BAckgRound: The renin-angiotensin aldosterone system (RAAS) is a hormonal cascade that functions in the homeostatic control of arterial pressure, tissue perfusion, and extracellular volume. dysregulation of the RAAS plays an important role in the pathogenesis of cardiovascular and renal disorders.oBjecTIveS: To review the role of the RAAS in the development of hypertensive cardiovascular disease and related conditions and provide an overview of the classes of pharmacologic agents that inhibit this system. ReSulTS: The RAAS is initiated by the regulated secretion of renin, the rate-limiting enzyme that catalyzes the hydrolysis of angiotensin (Ang) I from the n-terminus of angiotensinogen. Ang I is in turn hydrolyzed by angiotensin-converting enzyme (Ace) to form Ang II, a potent vasoconstrictor and the primary active product of the RAAS. Recent evidence has suggested that other metabolites of Ang I and II may have biological activity, particularly in tissues. development of agents that block the RAAS (e.g., beta blockers, Ace inhibitors [AceIs], and angiotensin receptor blockers [ARBs]) began as a therapeutic strategy to treat hypertension. Preclinical and clinical studies have indicated important additional cardiovascular and renal therapeutic benefits of AceIs and ARBs. However, blockade of the RAAS with these agents is incomplete.concluSIon: Therapeutic approaches that target more complete inhibition of the RAAS may offer additional clinical benefits for patients with cardiovascular and renal disorders. These approaches may include dual blockade using AceIs and ARBs in combination, or new therapeutic modalities such as direct renin inhibition with aliskiren, recently approved for the treatment of hypertension. Medicine, new York, and chief, Cardiology/ Hypertension/endocrinology Practice, and director, Hypertension Research laboratory, James J. Peters vA Medical Center, Bronx, nY. AutHoR CoRReSPonDenCe: Steven A. Atlas, MD, 130 W. Kingsbridge Rd., Bronx, nY 10468. tel: (718) Fax: (718) 741-4295; e-mail: steven.atlas@med.va.gov regulator of sodium and potassium balance. 4 These landmark discoveries established the concept that a single system, the RAAS, was involved in the regulation of both blood pressure and fluid and electrolyte balance. Steven A. AtlAS, MD, is an associate professor of medicine, Mount Sinai School of

Although increased blood viscosity occurs in several cardiovascular diseases, little is known of factors influencing blood rheology in normal adults. Accordingly, we examined the relations of whole blood viscosity (WBV) to its rheologic determinants (hematocrit level, plasma viscosity, protein concentration, and red cell aggregability and rigidity), to demographic and laboratory variables, and to cardiovascular risk factors in 128 normotensive employed adults. Hematocrit levels accounted for 67-84% of variability of WBV at shear rates from 208 to 0.1 sec`with lesser contributions from plasma viscosity, red cell aggregability, and rigidity (multiple r=0.95-0.97); WBV was predicted accurately from standard measurements of hematocrit and total plasma protein levels (multiple r=0.78-0.92 in "learning" and "test" analysis). Male sex, obesity, dietary Na+ intake, and increasing age had additive effects on WBV (multiple r.0.59, p<0.00001); the last three of these factors and black race independently predicted plasma viscosity (multiple r=0.36, p<0.001). Among regulators of plasma volume, plasma renin activity and urinary Na+ excretion bore independent positive relations to WBV. Diastolic and mean blood pressures were independent predictors of WBV and hematocrit levels (all p <0.05). Conventional risk factors (e.g., triglycerides, obesity, and cholesterol levels) were positively related to WBV or plasma viscosity. Thus, in apparently normal adults, 1) WBV or plasma viscosity are increased by male sex, obesity, high sodium intake, aging, and black race, 2) WBV is positively related to plasma renin activity, 3) WBV or plasma viscosity are related to diastolic and mean blood pressures, triglycerides and cholesterol concentrations, and 4) WBV can be predicted from simple measurements of hematocrit and total plasma protein levels. (Circulation 1990;81:107-117) Changes in whole blood viscosity (WBV) have been reported in several human cardiovascular diseases,'-22 indicating that blood viscosity may be a major cardiovascular risk factor. A positive relation between blood pressure and blood viscosity or All editorial decisions for this article, including selection of reviewers and the final decision, were made by a guest editor. This procedure applies to all manuscripts with authors from the

We investigated atrial natriuretic factor (ANF) in humans, measuring plasma immunoreactive (ir) ANF (in femtomoles per milliliter), and renal, hormonal, and hemodynamic responses to ANF infusion, in normal subjects (NL) and congestive heart failure patients (CHF). Plasma irANF was 11±0.9 fmol/ml in NL and 71±9.9 in CHF (P < 0.01); the latter with twofold night ventricular increment (P < 0.05). In NL, ANF infusion of 0.10 ig/ kg per min (40 pmol/kg per min) induced increases (P < 0.05) of absolute (from 160±23 to 725±198 iseq/min) and fractional(1-4%) sodium excretion, urine flow rate (from 10±1.6 to 20±2.6 ml/min), osmolar (from 3.2±0.6 to 6.8±1.2 ml/min) and free water (from 6.8±1.6 to 13.6±1.6 ml/min) clearances, and filtration fraction (from 20±1 to 26±2%). Plasma renin and aldosterone decreased 33% and 40%, respectively (P < 0.01). Systolic blood pressure fell (from 112±3 to 104±5 mmHg, P < 0.05) in seated NL; but in supine NL, the only hemodynamic response was decreased pulmonary wedge pressure (from 11±1 to 7±1 mmHg, P < 0.05). In CHF, ANF induced changes in aldosterone and pulmonary wedge pressure, cardiac index, and systemic vascular resistance (all P < 0.05); however, responses of renin and renal excretion were attenuated. ANF infusion increased hematocrit and serum protein concentration by 5-7% in NL (P < 0.05) but not in CHF.

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