Glu298Asp eNOS gene polymorphism causes attenuation in nonexercising muscle vasodilatation

1 Heart Institute (InCor), University of São Paulo Medical School, São Paulo 2 LabCardio, University of Campinas, Campinas 3 School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil The influence of Glu298Asp endothelial nitric oxide synthase (eNOS) polymorphism in exercise-induced reflex muscle vasodilatation is unknown. We hypothesized that nonexercising forearm blood flow (FBF) responses during handgrip isometric exercise would be attenuated in individuals carrying the Asp298 allele. In addition, these responses would be mediated by reduced eNOS function and NO-mediated vasodilatation or sympathetic vasoconstriction. From 287 volunteers previously genotyped, we selected 33 healthy individuals to represent three genotypes: Glu/Glu [ n = 15, age 43 ± 3 yr, body mass index (BMI) 22.9 ± 0.3 kg/m 2 ], Glu/Asp ( n = 9, age 41 ± 3 yr, BMI 23.7 ± 1.0 kg/m 2 ), and Asp/Asp ( n = 9, age 40 ± 4 yr, BMI 23.5 ± 0.9 kg/m 2 ). Heart rate (HR), mean blood pressure (MBP), and FBF (plethysmography) were recorded for 3 min at baseline and 3 min during isometric handgrip exercise. Baseline HR, MBP, FBF, and forearm vascular conductance (FVC) were similar among genotypes. FVC responses to exercise were significantly lower in Asp/Asp when compared with Glu/Asp and Glu/Glu ( = 0.07 ± 0.14 vs. 0.64 ± 0.20 and 0.57 ± 0.09 units, respectively; P = 0.002). Further studies showed that intra-arterial infusion of N G -monomethyl- L -arginine ( L -NMMA) did not change FVC responses to exercise in Asp/Asp, but significantly reduced FVC in Glu/Glu ( = 0.79 ± 0.14 vs. 0.14 ± 0.09 units). Thus the differences between Glu/Glu and Asp/Asp were no longer observed ( P = 0.62). L -NMMA + phentolamine increased similarly FVC responses to exercise in Glu/Glu and Asp/Asp ( P = 0.43). MBP and muscle sympathetic nerve activity increased significant and similarly throughout experimental protocols in Glu/Glu and Asp/Asp. Individuals who are homozygous for the Asp298 allele of the eNOS enzyme have attenuated nonexercising muscle vasodilatation in response to exercise. This genotype difference is due to reduced eNOS function and NO-mediated vasodilatation, but not sympathetic vasoconstriction. nitric oxide; nitric oxide synthase; genetics; exercise; genetic association study; endothelial nitric oxide synthese gene variant