The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

Monitoring pressure ulcer healing in persons with disabilities.

Pressure ulcers are a high-risk, high-volume, and high-cost problem for persons with disabilities. This article describes four tools published in the literature and reports the validity, reliability, strengths, and limitations of each. These tools include the Pressure Ulcer Scale for Healing (PUSH), the Pressure Sore Status Tool (PSST), the Sussman Wound Healing Tool (SWHT), and the Sessing Scale. Rehabilitation nurses should use a consistent framework with accurate quantification to assess, document, and monitor changes in pressure ulcers over time. Such a measurement tool must prove valid for the disabled population in which the tool is used. This will enable healthcare providers to communicate more effectively and evaluate the therapeutic plan of care.     

Immunostaining for P-glycoprotein in the diagnosis of thyroid carcinomas.

The morphologic distinction between thyroid carcinoma and certain benign thyroid conditions can be difficult in selected cases. P-glycoprotein (Pgp), a glycoprotein associated with tumor multidrug resistance, has been reported to be expressed in thyroid carcinoma but not in benign thyroid conditions. To determine the specificity of immunostaining for Pgp in the diagnosis of thyroid carcinoma, we studied formalin-fixed, paraffin-embedded tissue from 69 cases of various thyroid lesions using a commercially available monoclonal antibody to Pgp (C219, Centocor, Malvern, PA) and an avidin-biotin-peroxidase complex technique. Positive reactivity was seen in 15 of 37 (41%) benign thyroid conditions and in 23 of 32 (72%) thyroid carcinomas. We conclude that immunostaining for Pgp is not specific in the diagnosis of thyroid carcinoma.     

Skin necrosis complicating mallet finger splinting and vascularity of the distal interphalangeal joint overlying skin

Two patients are reported with full-thickness skin necrosis over the dorsum of the distal interphalangeal (DIP) joints after dorsal splint immobilization in hyperextension to treat acute mallet finger. An investigation was carried out to study the relationship of hyperextension to the dorsal circulation of the DIP joint. In 66 digits, the average degree of DIP joint hyperextension at which the skin blanches was 50% of the total passive hyperextension. It is recommended, therefore, when the DIP joint is immobilized to treat acute mallet finger, the degree at which the dorsal skin begins to blanch must be determined, and the amount of hyperextension should not exceed that degree. Excessive localized pressure to the dorsal skin should be avoided by adjusting the angle of the dorsal splint.     

Control of respiration by the hypothalamus and by feedback from contracting muscles in cats

Central command and feedback from contracting muscles are two mechanisms which are thought to control the respiratory and cardiovascular systems during exercise. In this study, we compared the individual and combined responses to activation of central command and to muscular contraction in anesthetized cats. Continuous electrical stimulation of the subthalamic locomotor region (STLR) was used to simulate central command (Eldridge et al., 1985). Static (tetanic) contraction of hindlimb muscles was produced by stimulating the cut peripheral ends of the L7-S1 ventral roots. Despite similar increases in arterial pressure, STLR stimulation caused larger increases in cardiac frequency and respiration than that evoked by muscular contraction. When performed during muscular contraction, STLR still caused large increases in respiration, arterial pressure and cardiac frequency. In contrast, muscular contraction when induced during STLR stimulation caused only small increases in respiration and modest changes in arterial pressure and cardiac frequency. These results suggest that central command and feedback from contracting muscles exert different respiratory and cardiovascular effects when activated simultaneously than when activated individually. In addition, central command, as activated by STLR stimulation, predominates over the responses caused by muscular contraction.     

Exchange-transfusion with pyridoxalated polymerized hemoglobin: effects on liver PO2

To examine the efficacy of modified stroma-free hemoglobin in maintaining liver PO2, rats were exchange-transfused to hematocrit 10% using pyridoxalated polymerized hemoglobin (plp-polyHb, 10-12 g/dl) prepared from crystalline Hb. Following hemodilution, plasma Hb was 7.4 g/dl, and rats were normotensive. Mean liver PO2 was 3.4 vs 23.3 mm Hg in sham-exchanged controls. Other rats, hemodiluted similarly with 6% albumin or hydroxyethylstarch, were hypotensive and died. At 24 hours plasma Hb was 2.0 g/dl, indicating an intravascular half-life of approximately 16 hours. Hepatic PO2 was 12.4 vs 26.8 mm Hg in nonhemodiluted controls. Data provided by clearance of low-dose indocyanine green suggested reduced plasma volume and depressed liver blood flow. Scattered foci of midzonal hypoxic damage were observed in liver lobules. The basis for hypoxic injury is considered to be due in part to the acute restriction of oxygen supply induced by exchange-transfusion with plp-polyHb. The rate of loss of intravascular hemoglobin and diminished plasma volume could have contributed to oxygen insufficiency as well. Endotoxin present in the plp-polyHb was not a factor.