Antinociceptive effect of some carboxypeptidase A inhibitors in comparison with D-phenylalanine

It had previously been shown that D-phenylalanine and hydrocinnamic acid, two in vitro inhibitors of carboxypeptidase A, possess an analgesic action when injected i.p. in mice. We have studied the in vivo effects of indole-3-acetic acid, another carboxypeptidase A inhibitor, and of the following analogs of D-phenylalanine substituted in position 4: D-tyrosine, p-fluoro-D-phenylalanine and trifluoroacetyl-p-fluoro-D-phenylalanine. Whereas indole-3-acetic acid caused a higher and shorter analgesia in comparison with D-phenylalanine, p-fluoro-D-phenylalanine and its N-trifluoroacetyl derivative yielded both a greater and a much longer lasting analgesic effect. Since the latter compound showed only slight inhibitory activity on carboxypeptidase A in vitro, we suggest that inhibition of this enzyme and analgesia might not be directly correlated.     

Pregnancy in carriers of high-affinity hemoglobins

Pregnancy in female carriers of abnormal hemoglobins with great avidity for oxygen provides a unique opportunity to assess the importance of the usual difference in oxygen affinity between fetal and maternal blood. Outcome of pregnancy was recorded for carriers of hemoglobins Bethesda, Osler, and Yakima, whose p50s (9.5, 9.1, and 12 mm Hg at pH 7.4) were far lower than that of a normal fetus (23 mm Hg at pH 7.3). Neither spontaneous abortions nor intrauterine growth retardation could be attributed to the presence of high oxygen affinity in the mothers. In vitro simulations suggested that neither maternal or fetal polycythemia alone was sufficient to adjust for perturbation of the normal situation, and increased uterine and/or fetal blood flow probably provided additional compensation.     

Long-segment femoropopliteal stenoses: is angioplasty a boon or a bust?

Analysis of 193 femoropopliteal angioplasties demonstrated patency rates in the stenotic group of 75.5% at 6 months and 54.4% at 54 months. The patency rates for the occlusive group were 93.7% at 6 months and 72.9% at 54 months; these rates were significantly better than those in patients with stenoses. A group of 14 patients with long-segment (greater than 7 cm) stenosis had the highest risk of early failure, with a 6-month patency of 23.1%. After removal of the long-segment stenosis group from the results, there were no significant differences between the long-term patencies for stenotic and occlusive lesions. If angioplasty of long stenoses is attempted, a high initial success rate but early failure should be anticipated.     

Surgical Management of Inflammatory Bowel Disease

Opinion statement Surgery continues to be a central component in the treatment of patients with inflammatory bowel disease (IBD). The most important aspect of caring for patients with IBD is a close and ongoing interaction between the surgeon and gastroenterologist both before and after surgery. Surgery in patients with chronic ulcerative colitis (CUC) is curative. In the appropriate patient, we recommend proctocolectomy with ileal pouch anal anastomosis (IPAA). In contrast, patients with Crohn’s disease cannot be cured with surgery. Instead, surgery is used in conjunction with maximal medical therapy to treat symptoms of the disease and improve the patient’s quality of life. Surgical interventions should be limited in scope. Small bowel disease should be treated with either limited resection or strictureplasty, if possible, to conserve bowel length. For limited involvement of the colon, segmental resection yields good results. Minimal surgical intervention, drainage of abscesses, placing draining setons, and aggressive medical therapy is recommended as treatment of perianal Crohn’s disease.     

Signaling mechanisms for the selective vasoconstrictor effect of norbormide on the rat small arteries

Norbormide (NRB) is a selective vasoconstrictor agent of the rat small vessels. The mechanisms underlying the selective vasoconstrictor effect of NRB are unknown. To investigate whether phospholipase C (PLC) signaling pathway plays a role in NRB-induced vasoconstriction, we performed experiments in NRB-contracted tissues, namely, rat caudal arteries (RCA) and smooth muscle cells derived from rat mesenteric arteries (MVSMCs). An NRB-insensitive vessel, namely rat aorta (RA), served as a control tissue. In RCA and RA we measured either isometric tension or formation of inositol phosphates (IPs), the latter taken as an index of PLC activation. In MVSMCs, we measured intracellular free calcium concentration ([Ca2+]cyt). In the presence of external Ca2+, NRB (2-50 microM) stimulated IPs formation in RCA but not in RA, and increased [Ca2+]cyt in MVSMCs. In the absence of external Ca2+, NRB (50 microM) increased IPs formation in RCA but was unable to increase [Ca2+]cyt in MVSMCs. In RCA, in the presence of external Ca2+, NRB-induced contraction was inhibited by calphostin C (0.2-1 microM), an inhibitor of protein kinase C (PKC), and by SK&F 96365 (30 microM), an inhibitor of the store-operated calcium channels, but was poorly affected by verapamil, an L-type calcium channel blocker. However, verapamil was much more effective when external Ca2+ was substituted by Sr2+. These results suggest that NRB elicits its tissue and species-selective vasoconstrictor effect by stimulating PLC-PKC pathway and increasing Ca2+ influx through both verapamil-sensitive and -insensitive calcium channels. Ca2+ release from sarcoplasmic reticulum seems not involved in NRB vasoconstriction.