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Biomedical subjects

M A Wilson

Publications and source records attributed to M A Wilson.

At least 91 records · Page 5Linked to original sources
PubMed1998

Anxiety levels, patient satisfaction and failed appointment rate in anxious patients referred by general practitioners to a dental hospital unit.

OBJECTIVE: To reduce the high failed appointment rate and anxiety levels among previously identified anxious new patients referred by general practitioners to a unit of restorative dentistry. A letter was drawn up which contained more explanatory information about the purpose and content of the initial dental appointment. DESIGN: The study was a single centre, double blind trial. SETTING: Referrals of nervous/anxious patients from general practitioners to the Manchester Dental Hospital. SUBJECTS: 185 patients were randomly allocated to the control group (n = 94) who received the standard hospital appointment information and the experimental group (n = 91) who received the new more informative letter. MAIN OUTCOME MEASURES: The effect of the new letter on patient attendance was recorded and anxiety levels were measured before and after seeing the clinician. RESULTS: 70 patients attended from the control group and 58 patients from the experimental group, giving 59 and 44 fully completed forms respectively. Both groups of patients were generally happy with the information that they were given. The attendance of patients in the experimental group and the control group were not significantly different. Preconsultation state anxiety levels were not reduced in the experimental group by the provision of the additional information but after the consultation both groups showed a significant reduction in state anxiety (P < 0.001). CONCLUSION: The new more informative letter did not improve attendance among this group of nervous patients. Other strategies for increasing initial attendance will therefore need to be identified and evaluated. In this study, the most important factor in reducing anxiety levels during the consultation appeared to be contact with the clinician rather than preparatory written postal information.

Adult↗
PubMed1998

Herpes virus-mediated preproenkephalin gene transfer to the amygdala is antinociceptive.

To evaluate the role of the amygdala in pain modulation and opioid-mediated antinociception, a recombinant, replication-defective herpes virus carrying the human preproenkephalin cDNA was injected bilaterally into the rat amygdala. Four days after gene delivery nociceptive behavior was assessed by the formalin test. Rats infected with the virus expressing preproenkephalin showed a selective, naloxone-reversible abolition of phase 2 flinching behavior compared to rats infected with a control virus. The results implicate the amygdala in the control of pain and in opioid analgesia and demonstrate the use of recombinant herpes viruses as tools for studying gene function in specific neural pathways of the central nervous system.

Amygdala↗
PubMed1998

Agonist occupation of an alpha2A-adrenoreceptor-Gi1alpha fusion protein results in activation of both receptor-linked and endogenous Gi proteins. Comparisons of their contributions to GTPase activity and signal transduction and analysis of receptor-G protein activation stoichiometry.

A fusion protein between a pertussis toxin-resistant (C351G) mutant of the alpha subunit of the G protein Gi1 and the porcine alpha2A-adrenoreceptor was stably expressed in Rat 1 fibroblasts. Agonists caused stimulation of high affinity GTPase activity, which was partially prevented by pertussis toxin treatment, demonstrating that the toxin-resistant component of the GTPase activity was derived from the receptor-fused G protein and the remainder from endogenous Gialpha. Half-maximal stimulation of the GTPase activity of endogenous Gi was achieved with lower concentrations of agonist. Although the Km for GTP of the fusion protein-linked Gi was lower than for the endogenous G protein, Vmax measurements demonstrated that adrenaline activated some 5 mol of endogenous Gi/mol of fusion protein-linked Gi. The isolated alpha2A-adrenoreceptor could activate Gs; however, the fusion protein did not. Compared with adrenaline, the efficacy of a range of partial agonists to stimulate endogenous Gialpha was greater than for the fusion protein-constrained C351G Gi1alpha. alpha2A-Adrenoreceptor agonists could stimulate both p44 mitogen-activated protein kinase and p70 S6 kinase and inhibit forskolin-amplified adenylyl cyclase activity in untreated alpha2A-adrenoreceptor-C351G Gi1alpha fusion protein-expressing cells, but these signals were abolished following pertussis toxin treatment. These results demonstrate conclusively, and for the first time, that agonist occupancy of a receptor-G protein fusion protein can result in activation of G proteins other than that physically linked to the receptor. This was selective between G protein classes. Analysis of the contributions of fusion protein-linked and endogenous G proteins to agonist-stimulated GTPase activity provided a direct and original measure of receptor-G protein activation stoichiometry.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1998

Microvascular endothelial cell control of peripheral vascular resistance during sepsis.

