Aldosterone has been suggested to elicit vessel contraction via a nongenomic mechanism. We tested this proposal in microdissected, perfused rabbit renal afferent arterioles. Aldosterone had no effect on internal diameter in concentrations from 10(-10) to 10(-5) mol/L, but aldosterone abolished the ability of 100 mmol/L KCl to induce vascular contraction. The inhibitory effect of aldosterone was observed from 1 pmol/L. The inhibitory effect was significant after 5 minutes and maximal after 20 minutes and was fully reversible. Actinomycin D (10(-6) mol/L) prolonged the effect of aldosterone. The effect was abolished by the mineralocorticoid receptor antagonist spironolactone (10(-7) mol/L) but not by the glucocorticoid receptor antagonist mifepristone (10(-6) mol/L). The K+-mediated increase of intracellular calcium concentration in afferent arterioles was not affected by aldosterone. Mineralocorticoid receptor was detected by reverse transcription-polymerase chain reaction and immunohistochemistry in rat renal vasculature and rabbit endothelial cells. Inhibition of phosphatidylinositol (PI)-3 kinase with LY 294002 (3x10(-6) mol/L) restored sensitivity to K+ in the presence of aldosterone, and afferent arterioles were immunopositive for PI-3 kinase subunit p110alpha. Inhibition of NO formation by L-NAME (10(-4) mol/L) or inhibition of soluble guanylyl cyclase with 1H-(1,2,4)Oxadiazolo[4,3-a]quinoxaline-1-one restored K+-induced vasoreactivity in the presence of aldosterone. Similar to aldosterone, the NO donor sodium nitroprusside inhibited K+-induced vascular contraction. Geldanamycin (10(-6) mol/L), an inhibitor of heat shock protein 90, abolished aldosterone-induced vasorelaxation. We conclude that aldosterone inhibits depolarization-induced vasoconstriction in renal afferent arterioles by a rapid nongenomic mechanism that is initiated by mineralocorticoid receptor activation and involves PI-3 kinase, protein kinase B, and heat shock protein 90-mediated stimulation of NO generation.

No abstract

Objectives To compare patient reported outcomes from before surgery to 52 weeks after surgery between individuals undergoing arthroscopic partial meniscectomy for traumatic meniscal tears and those for degenerative meniscal tears. Design Comparative prospective cohort study. Setting Four public orthopaedic departments in the Region of Southern Denmark. Participants were recruited between 1 February 2013 and 31 January 2014, and at one of the original four hospitals from 1 February 2014 to 31 January 2015. Participants Individuals selected from Knee Arthroscopy Cohort Southern Denmark, aged 18-55, and undergoing arthroscopic partial meniscectomy for a traumatic or degenerative meniscal tear (defined by a combination of age and symptom onset). Interventions Both participant groups underwent arthroscopic partial meniscectomy for a meniscal tear, with operating surgeons recording relevant information on knee pathology. Patient reported outcomes were recorded via online questionnaires. Main outcome measures Primary outcome was the average between-group difference in change on four of five subscales of the knee injury and osteoarthritis outcome score (KOOS). The four subscales covered pain, symptoms, sport and recreational function, and quality of life (KOOS4). A 95% confidence interval excluding differences greater than 10 KOOS points between groups was interpreted as absence of a clinically meaningful difference. Analyses adjusted for age, sex, and body mass index. Results 397 eligible adults (42% women) with a traumatic or degenerative meniscal tear (n=141, mean age 38.7 years (standard deviation 10.9); n=256, 46.6 years (6.4); respectively) were included in the main analysis. At 52 weeks after arthroscopic partial meniscectomy, 55 (14%) patients were lost to follow-up. Statistically, participants with degenerative meniscal tears had a significantly larger improvement in KOOS4 scores than those with traumatic tears (adjusted between-group difference −5.1 (95% confidence interval −8.9 to −1.3); P=0.008). In the analysis including KOOS4 score at all time points, a significant time-by-group interaction was observed in both the unadjusted (P=0.025) and adjusted analysis (P=0.024), indicating better self-reported outcomes in participants with degenerative tears. However, the difference between groups was at no time point considered clinically meaningful. Conclusions These results question the current tenet that patients with traumatic meniscal tears experience greater improvements in patient reported outcomes after arthroscopic partial meniscectomy than patients with degenerative tears. Trial registration ClinicalTrials.gov identifier NCT01871272.

