. In isolated DA rings from term (d 30) fetal rabbits, sildenafil (10(-6)-10(-4) M) and diethylamine NONOate (10(-7)-10(-5) M) induced dose-dependent relaxation of oxygen-constricted DA (-52 +/- 4% and -51 +/- 6%, respectively) that was inhibited by the soluble guanylyl-cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (5 x 10(-5) M). Sildenafil increased cyclic GMP levels. Iberiotoxin (200 nM), an inhibitor of calcium-sensitive potassium channels, decreased the vasodilatory effect of sildenafil and diethylamine NONOate (-30 +/- 2% and -27 +/- 4%, respectively). Oxygen inhibition of whole-cell K+ current and membrane depolarization were partially restored by sildenafil, and this was inhibited by iberiotoxin. Immunohistochemistry and immunoblotting confirmed the presence of phosphodiesterase type 5 and calcium-sensitive potassium channels in the DA smooth muscle cells. This is the first study to demonstrate that sildenafil dilates the DA by increasing soluble guanylyl-cyclase-derived cGMP levels and thereby activating calcium-sensitive potassium channels, causing membrane hyperpolarization. Sildenafil, already approved for human usage, might be an alternative or a useful adjunct to prostaglandin E1 as a bridge to cardiac surgery.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina.

BACKGROUND: The antiepileptic drug (AED) vigabatrin (VGB) causes concentric visual field constriction. Anecdotal reports involving tiagabine (TGB) have implied that this may be a class effect of all AEDs with gamma-aminobutyric acid (GABA)-related actions. We investigated the pharmacokinetic and pharmacodynamic profiles of VGB and TGB in rat brain and eye. METHODS: Adult male rats (n = 8) were administered 0.9% saline (control), VGB (500 or 1,000 mg/kg), or TGB (5, 10, or 20 mg/kg). At 1 (TGB) and 4 hours (VGB) postdosing, the animals were killed, a blood sample was obtained, their brains were dissected into five anatomic regions, and the retina and vitreous humor were isolated from each eye. Samples were analyzed for GABA concentrations and the activity of the enzyme GABA-transaminase (GABA-T). Plasma and tissue drug concentrations were also determined. RESULTS: VGB treatment produced a decrease in the activity of GABA-T and a rise in GABA concentrations in all tissues investigated. This effect was most pronounced in the retina. VGB concentrations were as much as fivefold higher in the retina than in the brain. TGB was without effect on GABA concentrations and activity of GABA-T. TGB concentrations were notably lower in the retina than in the brain. CONCLUSIONS: Accumulation of VGB in the retina, with or without an increase in GABA, may be responsible for the visual field constriction reported clinically. In contrast, TGB had no effect on GABA concentrations and did not accumulate in the retina. These results suggest that TGB is unlikely to cause visual field defects in humans.

Animals↗
PubMed2003

A chronic-constriction injury of the sciatic nerve reduces bilaterally the responsiveness to formalin in rats: a behavioral and hormonal evaluation.

UNLABELLED: Application of four loose ligatures to the sciatic nerve of a rat (chronic constriction injury [CCI]) induces clear hypersensitivity to non-noxious stimulation and chemical irritants. However, in this study, an injection of formalin in the hind paw of a rat with CCI-induced mononeuropathy resulted in an ipsilateral decreased flinching and licking or biting behavior in both phases of the formalin testing. The effect was independent of the formalin concentration used. This altered behavior was accompanied with smaller plasma levels of adrenocorticotrope hormone and corticosterone compared with sham and non-operated animals. Formalin injection in the contralateral nonligated hind paw of CCI rats also reduced the licking or biting behavior as compared with sham-operated and non-operated control animals only in the second phase of the formalin test. Thus, CCI reduces the pain reactivity and hypothalamic-pituitary-adrenal-axis activation to ipsilateral and contralateral formalin injection. Further research should investigate whether the decreased pain reactivity by CCI is situated at the peripheral, spinal, or supraspinal level or is result of changes in the stress reactivity and coping strategies. IMPLICATIONS: We evaluated the changes in the behavioral reactions and the hormonal effects of a noxious chemical stimulus, i.e., formalin injection in animals with previously induced chronic constriction injury to the sciatic nerve. The effect in animals injected at the ipsilateral and contralateral site, sham-operated and controls, were compared.

