Regional haemodynamic responses to infusion of lipopolysaccharide in conscious rats: effects of pre- or post-treatment with glibenclamide

1. To determine the putative contribution of K(ATP)-channels to the haemodynamic sequelae of endotoxaemia, three experiments were carried out in different groups of conscious, chronically-instrumented, unrestrained, male Long Evans rats. 2. In the first experiment, pretreatment with the K(ATP)-channel antagonist, glibenclamide, abolished the initial hypotension, but not the renal vasodilatation caused by LPS infusion. Subsequently, however, in the presence of glibenclamide and LPS there was a significant increase in mean arterial blood pressure, and a bradycardia, in contrast to the fall in mean arterial blood pressure and the tachycardia seen in the presence of vehicle and LPS. The pressor and bradycardic changes in the presence of glibenclamide and LPS were accompanied by significant reductions in hindquarters flow and vascular conductance, and these were significantly greater than those seen in the presence of vehicle and LPS, or glibenclamide and saline. 3. Administration of glibenclamide 6 h after the onset of saline and LPS infusion, or 6 h after the onset of saline and LPS infusion in the presence of the AT(1)-receptor antagonist, losartan, and the ET(A)-, ET(B)- receptor antagonist, SB 209670, in the absence or presence of dexamethasone, caused a significant increase in mean arterial blood pressure and reductions in renal, mesenteric and hindquarters conductances, although the latter was the only vascular bed in which there was a reduction in flow. 4. The results are consistent with a contribution from K(ATP)-channels to the vasodilatation caused by LPS, particularly in the hindquarters vascular bed.     

Cardiovascular responses to angiotensins I and II in normotensive and hypertensive rats; effects of NO synthase inhibition or ET receptor antagonism

1. We compared the cardiovascular responses to angiotensins (I and II), and any possible modulatory influences thereupon of nitric oxide (NO) or endothelin (ET) in conscious male, normotensive, Hannover Sprague-Dawley (SD) rats, and hypertensive, heterozygous ((mRen-2)27), transgenic (TG) rats. 2. The pressor effects of angiotensin I or of angiotensin II were not consistently different in SD and TG rats. The accompanying absolute reductions in renal and mesenteric vascular conductances were smaller in TG rats, but probably due to the baseline vasoconstriction in those animals. 3. Inhibition of NO synthase with L-NAME had no significant effects on the pressor responses to angiotensin I or angiotensin II in either SD or TG rats. L-NAME reduced the absolute, but not percentage, reductions in renal and mesenteric vascular conductances in response to angiotensin I and angiotensin II. L-NAME abolished the hindquarters vasodilator effects of angiotensin I and angiotensin II in both strains of rat. 4. ET receptor antagonism (with SB209670) had no significant influence on the pressor or renal or mesenteric vasoconstrictor effects of angiotensin II in SD rats. In TG rats, the pressor responses to angiotensin II were unaffected by SB209670; the accompanying falls in renal and mesenteric vascular conductances were enhanced in absolute, but not in percentage terms. 5. These results provide no evidence for a buffering action of NO, or a modulatory influence of ET, on the pressor or vasoconstrictor effects of angiotensin I and/or angiotensin II in SD rats. Furthermore, there is no evidence for an altered sensitivity to angiotensin I or angiotensin II, and no evidence for a differential modulatory influence of either NO or ET in TG, compared to SD, rats.     

Enhanced pulmonary epithelial replication and axial airway mucosubstance changes in F344 rats exposed short-term to mainstream cigarette smoke

Cigarette smoking is associated with respiratory diseases that may be caused by injury to specific pulmonary cells. The injury may manifest itself as site-specific enhanced cellular replication. In this study, rats were exposed either to mainstream cigarette smoke (CS; 250 mg total particulate matter/m(3)) or to filtered air (FA) for 6 h/day, 5 days/week, for 2 weeks. In one group, cells in S-phase were labeled over 7 days by bromodeoxyuridine (BrdU) released from implanted osmotic pumps (pump labeled), while another group received BrdU by injection 2 h prior to necropsy (pulse labeled). Morphometry showed that the type II epithelial BrdU labeling index (LI) was significantly elevated in the CS-exposed animals of both labeling groups. The axial airway and terminal bronchiolar LIs were enhanced by CS only in the pump-labeled group. In a third group (pulse labeled), 2 weeks of recovery following exposure to CS allowed a normalization in the type II LI. In the pump-labeled rats, the CS-induced elevation of the type II LI was greater than the LI elevation in conducting airways, suggesting that the parenchyma may have been injured more than the conducting airways. The terminal bronchiolar LI in the pump-labeled group, regardless of exposure, was significantly greater than the axial airway LI. Pump labeling, in contrast to pulse labeling, could therefore discern differences among replication rates of conducting airway epithelium in different regions of the lung. Mucosubstance (MS) within the axial airway epithelium was quantified by morphometry. The CS exposure did not increase the total number of MS-containing cells or the total number of axial airway epithelial cells, but there was a phenotype change in the MS cells. Neutral MS cells (periodic acid-Schiff-positive) were significantly decreased, while acid MS cells (alcian blue-positive) were slightly increased by CS exposure. Either cell replication and differentiation or differentiation alone may have changed the phenotype in the MS cell population.     

