Key points• Physical exercise is recommended as first line therapy for hypertensive patients. However, studies investigating long-term effects of high intensity exercise on the progression of hypertensive heart disease have revealed conflicting results.• We show that high intensity aerobic exercise accelerates hypertensive heart disease and improves fibrosis.• Surprisingly, high intensity aerobic exercise in the presence of an angiotensin converting enzyme inhibitor not only attenuated training induced mal-adaptation but exerts positive repair processes. These effects were independent of blood pressure effects.• The results of this study provide evidence that high physical activity in hypertensives must be considered as an important risk factor rather than a therapeutic intervention. AbstractIn the present study it was hypothesized that voluntary aerobic exercise favours a pro-fibrotic phenotype and promotes adverse remodelling in hearts from spontaneously hypertensive rats (SHRs) in an angiotensin II-dependent manner. To test this, female SHRs at the age of 1 year were started to perform free running wheel exercise. Captopril was used to inhibit the renin-angiotensin system (RAS). Normotensive rats and SHRs kept in regular cages were used as sedentary controls. Training intensity, expressed as mean running velocity, was positively correlated with the left ventricular mRNA expression of TGF-β 1 , collagen-III and biglycan but negatively correlated with the ratio of sarcoplasmic reticulum Ca 2+ -ATPase (SERCA)2a to Na + -Ca 2+ exchanger (NCX). A pro-fibrotic phenotype was verified by Picrosirius red staining. Sixty-seven per cent of SHRs performing free running wheel exercise died either spontaneously or had to be killed during a 6 month follow-up. In the presence of captopril, aerobic exercise did not show a similar positive correlation between training intensity and the expression of fibrotic markers. Moreover, in SHRs receiving captopril and performing free running wheel exercise, a training intensity-dependent reverse remodelling of the SERCA2a-to-NCX ratio was observed. None of these rats died spontaneously or had to be killed. In captopril-treated SHRs performing exercise, expression of mRNA for decorin, a natural inhibitor of TGF-β 1 , was up-regulated. Despite these differences between SHR-training groups with and without captopril, positive training effects (lower resting heart rate and no progression of hypertension) were found in both groups. In conclusion, high aerobic exercise induces an angiotensin II-dependent adverse Abbreviations ACE, angiotensin converting enzyme; NCX, Na + -Ca 2+ exchanger; Nrf-1, nuclear respiratory factor-1; PGC-1α, peroxisome proliferator activated receptor γ coactivator 1α; RAS, renin-angiotensin system; SERCA, sarcoplasmatic reticulum Ca 2+ -ATPase; SHR, spontaneously hypertensive rat; TGF-β1, transforming growth factor-β1.

The effect of exercise on the progression of hypertension and development of heart failure has been extensively studied in spontaneously hypertensive rats (SHRs), but results published thus far have not revealed a clear picture. Studies differ with respect to the age and sex of rats, duration of exercise and exercise protocols. This study was aimed to examine the influence of age at the start of exercise and the effect of the duration of exercise on blood pressure and hypertrophy, which has not been previously investigated. We identified 18 reports in the literature (with a total of about 410 rats) that investigated the effect of exercise on SHR. A reduction in blood pressure was observed in rats that started exercise protocols in the pre-hypertensive or very early hypertensive state, but not in older rats. Exercise lowered the heart weight-to-body weight ratio in rats starting exercise at a very early age, but not in rats at an advanced age. A reduction in blood pressure was observed in animals that had a short period of training, but the effect was lost when the duration of exercise was prolonged. Exercise reduced resting heart rates in all groups and increased the heart weight-to-body weight ratio in groups that were exposed to free running wheels, but not in rats that performed treadmill exercise. In conclusion, exercise per se does not reduce blood pressure in SHR with established hypertension and may increase the incidence of myocardial hypertrophy, depending on the form of exercise.

