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.     

Spastic pure motor monoparesis

Pure motor hemiplegia (PMH) is, in most cases, caused by a lacunar infarction. However, pure motor monoparesis (PMM), i.e., isolated motor involvement with spasticity in one limb, has drawn little attention. We studied prospectively 5 patients with PMM and found that it was always due to a mass lesion in the contralateral superficial cerebral hemisphere. Our observation suggests that PMM should not be regarded as simply a variant of PMH.     

Physiologic and pathologic evaluation of chronic extra-aortic counterpulsation with latissimus dorsi flap. Preliminary results

This study attempted to evaluate the efficacy of chronic extra-aortic counterpulsation with a latissimus dorsi neuro vascular flap. Five dogs had a preliminary procedure consisting of the creation of a latissimus dorsi flap and a thoracotomy in which the flap was wrapped around the descending aorta just distal to the left subclavian artery. An epicardial lead was placed on the left ventricle and a nerve stimulating lead placed around the thoraco-dorsal nerve. Three weeks later, both leads were connected to a cardiomyostimulator programmed to function in a counterpulsation mode with a 1:2 assist frequency. Hemodynamic measurements were made at 6 and 8 and 10 and 12 weeks and the dogs were sacrificed. Three dogs had all sets of hemodynamic measurements made. Two of the three dogs demonstrated diastolic augmentation at 6 and 8 and 10 and 12 weeks average 20 to 25 mmHg. The third dog failed to demonstrate any change. All dogs were sacrificed at 12 weeks and specimens were submitted for histologic evaluation. The muscle flap was preserved in all animals. The aorta subjacent to the flap showed, (1) normal intima with no evidence of disruption or thrombus in all animals, (2) in the animals in whom counterpulsation was observed, there appeared to be thinning of the media in the aorta subjacent to the muscle flap, and (3) no evidence of distal emboli. This study demonstrated that chronic counterpulsation can be obtained with a latissimus dorsi flap. The actual hemodynamic benefits are not determined from this study. The medial thinning in the aortic wall may limit the long-term benefit of this procedure.     

Cerebellar toxicity with high-dose cytosine arabinoside

CNS dysfunction, especially impaired cerebellar function, is the dose-limiting toxicity associated with high-dose cytosine arabinoside, which precludes doses of greater than 48 g/m2. Four hundred eighteen patients between the ages of 2 and 74 years with leukemia or lymphoma received 36 to 48 g/m2 cytosine arabinoside either alone or with anthracycline antibiotics, 4'-(9-acridinylamino) methane sulfon-m-anisidine (m-AMSA), or total body irradiation. In only 35 of 418 patients (8%) did severe cerebellar toxicity develop; it was irreversible or fatal in four (1%) patients. The age of the patient was a critical factor in the incidence of severe cerebellar toxicity. Patients greater than 50 years old had a statistically significant greater incidence of cerebellar toxicity compared with younger patients (26/137, 19%, v 9/281, 3%; P less than .0005, chi 2). Neither the diagnosis, disease status, sex, nor the regimen altered the incidence of severe cerebellar toxicity (when corrected for age). A second course of high-dose cytosine arabinoside, administered to 62 patients, did not increase the incidence of severe cerebellar toxicity, which occurred in five (8%) of these patients. Two of the five patients had severe toxicity with the initial course. Of the 60 patients with no antecedent cerebellar dysfunction, three (5%) had severe toxicity with the second course: one of 41 patients were less than 50 years old; two of 19 patients were greater than or equal to 50 years. Since the occurrence of severe cerebellar dysfunction is greatly affected by age, reduced doses of high-dose cytosine arabinoside should be given to patients greater than 50 years old, and methods for reducing the cerebellar toxicity should be investigated in these patients.     

Pseudomembranous tracheobronchitis caused by Aspergillus

Four immunosuppressed patients with a rapidly evolving, febrile, respiratory distress syndrome were found at autopsy to have Aspergillus pseudomembranes of their lower tracheobronchial tree. Steroids, neutropenia, broad spectrum antibiotic use, and alcoholism appear to be predisposing risk factors. Bronchoscopy may reveal the pathology but antemortem diagnosis is difficult because of the low yield of sputum cultures and fulminant nature of the disease.     