OBJECTIVE: To determine the endothelial-dependent control of decreased peripheral vascular resistance in skeletal muscle microvessels during evolving sepsis. MATERIALS AND INTERVENTIONS: Acute (4 hours, n=7), established (24 hours, n=7), or chronic (72 hours, n=8) infection was induced in Sprague-Dawley rats (150-175 g) by injecting Escherichia coli and Bacteroides fragilis (1 x 10(9) colony-forming units for both) into a subcutaneous sponge. Control animals were injected with an isotonic sodium chloride solution and analyzed at the same time points: (n=6-8 per group). Dilation in response to the topically applied endothelial-dependent agonist acetylcholine (ACH) (1 x 10(-9) to 1 x 10(-5) mol/L) was measured in inflow first-order (A1) and precapillary fourth-order (A4) arterioles in cremaster muscle in vivo with videomicroscopy. Acetylcholine dose-response curves were used to determine vascular reactivity by calculating the concentration of ACH necessary to elicit 50% of the maximal dilator response. MAIN OUTCOME MEASURES: In vivo reactivity of striated muscle microvessels to the dilation agonist ACH during acute, established, and chronic infection. RESULTS: A1 vessels were unresponsive to all doses of ACH at all time points. A4 vessels showed an increased dilator response during short-term treatment, which deteriorated over time to depressed dilation during chronic infection. CONCLUSIONS: Precapillary A4 vessels have increased dilator reactivity during early sepsis, which progresses to depressed levels with chronic infection. A1 microvessels remain dilated and are not substantially influenced by endothelial dilator mechanisms initiated by ACH. Maximum dilation of the large A1 vessels appears to contribute to the decrease in peripheral vascular resistance noted during systemic infection.

Acetylcholine↗
PubMed1998

Small intestinal production of nitric oxide is decreased following resuscitated hemorrhage.

BACKGROUND: Small intestine microvascular vasoconstriction and hypoperfusion develop after resuscitation (RES) from hemorrhage (HEM), despite restoration of central hemodynamics. The responsible mechanisms are unclear. We hypothesized that the microvascular impairment following HEM/RES was due to decreased intestinal microvascular nitric oxide (NO) production. METHODS: Male Sprague-Dawley rats (195-230 g) were utilized and three experimental groups were studied: (1) SHAM (cannulated but no HEM), (2) HEM only, and (3) HEM/RES. HEM was to 50% of baseline mean arterial pressure for 60 min, and RES was with shed blood and an equivalent volume of saline. Ex vivo isolated intestinal perfusion and a fluorometric modification of the Greiss reaction were used to quantify production of NO metabolites (NOx). Perfusate von Willebrand factor (vWF) was used as an indirect marker of endothelial cell activation or injury. To assess the degree of NO scavenging by oxygen-derived free radicals, immunohistochemistry was used to detect nitrotyrosine formation in the intestine. RESULTS: Intestinal NOx decreased following HEM/RES (SHAM 1.35 +/- 0.2 mM vs HEM/RES 0.60 +/- 0.1 mM, P < 0.05), but not with HEM alone (1.09 +/- 0.3 mM). There were no differences in serum NOx levels between the three groups. Release of vWF was increased during the HEM period (SHAM 0.18 +/- 0.1 g/dl vs HEM 1.66 +/- 0.6 g/dl, P < 0.05). There was no detectable nitrotyrosine formation in any group. CONCLUSIONS: Intestinal NO metabolites decrease following HEM/RES. Elevated vWF levels during HEM and the lack of detectable nitrotyrosine suggest that this is due to decreased endothelial cell production of NO. HEM/RES-induced endothelial cell dysfunction may contribute to persistent small intestine post-RES hypoperfusion and vasoconstriction.