Adrenocorticotropic Hormone↗
PubMed2004

Peroxisome elongation and constriction but not fission can occur independently of dynamin-like protein 1.

The mammalian dynamin-like protein DLP1 belongs to the dynamin family of large GTPases, which have been implicated in tubulation and fission events of cellular membranes. We have previously shown that the expression of a dominant-negative DLP1 mutant deficient in GTP hydrolysis (K38A) inhibited peroxisomal division in mammalian cells. In this study, we conducted RNA interference experiments to 'knock down' the expression of DLP1 in COS-7 cells stably expressing a GFP construct bearing the C-terminal peroxisomal targeting signal 1. The peroxisomes in DLP1-silenced cells were highly elongated with a segmented morphology. Ultrastructural and quantitative studies confirmed that the tubular peroxisomes induced by DLP1-silencing retained the ability to constrict their membranes but were not able to divide into spherical organelles. Co-transfection of DLP1 siRNA with Pex11pbeta, a peroxisomal membrane protein involved in peroxisome proliferation, induced further elongation and network formation of the peroxisomal compartment. Time-lapse microscopy of living cells silenced for DLP1 revealed that the elongated peroxisomes moved in a microtubule-dependent manner and emanated tubular projections. DLP1-silencing in COS-7 cells also resulted in a pronounced elongation of mitochondria, and in more dispersed, elongated Golgi structures, whereas morphological changes of the rER, lysosomes and the cytoskeleton were not detected. These observations clearly demonstrate that DLP1 acts on multiple membranous organelles. They further indicate that peroxisomal elongation, constriction and fission require distinct sets of proteins, and that the dynamin-like protein DLP1 functions primarily in the latter process.

Animals↗
PubMed1992

Molecular characterization of the secondary constriction region (qh) of human chromosome 9 with pericentric inversion.

Pericentric inversion of the secondary constriction region (qh) of human chromosome 9 is a frequent occurrence. This structural alteration is regarded as a normal familial variant, termed heteromorphism, and is inherited in a Mendelian fashion without any apparent phenotypic consequences. We characterized the qh region of chromosome 9 from five individuals using a series of molecular cytogenetic techniques. Four out of the five individuals have an additional area composed of alphoid DNA sequences on the inverted chromosome 9 while one case was found to have an apparently intact alphoid DNA sequence. Although the direct function(s) of alphoid DNA sequences remain unclear, the centromeric breakage involving these sequences in inverted chromosome 9 raises a series of questions pertaining to the monocentric, dicentric and pseudodicentric nature of pericentric inversions. Nevertheless, these findings have prompted us to suggest that the structural organization of alphoid DNA sequences of the centromeric region of chromosome 9 are apparently "breakage prone" and may be associated with a higher incidence of pericentric inversions. Furthermore, the hierarchical organization of various satellite DNA families (alpha-satellite, beta-satellite and satellite III) within the primary and secondary constriction regions of chromosomes 9 are elucidated here.

Adult↗
PubMed2005

Increased constriction of the ductus arteriosus by dexamethasone, indomethacin, and rofecoxib in fetal rats.

