Submitted on November 4, 2008
Revised on January 8, 2009
Accepted on January 16, 2009
Glu298Asp eNOS Gene Polymorphism Causes Attenuation in Non-Exercising Muscle Vasodilatation
Rodrigo Goncalves Dias1, Maria-Janieire N.N. Alves2, Alexandre C Pereira1, Maria Urbana P.B. Rondon1, Marcelo Rodrigues dos Santos3, Jose E. Krieger4, Marta H. Krieger5, and Carlos Eduardo Negrao6*
1 Heart Institute (InCor) University of Sao Paulo Medical School
2 Heart Institute (InCor), University of Sao Paulo Medical School
3 Heart Institute (InCor) University of Sao Paulo Medical Scho
4 Heart Institute (InCor)/Univ Sao Paulo Med Sch
5 Unicamp
6 Heart Institute (InCor), University of Sao Paulo Medical School and School of Physical Education and Sport, University of Sao Paulo
* To whom correspondence should be addressed. E-mail: cndnegrao{at}incor.usp.br.
The influence of Glu298Asp eNOS polymorphism in exercise-induced reflex muscle vasodilatation is unknown. We hypothesized that non-exercising forearm blood flow 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±3yr, BMI 22.9±0.3kg/m2), Glu/Asp (n=9, age 41±3yr, BMI 23.7±1.0kg/m2) and Asp/Asp (n=9, age 40±4yr, BMI 23.5±0.9kg/m2). Heart rate (HR), mean blood pressure (MBP), and forearm blood flow (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=.002). Further studies showed that intra-arterial infusion of 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±0.09units). Thus the differences between Glu/Glu and Asp/Asp were no longer observed (P=.62). L-NMMA + phentolamine increased similarly FVC responses to exercise in Glu/Glu and Asp/Asp (P=.43). MBP and MSNA 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 non-exercising muscle vasodilatation in response to exercise. This genotype difference is due to reduced eNOS function and NO-mediated vasodilatation, but not sympathetic vasoconstriction.
