Relationship between nifedipine sensitivity of aortae and blood pressure of stroke-prone spontaneously hypertensive rats

1. We have previously described an increased sensitivity to inhibition by nifedipine of noradrenaline-induced contractures of blood vessels in hypertension. In this study we have investigated whether changes in blood pressure (BP) change the sensitivity to nifedipine and K+ of aortic rings from normotensive (Wistar-Kyoto rats, WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were treated with: hydralazine plus hydrochlorothiazide; captopril plus hydrochlorothiazide; hydralazine plus guanethidine; or captopril alone. WKY rats were treated with deoxycorticosterone acetate (DOCA) and NaCl. Treatment commenced from 5 weeks of age and continued until 13-15 weeks. 3. The SHRSP treatments produced similar reductions in BP, and the BP of all the treated groups were significantly lower than the mean BP of untreated SHRSP (201.0 +/- 7.7 mmHg). The mean BP of the treated WKY rats (134.2 +/- 7.6 mmHg) was significantly higher than the mean BP of the untreated WKY rats (86.8 +/- 7.4 mmHg). 4. An area-under-curve (AUC) analysis of the inhibitory effects of nifedipine on responses of aortae to noradrenaline showed no differences between treated and untreated SHRSP groups (overall mean 40.6 +/- 1.9% and 43.4 +/- 3.4% inhibition of control AUC, respectively), or between DOCA-salt treated WKY and untreated WKY groups (58.8 +/- 5.9 and 64.8 +/- 2.3, respectively). Noradrenaline-induced contractures of aortae from all SHRSP groups were significantly more sensitive to inhibition by nifedipine than aortae from both WKY groups. 5. The molar concentration of agonist required to evoke 50% of the maximum response (EC50) values for potassium chloride (KCl) were significantly increased in the aortae of all treated SHRSP groups in comparison to those from untreated SHRSP (treated SHRSP groups, 15.53 +/- 0.68 mmol/L vs untreated SHRSP group, 11.36 +/- 1.10 mmol/L). The EC50 values for KCl for the aortae from the DOCA-treated WKY rats were significantly less than those from aortae of the untreated WKY (11.80 +/- 0.80 and 17.08 +/- 1.50 mmol/L, respectively). 6. We conclude that reduction (in SHRSP) or increase (in WKY) of the BP has no effect on the sensitivity of aortic smooth muscle to the inhibitory effects of nifedipine on responses to noradrenaline, suggesting that alterations in voltage-dependent Ca2+ mechanisms may be a primary phenomenon in the SHRSP. In contrast, the fact that sensitivity to KCl changes in the treated SHRSP and WKY aortae suggests such sensitivity is secondary to the BP and thus a separate phenomenon from voltage-dependent Ca2+ mechanisms.     

Simple methods for determination of the release limits for drug products

Gradients of cellular activities are ubiquitous in embryonic development. It is widely believed that the inhomogeneous spatial distribution of a morphogen would be able to set up such gradients. But how then does the morphogen propagate in the first place? Straightforward molecular diffusion is often proposed as a possible mechanism. We first show that, surprisingly, the mere binding of the diffusing morphogen to its membrane receptors suffices to prevent the establishment of a concentration-based positional signalling system. Instead, a flat, saturated distribution of receptor-bound morphogen builds up. Because the distribution spreads gradually from the morphogen source, however, cells may still know their position if they are able to integrate the morphogen signal in time. The irregularities of diffusion in the complex extracellular medium would in fact be partially compensated for by such time summation. Another, non-exclusive possibility is that morphogen transport does not occur by simple diffusion only. We put forth a novel model of receptor-aided, directed diffusion that achieves a spatial distribution of morphogen. Our model is based, as an illustration, on the properties of members of the TGFbeta family of molecules. We show that two simple hypotheses regarding the kinetics of TGBbeta binding to its receptors suffice to establish a remarkable transfer mechanism whereby a morphogen such as activin could be both propagated along cell membranes, and transferred between cells that are in contact. The model predicts that morphogen propagation properties depend strongly on the closeness of cell-cell appositions, does not necessitate protein synthesis, accumulation or slow degradation (in contrast to the diffusion/time integration model), and that the morphogen is localised mostly on or close to cell membranes.     

