W. Spiering

Angiotensin II Sensitivity Is Associated With the Angiotensin II Type 1 Receptor A 1166 C Polymorphism in Essential Hypertensives on a High Sodium Diet

Several investigations have shown heterogeneity in the functional responses to angiotensin II (Ang II) in patients with essential hypertension. The present study was initiated to evaluate whether the A1166C polymorphism of the Ang II type 1 receptor (AT1R) gene contributes to this variability in Ang II responses. After 7 days of a high-sodium diet (220 mmol Na+ per day), we measured in 42 essential hypertensive patients blood pressure, heart rate, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), active plasma renin concentration, aldosterone, and atrial natriuretic peptide (ANP) before and during Ang II infusion (increasing doses of 0.3, 1.0, and 3.0 ng/kg per minute). Calculated variables were filtration fraction and renal vascular resistance (RVR). Patients in the 3 genotype groups (AA : n=14;AC : n=17;CC : n=11) were matched for gender, age, and body mass index. At baseline, CC patients had decreased GFR (P =0.06) and aldosterone (P <0.05) and increased ANP (P <0.05) compared with AA patients. Moreover, responses of ERPF, GFR, and RVR to the lowest concentration of Ang II (0.3 ng/kg per minute) were more pronounced in CC patients than in AA patients (ERPF/GFR:P <0.05; RVR:P =0.07), whereas maximal responses were all comparable between the groups. Heart rate was decreased at all levels of Ang II infusion in CC patients, while it did not change in AA or AC patients. There were no differences in responses of active plasma renin concentration, aldosterone, and ANP to Ang II between the 3 groups. From these data, we conclude that the C allele of the AT1R A1166C polymorphism is associated with increased sensitivity but not reactivity to Ang II. An augmented response to Ang II may well be responsible for the increased incidence of cardiovascular abnormalities found in patients with 1 or 2 C alleles.

Effects of ACE I/D and AT1R-A1166C polymorphisms on blood pressure in a healthy normotensive primary care population: first results of the Hippocates study

Background Several studies have assessed the relationship between the angiotensin-converting enzyme (ACE) I/D or angiotensin II type 1 receptor (AT1R)-A1166C polymorphisms and blood pressure (BP). Since most data have been obtained in selected populations, the present study was performed in a healthy normotensive primary care population. Objective To investigate the individual effects of the aforementioned polymorphisms and their interaction on BP. Methods This cross-sectional study included 198 healthy subjects. Office BP was measured and polymorphisms were genotyped (polymerase chain reaction). Polymorphism interaction was tested using the following model: systolic blood pressure (SBP) (or diastolic blood pressure, DBP) = b0 + b1X + b2Y + b3XY, in which X and Y represent the polymorphisms’ risk alleles. Results The ACE I/D polymorphism was associated with SBP (P = 0.002) and DBP (P = 0.004); highest pressures tracked with the DD genotype. Furthermore, in multiple linear regression analysis the ACE D allele was associated with SBP (P = 0.005) and DBP (P = 0.001), when adjusted for body mass index (BMI) and age. With respect to the AT1R-A1166C polymorphism, SBP was highest in the CC genotype (P = 0.025). In linear regression analysis the C allele was not associated with SBP. No synergistic effect of ACE D and AT1R C alleles on BP was found. Nevertheless, highest DBP tracked with the DDCC combination in comparison with other homozygous allele combinations (P = 0.030). Conclusions This study confirmed an association of ACE I/D and AT1R-A1166C polymorphisms with BP in a healthy normotensive primary care population. Although synergistic effect of both polymorphisms on BP does not seem to be present, an additive effect on DBP is likely.

Comparison of impedance cardiography and dye dilution method for measuring cardiac output

Objective To assess the degree of agreement between impedance cardiography, using the NCCOM3-R7 device, and the gold standard—the dye dilution method—both under basal conditions and after stimulation of cardiac output. Patients 35 paired measurements in five healthy male volunteers. Interventions To obtain higher levels of cardiac output, cardiac performance was stimulated with a dopamine infusion. Results In 35 paired measurements, the mean of all the impedance values was higher than that of the dye dilution values, at 10.2 v 7.4 l/min (p < 0.0001). The mean discrepancy between the two methods was 3.3 l/min, and the mean bias −2.9 l/min, with limits of agreement of −9.0 and 3.2 l/min. A change in cardiac output could not adequately be predicted by the NCCOM3-R7. In 20 of 25 measurements obtained during continuous intravenous dopamine infusions there was a rise in dye dilution cardiac output (range 0.2 to 5.9 l/min). Neither the magnitude nor the direction of the change in dye dilution values corresponded with the change measured by impedance cardiography. The mean discrepancy here between the two methods was 1.8 l/min, and the mean bias −0.8 l/min, with limits of agreement of −4.9 and 3.3 l/min. Conclusions In healthy volunteers, impedance cardiography with NCCOM3-R7 is inadequate for assessing cardiac output when compared with the dye dilution method.

Dissociation between the renal effects of angiotensin I and II in sodium-restricted normal subjects

OBJECTIVE To determine whether the effects of angiotensin I (AngI) in humans can be explained entirely by its plasmatic conversion to angiotensin II (AngII). METHODS Ten healthy male volunteers on a sodium-restricted diet were studied on two separate occasions. during which, in random order, AngI or AngII was infused in increasing doses of 0.3, 1 and 3 pmol x kg-1 x min-1. Mean arterial pressure (MAP), effective renal plasma flow (ERPF), glomerular filtration rate (GER), active plasma renin concentration (APRC), AngII, aldosterone (Aldo) and catecholamines were assessed at baseline, after each dose of AngI or AngII and 30 and 60 min after discontinuation of the AngI/AngII infusion. RESULTS The rise in plasma AngII was significantly less during AngI infusion as compared to AngII infusion (P < 0.05). Changes in MAP, Aldo and GFR, however, were compatible during both infusions. In the kidney, on the other hand, the decrements in APRC and ERPF during AngII infusion exceeded those during AngI (P < 0.05). After cessation of either infusion. AngII concentrations, MAP, ERPF and Aldo returned to baseline levels within 1 h. Renin, however, was still significantly inhibited at that time (P < 0.05). Catecholamines remained virtually unchanged during all experiments. CONCLUSIONS Our data show that AngI and AngII have similar effects on blood pressure and Aldo, but they differ in their renal effects. The latter may be due to a low renal capacity to convert AngI. The prolonged inhibition of renin release after cessation of the infusions may be caused by reduced renin mRNA expression or by accumulation of AngII in the kidney.

Unravelling gene interactions to find the cause of artherosclerosis, a multigenic disease, using an artificial neural network

To understand the etiology of multigenic diseases like atherosclerosis, a polymerase chain reaction (PCR) based gene array containing 65 single nucleotide polymorphisms (SNPs) was analyzed. To asses the possibilities of pattern recognition techniques in detecting unfavorable genetic combinations, two approaches were analysed. A selection of these 65 SNPs formed the input both to binary logistic regression models and to self-learning artificial neural networks (ANNs). Repeated analyses showed that both methods performed equally well. Further research to improve the differentiating power of both methods should focus first on decreasing the number of otherwise indeterminable polymorphisms.

Genetics of Hypertension

High blood pressure is a common and major risk factor for cardiovascular disease. Still, the pathogenesis of essential hypertension remains incompletely understood. It is generally felt that different factors may contribute in an individual patient. Among those that have been intensively studied are salt intake, obesity and insulin resistance, the renin-angiotensin system, and the sympathetic nervous system. In the past few years, research has been increasingly directed towards the genetics of hypertension.