Adrenergic receptors are essential elements of a variety of physiological functions in humans and other animals. β1-adrenergic receptors are prominent in the regulation of heart rate and force of contraction, and β2-adrenergic receptors can evoke vasodilation, bronchodilation, and mobilization of glycogen and lipid stores. All of these responses are typically associated with exercise. In this context, recent genomic evidence demonstrates that there are common polymorphisms in both β1- and β2-receptors, and individuals with different β-receptor genotypes might have different physiological or pathophysiologic responses to exercise. Therefore, it is easy to hypothesize that even subtle differences in β-receptor function might cause profound alterations in cardiovascular, respiratory, or metabolic control.
In a recent study Bengtsson and colleagues (Circulation. 104:187–190, 2001) evaluated the impact of an arginine (for glycine) substitution at amino acid position 389 of the β1-adrenergic receptor gene. This substitution evokes higher in vitro isoproterenol-stimulated adenylcyclase activity than the more common variant, and the authors sought to investigate whether the substitution of arginine at position 389 was associated with hypertension in a group of Scandinavian subjects. To address this issue they studied a large number of unrelated nondiabetic hypertensive patients and unrelated control subjects with a case control association study design. They also performed a family study and looked at sibling pairs who were discordant for the Arg389 polymorphism. Using this approach they looked at genotypic frequencies in hypertensive patients and normotensive control subjects. They also compared blood pressure and heart rate between the different genotypes. In the case control study, subjects who were homozygous for the Arg389 allele were 1.9 times more likely to be hypertensive than individuals who are either homozygous for the Gly389 allele or the heterozygotes (1-Arg389 gene and 1-Gly389 gene). In the genotype discordant sibling pairs, siblings that were homozygous for the Arg389 allele had significantly higher diastolic blood pressures and heart rates than siblings carrying one or two copies of the Gly389 allele. Taken together these data suggest that β1-adrenergic receptor polymorphisms might contribute to hypertension in humans.
The findings of Bengtsson and colleagues are certainly provocative. It would also be interesting to see if individuals who are homozygous for the Arg389 allele have higher blood pressure and heart rate responses to exercise of various types. Additionally, would these individuals be more or less susceptible to positive effects of endurance exercise training on blood pressure? Clearly this observation on the possible contribution of β1-adrenergic receptor genes in hypertension deserves follow-up within the context of exercise in humans.
Bengtsson and colleagues have also evaluated the possible contribution of β2-adrenergic receptor gene variation to hypertension in subjects with type 2 diabetes (Hypertension. 37:1303–1308, 2001). There are a variety of common polymorphisms in the β2-adrenergic receptor gene. Several of these have been associated with hypertension in patients. In this study, they included a large number of hypertensive patients without type 2 diabetes, a large number of hypertensive patients with type 2 diabetes, and a variety of healthy control subjects. In addition to this cross-sectional study, normotensive sibling pairs who were discordant for the Arg16Gly and the Gln27Glu β2-receptor polymorphisms were identified in type 2 diabetic families from Finland. Individuals who were homozygous for the Arg16 allele had increased odds ratio for hypertension in the patients with type 2 diabetes. Other possible associations with other β2-receptor genotypes were also noted. The authors concluded that individuals with the Arg16 allele of the β2-receptor gene appear to be at increased risk for hypertension in subjects with type 2 diabetes and this receptor variant is also associated with higher body mass index in the sibling pairs discordant for this polymorphism.
As is the case with the β1-receptor noted above, it will be important to understand how β2-receptors interact with a variety of risk factors associated with hypertension and with endurance exercise training. Because body mass index appeared to be higher in patients with the Arg16 polymorphism, it will be important to try to understand how this receptor variant might contribute to the regulation of body composition in humans. Again, a host of exercise-related studies are possible.
In view of the information above on β2-adrenergic receptors, one question that occurs is how β2-adrenergic receptor polymorphisms at amino acid 16 might influence blood pressure and peripheral vascular resistance. Two papers with surprisingly different results highlight a variety of issues. In the first, Hoit and colleagues (Am. Heart J. 139:537–542, 2000) used systemic infusions of the β2-agonist terbutaline and studied individuals who were homozygous for the Arg16 variant of the β2-receptor or homozygous for the Gly16 variant or genotype. The idea was that because in vitro studies demonstrated that the Gly16 β2-adrenergic receptor is associated with enhanced receptor down-regulation in comparison to the Arg16 receptor, there would be less vasodilation in response to terbutaline infusion. These authors found that the baseline heart rates, blood pressures, and calf blood flows were similar in the two groups of subjects. However, as they infused increasing doses of terbutaline blood flow, vasodilation and calculated vascular resistance were all less, whereas systolic and diastolic pressures were greater in patients with the Gly16 allele. They concluded that the Gly16 β2-adrenreceptor polymorphisms attenuates the vasodilatory responses to catecholamines and that it is an important genetic component of the regulation of peripheral blood flow and perhaps systemic arterial pressure.
In contrast to the study by Hoit and colleagues, Cockcroft and colleagues (Hypertension. 36:371–375, 2000) used brachial artery infusions of β-agonists or measurements of diameter changes in dorsal hand veins to evaluate the contribution of β-adrenergic polymorphisms to vascular reactivity in humans. In contrast to the previously discussed study, these authors found that homozygotes of Arg16 allele had significantly lower baseline blood flow and attenuated increases in forearm blood flow in comparison to the Gly16 homozygotes. They comment that further studies are necessary to establish whether β2-adrenoreceptor polymorphism is important in the pathogenesis of hypertension.
Genetic polymorphisms in key regulatory systems are emerging as important in a variety of areas. The studies outlined above suggest that polymorphisms of both β1- and β2-adrenergic receptors might contribute to hypertension in selected patient groups. In the case of the β2-receptors, one epidemiologic paper demonstrates that individuals who are homozygous for the Arg16 allele may be at increased risk for hypertension. As discussed in this paper, other studies suggest that the Gly16 allele might be associated with hypertension. Similarly confusing data is available at a physiological level. One study shows that individuals who are homozygotes for the Gly16 allele have blunted vasodilation, whereas the other study shows individuals who are homozygotes for the Arg16 allele have blunted vasodilation. All of these observations demonstrate the tremendous work that lies ahead to determine first, if adrenergic receptor polymorphisms might contribute to important disease states such as hypertension, and second, what is the physiologic link between the receptor polymorphisms and blood pressure. Additionally, because β-receptors play such an important role in so many exercise responses, it will be important to determine if individuals with differing β-receptor polymorphisms respond differently to both short-term and long-term exercise.