Atrial natriuretic peptide (ANP) binds to natriuretic peptide receptor-A (NPR-A), a membrane guanylyl cyclase, and to natriuretic peptide receptor-C (NPR-C), which plays a role in peptide clearance. Rat ANP (rANP) mutants that bind rat NPR-A selectively over rat NPR-C were isolated from randomized libraries of rANP-display phage by differential panning. One variant was identified with reduced NPR-C binding; rANP (G16R, A17E, Q18A) [rANP(REA18)]. Synthetic rANP(REA18) was equipotent with rANP in stimulating cGMP production from cloned rat NPR-A (ED 50 ϭ 1.8 nM) and was reduced in NPR-C binding by ‫ف‬ 200-fold. When infused into conscious rats at 0.325 g/min for 30 min rANP elicited an identical decrease in blood pressure compared with 0.25 g/min of rANP(REA18), however the natriuretic ( P Ͻ 0.05) and diuretic ( P ϭ 0.07) responses to rANP(REA18) were greater. These data are consistent with a role for NPR-C as a local decoy receptor attenuating NPR-A effects in the kidney, where these receptors are coexpressed. Improved NPR-A specificity could provide more effective natriuretic peptides for treatment of acute renal failure or heart failure. ( J. Clin. Invest . 1996. 98:969-976.)

No abstract

A dominant major locus (allele frequency of .0025 +/- .0014), resulting in low levels of high density lipoprotein cholesterol (HDL-C), was revealed by likelihood analysis on 2,170 persons in 55 Utah pedigrees. This allele was expressed through HDL-C levels ranging from 20 to 30 mg/dl in seven persons in two pedigrees. Early coronary heart disease was associated with the allele in one pedigree, but not in the other. In the pedigree without associated heart disease, HDL subfractions HDL2 and HDL3 were both low in individuals with the low HDL-C allele. No other major locus determining either high or low levels of HDL-C was identified in our sample. Polygenic heritability as part of the mixed model was estimated as .561 +/- .035.

Household effects accounted for significant proportions of the observed variance of high density lipoprotein cholesterol (HDL-C) and subfractions HDL2 and HDL3. It was found that 19.3% of HDL-C variance could be attributed to a juvenile sib effect (under age 18); 17.4% of HDL2 variance could be attributed to a sib effect (of any age); and 22.1% and 32.6% of the HDL3 variance could be attributed to a parent-offspring effect and a sib effect (of any age), respectively. In addition, additive genetic effects accounted for 56.5%, 37.3%, and 28.3% of the variances of HDL-C, HDL2, and HDL3, respectively. These are maximum likelihood estimates obtained using a variance components model on 2,149 HDL-C levels measured on members of 54 Utah pedigrees, and 337 HDL2 and HDL3 levels measured on a subset of 14 pedigrees.

Spouse-spouse, sib-sib, and parent-offspring correlations were calculated for urinary, plasma, and intracellular sodium levels on over 1,900 persons aged 3-86 years in 98 Utah kindreds. For 36 hours prior to their clinic visit, 31% of the sample was salt-loaded with salt tablets, while the rest followed their normal diet. For those on their normal diet, urine creatine-, age-, and sex-adjusted urinary sodium excretion from a timed 12-hour overnight sample showed similar and significant correlations between spouses (r = .29), sibs less than 20 years old (r = .38), and parent-offspring pairs for offspring less than 20 years old (r = .29). This contrasted with the lower correlations between sibs 20 years of age and older (r = .10) and parent-offspring pairs for offspring 20 years of age and older (r = .13), presumed to live in different households. Adult plasma sodium sib-sib (r = .13) and parent-offspring (r = .15) correlations were similar to the urinary sodium correlations, while the spouse-spouse (r = .48), the sib-sib (r = .64), and the parent-offspring (r = .63) correlations for those presumed to live in the same household nearly doubled. Intracellular sodium correlations for the adult sibs (r = .32) and offspring (r = .36) were over twice as large as for urinary or plasma sodium, although the spouse-spouse correlation (r = .37) remained large also.(ABSTRACT TRUNCATED AT 250 WORDS)