Erik Frandsen

Renal Effects of Aliskiren Compared With and in Combination With Irbesartan in Patients With Type 2 Diabetes, Hypertension, and Albuminuria

OBJECTIVE We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR). RESULTS Placebo geometric mean albuminuria was 258 mg/day (range 84–2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m2. Aliskiren treatment reduced albuminuria by 48% (95% CI 27–62) compared with placebo (P < 0.001), not significantly different from the 58% (42–79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59–79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3–8.8) ml/min per 1.73 m2 by aliskiren, 8.0 (3.6–12.3) ml/min per 1.73 m2 by irbesartan, and 11.7 (7.4–15.9) ml/min per 1.73 m2 by the combination. CONCLUSIONS The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.

Activity assays and immunoassays for plasma renin and prorenin: Information provided and precautions necessary for accurate measurement

BACKGROUND Measurement of plasma renin is important for the clinical assessment of hypertensive patients. The most common methods for measuring plasma renin are the plasma renin activity (PRA) assay and the renin immunoassay. The clinical application of renin inhibitor therapy has thrown into focus the differences in information provided by activity assays and immunoassays for renin and prorenin measurement and has drawn attention to the need for precautions to ensure their accurate measurement. CONTENT Renin activity assays and immunoassays provide related but different information. Whereas activity assays measure only active renin, immunoassays measure both active and inhibited renin. Particular care must be taken in the collection and processing of blood samples and in the performance of these assays to avoid errors in renin measurement. Both activity assays and immunoassays are susceptible to renin overestimation due to prorenin activation. In addition, activity assays performed with peptidase inhibitors may overestimate the degree of inhibition of PRA by renin inhibitor therapy. Moreover, immunoassays may overestimate the reactive increase in plasma renin concentration in response to renin inhibitor therapy, owing to the inhibitor promoting conversion of prorenin to an open conformation that is recognized by renin immunoassays. CONCLUSIONS The successful application of renin assays to patient care requires that the clinician and the clinical chemist understand the information provided by these assays and of the precautions necessary to ensure their accuracy.

Angiotensinogen Polymorphisms and Elevated Blood Pressure in the General Population: The Copenhagen City Heart Study

In the present study, we tested the hypothesis that the Met235Thr and Thr174Met mutations were associated or not with elevated blood pressure. We genotyped 9100 women and men from the Danish general population, of whom 54% had elevated blood pressure. Of the 9100, 41% and 12% carried the Thr235 and Met174 mutations, respectively; the Met174 mutation always occurred on the same allele as the Thr235 mutation. On multifactorial logistic regression analysis, women homozygous for Thr235 versus noncarriers had an odds ratio for elevated blood pressure of 1.29 (95% CI 1.05 to 1.58), which increased to 1.50 (1.15 to 1.96) if they also were homozygous for Thr174 (noncarrier of Met174). Women homozygous for Thr235 also had an increased risk of isolated elevated systolic blood pressure (1.37; 1.02 to 1.84) and of mild blood pressure elevation (1.40; 1.10 to 1.77). We found no statistically significant association between elevated blood pressure and genotype in men or among genotype and systolic blood pressure, diastolic blood pressure, or pulse pressure in either gender. Homozygosity for both Thr235 and Thr174 was associated with a 10% increase in plasma angiotensinogen levels in both genders compared with homozygosity for Met235 and Thr174; however, systolic and diastolic blood pressures were positively correlated to plasma angiotensinogen levels in women only. In conclusion, in this large-scale study of the general population, double homozygosity for Thr235 and Thr174 in the angiotensinogen gene is associated with a 10% increase in angiotensinogen levels and is a risk factor for elevated blood pressure in women but not in men.

