Galanin receptor 3--a potential target for acute pancreatitis therapy.

BACKGROUND: Galanin participates in the pathogenesis of acute pancreatitis (AP). The galanin receptor (GALR) sub-types involved, however, are unclear. We aimed to determine GALRs messenger RNA (mRNA) expression in mouse pancreas, describe their localization, and ascertain if GALR2 and GALR3 are involved in AP. METHODS: Galanin receptor expression in murine whole pancreas, acinar, and islet cells was quantified by polymerase chain reaction amplification of reverse-transcribed RNA for mRNA, Western blot analysis for protein and in situ hybridization for GALR localization. Isolated acinar cells were used to determine galanin's effect on amylase secretion. Acute pancreatitis was induced in mice by caerulein injections. Mice, with and without AP, were treated with the highly selective GALR2 antagonist M871, or the specific GALR3 antagonist SNAP-37889. Indices of AP were measured at 12 h. KEY RESULTS: Murine pancreas expresses mRNA for GALRs. In islets the expression of all GALR are comparable, whereas in acinar cells GALR3 is predominantly expressed. Western blot analysis confirmed that the GALR proteins are expressed by acinar cells. In situ hybridization analysis confirmed that GALR3 mRNA is present in islet and acinar cells, while mRNA for GALR1 and 2 is confined to islets. Galanin did not influence basal and caerulein-stimulated amylase release from acinar cells. M871 treatment reduced some, whereas SNAP-37889 treatment reduced all indices of AP (by 40-80%). CONCLUSIONS & INFERENCES: Galanin receptor mRNA and protein are expressed in mouse pancreas, with GALR3 mRNA predominating. GALR3 antagonism reduced the severity of AP whereas GALR2 antagonism was less effective. GALR3 is a potential target for treatment of AP.

Galanin receptor antagonist m35 but not m40 or c7 ameliorates cerulein-induced acute pancreatitis in mice.

BACKGROUND/AIMS: We compared the galanin antagonists C7, M35, M40 and galantide, for their ability to ameliorate acute pancreatitis (AP). METHODS: Galanin antagonists were co-administered with 7 hourly cerulein injections used to induce AP. Plasma amylase and lipase activities were measured as indices of AP, and pancreata were harvested at 12 h for histological examination and estimation of myeloperoxidase (MPO) activity. RESULTS: Treatment with galantide, M35 and C7 ameliorated the AP-induced plasma hyperenzymemia by 40-75%. Administration of M40 did not significantly alter plasma hyperenzymemia. Galantide, M35 and M40 significantly reduced the pancreatic MPO activity by 65-80%, whereas C7 increased MPO activity. Galantide and M35 but not C7 or M40 treatment significantly reduced the AP-induced necrosis score by 30-50% compared to the AP alone group. C7 alone increased plasma lipase activity and the pancreatic necrosis score compared with saline treatment alone, whereas the other antagonists were without effect. CONCLUSION: Galantide and M35 ameliorated the severity of AP, but M40 and C7 had mixed effects. Complex galanin pathways may be involved in cerulein-induced AP. M35 and galantide are potential therapeutic peptides for the treatment of AP and further evaluation should be considered. and IAP.

A virtual reality 3D jigsaw for teaching anatomy.

Virtual Reality has some advantages over traditional teaching and learning media. Here we describe a VR Jigsaw which uses a novel interface to facilitate learning the anatomy of the skull. A small trial was performed which indicates that the software succeeds at engaging students and suggests that their comprehension of complex 3D structures was improved.

Sphincter of Oddi function in the Australian brush-tailed possum is inhibited by intragastric ethanol.

