Effects of angiotensin II receptor type 1 blockade combined with endurance training on haemoglobin mass and aerobic capacity: a randomized placebo-controlled trial

More than 700 million individuals worldwide are diagnosed with hypertension, 75% of them being treated with antihypertensive drugs. In the USA, at least 129 million individuals take antihypertensive drugs that inhibit the renin–angiotensin system (RAS), including angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB).1 In parallel, endurance training (ET) is strongly recommended for the treatment of hypertension, underpinned by the observation that high peak oxygen uptake (VO2peak) seems to prevent hypertension in healthy individuals.2 Moreover, high VO2peak independently associates with reduced morbidity and mortality. The physiological mechanisms by which ET elicits large increases in VO2peak mainly involve endocrine adaptations stimulating erythropoiesis and thereby blood volume expansion.3 Yet, in healthy individuals, short-term (4 weeks) treatment with RAS inhibitors leads to ∼20% decrement in circulating erythropoietin (EPO),4 i.e. the hormone that stimulates erythropoiesis, reaching up to 60% EPO decrements with longer treatment in patients with kidney disease.5 These antihypertensive drugs may indeed cause true anaemia, i.e. reduced red blood cells and haemoglobin mass (Hbmass) in the circulation.5 In fact, RAS inhibitors were introduced as the mainstay of treatment for excessive erythropoiesis in the 1990s. Collectively considered, a curtailment of ET-induced erythropoiesis by RAS inhibitors seems plausible. Such an effect could be exacerbated in the female population, concurring with the blunted or absent ARB-related reduction of hard clinical outcomes in women relative to men.6,7 Using a randomized, double-blind and placebo-controlled design, this study sought to determine whether angiotensin II receptor type I (AT1)-blockade modifies the effects of 8-week ET on aerobic exercise capacity and its haematological determinants in healthy women and men. The majority of potential ET-induced adaptations in Hbmass and VO2peak are observed after 6–8 weeks in healthy individuals.3 The ARB valsartan was chosen as the RAS inhibitor due to: (i) greater specific blockade (downstream the RAS signalling cascade) than ACEi; (ii) known antihypertensive effect and pharmacokinetics of a low dose (80 mg) in our study population.8 Healthy non-obese women [n = 28, 45.0 ± 14.3 (range: 21.0–65.7) yr] and men [n = 32, 42.6 ± 16.2 (range: 21.8–68.7) yr] matched by age and moderate physical activity (⁓4.5 h/week) (P ≥ 0.357) were recruited. Inclusion criteria comprised healthy status, absence of current medical symptoms and medication, and no history of disease. Prior to the start of the experiments, informed oral and written consents were obtained from the participants. They were randomly allocated to 8 weeks of ET along with (i) placebo (ET-PBO) or (ii) AT1-blockade (ET-AT1-blockade). Orally ingested tablets included calcium carbonate (500 mg, Shandong Yuwang Pharmaceutical) for PBO, and valsartan (80 mg, Novartis Pharmaceuticals) for AT1-blockade. The tablets were ingested 4 h before each ET session to maximize its physiological effects during and after exercise.8 The ideal PBO (a valsartan tablet without the active component but identical in shape, size, colour, and taste) was not obtained despite multiple requests to the company (Novartis Pharmaceuticals) were made. Nonetheless, in the second visit to the laboratory (post-ET) no participant was confident to conjecture the type of tablet (PBO or blood pressure-lowering) they had ingested during the intervention. The ET programme comprised 28 cycling ergometry exercise sessions (3–4 per week, every other day). All ET sessions had a fixed average intensity of 75% of peak heart rate (HRpeak) for 50 min of duration. VO2peak was determined with a mixing chamber system (KORR Medical), and Hbmass with CO-rebreathing, via established protocols in our laboratory.9 Arterial blood pressures (systolic (SBP), diastolic, and mean) were measured at supine rest (CNAP® Monitor 500 HD, CNSystems). EPO and EPO-regulating hormones (angiotensin II (ANGII), aldosterone, copeptin, and cortisol) were determined at fast and resting conditions in venous blood samples, as previously described.10 Statistical analyses were performed with SPSS 26.0 (IBM). Three-way ANOVA with repeated measures assessed the effects of the experimental condition, time and sex on the study variables, including the interaction between these factors (‘condition × time’ and ‘condition × time × sex’) and post hoc comparisons when ANOVA was significant (P < 0.05). Figure 1 displays the effects of ET-PBO or ET-AT1-blockade on VO2peak, peak power output (Wpeak) and Hbmass. In men, ET-PBO increased VO2peak (P < 0.001) and Wpeak (P < 0.001). In women, ET-PBO also increased VO2peak (P = 0.015) and Wpeak (P < 0.001). With ET-AT1-blockade, VO2peak, and Wpeak were increased in men (P = 0.036 and P = 0.043, respectively) but not in women (P = 0.085, P = 0.365). Interactions between conditions, time and sex were not detected (P ≥ 0.103). With respect to blood O2 carrying capacity, ET-AT1-blockade did not alter Hbmass