Neprilysin Inhibitors: Filling a Gap in Heart Failure Management, Albeit Amidst Controversy and at a Significant Cost.

Dual angiotensin and neprilysin inhibition using the combination drug sacubitril-valsartan has ushered in a new era in the treatment of heart failure (HF). The randomized controlled PARADIGM-HF trial, which randomized 8399 patients with HF to enalapril or sacubitril-valsartan, showed a 20% reduction in mortality and HF hospitalization with the new drug. This has been heralded as a step toward filling a crucial gap in HF management by providing strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin-angiotensin system alone in stable patients with chronic HF as it negates the deleterious effects of angiotensin while concomitantly augmenting the beneficial effects of the endogenous natriuretic peptide system. This new therapy is costly, and other confirmatory studies have been lacking for over 2 years since its approval by major regulatory authorities. As such, controversy and heated discussions have amassed, as has detailed information from a plethora of secondary analyses of this pivotal trial about the pros and cons of this promising new therapeutic strategy in HF management. The aim of this review was to provide a critical assessment of all these aspects.

Postpartum assessment of the renin angiotensin system in women with previous severe, early-onset preeclampsia.

CONTEXT: Women with a history of severe preeclampsia are at an increased risk for the development of vascular disease. OBJECTIVE: We hypothesized that abnormalities in the renin-angiotensin system (RAS) may be a predisposing factor. DESIGN AND SETTING: Physiological assessments were conducted at an academic center. PARTICIPANTS: Sixteen women with previous severe preeclampsia (PPE) were compared with nine previously pregnant controls (PPC) and 11 never-pregnant controls (NPC). INTERVENTIONS: Baseline circulating components of the RAS and expression of angiotensin (ANG) II type I (AT1) and type II (AT2) receptors in the skin were assessed along with the response to simulated orthostatic stress using incremental lower-body negative pressure (LBNP: -15, -25, and -40 mm Hg) and a graded ANG II infusion (1 and 3 ng/kg · min). MAIN OUTCOME MEASURES: Response to LBNP and ANG II was evaluated. RESULTS: RAS components were not different between previously pregnant groups, but were decreased compared with NPC subjects. In response to LBNP, there were significant increases in RAS components in all three groups, but the response to this stimulus was significantly lower and delayed in PPE subjects. Despite the blunted rise in circulating RAS mediators in PPE subjects, their blood pressure was maintained in 88% compared with only 33 and 55% in the PPC and NPC groups, respectively (P = 0.014). All three groups responded to the graded ANG II infusion with an increase in blood pressure that was significantly more pronounced in PPE subjects (P = 0.037) correlating with AT1/AT2 receptor expression. CONCLUSIONS: Alterations in the RAS in formerly preeclamptic patients may contribute to future vascular disease.

Olmesartan medoxomil: the seventh angiotensin receptor antagonist.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of olmesartan medoxomil, an angiotensin II receptor antagonist for the treatment of hypertension. DATA SOURCES: Information was obtained from MEDLINE searches (1996-April 2002) of English-language medical literature. Search terms included CS-866, olmesartan, olmesartan medoxomil, RNH-6270 (active metabolite of olmesartan), Benicar, angiotensin receptors, and antihypertensive agents. In addition, references from relevant articles were reviewed for additional citations. The authors independently reviewed literature identified in the searches. Studies evaluating olmesartan (i.e., abstracts, clinical trials, data on file with manufacturer) were considered for inclusion. STUDY SELECTION: All articles identified from data sources with pertinent information regarding olmesartan medoxomil were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: Olmesartan medoxomil is a competitively priced addition to the class of angiotensin II receptor antagonists. Monotherapy with olmesartan medoxomil in once-daily doses of 20-40 mg has produced significant reductions in systolic and diastolic blood pressure in hypertensive patients. Adverse effects have been minimal with olmesartan medoxomil, with dizziness being the only adverse effect occurring more often than with placebo in clinical trials. Additionally, animal studies indicate that olmesartan medoxomil may prove to be useful treatment for diabetic nephropathy, as well as atherosclerosis. CONCLUSIONS: Olmesartan medoxomil has a favorable safety and efficacy profile, with blood pressure-lowering effects comparable to those of other angiotensin receptor blockers (i.e., losartan, valsartan, irbesartan). At this time, formulary decisions will be driven primarily by economic issues. Theoretical benefits of olmesartan medoxomil in reducing atherogenesis and lowering angiotensin II concentrations better than the alternative agents will be determined only with more extensive research.