BACKGROUND: To find a better treatment for patent ductus arteriosus (PDA) in premature infants, the present study investigated the synergism of clinical doses of dexamethasone, indomethacin, and rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the fetal ductus arteriosus (DA) in rats. METHODS AND RESULTS: Dexamethasone (0.3 mg/kg), indomethacin (0.3 mg/kg), and rofecoxib (0.3 mg/kg), alone or in combination, were administered to preterm (d19) and near-term (d21) fetal rats. The ratio of the inner diameter of the DA to that of the main pulmonary artery (PA) (DA/PA) was studied at 2, 4 and 8 h after drug administration, using a rapid whole-body freezing method. In near-term rats, the combined administration of dexamethasone and indomethacin caused severe constriction, with a DA/PA ratio of 0.52+/-0.08 at 8 h, whereas the DA/PA ratios were 0.83+/-0.03 and 0.90+/-0.02 with dexamethasone and indomethacin, respectively. Combined administration of dexamethasone and rofecoxib also caused severe constriction, with a DA/PA ratio of 0.64+/-0.07 at 8 h, compared with the DA/PA ratio of 0.92+/-0.03 with rofecoxib alone. CONCLUSIONS: Combined therapy may be an option in the medical management of PDA in premature infants before considering surgical treatment.

Animals↗
PubMed1989

Different sensitivity changes of canine and simian femoral arterial and venous constrictions by cooling.

Using the cannula inserting method, effects of cooling (from 37 degrees C to 27 degrees C) on norepinephrine (NE)- and KCI-induced vasoconstrictions were investigated in isolated, perfused simian and canine femoral arteries and veins. KCI-induced constrictions were much greater in simian vessels than in canine vessels. NE-induced constrictions were similar in both arteries, but were greater in simian veins than in canine veins. In both arteries, NE- and KCI-induced vasoconstrictions were markedly depressed to almost the same degree by cooling. In both veins, the vasoconstrictions were not significantly affected by cooling.

Acetylcholine↗
PubMed1993

Constrictive effect of thyroxine on the ductus arteriosus in fetal rats.

This work was conducted to know whether thyroxine (T4) when injected into fetal rats would induce a constriction of the ductus arteriosus (DA). In Experiment 1, fetal rats on day 20 of gestation were given a subcutaneous injection of 1 or 10 micrograms T4 through the maternal uterine wall, and were autopsied 3 or 6 hr later. Similarly, in Experiment 2, the mother rats were given an injection of hydrocortisone (10 mg/kg) just after fetal T4 injections. In either series of experiments, uninjected littermates served as controls. According to the whole-body freezing and shaving method, the DA was exposed and calibrated under a dissecting microscope. In Experiment 1, the DAs of the T4-injected fetuses, 3 hr later, were significantly smaller in caliber than those of their controls, but recovered 6 hr later. In Experiment 2 with fetal T4 injection followed by maternal hydrocortisone injection, the DAs of the T4-injected fetuses were further smaller in caliber than those of their controls which were clearly shrunken as compared with those of controls in Experiment 1. These results indicate that T4 exerts a constrictive effect on the DA, an effect which is strengthened in the presence of hydrocortisone.

Animals↗
PubMed1994

Sequential morphological changes of the constrictive basilar artery in a canine model of experimental cerebral vasospasm by talc injection.

To demonstrate the possible role of foreign-body reaction to extravasated blood in provoking chronic cerebral vasospasm, talc (crystallized hydrous magnesium silicate) was injected as a non-biologic foreign material into the canine-cisterna cerebellomedullaris, and pathologic changes were followed. Angiographically, this cisternal talc injection induced delayed and prolonged constriction of the basilar artery, without any evidence of so-called early phase cerebral vasospasm that should occur shortly after an insult. Pathologically, around the spastic artery in the subarachnoid space with talc injection, the appearance of a moderate cellular migration coincided with cerebral vasoconstriction, which took place 2 days after the talc injection. In the spastic basilar arterial wall, marked constrictive and degenerative changes including myonecrosis and subintimal proliferation were induced by cisternal talc injection as early as on day 2, and the changes were progressive with time. These pathologic changes were extremely analogous to those of the human autopsy cases with chronic cerebral vasospasm (chronic VS) but more prominent than those observed in the experimental autologous blood-induced model. The present study demonstrated that a foreign-body reaction to talc alone could induce chronic VS in the absence of extravasated blood. Thus, it is possible to consider that inflammatory reactions to extravasated autologous blood in subarachnoid hemorrhage may give rise to chronic VS.

Animals↗
PubMed1995

Protective effects of prostaglandin E2 on the paraquat-induced constriction of the fetal ductus arteriosus in the rat.

