The purpose of this study was to elucidate the mechanism of the antihypertensive effect of the angiotensin I (Ang I) converting enzyme inhibitor captopril in spontaneously hypertensive rats (SHR). Drinking responses, peripheral vascular reactivity, and angiotensin II (Ang II) receptor binding in both the brain and vascular smooth muscle were examined in control and captopril-treated SHR. Pregnant and nursing dams were treated with oral captopril (100 mg/kg). After weaning, offspring were maintained on captopril (50 mg/kg). The average systolic pressures after 21 weeks of captopril treatment were 122 +/- 3 mm Hg (male) and 118 +/- 4 mm Hg (female) as compared with 169 +/- 4 mm Hg (male) and 162 +/- 2 mm Hg (female) in age-matched controls. Drinking responses to intracerebroventricular (10 ng) and subcutaneous (100 micrograms/kg) administration of Ang I and II were attenuated in captopril-treated SHR in comparison to control SHR. Ang II receptor binding in the hypothalamus, thalamus, and septum of captopril-treated SHR was also significantly reduced. In contrast to a depressed angiotensinergic system in the brain, peripheral vascular reactivity to Ang II, as determined in isolated, artificially perfused kidneys, was elevated. Threshold and ED50 values for Ang II were significantly lower in captopril-treated SHR than in controls. Ang II receptor binding in aortic smooth muscle cells prepared from captopril-treated SHR was also significantly greater than in cells from controls. Thus, lifetime treatment with captopril induced alterations in the renin angiotensin systems in the periphery and brain that were manifested by changes in receptor binding and responsiveness to Ang II.(ABSTRACT TRUNCATED AT 250 WORDS)
We layered fresh, unprocessed plasma from healthy rats with early (less than or equal to 7 days) or benign, chronic (greater than 3 wk) one-kidney, one-clip hypertension and from paired one-kidney normotensive control rats over confluent primary-cultured rat aortic smooth muscle cells. Plasma from all rats increased cellular ouabain-sensitive 86Rb+ uptake and sodium content and decreased ouabain-insensitive 86Rb+ uptake compared with uptakes and content in the presence of balanced salt solution (P less than 0.01). Cells incubated in the presence of plasma from rats with early (P less than 0.02) or chronic hypertension (P less than 0.01) had significantly reduced ouabain-sensitive 86Rb+ uptake when compared with cells incubated in normotensive plasma, but their intracellular Na+ contents were not lower. We no longer detected this uptake difference when chronic hypertensives drank 0.9% NaCl instead of water. Plasma from hypertensive rats also altered ouabain-insensitive 86Rb+ uptake by the cultured cells. These findings of this new, reproducible, and specific assay system support the hypothesis that plasma factors inhibit the membrane sodium-potassium pump in vascular smooth muscle cells in this form of hypertension. The abnormality occurs in both early and chronic stages, but may not be related to sodium intake. The data also provide evidence for plasma factors in hypertension altering membrane K+ permeability.
Transport and motility inhibitors have been used to classify different types of high-affinity cytochalasin B (CB) binding sites in 3T3 cells. The potency of phloretin and phlorizin as inhibitors of sugar uptake paralleled their effectiveness in displacing high-affinity bound CB from the cells, indicating that the two compounds compete with CB for binding to sites associated with sugar transport proteins. On the other hand, cytochalasins D and E, which did not inhibit sugar uptake, inhibited binding of CB to a portion of the high-affinity sites, most probably those associated with actin-containing cytoskeletal-contractile structures. A small amount of high-affinity CB binding remained in the presence of both phloretin and cytochalasin E, indicating that the cells have a third class of sites which is not related to either sugar transport or cell motility, When isolated membranes were examined, it was found that a fraction of each class of high-affinity CB binding sites were associated with the fraction. In contrast, only sites sensitive to cytochalasin D were recovered in a soluble extract of the cells.
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