The role of sphincter of Oddi (SO) function in alcoholic acute pancreatitis (AP) is unclear. We aimed to compare the effect of i.v. and intragastric (IG) ethanol on SO function (i.e. trans-sphincteric flow; TSF) and investigate possible neural mechanisms. The involvement of gastric mucosal damage was also investigated by pretreatment with pantoprazole. In anaesthetized Australian possums, blood pressure (BP), TSF and blood ethanol concentrations were measured after i.v. or IG ethanol. Possums were subjected to acute vagotomy, atropine, L-nitro arginine methyl ester (L-NAME) or pantoprazole pretreatment prior to IG ethanol. BP was not significantly altered by ethanol. Ethanol decreased TSF in a dose and route-dependent manner. The lowest dose of IG ethanol reduced TSF but this response was not duplicated by i.v. ethanol producing the same blood ethanol concentrations. Acute vagotomy, atropine or L-NAME pretreatment blocked the ethanol-induced decrease in TSF and simultaneously suppressed the blood ethanol concentration. Pantoprazole pretreatment reduced the TSF response and blood ethanol concentrations implicating mechanisms induced by gastric mucosal damage. We conclude that ethanol (and/or its metabolites) reduces TSF via humoral and neural mechanisms involving vagal pathways, muscarinic receptors and nitric oxide. Reduced TSF could contribute to the onset of AP.

A systematic review of common conservative therapies for arm lymphoedema secondary to breast cancer treatment.

Secondary arm lymphoedema is a chronic and distressing condition which affects a significant number of women who undergo breast cancer treatment. A number of health professional and patient instigated conservative therapies have been developed to help with this condition, but their comparative benefits are not clearly known. This systematic review undertook a broad investigation of commonly instigated conservative therapies for secondary arm lymphoedema including; complex physical therapy, manual lymphatic drainage, pneumatic pumps, oral pharmaceuticals, low level laser therapy, compression bandaging and garments, limb exercises and limb elevation. It was found that the more intensive and health professional based therapies, such as complex physical therapy, manual lymphatic drainage, pneumatic pump and laser therapy generally yielded the greater volume reductions, whilst self instigated therapies such as compression garment wear, exercises and limb elevation yielded smaller reductions. All conservative therapies produced improvements in subjective arm symptoms and quality of life issues, where these were measured. Despite the identified benefits, there is still the need for large scale, high level clinical trials in this area.

The effect of gentle arm exercise and deep breathing on secondary arm lymphedema.

The aim of this study was to explore the benefits of gentle arm exercise combined with deep breathing for secondary arm lymphedema. 38 women participated in 10 minutes of standardized arm exercise and deep breathing and were measured every 10 minutes for 1 hour, then 24 hours and 1 week post regime. A smaller cohort of 24 women continued the 10 minute exercise regime morning and evening for 1 month, with measurements being repeated at the end of this time. Directly after performing the regime, there was a reduction in arm volume of 52 mls (5.8%), with the reduction being sustained at 30 minutes (50 mls, 5.3%). Even though participants were told not to further do the exercise, at 24 hours the volume reduction was 46 mls (4.3%) and at 1 week, 33 mls (3.5%). At the one month follow-up, the reduction was 101 mls (9.0%). All reductions were statistically significant. Reported arm heaviness and tightness also statistically significantly decreased directly after the regime with the reduction in tightness being sustained at 24 hours. The reduction in heaviness was sustained at 24 hours, 1 week, and even one month after the program. Perceived limb size was significantly reduced at 1 week and at the 1 month follow-up. There was also a significant improvement in the anterior thorax tonometry reading at the 1 month follow-up.

Endothelial distribution of the membrane water channel molecule aquaporin-1: implications for tissue and lymph fluid physiology?

