Abstract-Essential hypertension has a familial predisposition, but the phenotype of elevated blood pressure has delayed penetrance. Because the kidney is a crucial determinant of blood pressure homeostasis, we studied early glomerular alterations in still-normotensive young subjects at genetic risk of hypertension. , although cGMP did not change during the amino acid infusion (Pϭ0.703). FH status, baseline GFR, and baseline serum insulin jointly predicted GFR response to amino acids (Pϭ0.0013), accounting for Ϸ45% of the variance in GFR response. Decline in FE Li ϩ, an inverse index of proximal tubular reabsorption, paralleled increase in GFR (rϭϪ0.506, Pϭ0.01), suggesting differences in proximal tubular reabsorption during amino acids between the FH groups. GFR response to amino acid infusion was blunted in the FHϩ group despite significantly higher serum concentrations of 6 amino acids (arginine, isoleucine, leucine, methionine, phenylalanine, and valine) in the FHϩ group, suggesting a novel form of insulin resistance (to the amino acid-translocating action of insulin) in FHϩ subjects. We conclude that blunted glomerular filtration reserve in response to amino acids is an early-penetrance phenotype seen even in still-normotensive subjects at genetic risk of hypertension and is linked to impaired formation of NO· in the kidney. Corresponding changes in GFR and fractional excretion of Li ϩ suggest that altered proximal tubular reabsorption after amino acids is an early pathophysiologic mechanism. Resistance to the amino acid-translocating actions of insulin may play a role in the biological response to amino acids in this setting. This glomerular reserve phenotype may be useful in genetic studies of renal traits preceding or predisposing to hypertension. (Hypertension. 2001;37:898-906.)

These results suggest that plasma amylin concentration is in part determined by heredity. Both basal and stimulated plasma amylin excess may identify a subgroup of individuals bearing an inherited predisposition to hypertension. Measurement of amylin might identify a useful 'intermediate phenotype' in the genetic analysis of essential hypertension and its relationship to insulin resistance.