Resistance artery phosphoinositide metabolism in genetic hypertension


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Abstract

Precapillary resistance arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) were found to contain three inositol lipids and to produce five inositol phosphate peaks. These were assessed by a highly sensitive procedure which involved the separation of radiolabelled inositol-containing components by anion-exchange high-performance liquid chromatography. Basal levels of radiolabelled inositol lipids were found to be significantly increased in SHR at 5 weeks of age, and also increased at 12 weeks, although this was only statistically significant for glycerophosphoinositol. At 5 weeks of age, exposure to a maximal concentration of noradrenaline brought about a significant increase in lipid radioactivity in WKY and in glycerophosphoinositol and glycerophosphoinositol 4-phosphate in SHR. The levels of these lipids remained significantly raised in the SHR at this time. At 12 weeks of age, exposure to noradrenaline produced reductions in radioactivity associated with inositol lipids. These new levels were elevated in SHR and significant for glycerophosphoinositol 4-phosphate. Basal levels of four inositol phosphates were not different between the two rat strains at 5 weeks of age. Inositol 1,3,4-trisphosphate was only present at minute levels and could not be measured. At 12 weeks of age, basal radiolabelling of inositol phosphates was not different between the two strains. The application of noradrenaline caused age-dependent changes in arterial inositol-containing compounds in both strains, which resulted in increased levels of inositol 1,4,5-trisphosphate in young SHR and also in adult rats in which the blood pressure level had become established. This abnormality in inositol lipid second-messenger metabolism in genetically hypertension-prone rats provides a mechanism by which the levels of cytosolic free calcium, which have been found to be raised in essential hypertension, would be increased, and the implication of the inositol lipid system in this process suggests that this system may be important in the cellular processes at work in structurally altering the vascular wall when the blood pressure is rising

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