BACKGROUND: Aquaporin-1 (AQ-1) is a transmembrane water channel protein reportedly expressed in continuous capillary endothelium and intestinal lacteals. We investigated endothelial AQ-1 expression in rat intestine and mesentery, and also in lymph nodes. METHODS AND RESULTS: Rat intestine, mesentery, and lymph nodes were immunolabeled for AQ-1, revealing membrane expression in endothelial cells of vascular continuous capillaries and venules, and of initial and conducting lymphatics. Blood vessel profiles were identified with RECA-1 and circulating FITC-albumin. In nodes, capillaries and high endothelium venules (HEVs) showed AQ-1 labeling, as did intranodal lymphatic sinusoidal endothelium and reticular cells. CONCLUSIONS: The labeling pattern of vessels with RECA-1, AQ-1, circulated FITC albumin, plus elastin autofluorescence permitted identification of arteriolar, continuous, and fenestrated capillaries and lymphatic vessels in tissue sections. Strong AQ-1 expression in continuous microvascular and initial lymphatic endothelium suggests its possible involvement in tissue fluid exchange between plasma and interstitial fluid, and perhaps between interstitial fluid and initial lymph. Endothelial AQ-1 expression was strong in lymphatic sinusoidal endothelium and intense in HEVs. This described endothelial AQ-1 expression has potential implications for tissue fluid physiology. Lymph protein is known to concentrate in lymph nodes by fluid loss, so AQ-1 may facilitate lymph to plasma water flux. Starling forces may not drive this flux, and we discuss a possible osmotic mechanism; consequently we hypothesize a suite of ion pumps/channels/exchangers/cotransporters in nodal vascular (probably HEV) endothelium, acting as a net ion pump from lymph to plasma, with water following osmotically.

Effects of acute pancreatic duct obstruction on pancreatic perfusion: implication of acute pancreatic duct decompression.

BACKGROUND: Acute pancreatitis can result in pancreatic ischaemia and necrosis. Pancreatic duct (PD) obstruction may be the first step causing ischaemia in acute pancreatitis. Nitric oxide donors can attenuate acute pancreatitis through improvement in compromised pancreatic perfusion (PP). In this study, we determined if (1) PD obstruction altered PP and (2) PD decompression or L-arginine administration reversed this change. METHODS: Fifteen Australian possums were randomly assigned to two groups: Animals in group A (n = 6) were subjected to 30 min of PD obstruction and 60 min of PD decompression. Animals in group B (n = 9) were subjected to 120 min PD ligation and 60 min PD decompression. A subset group B (n = 6) were subjected to intravenous L-arginine (100 microg/kg) at the end of 120 min of ligation and at the end of PD decompression. The PP (Laser Doppler fluxmetry), PD pressure and blood pressure were continuously monitored. RESULTS: PD pressure increased from 2.9 +/- 2.5 to 18.1 +/- 4.9 mmHg following PD ligation. PP was reduced to 67.1% +/- 4.5% (P<0.01) and 46.2% +/- 7.5% (P<0.001) of baseline following 30 and 120 min of PD ligation, respectively. Following 60 min of PD decompression, PP was restored to 89.1% +/- 13.4% (P<0.02) of the baseline in the 30-min group. However, following 120 min PD ligation, PP remained depressed. L-arginine administration after 120 min of PD ligation transiently increased PP from 46.2% +/- 7.5% to 81.1% +/- 8.6% (P<0.03) of baseline. This effect was reproduced if L-arginine was administered at the end of decompression (P<0.05). CONCLUSION: In patients with acute pancreatitis due to obstructive causes, early decompression of the PD may prevent early pancreatic ischaemia.

Aquaporin-1 expression in visceral smooth muscle cells of female rat reproductive tract.

The aquaporins (AQ-s) are a group of intrinsic membrane proteins which facilitate movement of water across cell membranes; their recent identification in the kidney has led to the reappraisal of the mechanisms and pathways of water movement across epithelia. Aquaporin-1, (CHIP-28) is reported distributed in cardiac myocytes and vascular smooth muscle cells of large arteries. A related protein, AQ-4, has been identified in the sarcolemma of skeletal muscle fibres. We report aquaporin expression in the cell membrane of smooth muscle cells of the rat genital tract; fluorescence immunohistochemistry of rat uterine (fallopian) tube and vagina demonstrated AQ-1 in visceral smooth muscle of these tissues. In the uterine tube, AQ-1 labelling is most pronounced in the innermost longitudinal and the inner cells of the circular muscle layer and is absent from the outer longitudinal muscle layer of the myosalpinx. The possibility of a specific role for AQ-1 in tubal transport by altering the tubal luminal diameter during the estrus cycle is suggested.

Human endometrial perfusion after tubal occlusion.