Pregnant rats on day 21 of gestation received a subcutaneous injection of paraquat (25 mg/kg). Two hr later, some fetuses of these rats received a subcutaneous injection of prostaglandin E2 (PGE2). The caliber of the ductus arteriosus (DA) of fetuses was measured 1 hr later. The DA of fetuses of paraquat-treated pregnant rats was significantly constricted compared with that of fetuses of control pregnant rats given physiological saline. However, the DA of PGE2-treated fetuses of paraquat-treated pregnant rats had a caliber comparable to that of control rats. The maternal plasma PGE2 level decreased following paraquat treatment. These results suggest that the decrease of maternal PGE2 level results in a constriction of the DA of fetuses.

Animals↗
PubMed1984

Nicorandil releases acetylcholine-induced sustained coronary arterial constriction in monkeys and baboons.

The spasmolytic action of nicorandil on coronary circulation was investigated in 3 Japanese monkeys (Macaca fuscata), 1 rhesus monkey (Macaca mulatta), and 1 anubis baboon (Papio anubis) anesthetized with pentobarbital. The arterial bed of the left anterior descending coronary artery (LAD) was perfused with autologous arterial blood at a constant pressure close to systolic arterial blood pressure. Single injections of nicorandil (10-300 micrograms) into the LAD produced a dose-dependent increase in blood flow without affecting either systemic arterial blood pressure or heart rate. With continuous infusion of acetylcholine into the LAD, the LAD flow decreased to nearly half the basal level, indicating sustained coronary arterial constriction. Under these conditions intra-LAD nicorandil increased the LAD flow virtually to the same extent as before acetylcholine-infusion. These effects of nicorandil resemble those of the Ca++-antagonists, diltiazem and nifedipine, but differ from those of nitroglycerin, which is less effective during sustained coronary arterial constriction. The results imply that nicorandil may be as effective as Ca++-antagonists in the treatment of vasospastic angina.

Acetylcholine↗
PubMed2006

Femoral artery constriction by norepinephrine is enhanced by methylprednisolone in a rat model.

BACKGROUND: Corticosteroids are associated with femoral head osteonecrosis and arterial hypertension. The patho-mechanism of femoral head osteonecrosis is often attributed to ischemia. The aim of this study was to investigate if corticosteroids directly constrict the femoral artery or if they have a permissive effect on norepinephrine and endothelin-1-induced vasoconstriction. METHODS: Femoral artery segments were harvested from twenty Wistar rats and mounted as ring preparations on a small-vessel myograph for the purpose of making isometric force measurements. For the norepinephrine study, twenty femoral artery segments from ten rats were stimulated cumulatively with norepinephrine before and after incubation with methylprednisolone (5 mug/mL). For the endothelin-1 study, forty femoral artery segments from ten rats were used. The four artery segments from each animal were randomized by pairs to either a corticosteroid treatment group (5 mug/mL methylprednisolone incubation, n = 20) or a control group (placebo incubation, n = 18, as two of the twenty control-group vessels did not meet protocol requirements). Isometric wall tension was plotted and quantified by the EC(50) (the plasma concentration of endothelin-1 required for obtaining 50% of maximal constriction in vivo). RESULTS: In the norepinephrine-stimulated group, incubation with methylprednisolone did not directly induce any vasoconstriction but did enhance norepinephrine-elicited vasoconstriction. The norepinephrine dose-response curve displayed a shift to the left after incubation with methylprednisolone. This shift was reflected by a significantly lower mean EC50 of 9.5 x 10(-7) M +/- 5.1 x 10(-7) M after methylprednisolone incubation compared with a mean of 2.5 x 10(-6) M +/- 1.1 x 10(-6) M before incubation (p < 0.005). In the endothelin-1-stimulated group, the endothelin-1 dose-response curve displayed a tendency toward stronger contraction in the vessels that were incubated with methylprednisolone, but this tendency did not reach significance. CONCLUSIONS: Incubation with methylprednisolone enhances norepinephrine-mediated contraction of the femoral artery in a rat model. CLINICAL RELEVANCE: Vasoconstriction of the vascular bed supplying the femoral head can diminish femoral head blood flow, and this may be a factor in the early pathogenesis of corticosteroid-associated femoral head osteonecrosis.

