Citations

Studies of normotensive offspring of hypertensive parents offer the potential to identify inherited abnormalities that contribute to essential hypertension. We compared renal and systemic hemodynamic responses to saline infusion between normotensive sons of two hypertensive parents (SOHT) and sons of two normotensive parents (SONT) selected from the general population of Rochester, Minn. Hemodynamic measurements were performed after a week of low sodium intake (10 meq/day) and were repeated after a week of high sodium intake (200 meq/day). Despite being in the normotensive range, blood pressures in SOHT were higher than those in SONT during low sodium (124 +/- 3/85 +/- 3 versus 118 +/- 2/71 +/- 2 mm Hg, p less than 0.01) and high sodium (122 +/- 3/80 +/- 3 versus 112 +/- 2/70 +/- 2 mm Hg, p less than 0.05) conditions. Higher pressures in SOHT were associated with elevated systemic and renal vascular resistance. After a high sodium diet, renal vascular resistance in SOHT rose further during acute saline infusion, whereas systemic vascular resistance did not change. After a low sodium diet, this renal vasoconstrictor response to saline infusion in SOHT was not present, and renal vascular resistance fell to levels not different from SONT. Plasma renin activity, aldosterone, and atrial natriuretic peptide did not differ between SONT and SOHT. Circulating levels of norepinephrine were higher in SOHT. These data demonstrate a renal vasoconstrictor response to saline infusion in normotensive SOHT, which depends on prior sodium intake. This alteration in renal hemodynamics may represent an inherited abnormality related to the development of hypertension.

Case-control studies suggest that increased erythrocyte sodium-lithium countertransport may predict increased susceptibility to the development of essential hypertension. To characterize interindividual variation in sodium-lithium countertransport and its relation to blood pressure levels in the general population, we studied 1,475 Caucasians between 5 and 89 years of age (711 males and 764 females) ascertained through 266 households with children in the schools of Rochester, Minnesota. Individuals who were taking antihypertensive agents or combinations of estrogen and progesterone were not included in the sample. A third-order polynomial regression on age accounted for only a small fraction of variability in sodium-lithium countertransport (2.8% in males, p less than 0.001; 2.1% in females, p less than 0.01), whereas a fourth-order regression on age accounted for a large proportion of variability in systolic blood pressure (45.7% in males, p less than 0.001; 52.5% in females, p less than 0.001) and diastolic blood pressure (39.8% in males, p less than 0.001; 33.0% in females, p less than 0.001). Mean sodium-lithium countertransport was higher in males than females at all ages; but the rank order of male and female means for systolic and diastolic blood pressure was age dependent. Positively skewed distributions for age-, height-, and weight-adjusted sodium-lithium countertransport in male and female cohorts between 5-19.9, 20-49.9, and 50-89.9 years of age were explained significantly better by postulating a mixture of two partially overlapping sodium-lithium countertransport distributions rather than a single normal distribution (p less than 0.01). Among men in the 20-49.9-year-old cohort, adjusted sodium-lithium countertransport values in the upper distribution were associated with higher systolic and diastolic blood pressure (mean +/- SD) than values in the lower distribution (for systolic blood pressure: 115 +/- 11 vs. 111 +/- 11 mm Hg, p less than 0.07; for diastolic blood pressure: 71.2 +/- 8.0 vs. 68.4 +/- 8.6 mm Hg, p less than 0.08). Among females in the 50-89.9-year-old cohort, adjusted sodium-lithium countertransport values in the upper distribution were associated with significantly greater diastolic blood pressure than values in the lower distribution (77 +/- 10 vs. 70 +/- 9 mm Hg, p less than 0.03).(ABSTRACT TRUNCATED AT 400 WORDS)

To identify genes influencing blood pressure response to an angiotensin II receptor blocker, single nucleotide polymorphisms identified by genome-wide association analysis of the response to candesartan were validated by opposite direction associations with the response to a thiazide diuretic, hydrochlorothiazide. We sampled 198 white and 193 blacks with primary hypertension from opposite tertiles of the race-sex–specific distributions of age-adjusted diastolic blood pressure response to candesartan. There were 285 polymorphisms associated with the response to candesartan at P <10 −4 in whites. A total of 273 of the 285 polymorphisms, which were available for analysis in a separate sample of 196 whites, validated for opposite direction associations with the response to hydrochlorothiazide (Fisher χ 2 1-sided P =0.02). Among the 273 polymorphisms, those in the chromosome 11q21 region were the most significantly associated with response to candesartan in whites (eg, rs11020821 near FUT4 , P =8.98×10 −7 ), had the strongest opposite direction associations with response to hydrochlorothiazide (eg, rs3758785 in GPR83 , P =7.10×10 −3 ), and had the same direction associations with response to candesartan in the 193 blacks (eg, rs16924603 near FUT4 , P =1.52×10 −2 ). Also notable among the 273 polymorphisms was rs11649420 on chromosome 16 in the amiloride-sensitive sodium channel subunit SCNN1G involved in mediating renal sodium reabsorption and maintaining blood pressure when the renin-angiotensin system is inhibited by candesartan. These results support the use of genomewide association analyses to identify novel genes predictive of opposite direction associations with blood pressure responses to inhibitors of the renin-angiotensin and renal sodium transport systems.

Dietary sodium and blood pressure regulation differs between normotensive men and women, an effect which may involve endothelial production of nitric oxide (NO). Therefore, we tested the hypothesis that differences in the NO component of endothelium-dependent vasodilation between low and high dietary sodium intake depend on sex. For 5 days prior to study, healthy adults consumed a controlled low-sodium diet (10 mmol/day, n = 30, mean age ± SE: 30 ± 1 yr, 16 men) or high-sodium diet (400 mmol/day, n = 36, age 23 ± 1 yr, 13 men). Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of acetylcholine (ACh, 4 μg·100 ml tissue−1·min−1) were measured before and after endothelial NO synthase inhibition with NG-monomethyl-l-arginine (l-NMMA, 50 mg bolus + 1 mg/min infusion). The NO component of endothelium-dependent dilation was calculated as the response to ACh before and after l-NMMA accounting for changes in baseline FBF: [(FBF ACh − FBF baseline) − (FBF AChL-NMMA − FBF baselineL-NMMA)]. This value was 5.7 ± 1.3 and 2.5 ± 0.8 ml·100 ml forearm tissue−1·min−1 for the low- and high-sodium diets, respectively (main effect of sodium, P = 0.019). The sodium effect was larger for the men, with values of 7.9 ± 2.0 and 2.2 ± 1.4 for men vs. 3.1 ± 1.3 and 2.7 ± 1.0 ml·100 ml forearm tissue−1·min−1 for the women ( P = 0.034, sex-by-sodium interaction). We conclude that the NO component of endothelium-dependent vasodilation is altered by dietary sodium intake based on sex, suggesting that endothelial NO production is sensitive to dietary sodium in healthy young men but not women.