High prevalence of obstructive sleep apnea among hypertensive patients with primary hyperaldosteronism

AJH–May 2003–VOL. 16, NO. 5, PART 2

P-345 HIGH PREVALENCE OF OBSTRUCTIVE SLEEP APNEA AMONG HYPERTENSIVE PATIENTS WITH PRIMARY HYPERALDOSTERONISM David A Calhoun, Mari K Nishizaka, Mohammad A Zaman. Vascular Biology and Hypertension Program, University of Alabama at Birmingham, Birmingham, AL. Purpose: Recent reports indicate that primary hyperaldosteronism (PA) is a much more common cause of hypertension than previously thought. The reason for this increased prevalence of PA is unknown. Even though obstructive sleep apnea and hypertension are highly correlated, the mechanism by which sleep apnea increases blood pressure remains obscure. The current study was undertaken to determine if there is an association between PA and OSA among patients with resistant hypertension consistent with the hypothesis that OSA induces hyperaldosteronism. Methods: In consecutive patients referred to a university clinic for resistant hypertension, we determined the 24-hour urinary aldosterone excretion during high dietary salt ingestion and baseline plasma renin activity and plasma aldosterone in all subjects. Primary hyperaldosteronism was defined as a plasma renin activity was ⬍1.0 ng/ml/hr and urinary aldosterone was ⬎12 mcg/24-hr during high urinary sodium excretion (⬎200 mEq/24-hr). In addition, all patients completed the Berlin Questionnaire, a survey designed to identify patients at risk of having sleep apnea. Results: Of the 117 patients evaluated, sleep apnea has been confirmed by polysomnographic evaluation (respiratory distress index ⱖ5 apnea/hypoapnea events per hour) in 32 patients. Forty-one patients had a low-probability of having sleep apnea based on their responses to the Berlin Questionnaire. Patients with confirmed sleep apnea were over 3 times more likely to have been diagnosed with hyperaldosteronism compared to patients at low-risk of having sleep apnea (50 vs. 16%), tended to lower plasma renin activity (0.7⫾0.8 vs. 2.0⫾4.2 ng/ml/hr) and had significantly greater urinary aldosterone excretion (16.6⫾12.2 vs. 9.4⫾7.2 mcg/24-hr, p⬍0.05). Conclusion: These data indicate a very high degree of association between sleep apnea and primary hyperaldosteronism suggesting that sleep apnea may contribute to the development of resistant hypertension by inducing hyperaldosteronism. Key Words: hyperaldosteronism, obstructive sleep apnea, resistant hypertension

P-346 RHO KINASE AND PAI-1 IN BARTTER’S AND GITELMAN’S SYNDROMES. RELEVANCE FOR ANGIOTENSIN II SIGNALING Lorenzo A Calo’, Elisa Pagnin, Francesca Zaghetto, Paul A Davis, Michelangelo Sartori, Andrea Semplicini. Clin Exp Med, Clinica Medica 4, University of Padova, Padova, Italy; Int Med, Clin Nutr, Univ California, Davis, Davis, CA. Activation of Rho kinase by angiotensin II (Ang II) is involved in the pathophysiology of hypertension and remodeling. Rho kinase activation also controls plasminogen activator inhibitor-1 (PAI-1) production which promotes vessel wall fibrosis and contributes to atherogenesis. In Bartter’s and Gitelman’s syndromes (BS/GS) short term signaling pathway of Ang II which mediated most hemodinamic and endocrine effects of Ang II, is blunted (reduced G␣q gene expression, intracellular IP3 and Ca⫹⫹ © 2003 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.