Hysteroscopy.

Hysteroscopy is a "new" endoscopic approach for the gynecologist. The development and refinement of the sophisticated fiberoptic light system can illuminate the darkness of the uterine cavity. Polyps can be differentiated from submucous myomas; intrauterine adhesions can be accurately "mapped" and classified, with synechiae lysed under direct vision; endometrial carcinoma can be diagnosed and possibly staged; embedded intrauterine devices can be identified and dislodged; the wastebasket diagnosis of "dysfunctional uterine bleeding" can be cleaned up; submucosal myomas and uterine septa can be resected; and successful transuterine sterilization may become a reality. If culdoscopy is menopausal and laparoscopy in its reproductive years, hysteroscopy is certainly in its infancy.     

Early increase of peripheral B cell levels in kidney transplant recipients with CMV infection or reactivation

BACKGROUND: Cytomegalovirus (CMV) infection or reactivation is a frequent complication of renal transplantation. Diagnosis of these conditions relies on the detection of circulating antigen, or of specific IgM and/or IgG, which develop over several weeks. Evocative clinical features may be detected earlier, but lack specificity. Rapid and early changes in the partition of lymphocyte subsets could be an additional indication of pending CMV infection. METHODS: A systematic follow-up of peripheral B lymphocytes identified immunophenotypically by the determination of surface immunoglobulins (sIg), performed in 97 kidney transplant recipients, allowed to identify transient increases apparently predictive of CMV primo-infection or reactivation over the next 3 months. To better define the nature of these B cells, an extended investigation was performed for 14 prospective patients. In addition to surface Ig, membrane CD19, HLA-DR, and CD80 expression were explored. The cytoplasmic presence of mu, kappa, and lambda chains was also examined. B cell function was investigated using the ELISPOT technique, which allows an enumeration of the populations of IgG, IgA, and IgM secreting B cells. RESULTS: Retrospective analysis of the clinical outcome of the cohort of 97 patients evidenced that early transient increases in B cell levels were significantly (P<0.0001) associated with CMV infection. The same trend was noted in the smaller series of patients who benefited from a more extensive investigation of B cells, 10 of whom presented clinical or biological signs of CMV infection. Mature B cells, expressing surface Ig, CD19, DR, and CD80 are those presenting transient increases. No significant variation of preB (cmu+/kappalambda-) or activated (spot-forming) cells was evidenced in these patients. CONCLUSION: Individual examination of each patient's immune reconstitution profile allows to detect transient peaks of mature B cell during the initial immunosuppressive therapy, that appear to be predictive of oncoming CMV infection or reactivation.     

Chronic inhalation exposure to mainstream cigarette smoke increases lung and nasal tumor incidence in rats.

An animal model of lung carcinogenicity induced by chronic inhalation of mainstream cigarette smoke would be useful for research on carcinogenic mechanisms, smoke composition-response relationships, co-carcinogenicity, and chemoprevention. A study was conducted to determine if chronic whole-body exposures of rats would significantly increase lung tumor incidence. Male and female F344 rats (n = 81 to 178/gender) were exposed whole-body 6 h/day, 5 days/week for up to 30 months to smoke from 1R3 research cigarettes diluted to 100 (LS) or 250 (HS) mg total particulate matter/m(3), or sham-exposed to clean air (C). Gross respiratory tract lesions and standard lung and nasal sections were evaluated by light microscopy. A slight reduction of survival suggested that the HS level was at the maximum tolerated dose as commonly defined. Cigarette smoke exposure significantly increased the incidences of non-neoplastic and neoplastic proliferative lung lesions in females, while nonsignificant increases were observed in males. The combined incidence of bronchioloalveolar adenomas and carcinomas in females were: HS = 14%; LS = 6%; and C = 0%. These incidences represented minima because only standard lung sections and gross lesions were evaluated. Mutations in codon 12 of the K-ras gene occurred in 4 of 23 (17%) tumors. Three mutations were G to A transitions and one was a G to T transversion. The incidence of neoplasia of the nasal cavity was significantly increased at the HS, but not the LS level in both males and females (HS = 6%, LS = 0.3%, C = 0.4% for combined genders). These results demonstrate that chronic whole-body exposure of rats to cigarette smoke can induce lung cancer.