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Rationale: Blood pressure reduction in response to antihypertensive agents is less for patients with obstructive sleep apnea (OSA). Increased sympathetic and inflammatory activity, as well as alterations in the renin-angiotensin-aldosterone system, may play a role in this context.Objectives: To address the cardiovascular mechanisms involved in response to an angiotensin II receptor antagonist, losartan, and continuous positive airway pressure (CPAP) as add-on treatment for hypertension and OSA.Methods: Newly diagnosed hypertensive patients with or without OSA (allocated in a 2:1 ratio for OSA vs. no OSA) were treated with losartan 50 mg daily during a 6-week two-center, open-label, prospective, case-control, parallel-design study. In the second 6-week, sex-stratified, open-label, randomized, parallel-design study, all subjects with OSA continued to receive losartan and were randomly assigned to either CPAP as add-on therapy or to no CPAP (1:1 ratio for CPAP vs. no CPAP). Study subjects without OSA were followed in parallel while they continued to take losartan. Blood samples were collected at baseline, after 6 weeks, and after 12 weeks for analysis of renin, aldosterone, noradrenaline, adrenaline, and inflammatory markers.Measurements and Main Results: Fifty-four patients with OSA and 35 without OSA were included in the first 6-week study. Losartan significantly increased renin levels and reduced aldosterone levels in the group without OSA. There was no significant decrease in aldosterone levels among patients with OSA. Add-on CPAP treatment tended to lower aldosterone levels, but reductions were more pronounced in measures of sympathetic activity. No significant changes in inflammatory markers were observed following treatment with losartan and CPAP.Conclusions: Hypertensive patients with OSA responded to losartan treatment with smaller reductions in aldosterone compared with hypertensive patients without OSA. Sympathetic system activity seemed to respond primarily to add-on CPAP treatment in patients with newly discovered hypertension and OSA. Clinical trial registered with www.clinicaltrials.gov (NCT00701428). [ABSTRACT FROM AUTHOR]

Aim: To search for a relationship between ultra-rapid metabolism catalysed by cytochrome P450 2C9 (CYP2C9) and its genotypes. Methods: DNA from a Swedish ultra-rapid metaboliser patient [losartan metabolic ratio (MR) <0.13] and three healthy Swedes with normal CYP2C9 activity and a MR of about 1 were assessed for variation in the CYP2C9 gene. Direct DNA sequencing was performed for all exons and exon-intron junctions and also for −2100 bp of the 5′-flanking regions of the CYP2C9 gene. This analysis revealed four intronic mutations [single nucleotide polymorphisms (SNPs) 1-4] in the three samples with normal MR while no variation was observed in the ultra-rapid metaboliser. PCR/restriction fragment length polymorphism and allele-specific PCR methods were subsequently developed to screen 85 Swedes and 128 Koreans without CYP2C9*2 or *3. Results: We found a significant relationship between SNP 4 (IVS8-109A>T) and CYP2C9 activity (χ-test, p = 0.011) in the Swedes. Twenty Swedes with the lowest MR were compared with 20 Swedes with the highest MR, revealing a strong association ( p = 0.001) between SNP4 and higher MR. For homozygous SNP 1 (IVS1+83T>C), SNP 2 (IVS2+73T>C), and SNP 3 (IVS6+95A>G), no phenotype and genotype relationships were found, but the MR was generally higher among the Swedes compared to the Koreans (Mann-Whitney test, p < 0.05). Conclusions: We found that the SNP 4 IVS8-109T allele is associated with a higher CYP2C9 MR in healthy Swedish subjects, but further investigations need to be carried out to establish a molecular explanation for ultra-rapid CYP2C9-catalysed metabolism. Haplotype based on SNPs 1-4 did not seem to contribute to variation in the MR of the Korean subjects nor play a role in determining the MR of the Swedish ones. [ABSTRACT FROM AUTHOR]

Background: Inhaled anesthetics cause a transient reversible depression of renal function by direct renal effects or indirectly by changes in neurohumoral systems or cardiovascular performance. When the sympathetic nervous activity is decreased during anesthesia, other vasoactive systems like vasopressin (AVP) and particularly the renin angiotensin system (RAS) are of importance for blood pressure maintenance. Little is known about how the renal circulation is affected by angiotensin receptor blockade during isoflurane anesthesia.Methods: The study was performed on isoflurane anesthetized sheep equipped with flow probes (placed around a femoral and a renal artery) and a pulmonary artery catheter. During stable conditions the sheep were given one or more of the following substances: isotonic saline (NaCl); losartan (LOS) 10 mg x kg(-1); prazosin (PRAZ) 0.2 mg x kg(-1) and a vasopressin V1-receptor antagonist (AVP-a) 10 microg x kg(-1).Results: LOS and AVP-a did not affect mean arterial pressure (MAP), whereas PRAZ lowered MAP significantly (from 98+/-12 to 65+/-7 mmHg). Renal blood flow (RBF) increased after LOS treatment (148+/-34 to 222+/-33 ml x min(-1)). The other substances were without effect on RBF. Femoral blood flow remained unchanged after all treatments.Conclusion: We conclude that the sympathoadrenal system is still the major determinant for blood pressure maintenance during isoflurane anesthesia in sheep. The apparently increased activity of the renin angiotensin system in this situation causes a reduction in renal blood flow, which is counteracted by angiotensin II AT1-receptor blockade. [ABSTRACT FROM AUTHOR]

In a 12-week, randomized, double-blind study, 24 patients with essential hypertension were given the angiotensin II antagonist losartan, or the beta-adrenoceptor blocker atenolol. Both drugs reduced blood pressure (BP) well, but losartan tended to reduce left ventricular mass (LVM) in contrast to atenolol. Following the double-blind phase 19 patients entered an open treatment period with losartan and additional treatment if BP was uncontrolled. LV structures were measured by echocardiography. The mean follow-up period was 29 +/- 2.6 (range 26-32) months. BP was reduced from 155.6 +/- 15.6/103.4 +/- 5.2 mm Hg to 131.3 +/- 10.5/82.7 +/- 3.3 mm Hg (P < 0.001). LV internal diameter was reduced (50.7 +/- 4.5 to 49.1 +/- 4.0 mm; P = 0.006), while there was an increase in interventricular septal thickness (10.2 +/- 1.1 to 11.2 +/- 1.3 mm; P = 0.001) and posterior wall thickness (10.0 +/- 0.9 to 10.6 +/- 1.1 mm; P = 0.023). Calculated LVM was not significantly altered during the follow-up period. In conclusion, losartan is effective in reducing BP during long-term treatment. No significant effect on LVM was observed, but there was an increase in LV wall thickness.