Beta-2 Adrenergic Receptor Polymorphic Variants: An Endotype of Salt Sensitive Hypertension.

1. Background and Significance

1. Importance of the Problem. Over 1/3 of adults in the USA have hypertension (HTN), of which 51.3% (over 34 million Americans) have uncontrolled blood pressure (BP)1, leading to a high prevalence of cardiovascular (CV) complications mediated by elevated BP1. Among the major hurdles to be addressed in HTN are: 1) the lack of specificity in treatment programs, and 2) the unclear mechanisms by which genetic and environmental factors (e.g. dietary Na+ intake) affect BP and CV function. Clearly, the first hurdle is - for the most part - a consequence of the second. A recent document from NIH provides the following guide to address these issues.

"To address interindividual variability [responder/ non-responder phenomena] in […] complex diseases [e.g., obesity, asthma, type 2 diabetes, hypertension, chronic kidney disease, and cardiovascular diseases], it has been instructive to take a lesson from the asthma field, noted for its early recognition of prioritizing elucidation of disease endotypes over phenotypes"3. Like asthma, HTN "is now considered an umbrella diagnosis for several diseases with distinct mechanistic pathways [endotypes] & variable clinical presentations [phenotypes]. A phenotype covers the clinically relevant or obvious properties of the disease [for example, HTN could be salt resistant, salt sensitive, orthostatic, pregnancy induced, etc.]. However, phenotypes do not necessarily show the direct relationship to underlying disease etiology and pathophysiology that may be a key for treatments to work; endotypes [or endophenotypes which require a genetic component] are meant to do that. Another aspect is that several endotypes can lead to the same phenotype or umbrella diagnosis. Classifying complex diseases [e.g., HTN] using pathogenetic mechanism-based subtypes (endotypes/endophenotypes) may have other advantages in epidemiological, genetic, and treatment-related studies"3.

Recent reviews have reported that for nearly 50% of the essential (primary) HTN population, all of whom have salt sensitive blood pressure (SSBP), a dozen or more endotypes potentially underpin their pathophysiologic mechanisms. To date, the pathophysiologic mechanisms of these endotypes ultimately involve dysfunction in sodium/volume homeostasis and the components of the two major pathways that regulate this process--- the renin-angiotensin-aldosterone (Aldo) system (RAAS) and the renal vasculature, i.e., renal plasma flow (RPF)10,11. In most cases, one or the other system is adversely affected, and the alternate system tends to compensate for the altered sodium handling. This project focuses on one of the less understood endotypes: beta-2 adrenergic receptor (β2AR) gene-mediated dysfunction in SSBP.

This endotype is unique because preliminary and published data suggest that the mechanism(s) causing the SSBP association with a common β2AR risk diplotype (Arg16Arg/Gln27Gln) may or may not be the direct consequence of the primary effect of the diplotype---a gain of function for the β2AR gene. On one hand, increased β2AR levels could directly activate the two major Na+/volume homeostatic pathways (Aldo and RPF) resulting in Na+ retention and SSBP. However, it is possible that the cause of the SSBP may be indirect: maladaptation of the Na+/volume homeostatic systems that "believe" that the β2AR-induced vasodilation is the result of volume depletion and therefore Na+ retention is required - a maladaptation like that documented in other CV conditions - most notably, in congestive heart failure (CHF). Either of the two mechanisms could lead to SSBP, but with quite different therapeutic implications. Thus, the project herein will assess the two contrasting hypotheses regarding the mechanism(s) underlying the β2AR endotype-associated SSBP.