A number of risk factors for cardiovascular disease, including
hypertension, are associated with the
insulin resistance syndrome. The hallmark of this syndrome is an impairment in
insulin action which provokes a compensatory increase in pancreatic beta-cell insulin secretion leading to chronic
hyperinsulinemia. Indirect studies show that
platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine, PAF), a potent
antihypertensive lipid produced by the kidney, may be decreased by
hyperinsulinemia. The present study was designed to evaluate the effect of chronic
hyperinsulinemia on renal PAF metabolism, arterial blood pressure and whole body
insulin sensitivity. Chronic catheterized, unstressed rats were infused with saline or
insulin plus
glucose to create a
chronic condition of sustained euglycemic (approximately 130 mg/dl)
hyperinsulinemia (approximately 90 mU 1. or 3-fold over basal levels). PAF is a metabolically unstable compound being susceptible to rapid degradation to the biologically inactive
lyso-PAF, a metabolite which also serves as a precursor for PAF synthesis. PAF synthesis and counter-regulatory
prostaglandins may be derived from the same arachidonate precursor. The
enzymes which catalyze these reactions were measured in plasma and in the subcellular fractions of the kidneys. Compared to saline-treated rats, sustained physiologic
hyperinsulinemia for 7 days: (i) decreased
insulin-mediated
glucose disposal by 30%; (ii) caused an increased plasma
PAF:acetylhydrolase, which degrades PAF to
lyso-PAF, without any change in cytosolic
PAF:acetylhydrolase activity; and (iii) completely inhibited microsomal
lyso-PAF:acetyl CoA acetyltransferase activity which catalyzes the conversion of
lyso-PAF back to bioactive PAF. The increased catabolism of PAF in plasma, combined with decreased renal PAF biosynthesis, would be expected to decrease circulating PAF levels leading to a rise in blood pressure. However, blood pressure remained unchanged. The sustained
hyperinsulinemia stimulated plasma membrane
CoA-independent transacylase activity, which is responsible for the mobilization of arachidonates into
lyso-PAF, to form l-alkylarchidonoyl-glycerophosphocholine. The latter is the stored precursor for the synthesis of PAF and vasodilatory
prostaglandins, which may have offset the effect of decreased PAF. We hypothesize that
hyperinsulinemia may alter the blood pressure only if the balance between the synthesis/catabolism of PAF and vasodilatory
prostaglandins is disrupted.