Animals↗
PubMed1998

Coordinated interactions between hippocampal ripples and cortical spindles during slow-wave sleep.

Sleep is characterized by a structured combination of neuronal oscillations. In the hippocampus, slow-wave sleep (SWS) is marked by high-frequency network oscillations (approximately 200 Hz "ripples"), whereas neocortical SWS activity is organized into low-frequency delta (1-4 Hz) and spindle (7-14 Hz) oscillations. While these types of hippocampal and cortical oscillations have been studied extensively in isolation, the relationships between them remain unknown. Here, we demonstrate the existence of temporal correlations between hippocampal ripples and cortical spindles that are also reflected in the correlated activity of single neurons within these brain structures. Spindle-ripple episodes may thus constitute an important mechanism of cortico-hippocampal communication during sleep. This coactivation of hippocampal and neocortical pathways may be important for the process of memory consolidation, during which memories are gradually translated from short-term hippocampal to longer-term neocortical stores.

Action Potentials↗
PubMed1998

Laparoscopic repair of lumbar hernias.

BACKGROUND: Lumbar hernias are rare defects in the posterolateral abdominal wall that may be congenital or acquired. Repairing these defects is difficult by virtue of their location and the inherent weakness of the surrounding tissues. We report a series of seven patients who had their lumbar hernias repaired laparoscopically at two institutions. STUDY DESIGN: We retrospectively reviewed all lumbar hernias repaired laparoscopically in our institutions within the last 16 months (August 1996 to November 1997). Postoperative followup was 1-15 months. RESULTS: Seven patients underwent laparoscopic repair. Five hernias were acquired defects and two were congenital. One to three defects were found per patient. The average size of the hernia defect was 77.8 cm2. We used a polypropylene or a polytetrafluoroethylene mesh in all patients; the average size of the mesh used was 336.4 cm2. The average length of hospital stay was 1.7 days. One patient returned with an abscess over the mesh, which necessitated removal of the graft. Otherwise, there were no complications, and the remaining six patients had no recurrences after followup of 1-14 months. CONCLUSIONS: The laparoscopic approach is safe and effective for repairing lumbar hernias. Advantages of this approach include excellent operative visualization, decreased hospital stay postoperatively, and a solid repair without recurrence during shortterm followup.

Hernia, Ventral↗
PubMed1998

Complement inhibition prevents gut ischemia and endothelial cell dysfunction after hemorrhage/resuscitation.

BACKGROUND: Complement, a nonspecific immune response, is activated during hemorrhage/resuscitation (HEM/RES) and is involved in cellular damage. We hypothesized that activated complement injures endothelial cells (ETCs) and is responsible for intestinal microvascular hypoperfusion after HEM/RES. METHODS: Four groups of rats were studied by in vivo videomicroscopy of the intestine: SHAM, HEM/RES, HEM/RES + sCR1 (complement inhibitor, 15 mg/kg intravenously given before resuscitation), and SHAM + sCR1. Hemorrhage was to 50% of mean arterial pressure for 60 minutes followed by resuscitation with shed blood plus an equal volume of saline. ETC function was assessed by response to acetylcholine. RESULTS: Resuscitation restored central hemodynamics to baseline after hemorrhage. After resuscitation, inflow A1 and premucosal A3 arterioles progressively constricted (-24% and -29% change from baseline, respectively), mucosal blood flow was reduced, and ETC function was impaired. Complement inhibition prevented postresuscitation vasoconstriction and gut ischemia. This protective effect appeared to involve preservation of ETC function in the A3 vessels (SHAM 76% of maximal dilation, HEM/RES 61%, HEM/RES + sCR1 74%, P < .05). CONCLUSIONS: Complement inhibition preserved ETC function after HEM/RES and maintained gut perfusion. Inhibition of complement activation before resuscitation may be a useful adjunct in patients experiencing major hemorrhage and might prevent the sequelae of gut ischemia.