Raised Plasma Aldosterone and Natriuretic Peptides in Atrial Fibrillation

Background and Aims: During atrial fibrillation (AF), the renin-angiotensin-aldosterone system (RAAS) may be activated.In this study, our aim was to evaluate at a long-term follow-up visit the levels of plasma aldosterone and natriuretic peptides as markers of neurohormonal remodeling in patients with earlier, documented AF in relation to present heart rhythm, clinical data, and the left ventricular ejection fraction (LVEF). We hypothesized that increased levels of aldosterone and natriuretic peptides were significantly associated with present AF as markers of RAAS activation during the arrhythmia. Methods: We studied 158 patients with earlier ECG-documented AF followed by restored sinus rhythm (SR) attending a follow-up visit 2.6 years (mean) after primary inclusion. Results: At follow-up, 93 patients had SR. Heart rhythm at follow-up visit (SR/AF), plasma aldosterone, plasma N-terminal pro Brain Natriuretic Peptide (Nt- proBNP), plasma N-terminal pro Atrial Natriuretic Peptide (Nt-proANP), LVEF, medication, and clinical characteristics were recorded. Standard linear multiple regression analysis including age, sex, weight, hypertension, congestive heart failure, ischemic heart disease, present AF at follow-up, total duration of AF disease, ongoing medication, and the LVEF as explanatory variables showed that only ongoing treatment with diuretics was significantly associated (likelihood ratio test, p = 0.0057) with a raised log-transformed plasma aldosterone, although present AF at follow-up was related to a high aldosterone level (p = 0.09). For the natriuretic peptides, present AF at follow-up (p < 0.0001), age (p < 0.0001), female gender (p = 0.0047), ischemic heart disease (p = 0.0154), and ongoing treatment with sotalol (p = 0.0003) were all independently associated with high log-transformed plasma Nt-proANP. Likewise, present AF at follow-up (p = 0.0008) as well as age (p < 0.0001) were associated with high log-transformed plasma Nt-proBNP. Conclusions: In patients with earlier AF, AF at long-term follow-up visit was independently associated with raised levels of Nt-proANP and Nt-proBNP and to some extent with plasma aldosterone indicating neurohormonal activation during arrhythmia.

Insulin‐like growth factor I administration induces fluid and sodium retention in healthy adults: possible involvement of renin and atrial natriuretic factor

Growth hormone induces fluid and sodium retention. The underlying mechanism is, however, incompletely understood. A possible mediator could be IGF‐I. To investigate the impact of IGF‐I administration on body fluid distribution and sodium homeostasis in healthy subjects, we examined normal subjects during six days IGF‐I treatment and during a six‐day control period.

Renal extraction and acute effects of glucagon-like peptide-1 on central and renal hemodynamics in healthy men

The present experiments were performed to elucidate the acute effects of intravenous infusion of glucagon-like peptide (GLP)-1 on central and renal hemodynamics in healthy men. Seven healthy middle-aged men were examined on two different occasions in random order. During a 3-h infusion of either GLP-1 (1.5 pmol·kg⁻¹·min⁻¹) or saline, cardiac output was estimated noninvasively, and intraarterial blood pressure and heart rate were measured continuously. Renal plasma flow, glomerular filtration rate, and uptake/release of hormones and ions were measured by Ficks Principle after catheterization of a renal vein. Subjects remained supine during the experiments. During GLP-1 infusion, both systolic blood pressure and arterial pulse pressure increased by 5±1 mmHg (P=0.015 and P=0.002, respectively). Heart rate increased by 5±1 beats/min (P=0.005), and cardiac output increased by 18% (P=0.016). Renal plasma flow and glomerular filtration rate as well as the clearance of Na⁺ and Li⁺ were not affected by GLP-1. However, plasma renin activity decreased (P=0.037), whereas plasma levels of atrial natriuretic peptide were unaffected. Renal extraction of intact GLP-1 was 43% (P<0.001), whereas 60% of the primary metabolite GLP-1 9-36amide was extracted (P=0.017). In humans, an acute intravenous administration of GLP-1 leads to increased cardiac output due to a simultaneous increase in stroke volume and heart rate, whereas no effect on renal hemodynamics could be demonstrated despite significant extraction of both the intact hormone and its primary metabolite.

Body fluids, circadian blood pressure and plasma renin during growth hormone administration: a placebo-controlled study with two growth hormone doses in healthy adults

