Abstract 13596: Neuronal Nitric Oxide Synthase Function is Impaired in Human Hypertension: Effects of Sildenafil
Introduction: Neuronal nitric oxide synthase (nNOS) plays a key role in regulating microvascular tone in healthy man at rest and during mental stress, but its function in hypertension is unknown. We hypothesized that basal release of nitric oxide from nNOS at rest and during mental stress is impaired in subjects with essential hypertension, and phosphodiesterase type 5 (PDE5) inhibition will improve nNOS mediated responses.
Methods: 14 hypertensive subjects (mean±SD age 39.6±13.5 years, BP 141±13/87.8±11 mmHg) and 14 normotensive controls matched for age, BMI and cholesterol (age 31.3±8.9 years, BP 121±6.6/77±6.9mmHg) participated in a single blinded 2-phase cross-over study receiving placebo and 50mg p.o. sildenafil 1 hour before forearm blood flow (FBF) studies. Strain gauge plethysmography was used to measure FBF in both arms, the right arm acting as control. The left brachial artery was cannulated for infusion of the selective nNOS inhibitor S-methyl-L-thiocitrulline (SMTC). FBF was measured at baseline, during a cumulative dose infusion of SMTC (0.05, 0.1 and 0.2 μmol/min) and during mental stress. The highest dose of SMTC was continued during mental stress, which was elicited by the Stroop test.
Results: At rest, SMTC reduced FBF to a similar degree in both groups (mean±SEM change from baseline): -19±5.4% and -17±4.6% in normotensive and hypertensive subjects respectively (p=NS). FBF responses to stress were lower in hypertensive compared to normotensive subjects (83±14% vs. 41±2% in normotensive and hypertensive subjects respectively, p=0.01). SMTC blunted FBF responses to stress in normotensive but not hypertensive subjects (40±11% vs. 13±8% reduction of FBF in normotensive and hypertensive subjects respectively, p=0.01). Sildenafil did not significantly affect FBF in the presence or absence of SMTC at rest. However during stress, sildenafil reduced the FBF response in normotensive subjects by 26±27% (P<0.05).
Conclusions: This first study of nNOS in vivo in human hypertension shows impaired function in this condition. PDE5 inhibition blunts rather than enhances nNOS mediated vasodilation during mental stress, possibly because sildenafil’s effects on sympathetic outflow outweigh its potentiation of nNOS responses.
- © 2013 by American Heart Association, Inc.