Acetylcholine↗
PubMed1998

Microvascular changes explain the "two-hit" theory of multiple organ failure.

OBJECTIVE: The objective was to determine intestinal microvascular endothelial cell control after sequential hemorrhage and bacteremia. SUMMARY BACKGROUND DATA: Sepsis that follows severe hemorrhagic shock often results in multiple system organ failure (MSOF) and death. The sequential nature of this clinical scenario has led to the idea of a "two-hit" theory for the development of MSOF, the hallmark of which is peripheral vasodilation and acidosis. Acute bacteremia alone results in persistent intestinal vasoconstriction and mucosal hypoperfusion. Little experimental data exist to support the pathogenesis of vascular dysregulation during sequential physiologic insults. We postulate that hemorrhagic shock followed by bacteremia results in altered microvascular endothelial cell control of dilation and blood flow. METHODS: Rats underwent volume hemorrhage and resuscitation. A sham group underwent the vascular cannulation without hemorrhage and resuscitation, and controls had no surgical manipulation. After 24 and 72 hours, the small intestine microcirculation was visualized by in vivo videomicroscopy. Mean arterial pressure, heart rate, arteriolar diameters, and A1 flow by Doppler velocimetry were measured. Endothelial-dependent dilator function was determined by the topical application of acetylcholine (ACh). After 1 hour of Escherichia coil bacteremia, ACh dose responses were again measured. Topical nitroprusside was then applied to assess direct smooth muscle dilation (endothelial-independent dilator function) in all groups. Vascular reactivity to ACh was compared among the groups. RESULTS: Acute bacteremia, with or without prior hemorrhage, caused significant large-caliber A1 arteriolar constriction with a concomitant decrease in blood flow. This constriction was blunted at 24 hours after hemorrhage but was restored to control values by 72 hours. There was a reversal of the response to bacteremia in the premucosal A3 vessels, with a marked dilation both at 24 and 72 hours. The sequence of hemorrhage and E. coli resulted in a progressive enhanced reactivity to the endothelial-dependent stimulus of ACh in the A3 vessels at 24 and 72 hours. Reactivity to endothelial-independent smooth muscle relaxation and subsequent vessel dilation was similar for all groups. CONCLUSIONS: These data indicate that there is altered endothelial control of the intestinal microvasculature after hemorrhage in favor of enhanced dilator mechanisms in premucosal vessels with enhanced constrictor forces in inflow vessels. This enhanced dilator sensitivity is most evident in small premucosal vessels. This experimental finding supports the premise that an initial pathophysiologic stress alters the subsequent microvascular blood flow responses to systemic inflammation. These changes in the intestinal microcirculation are in concert with the "two-hit" theory for MSOF.

Acute Disease↗
PubMed1998

Impact of trauma attending surgeon case volume on outcome: is more better?

OBJECTIVE: To examine the relationship between annual trauma volume per surgeon and years of attending experience with outcome in a Level I trauma center with a large panel of trauma attending surgeons. METHODS: The outcomes of trauma patients were examined in 1995 and 1996 in relationship to surgeon annual trauma volume and years of experience. Outcome variables studied included overall mortality, mortality stratified by Trauma and Injury Severity Score, mortality in patients with an Injury Severity Score greater than 15, and preventable or possibly preventable deaths. Morbidity outcomes examined were overall complication rate and length of stay per attending surgeon. Additionally, five difficult problems were evaluated for critical management decisions by the attending surgeons, and these outcomes were correlated to annual volume and experience. RESULTS: There was no difference in outcome in either morbidity or mortality that correlated with annual volume of patients treated or years of experience. Critical management errors occurred sporadically and were not related to volume or experience. CONCLUSIONS: Outcome after trauma seemed to be related to severity of injury rather than annual volume of cases per surgeon. Although our results may not be applicable to other institutions, they should urge caution in adopting and promulgating volume requirements for individual attending surgeons in trauma centers.