The significance of vascular hyperreaction as measured by the cold-pressor test

The majority of individuals with essential hypertension and some with usually normal blood pressure manifest unusual lability and marked reactions of blood pressure to various internal and external stimuli. This suggests that the mechanism for regulating blood pressure which is possessed by these individuals is hyperreactive. The cold-pressor test is a satisfactory method of determining the reactivity of the blood pressure. The test consists in measuring the reaction of the blood pressure to a standard cold stimulus.¹In this paper the expression, “person with usually normal blood pressure,” will appear frequently. It means a person who does not have persistent hypertension, one whose blood pressure remains within normal limits unless caused to rise by a stimulus. Later in this paper such persons will be divided into the classes called “normal hyporeactors” and “normal hyperreactor.”     

LIPOPROTEIN(α) IN HEALTH AND DISEASE

SUMMARY Elevated plasma levels of Lp(a) do seem to influence the progression of atherosclerosis. Evidence is emerging that certain apo(a) isoforms may be more atherogenic than others, and in transgenic mice free apo(a) has been shown to be associated with accelerated atherosclerosis. Currently it is not known whether treating elevated Lp(a) levels will reduce progression of atherosclerosis and, as therapeutic options are limited, mass screening of Lp(a) levels in populations is not indicated. The presence of raised Lp(a) levels, however, warrants aggressive treatment to reduce other cardiovascular risk factors. Continuing research to investigate the relationship of the apo(a) gene to other genes, including the plasminogen gene and apo(a)-related genes, will add further information pertaining to the evolution, function, regulation and clinical implications of Lp(a).     

The effect of asanguinous cardioplegic arrest on atrial preservation using atrial ATP as a marker

Changes in atrial adenosine triphosphate (ATP) and the presence of postoperative arrhythmias were studied in 14 patients during routine coronary artery bypass grafting to 1) attempt to evaluate atrial preservation, and 2) determine if a relationship exists between changes in ATP and the development of postoperative arrhythmias. Atrial biopsies were obtained at the time of cannulation (preischemic sample) and after the removal of the aortic crossclamp (postischemic sample). Methods of myocardial protection included systemic hypothermia (28 degrees C), periodic reinfusion of crystalloid cardioplegia into the aortic root and completed vein grafts, and iced slush in the pericardial well. Atrial temperature was monitored. Preischemic ATP was 0.412 +/- 0.32 mu mol/gm, and the postischemic value was 0.220 +/- 0.13 mu mol/gm (p less than .02). Atrial temperature routinely decreased to 13-18 degrees C after cardioplegic infusion but rose to 24 degrees C between infusions. There was no correlation between postoperative supraventricular arrhythmias (4 patients) and changes in ATP. In conclusion, routine coronary artery bypass grafting with standard methods of cardiac preservation does not appear to satisfactorily preserve atrial tissue. The clinical correlation and significance of this remains to be elucidated.     

Measurement of self-esteem in repeat assault victims.

Background characterization of assault-related injuries have demonstrated that lifestyle, substance abuse, education, employment, mental illness, and high-risk behavior contribute to low self-esteem in repeat assault victims. Recurrent-assault patients have never been studied with respect to self-esteem. This study evaluated self-esteem and assault-related injury in 28 consecutive male assault patients (11 first-assault and 17 recurrent-assault patients) and 19 controls with no previous assault history. Study participants were administered the Walmyr Assessment Scales Index of Self-Esteem (WASISE) as part of a three-item survey to determine the relationship between self-esteem and assault-related injury. No demographic differences were found between the groups. The mean (+/- standard error) WASISE score for recurrent-assault patients (34.9 +/- 3.4) was significantly higher than mean scores for no-assault and first-time assault-injured patients (14.7 +/- 1.4 and 15.0 +/- 2.3, respectively). The recurrent-assault patients had a lower mean education level than both no-assault and first-time assault-injured patients (2.1 +/- 0.26 and 1.9 +/- 0.57, respectively). Eighteen (2%) first-time assault-injured and 11 (7%) recurrent-assault patients were employed. These data suggest that self-esteem, education, and employment history need to be considered when evaluating and developing interventions for repeat-assault patients.