We examined variations in human endometrial microvascular perfusion across one menstrual cycle in women who had undergone tubal ligation and did not report unusual menstruation. Endometrial red blood cell flux was monitored by laser Doppler fluxmetry via a fibreoptic probe atraumatically inserted transvaginally into the uterus of each of 13 conscious volunteers. The observations obtained have been compared with those previously reported from a matched control group of women [B.J. Gannon et al., Hum. Reprod., 12, 132-139 (1997)]. Women who had undergone tubal occlusion for sterilization exhibited greater endometrial perfusion during menstruation (cycle days 0-5), at the time of ovulation (cycle days 13-16) and in the late secretory phase (cycle days 23-28) than occurred in controls. In addition, vasomotion in the study group was lower than that in controls in the early and late secretory phase (cycle days 17-22 and 23-28). Tubal occlusion appeared to alter endometrial perfusion. It is possible that the reported menstrual changes in women following tubal ligation are a consequence of altered endometrial perfusion; a possible causative relationship is discussed.

PIP: Tubal ligation has been associated with an increase in postsurgical dysmenorrhea or menorrhagia. The present study used laser Doppler fluximetry to measure endometrial perfusion in 13 South Australian women who had undergone tubal ligation an average of 5.7 years earlier and did not report subsequent menstrual dysfunction. This technique provides a measure of the flux of red blood cells through a small sphere of tissue immediately adjacent to a probe placed over the endometrium. Measurements were taken once a week over 4 weeks (usually 1 menstrual cycle) and were compared with those obtained earlier by the authors from a matched control group of 19 women. Women who had undergone tubal occlusion exhibited greater endometrial perfusion than controls during menstruation (cycle days 0-5), at the time of ovulation (cycle days 13-16), and in the late secretory phase (cycle days 23-28). In addition, vasomotion was lower in the study group than among controls in the early (cycle days 17-22) and late (cycle days 23-28) secretory phase. Further exploration of the potential pathophysiology associated with tubal sterilization is warranted.

Endometrial perfusion across the normal human menstrual cycle assessed by laser Doppler fluxmetry.

This study investigated variations in microvascular perfusion of human endometrium across the menstrual cycle, using a laser Doppler technique to assess red blood cell (RBC) flux. Endometrial RBC flux was monitored by laser Doppler fluxmetry via a fibre optic probe inserted transvaginally into the uteri of 19 conscious normal volunteer women, on four occasions at weekly intervals over one menstrual cycle. Regional variation in RBC flux was investigated in 16 surgical patients under general anaesthesia and in five excised uteri. Endometrial perfusion exhibited short-term temporal variations consistent with the cardiac cycle and often also showed vasomotion (5-12 cycles/min). Mean endometrial perfusion differed between phases of the menstrual cycle in conscious women, being highest during early proliferative and early follicular phases. There were no significant regional differences in local mean endometrial perfusion in anaesthetized patients. No evidence of endometrial ischaemia/reperfusion episodes was found in any subject using this technique. This study provides benchmark data of variations in RBC flux per unit volume of tissue in the luminal approximately 1 mm of endometrium, across the normal human menstrual cycle. Flux values were highest at times associated with endometrial growth and preparation for implantation, indicating that RBC flux may be a useful parameter for assessment of endometrial physiology.

The effects of radiation on the contractile activity of guinea pig mesenteric lymphatics.

In order to assess the effects of irradiation on lymphatic function, the contraction frequency and maximum and minimum diameters of guinea pig mesenteric collecting lymphatic vessels were measured in vivo 4 hours after 1000 rads of abdominal irradiation. The mean contraction frequency for lymphatics from irradiated guinea pigs (7.6 +/- 0.7) was significantly higher than for normals (non-irradiated) (4.7 +/- 0.7) during an initial control observation period, but there was no difference in maximum or minimum diameter between the two groups during this period. Topical application of 10(-4) M noradrenaline (NA) significantly increased contraction frequency in both groups; lymph vessel diameter significantly decreased after NA in irradiated, but not in normal guinea pigs. Intravenous infusion of calcium dobesilate (200 mg/kg) caused a significant increase in the contraction frequency of lymphatic vessels in both normal (to 9.4 +/- 1.5) and irradiated (to 9.8 +/- 1.2) animals, but diameter was not significantly altered. Thus, lymphatic vessels from irradiated guinea pigs were still responsive to exogenous stimuli 4 hours post-irradiation and were initially pumping more actively than those from normal guinea pigs, presumably in response to radiation-induced edema. They also exhibited a supersensitivity to the vasoconstrictive effects of NA, perhaps due to an alteration of the pacemaker or smooth muscle cells by irradiation.