Emergencies↗
PubMed1998

Alternatives in the management of penetrating injuries to the iliac vessels.

BACKGROUND: The high mortality and morbidity rates after iliac vessel injuries remain a challenging problem for trauma surgeons. Several controversial issues surround the management of iliac vessel injuries, including the value of abbreviated laparotomy, the role of extra-anatomic bypass reconstruction (EABR), the use of vascular prostheses in the presence of contamination, and the need and timing for fasciotomy. METHODS: Retrospective review of the records of patients who sustained an injury to the iliac vessel between 1987 and 1996. RESULTS: A total of 64 patients were treated, including 23 with isolated iliac vein injuries, 17 with arterial injuries, and 24 with combined arteriovenous injuries. Vascular prostheses were placed in 17 patients with arterial injuries, including 12 with associated intestinal wounds. Graft infection did not occur. Of the 24 patients with combined injuries, 11 underwent abbreviated laparotomy and 1 died. Five deaths, however, occurred in 13 patients in whom no attempts were made for damage control laparotomy. Significant differences between survivors and nonsurvivors included final arterial pH, final prothrombin time, length of hypotension, and number of transfusions. Arterial ligation with EABR was performed in five patients and failed in two. Deep venous thrombosis and pulmonary embolism occurred in four patients, in three of them after venous injuries were ligated. The overall mortality rate was 23%. CONCLUSION: Our findings show that (1) abbreviated laparotomy reduces mortality in iliac injuries; (2) EABR should be performed early after stabilization to prevent limb ischemia; (3) the use of vascular prostheses with associated intestinal injuries did not appear to increase the incidence of graft infection; and (4) after vein ligation, early fasciotomy and prophylaxis against extremity swelling, deep venous thrombosis, and pulmonary embolism should be considered.

Adolescent↗
PubMed1998

Selective microvascular endothelial cell dysfunction in the small intestine following resuscitated hemorrhagic shock.

Following resuscitation (RES) from hemorrhagic shock (HEM), intestinal microvessels develop progressive vasoconstriction that impairs mucosal blood flow, despite central hemodynamic RES. These events might have clinical consequences secondary to occult intestinal ischemia. We hypothesized that the microvascular impairments were due to progressive endothelial cell dysfunction and an associated reduction in the dilator, nitric oxide (NO), following HEM/RES. Male Sprague-Dawley rats, were monitored for central hemodynamics and the terminal ileum was studied with in vivo videomicroscopy. HEM was 50% of baseline mean arterial pressure (MAP) for 60 min, and RES was with shed blood + 1 volume of normal saline (NS). Following HEM/RES, acetylcholine (10)(-7), 10(-5) M) was topically applied and ileal inflow (A1) and premucosal arteriolar diameters were measured to assess endothelial-cell function at 60 and 120 min post-RES. Normalization of MAP, cardiac output, and heart rate demonstrated adequate systemic resuscitation. Post-RES vasoconstriction developed in A1 (-25%) and premucosal (-28%) arterioles with an associated reduction in A1 flow (-47%). However, there was a selective impairment of endothelial-dependent dilation that was manifested only in the smaller premucosal arterioles and not in the inflow, A1 arterioles. This suggests that multiple mechanisms are involved in the development of the post-RES vasoconstriction. The premucosal response was likely mediated by endothelial cell dysfunction, while the A1 response was probably the result of enhanced vasoconstrictor forces. This early microvascular dysfunction might contribute to the late sequelae of intestinal ischemia and might alter microvascular responses to subsequent systemic insults.

Acetylcholine↗
PubMed1998

Human FGF-1 gene delivery protects against quinolinate-induced striatal and hippocampal injury in neonatal rats.

