Abstract 234: Plasma Renin-Independent Generation of Angiotensin II and its Role in the Supine Hypertension of Autonomic Failure
At least 50% of primary autonomic failure [AF] patients exhibit supine hypertension, despite profound impairments in sympathetic activity. Plasma renin activity is often undetectable in AF suggesting renin mechanisms are not involved in the hypertension. However, since aldosterone levels are preserved we examined the status and contribution of the renin-angiotensin [Ang] system in AF. Supine plasma Ang peptide levels were measured in hypertensive AF patients [AF-HT, n=18], normotensive patients [AF-NT, n=11] and matched healthy subjects [n=10]. Despite suppressed renin activity, total renin concentration was intact in AF [16 ± 5 AF-HT vs 11 ± 4 AF-NT vs 7 ± 1 pg/mL healthy; p=0.29] and plasma prorenin was selectively elevated in hypertensive patients [2.0 ± 0.5 AF-HT vs 0.7 ± 0.1 AF-NT vs 0.6 ± 0.1 ng/mL healthy; p < 0.05]. While levels of Ang I were similar among groups, Ang II was paradoxically elevated [39 ± 4 AF-HT vs 42 ± 6 AF-NT vs 27 ± 4 pg/mL healthy; p<0.05] in AF. In contrast, Ang-(1-7) was suppressed in AF patients [7 ± 1 AF-HT vs 4 ± 1 AF-NT vs 22 ± 6 pg/mL healthy; p<0.05]. Plasma aldosterone was preserved in AF and did not correlate with Ang II levels, suggesting Ang II-independent regulation. The Ang II AT1 receptor antagonist losartan [50mg, PO] significantly reduced supine systolic blood pressure [25 ± 15 mmHg at 6 hrs after administration; p<0.05] in 9 AF-HT patients, indicating that elevated Ang II contributes to hypertension in AF. These findings suggest an imbalance in Ang II and Ang-(1-7) activity in AF independent of hypertensive status, which may reflect differences in ACE and ACE2 enzyme activity. The source of Ang II in these patients, in the absence of plasma renin activity, is still under investigation. The loss of renin activity is not due to reduced renin content, but may result from low substrate availability or defective enzyme activation. Regardless, Ang II appears to contribute to the supine hypertension of AF. Further, prorenin levels are elevated in hypertensive patients which could provide a stimulus for Ang II generation and actions. Collectively, these patients offer a unique model to study cardiovascular regulation and Ang II production in the absence of autonomic and traditional renin influences.
- © 2012 by American Heart Association, Inc.