Effect of carbon monoxide intoxication on skin perfusion in anaesthetized rats.

Carbon monoxide intoxication decreases systemic blood pressure and peripheral resistance. In order to assess the role of the skin in this process, we measured the perfusion of hind limb shaven skin in anaesthetized rats during acute moderate carbon monoxide intoxication. At a steady blood level of 25% carboxyhaemoglobin, the red blood cell flux was measured as an index of tissue perfusion, using laser Doppler fluxmetry. The mean blood pressure decreased by 30% during carbon monoxide exposure, but there was no change in mean red blood cell flux of the hind limb skin microvessel bed. Thus, rat hind limb skin perfusion was not affected by acute moderate steady state carbon monoxide intoxication.

The physiology of penile erection.

Erection of the penis results from increase in blood flow into the corpora. The blood flows through the corpus spongiosum and glans which increase in volume, whereas the blood becomes trapped in the corpus cavernosum which becomes rigid as the pressure increases. The protrusion of the penis may be aided by relaxation of the retractor penis muscle. The major erectile fibres lie in the pelvic nerve and anti-erectile fibres in the sacral sympathetic outflow. The hypogastric nerves may contain both nerve types but there is considerable species and individual variation. The neurotransmitters mediating erection have yet to be determined. There is some evidence that acetylcholine is involved in the increase in blood flow through the corpus spongiosum but not in the corpus cavernosum. Vasoactive intestinal peptide may also have a role. It is possible that these and other substances interact to control the complete process. Erection is inhibited by noradrenaline released from sympathetic nerves, and this acts mainly on alpha-1 adrenoceptors within the penis and on the retractor penis muscle. During tumescence blood flows into the sinusoids from the helicine arterioles which supply them. The sinusoids become dilated due to relaxation of smooth muscle within the trabeculae. Blood may also be redirected from anastomoses between the dorsal arteries and corpus spongiosum through other helicine arterioles supplying the sinusoids of the corpus cavernosum. The significance of polsters (smooth muscle projections into the blood vessel lumen) remains controversial. Occlusion of venous drainage from the corpora cavernosa is both passive (due to increased corpus cavernosum pressure) and active. Relaxation of trabecular smooth muscle may also modify blood flow through the corpora cavernosa.

Treatment of impotence by intrapenile injections. A comparison of papaverine versus papaverine and phentolamine: a double-blind, crossover trial.

The efficacy of papaverine, and a combination of papaverine and phentolamine as a pharmacological treatment of impotence was compared in a double-blind, crossover trial. A total of 40 impotent men received intracavernous injections of papaverine (40 mg.) or a combination of papaverine (20 mg.) and phentolamine (0.5 mg.) at monthly intervals. Observations at 20 minutes after injection demonstrated that papaverine caused full erections in 27 per cent of the men and partial erections in 65 per cent. The combined injection resulted in full erections in 48 per cent of the men and 52 per cent had partial erections. The difference was significant (Z equals 2.29, p less than 0.05).

Responses of erectile tissue from impotent men to pharmacological agents.

Erectile tissue was removed from the corpora cavernosa of 25 impotent men undergoing surgery for insertion of penile prostheses. Strips, set up in an organ bath, were contracted by the alpha-adrenergic agonist phenylephrine. There was no significant difference between tissue taken from men with diabetes, alcoholism, Peyronie's disease or men with no obvious condition causing the impotence. The sensitivity of tissues from hypertensive patients was significantly reduced but this was probably due to drugs being taken for hypertension. Precontracted tissues could be relaxed by acetylcholine or isoprenaline. The responses, however, were inconsistent, so that no difference between the different groups of patients was apparent.

Treatment of impotence by intrapenile injections of papaverine and phenoxybenzamine: a double blind, controlled trial.