in men (P = 0.237) but did decrease Hbmass in women (P = 0.002). ET-PBO did not modify Hbmass in men (P = 0.428) and women (P = 0.372). ‘Condition × time’ interactions were observed for Hbmass (P = 0.004). Hb concentration was decreased with ET-AT1-blockade in men (14.4 ± 1.3 vs. 13.6 ± 1.2 g·dL−1, P = 0.001) and women (12.9 ± 0.9 vs. 12.3 ± 0.9 g·dL−1, P = 0.004). Regarding the effects of ET-PBO or ET-AT1-blockade on resting arterial blood pressure, ET-PBO and ET-AT1-blockade decreased SBP by ⁓5 mm Hg (P = 0.037). Both interventions also increased plasma EPO concentration by ⁓3 mLU·mL−1 (P < 0.001). Interactions between conditions, time, and sex were not detected for arterial blood pressure or EPO (P ≥ 0.217). Effects of endurance training combined with placebo (ET-PBO) or angiotensin II type 1 receptor blockade (ET-AT1-blockade) on aerobic exercise capacity and haemoglobin mass (hbmass). Data in bars represent mean values. Significant P values (P < 0.05) for main factors in ANOVA (condition, sex, or time) are highlighted in bold. ‡:P < 0.05 between time points (‘post’ vs. ‘pre’) in a given condition and sex. The significance symbol (‡) is only illustrated above the ‘post’ point for visual clarity. ‘Condition × time’ interaction was present for Hbmass (P ≥ 0.004). ‘Condition × sex × time’ interactions were not observed (P ≥ 0.075). Number of biological observations for each graph: VO2peak (n = 64 (men), n = 56 (women)); Wpeak (n = 64 (men), n = 56 (women)); Hbmass (n = 64 (men), n = 56 (women)). VO2peak, peak O2 uptake; Wpeak, peak power output. This study determined the effects of 8 weeks of AT1-blockade on ET-induced adaptations. ET-AT1-blockade prevented the increase of aerobic exercise capacity and reduced Hbmass in women, but not in men. To our knowledge, there is not a single pharmacological intervention, other than RAS inhibitor administration, proven to abolish the effect of ET on aerobic exercise capacity and its haematological determinants. The fact that such a curtailment was induced with only 3–4 low-dose valsartan tablets per week (before the training sessions) is remarkable. This effect might contribute to explain (i) why valsartan does not improve exercise capacity in large clinical trials,11 and (ii) the yet unaccounted sex-specific effects of RAS inhibitors on hard clinical outcomes. When comparing the effects of ARB with those of antihypertensive drugs not altering the RAS (calcium channel blockers), valsartan is associated with higher cardiac events and incidence of heart failure in women but not in men.6 The sex-specific effects of ET-AT1-blockade in women could be explained by between-sex differences in the relative dose of ARB. Valsartan tablets are only available at discrete dosages, which make nonviable the delivery of a fixed dose relative to body weight. The dosage chosen, 80 mg, is the recommended low dosage to treat hypertension in adult women and men.12 Consequently, per kg of body weight, women took 1.5 mg of valsartan, 32% more than men during the ET-AT1-blockade intervention. The possibility thus exists that men were underdosed with respect to the haematological effects of AT1-blockade. In this regard, clinical evidence denotes that men experience the largest effects with higher (two-fold or higher) doses of ARB and ACEi than women.13 The impact ET-AT1-blockade in men could be explained by a dose-dependent effect, which can be elucidated in future studies using higher, still prevalent doses of ARB, matched relative to body weight, lean mass, or size with women. Notwithstanding, exercise recommendations aiming to improve aerobic capacity in hypertensive women and men should consider the interaction with RAS inhibitors. Discontinuation or substitution of RAS inhibitors for other type of antihypertensive drugs may be required for a substantial enhancement of cardiorespiratory fitness, notably in women. Considering the pharmacological differences among antihypertensive drugs that inhibit the RAS, mainly between ARB and ACEi, the present findings should not yet be extrapolated to the whole class of RAS inhibitor drugs. For instance, the fact that ARB does not oppose ANGII receptor type 2 stimulation, potentially influencing erythropoiesis via inflammatory modulation, while ACEi increases a potent vasoactive peptide (bradykinin) in the circulation, among others, might result in distinct haematological and haemodynamic outcomes when combined with ET. The authors thank all study participants for their efforts devoted to this study. The study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority West Cluster (UW 22-025) and conducted in accordance with the declaration of Helsinki. The randomized controlled trial (RCT) was registered at ClinicalTrials.gov (NCT05269615) on April 2022. D.M. designed the study. M.G., X.L., S.M.D., and D.M. collected and analysed the data. D.M. drafted the manuscript. M.G., X.L., S.D., H.F.T., and D.M. critically revised the manuscript and provided the final approval. This work was funded by the Health and Medical Research Fund (19200831 to D.M.). All data relevant to this study are presented in the manuscript and the Supplementary material.

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