Thromboxane A2 (TXA2) promotes various physiological responses including pulmonary artery (PA) contraction, and pathophysiological implications have been suggested in cardiovascular diseases including pulmonary hypertension. Here, we investigated the role of TXA2 receptor (TP)-mediated signaling in the pathophysiology of pulmonary arterial hypertension (PAH). The sensitivity of PA to the contractile agonist could be set by relaxing signals such as the nitric oxide (NO), soluble guanylate cyclase (sGC), and cGMP-dependent kinase (PKG) pathways. Changes in the TP agonist (U46619)-induced PA contraction and its modulation by NO/cGMP signaling were analyzed in a monocrotaline-induced PAH rat model (PAH-MCT). In the myograph study, PA from PAH-MCT showed higher responsiveness to U46619, that is decreased EC50. Immunoblot analysis revealed a lower expression of eNOS, sGC, and PKG, while there was a higher expression of RhoA-dependent kinase 2 (ROCK2) in the PA from PAH-MCT than in the control. In PAH-MCT, the higher sensitivity to U46619 was reversed by 8-Br-cGMP, a membrane-permeable cGMP analog, but not by the NO donor, sodium nitroprusside (SNP 30 μM). In contrast, in the control PA, inhibition of sGC by its inhibitor (1H− [1,2,4] oxadiazolo [4,3−a] quinoxalin-1-one (ODQ), 10 μM) lowered the threshold of U46619-induced contraction. In the presence of ODQ, SNP treatment had no effect whereas the addition of 8-Br-cGMP lowered the sensitivity to U46619. The inhibition of ROCK by Y-27632 attenuated the sensitivity to U46619 in both control and PAH-MCT. The study suggests that the attenuation of NO/cGMP signaling and the upregulation of ROCK2 increase the sensitivity to TXA2 in the PAH animal, which might have pathophysiological implications in patients with PAH.

Purpose: This study aimed to examine the exercise-mediated musculoskeletal recovery following hindlimb suspension (HS) in order to identify whether bone modeling and muscle hypertrophy would eventuate in a synchronized manner during recovery stage.Methods: To identify whether 2-week HS would be sufficient to induce a significant reduction of physiological indices in both tibia and adjacent hindlimb muscles, a total of 20 rats was randomized into 2-week HS (n = 10) and age-matched control group (n = 10, CON). Another batch of rats were randomly assigned to three different groups to identify recovery intervention effects following suspension: (1) 2-week HS followed by 4-week spontaneous reloading recovery (HRE, n = 7). (2) 2-week HS followed by 4-week progressive resistance ladder climbing exercise (HEX, n = 7). (3) Age-matched control (CON, n = 7). DXA, micro-CT, and 18F-sodium fluoride (NaF) imaging, and EIA analysis were utilized to measure tibia bone indices. Hindlimb muscle wet weight and grip strength were measured to evaluate muscle mass and strength, respectively.Results: In study 1, bone quality values [bone volume/total volume (BV/TV): -27%, areal bone mineral density (aBMD): -23%, mineral contents: -7.9%, mineral density: –4.1%, and bone density: -38.9%] and skeletal muscle weight (soleus: -46.8%, gastrocnemius: -19.6%, plantaris: -20.8%, TA: -22.8%, and EDL: -9.9%) were significantly lower in HS group compared to CON group. In study 2, micro-CT and DXA-based bone morphology (bone density, BT/TV, and aBMD) were fully recovered in HRE or HEX group. However, suspension-induced dysregulation of bone mineral metabolism was returned to age-matched control group in only HEX group, but not in HRE group. A greater level of biomarkers of bone formation (P1NF) and resorption (CTX-1) was observed in only HRE group compared to CON. The hindlimb skeletal muscle mass was significantly lower in both HRE and HEX groups compared to CON group. Hindlimb grip strength was the greatest in HEX group, followed by CON and HRE groups.Conclusion: Following HS, progressive resistance exercise promotes recovery rates of bone and skeletal muscle strength without a significant increase in muscular mass, suggesting that exercise-induced reacquisition of bone and muscle strength is independent of muscle hypertrophy during early recovery stage.

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Endothelium-dependent vasorelaxation is partly mediated by small-conductance (SK3) and intermediate-conductance Ca 2+-activated K + channels (SK4) in the endothelium that results in endothelium-dependent hyperpolarization (EDH). Apart from the electrical propagation through myoendothelial gap junctions, the K + released from the endothelium facilitates EDH by increasing inward rectifier K + channel (Kir) conductance in smooth muscle cells. The EDH-dependent relaxation of coronary artery (CA) and Kir current in smooth muscle cells (CASMCs) of hypertensive animals are poorly understood despite the critical role of coronary flow in the hypertrophic heart. In spontaneously hypertensive (SHR) and control (WKY) rats, we found attenuation of the CA relaxation by activators of SK3 and SK4 (NS309 and 1-EBIO) in SHR. In isolated CASMCs, whole-cell patch-clamp study revealed larger I Kir in SHR than WKY, whereas the myocytes of skeletal and cerebral arteries showed smaller I Kir in SHR than WKY. While the treatment with I Kir inhibitor (0.1 mmol/L Ba 2+) alone did not affect the WKY-CA, the SHR-CA showed significant contractile response, suggesting relaxing influence of the higher I Kir in the CASMCs of SHR. Furthermore, the attenuation of NS309-induced relaxation of CA by the combined treatment with 0.1 mmol/L Ba 2+ was more prominent in SHR than WKY. Our study firstly shows a distinct increase of I Kir in the CASMCs of SHR, which could partly compensate for the attenuated relaxation via endothelial SK3 and SK4. K E Y W O R D S coronary artery, endothelium, hypertension, inward rectifier K + channel, K + channel, smooth muscle 1 | INTRODUC TI ON Both agonist-and flow-dependent vasodilation depend on normal functions of endothelial cells; endothelium-derived relaxing factors (EDRFs) such as nitric oxide (NO) and prostacyclin, and endothelial-derived hyperpolarization (EDH) mechanisms. While the EDRF-dependent vasodilation is predominant in conduit arteries, the contribution of EDH seems to be also important in small arteries and arterioles. 1 As for the mechanisms of EDH, both diffusible endothelium-derived hyperpolarizing factor (EDHF) and direct | 39 How to cite this article: Kim HJ, Yin MZ, Cho S, et al. Increased inward rectifier K + current of coronary artery smooth muscle cells in spontaneously hypertensive rats; partial compensation of the attenuated endothelium-dependent relaxation via Ca 2+-activated K + channels.