POSTERS: Renin-Angiotensin-Aldosterone

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release and PKC activity) (Calo L et al, Kidney Int, 60:882-889, 2001). BS/GS have also signs that Agn II long term signaling pathway, which contributes to determine cardiovascular remodeling and atherogenesis mostly through oxidative stress, is altered (reduced gene expression of p22phox,key subunit of NAD(P)H oxidase for O2- production, and TGF␤, fibrogenic cytokine effector of oxidative stress, reduced susceptibility of LDL to oxidation, increased plasma antioxidant power) (Calo L et al, JASN, 12:587A, 2001). We now evaluate in our cohort of 9 BS/GS patients, Rho kinase gene expression (RT-PCR expressed as densitometric units (d.u.) using ␤ actin for normalization) as well as gene expression of Rac 2, member of the Rho family monomeric G protein, cytosolic subunit of NAD(P)H oxidase and the Ang II effect on p22phox, TGF␤ and PAI-1 gene expression, given PAI-1’s link to both Rho kinase activity and atherosclerosis and the close relationships between Rho kinase, Ang II, Rac, p22phox and NAD(P)H oxidase. 10 healthy age and sex matched subjects were used as controls (C). In BS/GS Rho kinase gene expression was reduced compared to C (0.47⫾0.11 d.u. vs 0.7⫾0.04, p⬍0.003) as well as Rac 2 (0.59⫾0.11 vs 0.75⫾0.07, p⬍0.03).Ang II icreased p22phox, TGF␤ and PAI-1 gene expression only in controls (from 0.43⫾0.04 to 0.46⫾0.05, n.s. in BS/GS vs 0.59⫾0.12 to 0.96⫾0.12, p⬍0.001 in C, from 0.76⫾0.07 to 0.78⫾0.05 n.s. vs 0.97⫾0.11 to 1.27⫾0.22 p⬍0.001 and from 0.39⫾0.01 to 0.39⫾0.02 n.s. vs 0.4⫾0.02 to 0.63⫾0.03, p⬍0.001 respectively. These data and our previous observations, add more light on the cellular mechanisms of BS/GS reduced Ang II short and long term signaling pathways and, since BS/GS represent the mirror image of derangements involved in hypertension, confirm BS/GS as a human model to study interrelated systems involved in the pathophysiology of hypertension and remodeling. Key Words: Angiotensin II signaling, Rho Kinase, Bartter’s and Gitelman’s syndromes

P-347 DIETARY NACL REGULATES RENAL SERUM GLUCOCORTICOID-REGUALTED KINASE 1 (SGK1) ABUNDANCE: RELEVANCE TO SALT-SENSITIVITY IN THE DAHL RAT Bryan P. Roxas, Mariam Farjah, David L. Geenen, Robert S. Danziger. Cardiology/Internal Medicine, University of Illinois, Chicago, IL; West Side Veterans Administration, Chicago, IL. Introduction: SGK1 activates the epithelial sodium channel (eNaC) in tubules and is stimulated by aldosterone and glucocorticoids. Whether it plays a role in salt-adaptation and/or the pathogensis of hypertension is not known. Methods: Renal SGK1 transcript and protein abundance was measured, using real-time RT/PCR and Western analysis respectively, in Sprague Dawley (SD) and Dahl salt-sensitive (SS) rats on either 8% or 0.3% NaCl diets for 10 days. Plasma aldosterone levels were measured by radioimmunoassay. The transcript was sequenced using standard dedeoxy methods. Results: Plasma aldosterone levels were approximately 2.5 fold greater on 0.3% versus 8% NaCl diets in both rat strains. Both SGK1 transcript (Figure 1) and protein abundance were less (p⬍0.01) in SD rats and greater (p⬍0.05) in Dahl salt-sensitive (SS/Jr) rats on 8% versus 0.3% NaCl diets. The cDNA sequences of SGK1 in both strains of rat were the same (n ⫽ 4 rats of each strain). Conclusions: The present results suggest that 1) regulation of the transcription of SGK1 in rat kidney may play a role in salt-adaptation and the pathogenesis of salt-sensitive hypertension; 2) aldosterone is not the primary inducer of SGK1 in the SD rat; 3) a polymorphism of an untranslated regulatory region of the SGK1 gene may underlie saltsensitive hypertension in the Dahl SS/Jr rat. Figure 1. SGK1 transcript 0895-7061/03/$30.00