Animals↗
PubMed1995

Dilating effect of prostaglandin on the constricted ductus arteriosus in newborn rats.

The dilating effect of prostaglandin (PG) E1 and E2 on the once-constricted ductus arteriosus (DA) was examined in newborn rats. The animals were given subcutaneously PGs 3hr after caesarean delivery. The ratio of the DA to the pulmonary artery (PA) was determined 15, 30, 60, 90 and 180 min after injection. Both PGE1 and PGE2 dilated the DA for over 90 min. The maximal effect appeared 15 or 30 min after injection. The DA/PA ratio was significantly higher in PGE2 than in PGE1. In addition, another series of newborn rats were given subcutaneously PGE2 6 hr after caesarean delivery to examine the age-related changes in the DA-dilating effect. The DA/PA ratio was significantly decreased in 6-hr-old pups than in 3-hr-old pups. These findings indicate that both PGE1 and PGE2 have a dilating effect on the once-constricted DA and that the effect decreases with time.

Alprostadil↗
PubMed2005

Subtotal pericardectomy and epicardial excision for treatment of coccidioidomycosis-induced effusive-constrictive pericarditis in dogs: 17 cases (1999-2003).

OBJECTIVE: To determine the history, clinicopathologic findings, and results of surgery for effusive-constrictive pericarditis associated with Coccidioides immitis infection in dogs. DESIGN: Retrospective study. ANIMALS: 17 client-owned dogs that underwent a subtotal pericardectomy and epicardial excision. PROCEDURE: Hospital records from May 1999 to June 2003 were reviewed. Data collected included history, clinicopathologic findings, treatments, and outcome. Follow-up information was obtained via recheck examination and by use of standardized telephone interviews with referring veterinarians and owners. RESULTS: All dogs were of large breeds, and most were male (mean age, 4.66 years). Ten dogs had no prior history of C. immitis infection, and 7 dogs had chronic infection with C. immitis. Having a chronic C. immitis infection reduced the odds of survival, compared with no previous infection. All dogs had clinical signs of right-sided heart failure. All dogs had serum titers (range, 1:8 to 1:256) for antibodies against C. immitis prior to surgery, and titers were not significantly associated with outcome. Predominant echocardiographic findings were thickened pericardium, reduced right ventricular filling, and pleural or pericardial effusion. All dogs underwent a subtotal pericardectomy and epicardial excision and had fibrosing pyogranulomatous pericarditis in biopsy specimens obtained during surgery. The perioperative mortality rate was 23.5%, and the 2-year postdischarge survival rate was 82%. CONCLUSIONS AND CLINICAL RELEVANCE: Surgical treatment via subtotal pericardectomy and epicardial excision is successful at relieving right-sided heart failure in dogs with effusive-constrictive pericarditis secondary to C. immitis infection, but long-term treatment with antifungal agents may still be required.

Animals↗
PubMed1978

Closure difficulty, figure-size expansion, and figure-size constriction on 240 Graham-Kendall Memory-for-Designs records.

To determine the frequency of occurrence of closure difficulty, figure-size expansion, and figure-size constriction, 240 university students were administered the Graham-Kendall Memory-For-Designs test. Subjects were volunteers enrolled in undergraduate psychology courses and were between 18 and 23 yr. of age, male or female, and U.S. citizens. The purpose was to define a sampling of drawing styles exhibited in a normal group on this test. Each drawing style, or factor, was treated as an independent variable, and the frequency of occurence of each level (dependent variable) was compared via chi square. It was noted that a significant number of subjects exhibited some degree of closure difficulty with the designs (X2 = 101.72, p less than .01). Figure-size expansion was noted as extremely rare for this sample (X2 = 444.78, p less than .01). Finally, extreme figure-size constriction occurred significantly more often than either moderate or no contriction of the designs (X2 = 62.58, p less than .01).

