As shown in Fig. 3A, the gene expression of NPR-A in the kidney was significantly lower in the SW compared to the SD group. However, the expression of NPR-A in the RN group compared to the SD group did not reach significance. Similarly, only the gene expression of NPR-C was significantly decreased in the SW group, but not in the RN group, when compared to the SD group (Fig. 3B). The ability of natriuretic peptide receptors to bind 125I-ANP was investigated in mesenteric adipose tissue by in vitro autoradiography. Unlabeled ANP displaces 125I-ANP

bound to both receptors, NPR-A and NPR-C, and c-ANF displaces 125I-ANP bound specifically to NPR-C. The displacement of 125I-ANP from NPR-A can be inferred by the difference between ANP and cANF displacements.

125I-ANP bound reversibly and with high affinity to the mesenteric adipose tissue of all groups, but SB431542 as Fig. 4A–C shows, the SW group presented higher total 125I-ANP binding compared to the other groups. Unlabeled ANP almost completely inhibited 125I-ANP binding to the mesenteric adipose tissue of the SD group. A high displacement rate was also observed using c-ANF, which indicates a high level of NPR-C in the mesenteric adipose tissue of SHR. The percentage of displacement by ANP in the SW group was similar to the SD group, but the displacement by c-ANF was reduced, indicating a reduction of NPR-C ( Fig. 4A, B, D and E). Although no difference in total binding was observed in the RN group compared to the SD group, displacement by ANP Saracatinib or c-ANF was reduced, indicating a reduction in the specific receptors, NPR-A and NPR-C, respectively ( Fig. 4C Nintedanib (BIBF 1120) and F). This

study demonstrated for the first time that chronic swimming and running training promote significant changes in endogenous ANP of SHR at rest through alterations in the synthesis and bioavailability of ANP as well as within its gene expression receptors. The data showed increased plasma ANP levels in the SW group and decreased ANP expression in the LA only in the RN group. In the kidney, a decrease in NPR-A such as in NPR-C gene expression was only noticed in the SW group; however, swimming increased 125I-ANP binding to mesenteric adipose tissue and displacement by c-ANF was reduced, indicating a reduction of NPR-C. We did not observe any influence of physical training by running or swimming on HR at rest in SHR. Previously, Schaible and Scheuer had shown decreases in HR after eight weeks of training on running and swimming in normotensive animals [37]. Besides using hypertensive rats, the intensity of training used in our study was different. We used the intensity of the maximal lactate steady state (i.e., the highest intensity at which aerobic metabolism still predominates over anaerobic metabolism) [11] and [33]. This was done so that both training modalities had similar intensities and in order to promote adaptations from predominantly aerobic activities.