Purpose: According to the current therapeutic guidelines of the WHO physical activity and exercise are recommended as first-line therapy of arterial hypertension. Previous results lead to the conclusion, however, that hearts of spontaneously hypertensive rats (SHR) with established hypertension cannot compensate for the haemodynamic stresses caused by long-term exercise. The current study was initiated to investigate the effects of aerobic exercise on the cardiac remodeling as the sole therapeutic measure before and during hypertension became established.Methods: Beginning at their 6th week of life, six SHR were provided with a running wheel over a period of 6 months. Normotensive Wistar rats served as non-hypertensive controls.Results: In Wistar rats and SHR, voluntary exercise led to cardioprotective adaptation reactions that were reflected in increased mitochondrial respiration, reduced heart rate and improved systolic function. Exercise also had antioxidant effects and reduced the expression of maladaptive genes (TGF-β1, CTGF, and FGF2). However, at the end of the 6-months' training, the echocardiograms revealed that SHR runners developed a restrictive cardiomyopathy. The induction of lysyl oxidase (LOX), which led to an increased network of matrix proteins and a massive elevation in collagen III expression, was identified as the underlying cause.Conclusions: Running-induced adaptive mechanisms effectively counteract the classic remodeling of hearts subject to chronic pressure loads. However, with sustained running stress, signaling pathways are activated that have a negative effect on left ventricular relaxation. Our data suggest that the induction of LOX may play a causative role in the diagnosed filling disorder in trained SHR.

The missing influence of estrogen on endothelial nitric oxide (NO) synthase often forms the basis for a worsening of the cardiac risk profile for women in postmenopause. Various studies have shown that decreasing estrogen levels also directly effect the expression of PTHrP and TGFbeta1. PTHrP is involved in the endothelium-dependent regulation of coronary resistance and cardiac function. The current study investigates to what extent chronic NO deficit affects the cardiac effects of PTHrP. NO deficit was achieved in female adult rats by feeding them the NO synthase inhibitor N-omega-nitro-L-arginine methyl ester over a period of 4 wk. Isolated hearts of the conditioned animals were investigated in Langendorff technique and perfused for 3 min with 100 nM PTHrP. The contraction behavior of isolated cardiomyocytes was registered in a cell-edge detection system. Hearts from untreated animals displayed a significant drop in left ventricular developed pressure and a pronounced increase in heart rate in consequence of short term PTHrP stimulation. In hearts from NO-deficient rats PTHrP no longer affected the inotropy and chronotropy. The vasodilating effect of PTHrP on coronary vessels was, however, independent of the NO level. These changes were accompanied by a differing expression of the PTH1 receptor. TGFbeta1 was identified as an important mediator for the regulation of the PTH1 receptor in myocytic but not endothelial cells. These results indicate that chronic NO deficit down-regulates the PTH1 receptor in a TGFbeta1-dependent way. These findings are important with respect to the relatively new therapy of postmenopausal osteoporosis with PTHrP analogs.

Aims: The study was aimed to investigate whether nicotine affects endothelial expression of PTHrP and PTHrP receptor, a peptide system involved in endothelial protection against apoptosis. Methods: Isolated and cultured rat coronary endothelial cells were used. Immunoblot techniques were used to study activation of mitogen-activated protein (MAP) kinases and to quantify PTHrP and PTHrP receptor expression. Real-time RT-PCR was used to quantify PTHrP, PTHrP-receptor, bcl-2, and bax mRNA expression. The rate of apoptosis was determined by HOE33258 staining and confirmed by quantification of the bcl-2-to-bax ratio. In vitro data were compared to hearts from rats exposed to cigarette smoking. Results: Nicotine induced PTHrP protein expression at nanomolar levels and small increases of PTHrP release (≈8%). Antagonists directed against the α7 subunit of cholinergic receptors, the most prominent isoform, attenuated nicotine-dependent increases of PTHrP expression. This effect of nicotine was p38 MAPK dependent. Nicotine at micromolar concentrations reduced PTHrP receptor expression. In vitro and in vivo we found a correlation between PTHrP receptor expression and bcl-2 expression. Conclusion: Nicotine induces PTHrP expression in endothelial cells but excessive concentrations of nicotine reduce PTHrP receptor expression thereby attenuating any protective effects of PTHrP against apoptosis.