Adolescent↗
PubMed1986

Classical conditioning of pupillary constriction.

Previous attempts to condition classically the pupillary response have resulted in mixed outcome. Studies using light as the UCS have generally been unsuccessful while those studies using shock as the UCS have been more successful. In the present study six subjects were visually presented 15 CVC trigrams while their pupil sizes were monitored. Five of the CVCs had been previously presented, five had been previously presented while paired with shock, and five had not been previously presented. Analysis indicated that more pupillary constriction occurred to the five CVCs paired with shock than those presented without shock or those not previously presented. The resulting classically conditioned pupillary constriction is discussed in terms of the development of meaning through classical conditioning.

Cognition↗
PubMedDate not supplied

Combinatorial mutagenesis analysis of residues in the channel constriction loop L3 and neighbouring beta-strands in the LamB glycoporin of Escherichia coli.

Members of the LamB family of sugar-selective porins (glycoporins) are beta-barrel proteins in the outer membrane of Gram-negative bacteria. To study the determinants of structure and sugar selectivity, 68 non-identical single amino acid substitutions were introduced into the stretch of sequence consisting of residues 106 through 125 in Escherichia coli LamB. This region includes all bar one residue of the channel constriction loop L3 and extends into the transmembrane beta 6 strand in the LamB structure. Mutants were assayed for dextrin utilization, starch binding, A binding, monoclonal antibody binding and for qualitative changes in protein expression. The importance of the L3 amino acids was emphasized by the observation that only four residues permitted a majority of neutral substitutions. Changes to the channel constriction zone strongly affected sugar binding yet no single amino acid change of residues exposed to the channel lumen caused a complete defect in maltodextrin utilization (i.e. were still Dex+). Substitutions in the L3 loop did not affect phage lambda binding, except one change at residue 122, nor changed recognition by anti-LamB antibodies specific for surface epitopes, consistent with the lack of a role of L3 residues in surface receptor function. In marked contrast, four substitutions in transmembrane strand beta 5 resulted in a Dex- phenotype and gross changes in protein properties, indicating the significance of beta 5 in the architecture of LamB.

Amino Acid Sequence↗
PubMed1995

Flow-dependent dilation and myogenic constriction interact to establish the resistance of skeletal muscle arterioles.

OBJECTIVE: To test the hypothesis that the diameter of skeletal muscle arterioles is determined by the interaction of responses elicited by intravascular pressure and flow. METHODS: Experiments were conducted on isolated, cannulated, first-order arterioles of cremaster muscle of male Wistar rats. The diameter of arterioles was followed by videomicroscopy. Perfusion pressures and flows were controlled. RESULTS: In the absence of perfusate flow, increases in perfusion pressure (from 0 to 120 mm Hg), after initial dilation, elicited endothelium independent constrictions of arterioles. At 60 mm Hg of perfusion pressure, the active diameter of vessels was 84.9 +/- 1.9 microns. The passive diameter of arterioles (Ca2(+)-free solution)was 150.6 +/- 2.4 microns. Increases in perfusate flow resulted in a significant upward shift in the pressure-diameter curves; in the presence of perfusate flows of 20, 40, and 60 microL/min, the constriction of the vessels at a pressure of 60 mm Hg was attenuated by 25.1 +/- 3.9%, 35.2 +/- 3.0%, and 46.8 +/- 4.4%, respectively. In contrast, the corresponding diameter of arterioles at perfusate flows of 10 to 60 microL/min was significantly reduced when perfusion pressure was increased from 60 to 80 and 100 mm Hg (at a flow of 60 microL/min) by 12.0 +/- 4.3% and 37.1 +/- 2.8%, respectively. Hence, both flow- and shear stress-diameter curves were significantly shifted downward when perfusion pressure increased from 60 to 100 mm Hg. CONCLUSION: These results demonstrate that an interplay between pressure and flow-sensitive mechanisms is an important determinant of the arteriolar resistance in skeletal muscle.

Animals↗