Fibroblast growth factors (FGFs) are cell mitogens and differentiating factors with neuroprotective properties in the CNS. We have already shown that endothelial cells genetically engineered to secrete human FGF-1 (RBEZ-FGF) survive implantation to neonatal rat brain (Johnston et al. (1996) J. Neurochem. 67, 1643-1652]. In this study, the effects of cell-based FGF-1 gene delivery on quinolinate-induced neurotoxicity in the developing rat brain were examined. Control endothelial cells (RBE4), and RBEZ-FGF cells were implanted into right striatum at post-natal day (PND) 7. On PND 10, quinolinate (150 nmol), an endogenous N-methyl-d-aspartate (NMDA) receptor agonist, or vehicle alone was injected into striatum ipsilateral to cell implantation. Injury was quantified in coronal sections obtained from PND 17 animals by comparing striatal and hippocampal volumes ipsilateral and contralateral to the site of quinolinate injection. Human FGF-1 specific transgene expression in vivo was shown by Northern blot and RT-PCR up to 14 days after cell implantation in control animals, and up to 4 days after quinolinate exposure. Quinolinate reduced the size of ipsilateral striatum by 37% and hippocampus by 38% in animals preimplanted with control endothelial cells. In contrast, quinolinate reduced the size of striatum by only 14% and had no effect on hippocampal size in animals preimplanted with RBEZ-FGF cells. Thus, FGF-1 gene delivery protected the developing striatum and hippocampus from quinolinate-induced volume loss by 62% and 100%, respectively. Intrastriatal quinolinate resulted in a significant decrease in density of NOS+ CA3 hippocampal neurons (-38%) without affecting the density of NOS+ neurons in hippocampal regions CA1, dentate gyrus or striatum. This response of CA3 NOS+ neurons appeared to be only partially reversed by FGF-1 gene delivery. Our results show that intracerebral FGF-1 gene expression within the developing brain can protect striatum and hippocampus from quinolinate-mediated injury.

Animals↗
PubMed1998

Impression materials and techniques for crown and bridgework: a survey of undergraduate teaching in the UK.

The aim of this study was to document the teaching of impression materials and techniques for crown and bridgework in the undergraduate curriculum in UK dental schools. A questionnaire sent to each school during the 1993/1994 academic year elicited fourteen replies (100% response). Addition-cured silicones were found to predominate; 71% of schools taught and used clinically a one-stage, full arch impression technique involving stock trays, and 57% of schools a full-arch custom tray technique. Routine disinfection of impressions was taught and practised in 43% of schools. The results demonstrated variation between UK dental schools in their teaching of impression materials and techniques for crown and bridgework in the undergraduate curriculum.

Crowns↗
PubMed1997

Heme oxygenase-dependent carbon monoxide production is a hepatic adaptive response to sepsis.

The hemodynamic effects of sepsis have been attributed in part to increased nitric oxide (NO) production and activation of guanylate cyclase, resulting in increased cGMP and relaxation of vascular smooth muscle. Heme oxygenase-1 (HO-1), a heat shock protein, has been shown to increase intracellular cGMP levels by formation of carbon monoxide (CO). We hypothesized that HO may be an important mediator of the hepatic response to infection. Male Swiss Webster mice underwent standard cecal ligation and puncture (CLP, 18 gauge 2X) or sham operation, and received either normal saline (NS) or Zn protoporphyrin IX (ZN PP IX), a competitive HO inhibitor (n = 6-8/group). Hepatic tissue samples were collected at 3, 6, 12, and 24 hr from separate mice. Serum was collected at 3 and 24 hr. A semiquantitative reverse transcriptase polymerase chain reaction method was used to measure HO-1 mRNA levels. Hepatic cGMP levels were measured by ELISA. Groups were repeated (n = 10/group) to assess mortality. Serum was collected at 3 and 24 hr to measure serum aspartate aminotransferase (AST) levels. HO-1 mRNA expression increased significantly by 3 hr after CLP and with HO inhibition alone (P < 0.05 vs sham + NS). HO-1 mRNA remained elevated through 24 hr. CLP animals with HO inhibition showed a significant reduction of hepatic cGMP following CLP compared with CLP + saline at 24 hr (P < 0.05). Mortality was significantly increased in the CLP + ZN PP group at 24 hr (P < 0.05 CLP NS vs CLP ZN PP). CLP caused a marked increase in AST activity, which was increased further with HO inhibition. HO-1 mRNA expression was induced by CLP. AST levels following CLP were markedly increased with HO inhibition. HO-1 function appeared to contribute to elevation of hepatic cGMP during peritonitis and may be an important hepatic adaptive response to infection.

