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.     

Rapid desensitization of the acute stimulatory effects of nicotine on rat plasma adrenocorticotropin and prolactin

The dose of nicotine and the frequency of its administration appear to be essential determinants of its action on multiple systems including the neuroendocrine regulation of the adrenocorticotropin (ACTH)-corticosterone and prolactin (PRL) axes in the rat. Because desensitization to the acute depressive effects of nicotine has been observed after both acute and chronic administration, these investigations assessed whether desensitization to the stimulative effects of nicotine on ACTH and PRL secretion occurs with repetitive dosing. Extensive dose and time course experiments showed that nicotine rapidly elevates rat plasma ACTH and PRL levels with a threshold dose between 0.1 to 0.25 mg/kg b.wt. i.p. After the stimulation of PRL, levels became significantly depressed. Desensitization to the acute stimulatory effects of nicotine on both hormones was induced by a single dose of nicotine (0.5 mg/kg). One hour later nicotine (1.0 mg/kg) failed to significantly stimulate PRL levels and resulted in a modest increase of ACTH. Desensitization was maximal by 1 hr after the first dose and persisted for at least 6 hr. Adrenalectomy, performed to eliminate corticosterone-induced negative feedback, did not enhance PRL responsiveness to a second dose of nicotine but it partially restored the ACTH response. Pretreatment with corticosterone also failed to modify the PRL response to a single dose of nicotine whereas it partially suppressed the ACTH response. Rapid desensitization to the acute stimulatory effects of nicotine on plasma PRL is independent of glucocorticoid negative-feedback whereas desensitization of the ACTH response is modestly dependent.     

Effects of eight weeks of bicycle ergometer sprint training on human muscle buffer capacity

This investigation was undertaken to determine whether human skeletal muscle buffer capacity (BCm) is affected by training. Eight untrained males participated in 8 weeks of sprint training on bicycle ergometers. Muscle biopsy samples were taken from the vastus lateralis before and at several times following an incremental bicycle ergometer test (0 min, 5 min, 15 min). These subjects were tested before (PRE) and following (POST) the training period. Seven endurance-trained cyclists (ET) were also tested for the purpose of comparing the BCm of ET to that of PRE and POST. Biopsy samples were quick-frozen in liquid nitrogen and later analyzed for lactate concentration (HLam), homogenate pH (pHm), and creatine phosphate concentration. BCm was calculated from the change in HLam and pHm observed from rest to exhaustion and was expressed as mmol X kg-1 X pH-1 (Slykes). There was no significant difference in resting HLam or resting pHm among the groups. There was a significant difference in HLam at exhaustion between PRE (21.41 +/- 1.65 mmol X kg-1), POST (25.61 +/- 2.38 mmol X kg-1), and ET (11.16 +/- 0.31 mmol X kg-1) but no significant difference in pHm at exhaustion between PRE (6.65 +/- 0.03 pH units) and POST (6.69 +/- 0.06 pH units). pHm at exhaustion for the ET group was significantly higher than the others at 6.91 +/- 0.02 pH units. A significant difference between PRE and POST BCm was found (PRE: 44.68 +/- 3.03 S1; POST: 61.04 +/- 4.11 S1) while ET BCm (47.21 +/- 7.26 S1) was not significantly different from PRE. These data indicate that muscle buffer capacity is increased with highly intense sprint training but provide no evidence to suggest that muscle buffer capacity is affected by endurance training.     

A metropolitan experience with infrainguinal revascularization. Operative risk and late results in northeastern Ohio

Despite being of fundamental importance, the late results of major arterial reconstruction rarely have been documented throughout a large metropolitan area. In this study of 932 patients entered into the computer registry of the Cleveland Vascular Society, 19 surgeons representing 13 community hospitals and referral centers in Cleveland and Akron report the intermediate-term outcome during a mean interval of 35 months after infrainguinal lower extremity revascularization performed in northeastern Ohio from 1978 through 1982. Operative risk (5%), the early amputation rate (7%), and actuarial 5-year survival (48% to 55%) for patients with rest pain or tissue necrosis were significantly worse (p less than 0.05) than comparable figures (0.6%, 0%, and 77%, respectively) for others who underwent procedures for disabling claudication. Although both materials had similar success above the knee, the cumulative 3-year patency rate of autogenous vein bypass to the distal popliteal (69% to 88%; p less than 0.05) and tibioperoneal arteries (43%; 0.05 less than p less than 0.1) was superior to the results of polytetrafluoroethylene grafts (32% to 50% and 19%, respectively). Moreover, polytetrafluoroethylene grafts required reoperations at three times the rate of vein grafts to maintain limb salvage.     

Breast screening: a subject for debate.

The National Health Service Breast Screening Programme was instituted in 1988 following the recommendations of the Forrest report in 1986. From the beginning it has been controversial. Is breast cancer screening efficacious? Can the efficacy produced in trials be reproduced nationwide in the UK? Do the benefits of screening outweigh the adverse effects? Answers to all these questions are not yet available but in the light of current evidence, breast screening does appear to offer a realistic opportunity to reduce the mortality from a disease which constitutes a major public health problem in the UK. The role of the general practitioner and the primary care team is considered in the light of the experience gained in the first phase of the screening programme.