The efficacy of papaverine and phenoxybenzamine as a pharmacological treatment of impotence was compared in a double blind, crossover, placebo controlled trial. Thirty-four impotent men received intra-cavernosal injections of papaverine (60 mg), phenoxybenzamine (6 mg) or normal saline (10 ml) at monthly intervals. Observations by EJK up to 45 minutes after injection demonstrated that papaverine caused full erections in 35% of men and partial erections in 62%. Phenoxybenzamine injection resulted in full erections in 20% of men and 62% had partial erections. The differences were not significant. Despite 82-97% of patients attaining some degree of erection in the clinical setting only six of the patients decided to use this mode of treatment for more than three months. Sexual function during the month after injection was better with either drug when compared with placebo.

Experience in the management of erectile dysfunction using the intracavernosal self-injection of vasoactive drugs.

We report the results of a survey of 75 patients with erectile dysfunction, all of whom were treated by self-injection of the corpora cavernosa with vasoactive agents. At the time of the survey each patient had been self-injecting at home for at least 3 months. Of the patients 62 were followed for 3 to 21 months. Patients used this form of treatment with minimal assistance from our clinic staff. It was acceptable to them with few complications except for prolonged erections in 11 per cent of the men. Fifteen patients (24 per cent) with psychogenic impotence reported spontaneous improvement in erections during treatment and 4 discontinued treatment for this reason. Another 26 patients (42 per cent) continue to use self-injection as the definitive mode of treatment for erectile dysfunction.

Prolonged erections following intracorporeal injection of medications to overcome impotence.

We describe the management of 17 men who developed prolonged erections following the intracorporeal injection of vasoactive drugs (e.g. papaverine) for the treatment of erectile dysfunction. Twelve men who had psychogenic impotence developed prolonged erections following injection compared with 5 who had an organic aetiology. The aspiration of 20 to 50 ml of blood from the penis together with the intracorporeal injection of 1 to 2 mg metaraminol is an effective treatment of this complication.

Vascular changes during penile erection in the dog.

1. The vascular effects of pelvic nerve stimulation on the penis were studied in dogs anaesthetized with sodium pentobarbitone and halothane. Changes in pressure and blood flow were measured through scalp vein needles inserted into the erectile bodies. 2. The penis contains two types of erectile body, which responded independently during erection induced by pelvic nerve stimulation. Pressure in the corpus spongiosum increased immediately upon stimulation, but only reached one-third of the more delayed pressure response of the corpora cavernosa. 3. At rest, arterial inflow resistance into the corpora cavernosa was high, whereas venous outflow resistance was low. Pelvic nerve stimulation (10-50 V, 10-16 Hz, 1 ms) caused an immediate increase in arterial flow, an increase in corpus cavernosal pressure (CCP), and a decrease in venous outflow. Saline infusion experiments showed there was active venous occlusion. Upon cessation of stimulation, these parameters returned to pre-stimulation levels. 4. The time taken to reach 50% of maximum change in arterial inflow was significantly less than for CCP, which was significantly less than for venous outflow. Occlusion of the aorta 1 min after cessation of stimulation decreased the pressure in the arterial tree supplying the corpora cavernosa, but CCP remained elevated, indicating that both inflow and outflow resistances were high. Thus, inflow resistance had returned to its pre-stimulation state before outflow resistance. 5. Direct measurements of blood flow through the corpus cavernosum were made with a hydrogen probe. There was a transient increase in blood inflow as CCP increased during pelvic nerve stimulation. There was some blood flow while CCP was elevated, indicating that the venous occlusion was not complete. 6. Sympathetic chain stimulation caused an increase in arterial resistance, and a decrease in CCP and venous resistance. 7. Infusions of acetylcholine (330 micrograms min-1) and vasoactive intestinal polypeptide (1-3.3 micrograms min-1) decreased arterial resistance and increased CCP and venous resistance. 8. This study suggests that during pelvic nerve-induced erection, arterial flow into the corpus cavernosum increases, followed by an increase in CCP and an actively controlled decrease in venous outflow.(ABSTRACT TRUNCATED AT 400 WORDS)