Animals↗
PubMed1997

Mitogenic signalling by delta opioid receptors expressed in rat-1 fibroblasts involves activation of the p70s6k/p85s6k S6 kinase.

The regulation of mitogenic signalling pathways by G-protein-coupled receptors has been studied in Rat-1 fibroblasts stably transfected with the murine delta opioid receptor. We showed recently that stimulation of this receptor led to the activation of the p42 and p44 isoforms of mitogen-activated protein (MAP) kinase [Burt, Carr, Mullaney, Anderson and Milligan (1996) Biochem. J. 320, 227-235]. The present study has examined the role of the ribosomal S6 kinase p70(s6k) in mitogenic signalling by the delta opioid receptor. Treatment of Rat-1 fibroblasts expressing this receptor with the synthetic enkephalin [d-Ala,d-Leu]-enkephalin (DADLE) led to a dose-dependent increase in p70(s6k) enzyme activity. Activation of p70(s6k) was dependent on the level of delta opioid receptor expressed and was sustained above basal levels for several hours. Immunoblotting revealed that p70(s6k) was subject to increased phosphorylation, the extent of which coincided temporally with enzyme activation. Activation of p70(s6k) by DADLE, but not by platelet-derived growth factor, was blocked by pretreatment of cells with pertussis toxin. Activation of p70(s6k) was also partly blocked by wortmannin, indicating that phosphoinositide 3-OH kinase is required for full activation of p70(s6k) by opioid receptor agonists. Activation of the delta opioid receptor in transfected cells led to increased DNA synthesis. This increase was prevented by rapamycin, which also completely blocked activation of p70(s6k) by DADLE. In addition, prevention of the activation of p42 and p44 MAP kinases also blocked the induction of DNA synthesis by DADLE. These results suggest that the activation of both MAP kinases and p70(s6k) might be crucial to the induction of mitogenic responses by Gi-linked receptors such as the delta opioid receptor.

Androstadienes↗
PubMed1997

Lazaroids prevent acute cyclosporine-induced renal vasoconstriction.

BACKGROUND: Cyclosporine (CsA)-induced nephrotoxicity may be due to intrarenal vasoconstriction and glomerular hypoperfusion. Several factors, including endothelin and prostanoids, are suggested mediators of this response. Recent evidence suggests that CsA leads to increased oxygen-derived free radical (ODFR) production and lipid peroxidation in renal tissue. Whether this leads to alterations in renal vessel reactivity is unclear. Lazaroids, such as U74389G, are radical-quenching antioxidants that inhibit ODFR-induced lipid peroxidation and may improve renal function after ischemia and reperfusion. We hypothesized that ODFRs contribute to CsA-induced alterations of the renal microcirculation. METHODS: Rat hydronephrotic kidneys were studied by video microscopy. Interlobular arteriolar diameter and flow, afferent and efferent arteriolar diameters, and cardiac output were measured at 15-min intervals for 120 min. U74389G or its vehicle was infused 15 min before topical application of CsA to the kidney. The results were compared with U74389G alone and normal saline. RESULTS: CsA administration caused renal microvascular vasoconstriction (10-25% below baseline) and hypoperfusion (35% below baseline). Both vasoconstriction and hypoperfusion were significantly attenuated by U74389G (5-8% and 20% below baseline, respectively). CONCLUSIONS: Inhibition of lipid peroxidation by U74389G maintained renal blood flow during acute CsA administration. These data suggest that ODFRs are involved in the renal microvascular response to CsA. Inhibition of ODFR-induced lipid peroxidation may help prevent CsA-induced glomerular hypoperfusion. Lazaroids may prove an effective adjunct in reducing CsA-induced nephrotoxicity.

Animals↗