Prospective, randomized trial of prolonged intracoronary urokinase infusion for chronic total occlusions in native coronary arteries

OBJECTIVES: The purpose of this study was to determine the safety and efficacy of three dosing regimens of intracoronary urokinase for facilitated angioplasty of chronic total native coronary artery occlusions. BACKGROUND: Percutaneous transluminal coronary angioplasty of chronically occluded (>3 months) native coronary arteries is associated with low initial success secondary to an inability to pass the guide wire beyond the occlusion. METHODS: Patients were enrolled if a chronic total occlusion >3 months old could not be crossed with standard angioplasty equipment. Of the 101 patients enrolled, 41 had successful guide wire passage and were excluded from urokinase treatment. The remaining 60 patients were randomized to receive one of three intracoronary dosing regimens of urokinase over 8 h (group A = 0.8 million U; group B = 1.6 million U; group C = 3.2 million U), and angioplasty was again attempted after completion of the urokinase infusion in 58 patients. RESULTS: Coronary angioplasty was successful in 32 patients (53%) (group A 52%, group B 50%, group C 59%, p = 0.86). This study had a 90% power to detect at least a 50% difference between dosing groups at alpha 0.05. Bleeding complications requiring blood transfusion did not differ significantly among the dosing groups (A 0%, B 15%, C 6%, p = 0.14), although major bleeding episodes were less common in group A (p < 0.05). There were no major procedural or in-hospital complications. Angiographic follow-up in 69% of the patients with successful angioplasty revealed target vessel patency in 91% but an angiographic restenosis rate of 59%. CONCLUSIONS: A prolonged supraselective intracoronary infusion of urokinase can be safely administered and may facilitate angioplasty of chronic total occlusions. Lower doses of urokinase are equally effective and result in fewer bleeding complications than do higher dosage regimens. Vessel patency is frequently maintained, but restenosis remains a problem.     

Assessment of childhood phobias

Childhood phobias can be successfully treated using a variety of behavioral strategies, provided there has been a psychometrically sound assessment. Measures are also important for the evaluation of treatment efficacy and the testing of hypotheses generated by new ideas and theories of children's phobias. This paper outlines broad-based assessment procedures used in the evaluation of children's phobias, including the behavioral or problem-focused interview, the diagnostic interview, self-report inventories, caregiver completed instruments, behavioral observations, self-monitoring and physiological assessment. Reflecting recent theoretical and clinical advances in the study of childhood internalizing disorders, we also explore laboratory-based measures and family assessment measures. Particular attention is given to psychometric issues and developmental sensitivity in our discussion of these assessment procedures.     

ATP-dependent transport of reduced glutathione on YCF1, the yeast orthologue of mammalian multidrug resistance associated proteins

The transport systems involved in the export of cellular reduced glutathione (GSH) have not been identified, although recent studies implicate a role for some of the multidrug resistance associated proteins (MRP), including MRP1 and MRP2. The present study examined the hypothesis that the yeast orthologue of MRP, Ycf1p, mediates ATP-dependent GSH transport. [3H]GSH transport was measured in vacuolar membrane vesicles isolated from a control strain of Saccharomyces cerevisiae (DTY165), the isogenic DTY167 strain that lacks a functional Ycf1p, and in DTY167 transformed with a 2-micrometer plasmid vector containing YCF1. GSH transport in control vacuolar membrane vesicles was mediated largely by an ATP-dependent, low affinity pathway (Km = 15 +/- 4 mM). ATP-dependent [3H]GSH transport was cis-inhibited by substrates of the yeast Ycf1p transporter and inhibited by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, probenecid, and sulfinpyrazone, inhibitors of MRP1 and MRP2, but was minimally affected by membrane potential or pH gradient uncouplers. In contrast, ATP-dependent GSH transport was not seen in vacuolar membrane vesicles isolated from the DTY167 yeast strain without a functional Ycf1p but was restored to near wild-type levels in the DTY167 strain transformed with YCF1 and expressing the vacuolar Ycf1p transporter. On the other hand, expression and functional activity of a bile acid transporter, Bat1p, and of the V-type ATPase were similar in all three yeast strains. These results provide direct evidence for ATP-dependent low affinity transport of GSH by the yeast Ycf1p transporter. Because of the structural and functional homology between Ycf1p and MRP1 and MRP2, these data support the hypothesis that GSH efflux from mammalian cells is mediated by these membrane proteins.     

Morphological changes in a hyperfunctioning thyroid adenoma after percutaneous ethanol injection: histological, enzymatic and sub-microscopical alterations

Autonomic nervous dysfunction has recently been considered to be an etiological factor in syncope and sudden death in cases of hypertrophic cardiomyopathy. However, the precise mechanism is still unknown. A 73-year-old woman with obstructive hypertrophic cardiomyopathy was hospitalized with complaints of impaired consciousness; faintness 3 to 4 h after meals, lightheadedness while walking, and syncope during and after defecation and micturition. Faintness was induced by alimentary hypoglycemia related to gastrectomy performed 5 years previously. Lightheadedness and syncope were accounted for by autonomic nervous failure combined with an impairment of alpha 1-adrenoceptor in vasoconstriction and the carotid sinus hypersensitivity which accompanied preceding events such as abdominal pain, defecation and micturition, which could enhance the vagally-mediated baroreceptor reflex.