Mediation by B1 and B2 receptors of vasodepressor responses to intravenously administered kinins in anaesthetized dogs.

1. Vasodepressor responses to intravenous (i.v.) injection of bradykinin (BK) and des-Arg9-BK, a selective B1 kinin receptor agonist, were characterized following i.v. pretreatment with selective B1 ([Leu8]-des-Arg9-BK) and B2 (Hoe 140) kinin receptor antagonists in anaesthetized dogs. 2. Des-Arg9-BK (0.05-3.3 nmol kg-1) produced dose-dependent decreases in mean arterial blood pressure with a ED50 0.4 nmol kg-1. The vasodepressor effects evoked by des-Arg9-BK (0.6 nmol kg-1) and BK (0.2 nmol kg-1) were greater after i.v. and i.a. injections, respectively. 3. The vasodepressor response to BK (0.6 nmol kg-1) but not to des-Arg9-BK (0.6 nmol kg-1) was significantly (P < 0.001) blocked by pretreatment with the B2 receptor antagonist, Hoe 140. 4. The vasodepressor response to des-Arg9-BK (0.6 nmol kg-1) but not to BK (0.6 nmol kg-1) was significantly (P < 0.001) reduced by pretreatment with the selective B1 receptor antagonist, [Leu8]-des-Arg9-BK. Although both B1 and B2 receptor antagonists caused a transient fall in blood pressure, their inhibitory action was unlikely to be related to a desensitization mechanism. 5. Inhibition of prostaglandin synthesis with indomethacin prevented the vasodepressor response induced by arachidonic acid (1 mg kg-1, i.v.) but not that to BK or des-Arg9-BK (0.6 nmol kg-1). 6. These results suggest, firstly, that the vasodepressor responses to i.v. BK and des-Arg9-BK are mediated by the activation of B2 and B1 receptors, respectively; secondly, that prostaglandins are not involved in the vasodepressor responses to kinins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epicardial distribution of ST segment and T wave changes produced by stimulation of intrathoracic ganglia or cardiopulmonary nerves in dogs

Sixty-three ventricular epicardial electrograms were recorded simultaneously in 8 atropinized dogs during stimulation of acutely decentralized intrathoracic autonomic ganglia or cardiopulmonary nerves. Three variables were measured: (1) isochronal maps representing the epicardial activation sequence, (2) maps depicting changes in areas under the QRS complex and T wave (regional inhomogeneity of repolarization), and (3) local and total QT intervals. Neural stimulations did not alter the activation sequence but induced changes in the magnitude and polarity of the ST segments and T waves as well as in QRST areas. Stimulation of the same neural structure in different dogs induced electrical changes with different amplitudes and in different regions of the ventricles, except for the ventral lateral cardiopulmonary nerve which usually affected the dorsal wall of the left ventricle. Greatest changes occurred when the right recurrent, left intermediate medial, left caudal pole, left ventral lateral cardiopulmonary nerves and stellate ganglia were stimulated. Local QT durations either decreased or did not change, whereas total QT duration as measured using a root-mean-square signal did not change, indicating the regional nature of repolarization changes. Taken together, these data indicate that intrathoracic efferent sympathetic neurons can induce regional inhomogeneity of repolarization without prolonging the total QT interval.     

Contribution of glucose tolerance and plasma insulin levels to the relationships between body fat distribution and plasma lipoprotein levels in women.

Numerous interrelated metabolic and morphological variables such as plasma insulin levels, glucose tolerance and abdominal obesity are associated with changes in plasma lipoprotein levels. The present study was undertaken to differentiate, using a multivariate approach, the respective contributions of plasma glucose and insulin levels, obesity and regional adipose tissue distribution to the variance in plasma lipoproteins. The study group was composed of 69 healthy premenopausal women (age 35.4 +/- 5.0 years (mean +/- s.d.); percent body fat 40.7 +/- 10.1). Indices of carbohydrate metabolism showed significant univariate correlations with triglyceride (TG) and/or cholesterol (CHOL) content of plasma VLDL, LDL and HDL (P less than 0.05). Multivariate analyses indicated that the explained variance in plasma VLDL-TG (R2 x 100 = 44 percent, P less than 0.05) and LDL-apoprotein (apo) B levels (R2 x 100 = 33.1 percent, P less than 0.08) was entirely accounted for by indices of carbohydrate metabolism and body fat distribution, whereas total body fatness added no significant contribution to these models. Multivariate analyses also revealed that the best possible regression model to predict the variation in plasma HDL2-CHOL levels only included computed tomography-derived deep abdominal adipose tissue area (P less than 0.0001). All other variables were unable to further improve the explained variance in plasma HDL2-CHOL levels. In partial correlation analyses, indices of carbohydrate metabolism and the waist-to-hip circumference ratio (WHR) remained significantly correlated with plasma VLDL-TG and LDL-apo B levels after adjustment of VLDL-TG and LDL-apo B for either insulin and glucose levels, or for the WHR (P less than 0.08). After correcting for deep abdominal fat accumulation, no significant correlation was observed between indices of carbohydrate metabolism and plasma HDL2-CHOL levels whereas deep abdominal fat showed significant correlations with HDL2-CHOL levels (P less than 0.05) after correction for indices of carbohydrate metabolism. These results suggest that both disturbances in glucose-insulin homeostasis and abdominal obesity are significantly associated with changes in plasma VLDL-TG and LDL-apo B levels and that these associations are partly independent from each other. These results also indicate that mechanisms other than disturbances in glucose homeostasis and hyperinsulinemia are responsible for the association between the level of deep abdominal fat and plasma HDL2-CHOL levels.     