Structure elucidation and conformational properties of eprosartan, a non peptide angiotensin II AT1 antagonist.

A novel approach to treat hypertension is to interfere with the Renin-Angiotensin system (RAS) by blocking the binding of vasoconstrictive hormone Angiotensin II to the AT(1) receptor site. This approach led to the beneficial drug losartan (COZAAR) and other similar in structure to the antihypertensive drugs (sartans). In an effort to compare the stereoelectronic features of pharmacophoric segments of the different sartans, a research activity was initiated in our laboratory related to the conformational properties of these drugs. In a previous study, the structural features which determine the pharmacophoric segments of losartan were examined. In this study, the conformational properties of eprosartan (TEVETEN), a drug with fewer side effects, were examined. In addition, the superimposition ability of losartan and eprosartan with the peptide antagonist sarmesin was studied.

Reduced atrial angiotensin receptor type 1 mRNA content in end-stage human heart failure: assessment by a novel quantitative PCR-ELISA technique.

The number of atrial angiotensin II binding sites is reduced in end-stage human heart failure. The goals of our study were the development of a quantitative polymerase chain reaction for angiotensin II receptor type 1 mRNA to determine the angiotensin receptor type 1 (AT1) mRNA content in the atria of patients with end-stage heart failure. We established a quantitative PCR based on coamplification of AT1 wild-type and an internal standard in the same PCR, followed by liquid-phase hybridization of PCR products in microtiter plates and quantitation by ELISA. Glyceraldehyde phosphate dehydrogenase mRNA in the same samples was used to relate the AT1 mRNA content to a stably expressed reference gene. Atrial samples from 11 patients with end-stage heart failure obtained at cardiac transplantation were compared with atrial samples from 11 patients with normal cardiac function undergoing routine cardiac surgery. A PCR/ELISA system with a variance of about 6% after reverse transcription and a linear measuring range was established. In the samples from 11 patients with end-stage heart failure a 58% decrease in AT1 mRNA content was found in comparison with 11 controls (heart failure: 185,680 +/- 196,912 AT1 mRNA copies/microgram RNA, controls: 440,555 +/- 268,456, P < 0.02). When AT1 mRNA content was related to glyceraldehyde phosphate dehydrogenase mRNA, a 65% decrease was detected (AT1/glyceraldehyde phosphate dehydrogenase: heart failure: 4.84 +/- 5.18; controls: 13.74 +/- 7.77; P < 0.005). Standardization of PCR resulting in a low coefficient of variance, high reproducibility, and large sample capacity is possible using optimal internal standardization and the liquid-phase hybridization/ELISA system for detection. The optimized PCR procedure indicated downregulation of atrial AT1 in end-stage human heart failure, suggesting a reduced capacity of the atria to respond to angiotensin II stimulation in end-stage heart failure.

Angiotensin II receptor in human placental syncytiotrophoblast plasma membranes.

Previous studies have reported the presence of high-affinity angiotensin II (Ang II) binding sites in human placental tissue, but it has not been determined whether these are located in brush border (BBM) or basolateral plasma (BPM) membranes of the syncytiotrophoblast. Our findings provide no evidence for Ang II receptors in BBM, yet they reveal a single class of binding sites in BPM preparations (Kd of 4.08+/-0.61 nM and B(max) of 2368.7+/-658.2 fmol/mg protein). Pharmacological characterization also revealed that this receptor was an AT1 receptor subtype. Moreover, isoelectric focusing analysis demonstrated a predominant Ang II-receptor complex migrating to pl 7.0, and two minor receptors at pl 7.2 and 6.5. These data suggest a physiological role of the renin-angiotensin system on syncytiotrophoblast BPM in regulating placental function.