Renal Haemodynamics are not Related to Genotypes in Offspring of Parents with Essential Hypertension

Abstract

Introduction. The pathogenesis of essential hypertension (EH) has a major genetic component and is associated with renal abnormalities. Normotensive offspring of hypertensive parents are likely to develop EH and are a suitable population for identifying possible relations between genetic and renal abnormalities. Methods. We investigated if renin-angiotensin-aldosterone system associated genotypes (angiotensinogen [M235T] and ACE [I/D]) are related to blood pressure (BP), renal haemodynamics and sodium excretion in sex and age-matched (18—35 years) healthy Caucasian offspring of either two parents with EH (n=101, EH-offspring) or two normotensive parents (n=50, controls). The alpha-adducin polymorphism (G460W) was also investigated. Results. Compared to controls, BP, heart rate, renal vascular resistance (RVR) and urinary sodium excretion were, respectively, 5%, 7%, 15% and 20% higher in EH-offspring. In controls, the TT-genotype of the M235T angiotensinogen polymorphism was associated with higher BP and higher plasma angiotensinogen. By contrast, in EHoffspring the TT-genotype was associated with lower BP and unchanged plasma angiotensinogen. Plasma angiotensinogen correlated positively with BP in EH-offspring, with a similar tendency (p=0.08) in controls. The distributions of the three candidate polymorphisms were similar in EH-offspring and controls. There were no associations between any of the polymorphisms and any of the renal parameters measured. Conclusion. The markedly greater RVR, proportionally larger than the greater BP, supports a role for RVR in the pathogenesis of EH. The lack of association between the candidate polymorphisms and the investigated parameters, even in this homogenous and for hypertension strongly predisposed group, suggests that the polymorphisms investigated do not play important roles in the pathogenesis of hypertension.

Treatment of Young Subjects at High Familial Risk of Future Hypertension With an Angiotensin-Receptor Blocker

“…22,24,26 In the present study, the reduction in renal vascular resistance corresponded to the reduction in blood pressure, and renal vascular resistance was still higher than that which we have measured in a parallel study in offspring of normotensive parents. 11 This suggests that the intervention did not have a specific effect on renal hemodynamics, as confirmed in other long-term studies on hypertensives. 27,28 A third possible reason is that the dose of candesartan (16 mg o.d.)…”

“…11 We suggest that the lack of rise could be attributable to the placebo-effect of the subjects, which can reduce blood pressure by a significant amount, as for example in the SYSTolic hypertension in EURope (SYS-EUR) trial 34 or to the natural history of blood pressure in these young study subjects.…”

“…If daytime AMBP exceeded 135 mm Hg systolic and/or 85 mm Hg diastolic, subjects were advised extra control of blood pressure at their general practitioner, and taken out of the study if treatment was started. Secondary outcomes were changes during intervention in mean AMBP, renal hemodynamics (determined using 51 Cr-EDTA and 125 I-hippuran as previously described 11 ; at month 12, 24-hour after last dose, with successful measurements in 89 subjects at both baseline and month 12), and LVMI (determined by 2-dimensional echocardiography 17,18 ); adverse events during intervention; plasma renin activity (determined by a double-sided immunoradiometric method, using two monoclonal antibodies against human-active renin linked to biotin and 125 I [Nichols Institute, Geneva, Switzerland]); angiotensin II (Ang II rabbit-antibody kindly provided by Prof Jan Danser, Rotterdam, Holland); aldosterone (measured in plasma by radioimmunoassay using DSL-8600 active aldosterone Coated-Tube Ria Kit, Diagnostics Systems Laboratories Inc, Webster, Tex). 11…”

“…We have included young normotensive persons for whom both parents had essential hypertension, and these were treated with candesartan or placebo for 1 year with 2-year follow-up. As we 11 and others 12,13 have shown, these individuals have early markers of cardiovascular disease including higher blood pressure, increased body mass index, increased left ventricular mass index (LVMI), and increased renal vascular resistance. Because we wanted the subjects to remain in the study throughout the intervention period, we included only subjects with diastolic blood pressure below 85 mm Hg at baseline.…”

Renal resistance and long-term blood pressure in individuals genetically predisposed for essential hypertension

“…However, findings of abnormal high renal resistance in off-spring of parents with hypertension render intrarenal vascular involvement in the very early stages of hypertension possible [19,20]. If elevated preglomerular resistance is important for the development of hypertension, a reduction of this parameter could prevent or postpone an increase in BP.…”