Lung hydrolases in paraquat poisoning: early response of alkaline phosphatase

In order to evaluate the early response of the alveolar epithelium following lung injury, male Long-Evans adult rats (280-350 g) were treated with a single dose (30 mg/kg, ip) of the herbicide paraquat. No animal died during the 72 h that followed the acute administration of the herbicide. When compared to control, total lipid, phosphatidylcholine, and disaturated phosphatidylcholine contents of lung homogenates from the paraquat-treated rats were significantly reduced 48 h postdose (respectively 10, 24, and 37%). Comparatively, the total lung alkaline phosphatase activity was significantly reduced as early as 12 h postdose, and by 48 h the activity had decreased by approximately 50%. Although a significant decrease in total lung acid phosphatase activity was observed 24 and 48 h after the treatment, the effect was much less than with the alkaline phosphatase activity (15% versus 50%, respectively). The lysosomal beta-N-acetylglucosaminidase and the cytoplasmic lactate dehydrogenase activities were not affected by the herbicide treatment. A subcellular fractionation of the treated lungs showed that 48 h postdose, the total alkaline phosphatase activities associated with lamellar body and surfactant fractions were decreased respectively by 60% and 49%. Due to the intrinsic association of a strong alkaline phosphatase activity with the pulmonary surfactant system, these data suggest that the monitoring of the alkaline phosphatase activity in lung fractions could represent an early and sensitive indicator of toxicity to the alveolar epithelium, most probably to type II cells.     

Tumor vascular signals in renal masses: detection with Doppler US

The vascularity of 49 renal masses (26 malignant and 23 benign lesions) was investigated with duplex Doppler ultrasound. Doppler signals obtained at the margins of renal masses were defined as "tumor signals" when the Doppler-shifted frequency of the lesion exceeded the frequency shift in the ipsilateral main renal artery. These exceeded 2.5 kHz with a 3-MHz insonating frequency. Among the 26 renal masses that subsequently proved to be malignant, tumor signals were obtained in 15 of 18 (83%) untreated renal cell carcinomas, in three of four Wilms tumors, and in two patients with metastases to the kidney, but not in the one patient with lymphoma. None of the 23 benign renal masses demonstrated tumor signals. Tumor vascularity in malignant lesions gives rise to abnormal, high-velocity, Doppler-shifted signals that can help in the differential diagnosis of renal masses.     

Predicting development of sustained unresponsiveness to milk oral immunotherapy using epitope-specific antibody binding profiles

1. Download high-res image (260KB)
2. Download full-size image

     

ROMK1 (Kir1.1) causes apoptosis and chronic silencing of hippocampal neurons

Lentiviral vectors were constructed to express the weakly rectifying kidney K(+) channel ROMK1 (Kir1.1), either fused to enhanced green fluorescent protein (EGFP) or as a bicistronic message (ROMK1-CITE-EGFP). The channel was stably expressed in cultured rat hippocampal neurons. Infected cells were maintained for 2-4 wk without decrease in expression level or evidence of viral toxicity, although 15.4 mM external KCl was required to prevent apoptosis of neurons expressing functional ROMK1. No other trophic agents tested could prevent cell death, which was probably caused by K(+) loss. This cell death did not occur in glia, which were able to support ROMK1 expression indefinitely. Functional ROMK1, quantified as the nonnative inward current at -144 mV in 5.4 mM external K(+) blockable by 500 microM Ba(2+), ranged from 1 to 40 pA/pF. Infected neurons exhibited a Ba(2+)-induced depolarization of 7 +/- 2 mV relative to matched EGFP-infected controls, as well as a 30% decrease in input resistance and a shift in action potential threshold of 2.6 +/- 0.5 mV. This led to a shift in the relation between injected current and firing frequency, without changes in spike shape, size, or timing. This shift, which quantifies silencing as a function of ROMK1 expression, was predicted from Hodgkin-Huxley models. No cellular compensatory mechanisms in response to expression of ROMK1 were identified, making ROMK1 potentially useful for transgenic studies of silencing and neurodegeneration, although its lethality in normal K(+) has implications for the use of K(+) channels in gene therapy.