Current Hypertension Reviews (v.8, #3)
Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets? by Xiang Wang, Ana-Maria Bosonea, Jeffrey Odenbach, Carlos Fernandez-Patron (159-180).
Hypertension, the condition characterized by sustained elevated blood pressure, affects over 25% of adults in developed countries and is accompanied by pathological cardiac remodeling (i.e., hypertrophy and fibrosis), thus being a major risk factor for cardiac failure. Life style, the environment, genetic factors, diabetes or obesity can all promote development and progression of hypertension associated cardiovascular disease in part because these conditions induce an excess production of pro-hypertensive, pro-hypertrophic and pro-fibrotic agonists. Here we review signaling pathways shared by major agonists including angiotensin II, catecholamines and endothelins. At the cellular level, these agonists initiate disease signaling by activating cognate G protein-coupled receptors (GPCRs). Early events in agonist-signaling include Ca2+ release from intracellular stores, Ca2+ uptake from extracellular millieu into cells and reactive oxygen species (ROS) generation by NADPH oxidase. ROS production in turn contributes to activation of matrix metalloproteinases (MMPs) and ‘a disintegrin and metalloproteinases’ (ADAMs). Activated MMPs and ADAMs cleave growth factors, cytokines as well as cell surface receptors, including GPCRs. Excessive activation of MMPs and ADAMs links agonist receptors with transcription and translation of disease-associated genes, including those of MMPs and ADAMs. Recent research indicates a complex and dynamic regulation of MMPs and ADAMs activity and expression by agonists, which poses a significant challenge to strategies aiming at targeting specific MMPs or ADAMs in cardiovascular disease.
TRP Channels: Emerging Links Between Ca2+, Kidney and Hypertension by Paolo Mene, Anna Giuliani, Jacopo Scrivano, Francesca Apponi, Giorgio Punzo, Nicola Pirozzi (181-189).
Cationic channels with variable selectivity for Ca2+, K+, and Na+ are ubiquitous in non-excitable tissues as well as contractile cardiac cells and vascular smooth muscle (VSMC). They are involved in multiple cell functions, including contraction and proliferation of VSMC, key to the regulation of vascular tone and blood pressure. A large superfamily includes at least 28 highly conserved heterotetramer homologues of Drosophila TRP (transient receptor potential) channels. Direct evidence exists for TRPC, TRPV, TRPP gating ion entry in vascular cells, as well as in epithelial cells of kidney and intestine, thus controlling homeostasis and external balance of divalent cations. Mice deficient in TRPV5 display phenotypic defects resembling human idiopathic hypercalciuria and impaired bone mineral density. Polycystin 2, encoded by the PKD2 gene, is an epithelial transmembrane TRPP2 protein, whose mutation is associated with autosomal dominant polycystic kidney disease (ADPKD). TRP ion channels may therefore play a role in the pathogenesis of systemic arterial hypertension, pulmonary hypertension, as well as hypertension complicating renal disease via effects on vascular tone and/or on the electrolyte composition of body fluids.
Review of Olmesartan Medoxomil in Achieving Guideline-Recommended Target BP Goals and Implications for Managed Care by Joseph J. Saseen (190-195).
Uncontrolled hypertension is directly associated with an increased risk of cardiovascular (CV) events and CV disease. Hypertension has been a major health care concern for decades, and numerous clinical guidelines recommend specific target blood pressure (BP) goals and evidence-based treatments. New data from outcomes studies continue to evolve after the publication of hypertension treatment guidelines. Considering the current environment of rising health care costs, managed care must continue to make decisions about how to best allocate resources for the management of hypertension. This paper reviews current clinical practice guidelines in hypertension and highlights the role that the angiotensin type II receptor blocker olmesartan medoxomil can play in the achievement and maintenance of recommended BP goals.
A Systematic Review of Randomized Controlled Trials Examining the Nephroprotective Properties of Antihypertensive Medications by Leslie Griffin, John B. Standridge (196-226).
Introduction: Despite improved control rates of hypertension in the United States during the last thirty years, the rate of chronic kidney disease and end-stage renal disease has not demonstrated a similar resultant improvement. Purpose: The purpose for this review is to determine interventions in the treatment of hypertension that improve outcomes in the promotion of nephroprotection. Method: A systematic comprehensive search of the National Library of Medicine utilizing Medline was conducted with search limits confined to randomized controlled trials. Results: Angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) are nephroprotective alone and in combination with other classes of antihypertensive agents, but can result in renal dysfunction when used in combination with each other or with a direct renin inhibitor (DRI). Older L-type calcium channel blockers (CCBs) can be nephrotoxic when used as monotherapy. CCBs are additionally nephroprotective when combined with ACEIs or ARBs. Thiazide-type diuretics (TTDs) with the exception of indapamide are not nephroprotective and TTDs may have nephrotoxic properties. Conclusion: ACEIs and ARBs are preferred first-line agents because they are effective in the prevention of renal as well as cardiovascular and cerebrovascular target organ damage associated with hypertension. CCBs are preferred when a second medication is needed for hypertension control. When diuretic therapy is indicated for hypertension control, indapamide is preferred over other TTDs for nephroprotection.
Prevention and Treatment of Cardiovascular Disease in Adolescents and Adults through the Transcendental Meditation® Program: A Research Review Update by Vernon A. Barnes, David W. Orme-Johnson (227-242).
The pathogenesis and progression of cardiovascular diseases are thought to be exacerbated by stress. Basic research indicates that the Transcendental Meditation® technique produces acute and longitudinal reductions in sympathetic tone and stress reactivity. In adolescents at risk for hypertension, the technique has been found to reduce resting and ambulatory blood pressure, left ventricular mass, cardiovascular reactivity, and to improve school behavior. Research on adults with mild or moderate essential hypertension has reported decreased blood pressure and reduced use of anti-hypertensive medication. The technique has also been reported to decrease symptoms of angina pectoris and carotid atherosclerosis, to reduce cardiovascular risk factors, including alcohol and tobacco use, to markedly reduce medical care utilization for cardiovascular diseases, and to significantly decrease cardiovascular and all-cause morbidity and mortality. These findings have important implications for inclusion of the Transcendental Meditation program in efforts to prevent and treat cardiovascular diseases and their clinical consequences. ®Transcendental Meditation and TM are trademarks registered in the US. Patent and Trademark Office, licensed to Maharishi Vedic Education Development Corporation and are used with permission.