Exercise-induced Erythropoiesis: the Mechanistic of Angiotensin II

Study Overview
=================
Brief Summary
-----------------
The major aims are to determine the effect of acute (single dose) blockade of ANGII receptor 1 (AT1) on the EPO response to a single session of endurance exercise, as well as determine the effect of chronic (8-week) blockade of AT1 on ET-induced adaptations in total circulating red blood volume and hemoglobin.

Detailed Description
-----------------
Physical activity, particularly when comprised of endurance training (ET) leading to cardiovascular adaptations, is considered the most effective intervention to augment life expectancy. Major health benefits induced by ET are closely associated (independently of traditional risk factors) with improvements in maximal oxygen consumption (VO2max), a hallmark of aerobic exercise capacity. The higher the VO2max the greater the likelihood to be free of cardiovascular disease, the main cause of mortality worldwide. Understanding the mechanisms explaining the improvement in VO2max with ET can provide sound basis for highly effective lifestyle and pharmacological interventions aimed to enhance cardiovascular health in the general population. So far, the essential role of ET-induced increased formation of red blood cells, i.e., erythropoiesis, has been firmly established for any improvement in VO2max. Yet, the underlying mechanism remains elusive. Clinical studies and recent investigations by the PI point towards the endocrine effects of key hormones that regulate blood volume (BV). Notably, the impact of ET-induced changes in angiotensin II (ANGII), a multifaceted hormone that modulates erythropoiesis through its effects on kidney erythropoietin (EPO) production, has to be experimentally elucidated in humans.

Official Title
-----------------
Exercise-induced Erythropoiesis: the Mechanistic of Angiotensin II

Conditions
-----------------
Exercise Physiology

Intervention / Treatment
-----------------
* Drug: Valsartan 80 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy status, absence of current medical symptoms or medication limiting incremental exercise testing No history of cardiac, pulmonary or kidney disease. Exclusion Criteria: - Individuals fulfilling the above criteria but currently involved in regular exercise training (> 5 hr/week)

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Valsartan tablets<br> | Drug: Valsartan 80 mg<br>* The well-established angiotensin II receptor blocker (ARB) valsartan will be used in the present study to selectively block AT1 receptors. Valsartan is a generic medication widely used in hypertensive patients since 1996 as well as safely applied in physiological studies comprising healthy individuals.1-3 A minimal valsartan dose of 80 mg known to acutely reduce circulating EPO levels in healthy individuals will be provided 4 hours before starting Study 1 to optimize AT1 blockade according to valsartan's half-life.1-3 The same dose of valsartan (80 mg) will be provided 4 hours before each ET session in Study 2. The participants will be randomly allocated in a 1:1 ratio to valsartan or placebo. Valsartan and placebo tablets will be indistinguishable in taste, smell, appearance and dosage. The protocol will be developed in a double-blind manner in that both participants and investigators will be blinded toward the intervention condition.<br>|
| Placebo Comparator: Placebo tablets<br> | Drug: Placebo<br>* The participants will be randomly allocated in a 1:1 ratio to valsartan or placebo. Valsartan and placebo tablets will be indistinguishable in taste and smell. The protocol will be developed in a double-blind manner in that both participants and investigators will be blinded toward the intervention condition.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| stroke volume in ml/m2 | Stroke volume (SV) will be determined as left ventricular end-diastolic volume (LVEDV) minus left ventricular end-systolic volume (LVESV) | 10 weeks | 
| maximal oxygen consumption in ml/kg/min | Maximal oxygen consumption (VO2max), a hallmark of aerobic capacity, will be determined with continuous measurements of oxgyen uptake using an online gas collection system (Quark CPET, Cosmed, Italy) | 10 weeks | 
| Blood volume (BV)-regulating hormone: Plasma ANGII in ng/dL | Plasma ANGII concentrations will be quantified by means of established competitive enzyme immunoassays | 10 weeks |