BackgroundMeniscus surgery is a high-volume surgery carried out on 1 million patients annually in the USA. The procedure is conducted on an outpatient basis and the patients leave the hospital a few hours after surgery. A critical oversight of previous studies is their failure to account for the type of meniscal tears. Meniscus tears can be categorised as traumatic or non-traumatic. Traumatic tears (TT) are usually observed in younger, more active individuals in an otherwise ‘healthy’ meniscus and joint. Non-traumatic tears (NTT) (ie, degenerative tears) are typically observed in the middle-aged (35–55 years) and older population but the aetiology is largely unclear. Knowledge about the potential difference of the effect of arthroscopic meniscus surgery on patient symptoms between patients with traumatic and NTT is sparse. Furthermore, little is known about the natural time course of patient perceived pain, function and quality of life after meniscus surgery and factors affecting these outcomes. The aim of this prospective cohort study is to investigate the natural time course of patient-reported outcomes in patients undergoing meniscus surgery, with particular emphasis on the role of type of symptom onset.Methods/designThis prospective cohort study enrol patients assigned for meniscus surgery. At the baseline (PRE surgery), patient characteristics are assessed using an email-based questionnaire also comprising several validated questionnaires assessing general health, knee-specific characteristics and patient's expectations of the surgery. Follow-up will be conducted at 12 and 52 weeks after meniscus surgery. The major outcomes will be differences in changes, from before to 52 weeks after surgery, in each of the five domains on the Knee injury and Osteoarthritis Outcome Score (KOOS) between patients undergoing surgery for traumatic compared with non-traumatic meniscus tears.DisseminationThe study findings will be disseminated in peer-reviewed journals and presented at national and international conferences.Trial registration numberClinicalTrials.gov Identifier: NCT01871272.

Schjerning J, Uhrenholt TR, Svenningsen P, Vanhoutte PM, Skøtt O, Jensen BL, Hansen PB. Histamine-dependent prolongation by aldosterone of vasoconstriction in isolated small mesenteric arteries of the mouse. Am J Physiol Heart Circ Physiol 304: H1094 -H1102, 2013. First published February 8, 2013 doi:10.1152/ajpheart.00524.2012.-In arterioles, aldosterone counteracts the rapid dilatation (recovery) following depolarization-induced contraction. The hypothesis was tested that this effect of aldosterone depends on cyclooxygenase (COX)-derived products and/or nitric oxide (NO) synthase (NOS) inhibition. Recovery of the response to high K ϩ was observed in mesenteric arteries of wild-type and COX-2 Ϫ/Ϫ mice but it was significantly diminished in preparations from endothelial NOS (eNOS) Ϫ/Ϫ mice. Aldosterone pretreatment inhibited recovery from wild-type and COX-2 Ϫ/Ϫ mice. The NO donor sodium nitroprusside (SNP) restored recovery in arteries from eNOS Ϫ/Ϫ mice, and this was inhibited by aldosterone. Actinomycin-D abolished the effect of aldosterone, indicating a genomic effect. The effect was blocked by indomethacin and by the COX-1 inhibitor valeryl salicylate but not by NS-398 (10 Ϫ6 mol/l) or the TP-receptor antagonist S18886 (10 Ϫ7 mol/l). The effect of aldosterone on recovery in arteries from wild-type mice and the SNPmediated dilatation in arteries from eNOS Ϫ/Ϫ mice was inhibited by the histamine H2 receptor antagonist cimetidine. RT-PCR showed expression of mast cell markers in mouse mesenteric arteries. The adventitia displayed granular cells positive for toluidine blue vital stain. Confocal microscopy of live mast cells showed loss of quinacrine fluorescence and swelling after aldosterone treatment, indicating degranulation. RT-PCR showed expression of mineralocorticoid receptors in mesenteric arteries and in isolated mast cells. These findings suggest that aldosterone inhibits recovery by stimulation of histamine release from mast cells along mesenteric arteries. The resulting activation of H2 receptors decreases the sensitivity to NO of vascular smooth muscle cells. Aldosterone may chronically affect vascular function through paracrine release of histamine. mast cells; mineralocorticoid; endothelial function; microcirculation CHANGES IN INTERNAL VASCULAR diameter and thus local peripheral resistance contribute to the regulation of arterial blood pressure and the distribution of blood flow to distal tissues. In renal arterioles, depolarization-elicited vasoconstriction is counter-regulated by a secondary, nitric oxide (NO)-mediated dilatation termed recovery (38). This phenomenon is associated with transfer of a calcium signal from the smooth muscle cells to the endothelial cells. Another type of rapid interference with vasoconstrictor responses occurs after 5 min of exposure to aldosterone, which inhibits depolarization-induced constriction in the afferent arteriole also in a NO-dependent manner (37). Longer (50 min) exposure of renal arterioles to aldosterone significantly inhibits recovery (37).Aldoste...