Side effects that can be related to fluid retention are common during the initial phases of growth hormone (GH) administration. The aim of this study was to examine the changes in body fluid compartments, diurnal blood pressure and plasma renin concentration during GH administration with two different dosages in healthy adults. Eight healthy male subjects aged 24-32 years were examined during three 2-week study periods in a double-blind placebo controlled study. They received, in random order, GH (3 or 6 IU m-2 daily) or placebo during 2 weeks. Bio-impedance was measured every 2nd day, and extracellular volume (ECV) and plasma volume (PV) were isotopically determined at day 6. Blood samples were obtained regularly. Diurnal blood pressure was recorded and 24-h urinary samples were collected at days 0, 6 and 14. ECV (l) was increased by GH (placebo, 19.58 +/- 0.82; 3 IU m-2, 20.77 +/- 1.22; 6 IU m-2, 20.65 +/- 0.94; p<0.01), whereas PV (l) was unaffected (placebo, 3.91+/- 0.20; 3 IU m-2, 4.04 +/- 0.22; 6 IU m-2, 3.90 +/- 0.27). Total body water (l) increased significantly during GH administration (placebo, 50.8 +/- 2.6; 3 IU m-2, 52.6 +/- 2.3; 6 IU m-2, 53.9 +/- 1.8, p<0.05). After 6 days of treatment a significant increase in renin (p = 0.03) was observed. Mean diurnal blood pressure levels remained unchanged, whereas mean diurnal heart rate (min-1) increased significantly (placebo, 75 +/- 3.6; 3 IU m-2, 79 +/- 3.2; 6 IU m-2, 79 +/- 3.7; p<0.01). In conclusion, GH administration induces an elevation in total body water which may involve a stimulation of plasma renin and an increased ECV without any changes in PV or diurnal blood pressure.

Genetic Variation and Activity of the Renin-Angiotensin System and Severe Hypoglycemia in Type 1 Diabetes

BACKGROUND The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated. METHODS Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity. RESULTS Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia. CONCLUSIONS High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation.

Calcitonin gene-related peptide in cervicogenic headache.

Trigeminovascular activation is involved in the pathophysiology of migraine and cluster headache. The marker evaluated best for trigeminovascular activation is calcitonin gene-related peptide (CGRP) in the cranial circulation. It is unknown whether trigeminovascular activation plays any role in cervicogenic headache (CEH). The objective of this study was to investigate CGRP plasma levels in CEH patients in relation to headache state. To compare plasma CGRP levels between the peripheral and the cranial circulation. Blood from both external jugular veins and from the antecubital vein was drawn from 11 patients with CEH. Plasma CGRP levels were measured by radioimmunoassay. No difference was found between CGRP levels assessed on days with and without headache. There was no difference beween CGRP levels from the symptomatic and the asymptomatic external jugular vein and the antecubital vein. There is no evidence for an activation of the trigeminovascular system in CEH. In certain cases, clinical differentiation between CEH and migraine without aura is difficult. Plasma CGRP levels might serve as a biological marker to distinguish the two headache entities.

AT1 and AT2 Receptor Blockade and Epinephrine Release During Insulin-Induced Hypoglycemia

Angiotensin II facilitates epinephrine release during insulin-induced hypoglycemia, and this effect appears to be independent of type 1 angiotensin II (AT1) receptors in man. In the present study, we hypothesized that the action of angiotensin II on adrenomedullary epinephrine release is mediated by an AT2 receptor-dependent mechanism. In conscious chronically instrumented rats, we measured plasma concentrations of catecholamines during acute insulin-induced hypoglycemia in groups of rats pretreated with the AT1 receptor antagonist losartan (10 mg/kg i.v.), the AT2 receptor antagonist PD123319 (30 mg/kg i.v.), combined losartan + PD123319, the converting enzyme inhibitor enalapril (1 mg/kg i.v.), or vehicle. In vehicle-treated rats, the area under the curve for changes in plasma epinephrine concentration [AUC(plasma epinephrine)] during insulin-induced hypoglycemia was 111+/-8 nmolXh/L (+/-SEM). Pretreatment with losartan alone did not affect AUC(plasma epinephrine) (113+/-17 nmol x h/L), while pretreatment with PD123319 tended to reduce the response (87+/-10 nmol x h/L; P=.08 versus vehicle). However, AUC(plasma epinephrine) was significantly reduced in rats that were pretreated with combined losartan + PD123319 (68+/-5 nmol x h/L; P<.001 versus vehicle) or enalapril: 86+/-10 nmol x h/L (P<.05 versus vehicle). Thus, combined treatment with losartan + PD 123319 proved more effective in attenuating the reflex increase in plasma epinephrine concentration during hypoglycemia than either of the two AT receptor antagonists given alone. We speculate that angiotensin II through binding to both receptor subtypes facilitates the sympathoadrenal reflex response by actions at several anatomical levels of the neural pathways involved in the sympathoadrenal reflex response elicited during insulin-induced hypoglycemia.