Effects of a novel β3‐adrenoceptor agonist,AJ‐9677, on relaxation of the detrusor muscle: An in vitro study

Objectives: To examine the relaxant effects of AJ‐9677, a novel β₃‐adrenoceptor agonist, on the isolated rat, monkey and human detrusor muscle. Methods: The isolated detrusor strips of rats, monkeys and humans were mounted in organ baths containing Krebs solution. By the cumulative addition of β‐adrenoceptor agonists (isoproterenol, AJ‐9677, CL 316,243 and salbutamol in rats; isoproterenol, AJ‐9677 and CL 316,243 in monkeys and humans), concentration–relaxation curves were obtained. The maximal relaxation responses and pEC₅₀ values were calculated. In rats, concentration–relaxation curves to isoproterenol and AJ‐9677 were obtained in the presence and absence of propranolol or SR 59230A. Results: Isoproterenol, AJ‐9677, CL 316,243 and salbutamol induced concentration‐dependent relaxation in rats. The rank order of their relaxing potency in the rat detrusor muscle was AJ‐9677 > isoproterenol > CL 316,243 > salbutamol. Isoproterenol and AJ‐9677 also produced a concentration‐dependent relaxation with high potency in monkeys and humans, whilst CL 316,243 had low relaxing potency. According to the antagonist studies in rats, propranolol and SR 59230A caused a rightward shift of the concentration–relaxation curves to isoproterenol or AJ‐9677, respectively. Conclusions: AJ‐9677 has a high relaxant potency on the rat, monkey and human detrusor smooth muscle, and it may have the potential to treat overactive bladder.     

Interleukin‐1β stimulates stromal‐derived factor‐1α expression in human subacromial bursa

Chemokines produced by synoviocytes of the subacromial bursa are up‐regulated in subacromial bursitis and rotator cuff disease. We hypothesized that SDF‐1α production in bursal synoviocytes may be induced by local cytokines such as interleukin IL‐1β and IL‐6. Subacromial bursa specimens were obtained from patients undergoing shoulder surgery. Bursal specimens were stained with anti‐human antibodies to IL‐1, IL‐6, and SDF‐1α by immunohistochemistry and compared to normal and rheumatoid controls. Bursal cells were also isolated from specimens and cultured. Early passaged cells were then treated with cytokines (IL‐1β and IL‐6) and SDF‐1α expression was measured by ELISA and RT‐PCR. SDF‐1α, IL‐1β, and IL‐6 were expressed at high levels in bursitis specimens from human subacromial bursa compared to normal controls. In cultured bursal synoviocytes, there was a dose‐dependent increase in SDF‐1α production in the supernatants of cells treated with IL‐1β. SDF‐1α mRNA expression was also increased in bursal cells treated with IL‐1β. IL‐6 caused a minimal but not statistically significant increase in SDF‐1α expression. SDF‐1α, IL‐1β, and IL‐6 are expressed in the inflamed human subacromial bursal tissues in patients with subacromial bursitis. In cultured bursal synoviocytes, SDF‐1α gene expression and protein production are stimulated by IL‐1β. IL‐1β produced by bursal syvoviocytes and inflammatory cells in the human subacromial bursa is an important signal in the inflammatory response that occurs in subacromial bursitis and rotator cuff disease. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1695–1699, 2011     

New clinical evidence of silodosin,an α1A selective adrenoceptor antagonist,in the treatment for lower urinary tract symptoms

Lower urinary tract symptoms associated with benign prostatic hyperplasia are highly prevalent in older men. Pharmacological treatment is the first‐line treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia. The first choice in the pharmacological treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia is the α₁‐adrenoceptor antagonists. Many α₁‐adrenoceptor antagonists are available in the world. Silodosin is an α₁‐adrenoceptor antagonist developed by Kissei Pharmaceutical, and has a specific selectivity for the α_1A‐adrenoceptor subtype. By antagonizing α_1A‐adrenoceptor in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. As a result of the high affinity for the α_1A‐adrenoceptor than for the α_1B‐adrenoceptor, silodosin minimizes the propensity for blood pressure‐related adverse effects caused by blockade of α_1B‐adrenoceptor. The efficacy and safety of silodosin for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia was first reported by Japanese investigators in 2006. At present, silodosin is used in many countries. In the present review, we summarize the new clinical evidence for lower urinary tract symptoms associated with benign prostatic hyperplasia and introduce the data supporting the new clinical indications of silodosin.     

Combined effects of TNF‐α, IL‐1β, and HIF‐1α on MMP‐2 production in ACL fibroblasts under mechanical stretch: An in vitro study

The dynamics between inflammatory factors, mechanical stress, and healing factors, in an intra‐articular joint, are very complex after injury. Injury to intra‐articular tissue [anterior cruciate ligament (ACL), synovium] results in hypoxia, accumulation of various pro‐inflammatory factors, cytokines, and metalloproteases. Although the presence of increased amounts of matrix‐metalloproteinases (MMP) in the joint fluid after knee injury is considered the key factor for ACL poor healing ability; however, the exact role of collective participants of the joint fluid on MMP‐2 activity and production has not been fully studied yet. To investigate the combined effects of mechanical injury, inflammation and hypoxia induced factor‐1α (HIF‐1α) on induction of MMP‐2; we mimicked the microenvironment of joint cavity after ACL injury. The results show that TNF‐α and IL‐1β elevate the activity of MMP‐2 in a dose‐ and time‐dependent manner. In addition, mechanical stretch further enhances the MMP‐2 protein levels with TNF‐α, IL‐1β, and their mixture. CoCl₂‐induced HIF‐1α (100 and 500 µM) also increases the levels and activity of MMP‐2. Mechanical stretch has a strong additional effect on MMP‐2 production with HIF‐1α. Our results conclude that mechanical injury, HIF‐1α and inflammatory factors collectively induce increased MMP‐2 production in ACL fibroblasts, which was inhibited by NF‐κB pathway inhibitor (Bay‐11‐7082). © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1008–1014, 2011     

Anti‐gal antibodies in α1,3‐galactosyltransferase gene‐knockout pigs

Fang J, Walters A, Hara H, Long C, Yeh P, Ayares D, Cooper DKC, Bianchi J. Anti‐gal antibodies in α1,3‐galactosyltransferase gene‐knockout pigs. Xenotransplantation 2012; 19: 305–310. © 2012 John Wiley & Sons A/S. Abstract Serum anti‐galactose‐α1,3‐galactose (Gal) IgM and IgG antibody levels were measured by ELISA in α1,3‐galactosyltransferase gene‐knockout (GTKO) pigs (78 estimations in 47 pigs). A low level of anti‐Gal IgM was present soon after birth, and rose to a peak at 4–6 m, which was maintained thereafter even in the oldest pigs tested (at >2 yr). Anti‐Gal IgG was also present at birth, peaked at 3 m, and after 6 m steadily decreased until almost undetectable at 20 m. No differences in this pattern were seen between pigs of different gender. Total IgM followed a similar pattern as anti‐Gal IgM, but total IgG did not decrease after 6m. The data provide useful baseline data for future experimental studies in GTKO pigs, e.g., relating to the antibody response to WT pig allografts.