Abstract-Polymorphic variants of the cytoskeletal protein adducin have been associated with hypertension in humans and rats. However, the direct role of this protein in modulating arterial blood pressure has never been demonstrated. To assess the effect of ␤-adducin on blood pressure, a ␤-adducin-deficient mouse strain (Ϫ/Ϫ) was studied and compared with wild-type controls (ϩ/ϩ). Aortic blood pressure was measured in nonanesthetized, freely moving animals with the use of telemetry implants. It is important to note that these mice have at least 98% of C57Bl/6 genetic background, with the only difference from wild-type animals being the ␤-adducin mutation. We found statistically significant higher levels of systolic blood pressure (mm Hg) (meanϮSE values: Ϫ/Ϫ: 126.94Ϯ1.14, nϭ5; ϩ/ϩ: 108.06Ϯ2.34, nϭ6; PՅ0.0001), diastolic blood pressure (Ϫ/Ϫ: 83.54Ϯ1.07; ϩ/ϩ: 74.87Ϯ2.23; PՅ0.005), and pulse blood pressure (Ϫ/Ϫ: 43.32Ϯ1.10; ϩ/ϩ: 33.19Ϯ1.96; PՅ0.001) in ␤-adducin-deficient mice. Western blot analysis showed that as a result of the introduced genetic modification, ␤-adducin was not present in heart protein extracts from Ϫ/Ϫ mice. Consequently, this deficiency produced a sharp decrease of ␣-adducin and a lesser reduction in ␥-adducin levels. However, we found neither cardiac remodeling nor modification of the heart function in these animals. This is the first report showing direct evidence that hypertension is triggered by a mutation in the adducin gene family. Key Words: hypertension, genetic Ⅲ adducin Ⅲ mice, knockout Ⅲ echocardiography Ⅲ cytoskeleton Ⅲ telemetry Ⅲ electrocardiography T he adducin protein family is composed of 3 members encoded by closely related genes: ␣-, ␤-, and ␥-adducin. 1,2 The ␣ and ␤ subunits, but not the ␥ subunit, are found in membrane cytoskeletons of human erythrocytes at the actin-spectrin junctions as a mixture of heterodimers and heterotetramers. Combinations of ␣/␤ and ␣/␥ oligomers are found in the actin cytoskeleton at cell-cell contact sites in other cells. 2,3 Adducin, an unexpected cytoskeletal player as blood pressure (BP) modulator, has been the subject of several association studies that attempted to link adducin variants to hypertension. Since the publication of the first positive association of adducin polymorphism with human hypertension, 4 contradictory results have appeared in the literature. In fact, the human ␣-adducin gene polymorphism (G460W) has been found to be significantly associated with hypertension and salt sensitivity in certain patient groups, 4 -8 although this observation was not confirmed by other groups. 9 -14 The attention to adducin in hypertension was originally drawn by a rat model (Milan hypertensive strain [MHS]), after our characterization of the ␣-and ␤-adducin-specific variants associated with high BP levels. 15 These mutated adducins lead to a higher level of filamentous actin, enhanced actin bundling in cell-free systems, and increased Na-K pump activity when transfected into kidney epithelial cells. 16 However, in both humans and rats, there...

We tested the hypothesis that pyridostigmine bromide (PB) intake and/or low-level sarin exposure, suggested by some as causes of the symptoms experienced by Persian Gulf War veterans, induce neurobehavioral dysfunction that outlasts their effects on cholinesterase. Adult male Sprague-Dawley rats were treated during 3 weeks with s.c. saline, PB in drinking water (80 mg/l), sarin (62.5 g/kg; 0.5ϫ LD 50 , three times/week s.c.), or PB in drinking water ϩ sarin. Animals were tested for passive avoidance, nociceptive threshold, acoustic startle, and open field activity 2, 4, or 16 weeks after treatment. Two weeks after sarin, acoustic startle was enhanced, whereas distance explored in the open field decreased. These effects were absent with PB ϩ sarin or PB by itself. No effect on any variable was found at 4 weeks, whereas at 16 weeks sarin induced a decrease and PB ϩ sarin induced an increase in habituation in the open field test. Nociceptive threshold was elevated in the PB ϩ sarin group at 16 weeks. No effect of treatment on passive avoidance was noted in any group. Brain regional acetylcholinesterase and cholineacetyltransferase activities were not affected at any time after treatment, but muscarinic receptors were down-regulated in hippocampus, caudate putamen, and mesencephalon in the sarin group at 2 weeks. In conclusion, this study gives further support to the use of PB against nerve agent poisoning and does not support the hypothesis that delayed symptoms experienced by Persian Gulf War veterans could be due to PB, alone or in association with low-level sarin exposure.

Mice deficient in monoamine oxidase A have previously been shown to demonstrate a chronic elevation of serotonin and norepinephrine in the brain. Using the autoradiographic [14C]iodo-antipyrine method, we examined cerebral cortical blood flow in conscious, restrained four- to five-month-old knock-out and wild-type animals following the intraperitoneal administration of either saline or D-fenfluramine. Knock-out animals administered saline, compared to their wild-type counterparts, demonstrated a significantly higher regional cortical blood flow in somatosensory and barrel field neocortex, an area which previous histological studies have shown to be characterized by abnormal serotonergic projection fibers and absent barrel formation. Regional cortical blood flow was significantly lower in knock-out than in wild-type mice in the entorhinal and midline motor cortex, with non-significant decreases noted in the olfactory, piriform and retrosplenial cortices and the amygdala. We compared the above findings to those obtained in response to D-fenfluramine which, in conjunction with its metabolite D-norfenfluramine, results in acute elevations of brain levels of serotonin and norepinephrine. Administration of D-fenfluramine (21. 2mg/kg) resulted in changes in regional cortical perfusion in most brain regions of both knock-out and wild-type mice that were opposite to the genotypic differences seen in perfusion in response to saline. Fenfluramine significantly increased regional cortical blood flow in the allocortex (olfactory, piriform, entorhinal) and the amygdala, and significantly decreased regional cortical blood flow in the somatosensory, barrel field, midline motor and retrosplenial cortices. Changes in regional perfusion in response to fenfluramine were topographically equivalent in knock-out and wild-type mice, although in knock-out mice such changes were of greater magnitude. Our study suggests that the effects on regional cortical blood flow of a lifelong absence of monoamine oxidase A, and the consequent chronic increase in serotonin and norepinephrine, differ from those attributable to acute increases in these neurotransmitters following fenfluramine administration. Such a differential response may reflect neurodevelopmental abnormalities and/or effects of a chronic physiological adaptation on the regulation of cortical activation.

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