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Thromboxane-induced contractile response of mesenteric arterioles is diminished in the older rats and the older hypertensive rats.

ABSTRACT: Nearly all physiological processes are controlled at some level by G-protein-coupled receptor (GPCR) signaling activity. The thromboxane A2 (TXA2) receptor (TP) is a member of the GPCR family. The ultimate effect of TP receptor activation depends on the availability of specific G proteins, which in turn depend on the cell type, tissue, and disease state. However, the roles of the TXA2-TP signaling pathway executed under disease states are poorly defined. In this study, 16-week-spontaneously hypertensive rats (SHR), the 18-month-SHR (OldSHR), and the age-matched Wistar-Kyoto (WKY) rats were used to study the vasoconstriction of mesenteric resistance artery induced by TP-specific agonist, U-46619. Vasoconstriction induced by U-46619 was significantly attenuated in OldWKY and OldSHR rats, and mesenteric arteries with impaired response to U-46619 responded strongly to the adrenergic receptor agonist, phenylephrine. Similar vascular responses to U-46619 were obtained in endothelium-denuded mesenteric arteries. Accordingly, the expression of TP membrane proteins in mesenteric vessels was decreased, and the endogenous TP competitor, 8, 9-EET, in serum was increased, which was partly responsible for the decreased vascular reactivity of U-46619. Decreased TP membrane expression was associated with TP endocytosis, which involved actin cytoskeletal remodeling, including increased ratio of F-actin/G-actin in OldWKY and OldSHR rats. Hence, we studied the effects of TXA2 and its receptors on blood vessels and found that the TXA2-TP prostaglandin signaling pathway was impaired in older adults, which would facilitate the creation of "precision therapeutics" that possess selective efficacy in diseases.

SUBMITTER: Zhang M

PROVIDER: S-EPMC9602936 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Thromboxane-induced contractile response of mesenteric arterioles is diminished in the older rats and the older hypertensive rats.

Zhang Min M Li Chunshu C He Chunxia C Cui Yiqin Y Li Yuan Y Ma Ying Y Cheng Jun J Wen Jing J Li Pengyun P Yang Yan Y

Frontiers in pharmacology 20221012

Nearly all physiological processes are controlled at some level by G-protein-coupled receptor (GPCR) signaling activity. The thromboxane A2 (TXA2) receptor (TP) is a member of the GPCR family. The ultimate effect of TP receptor activation depends on the availability of specific G proteins, which in turn depend on the cell type, tissue, and disease state. However, the roles of the TXA2-TP signaling pathway executed under disease states are poorly defined. In this study, 16-week-spontaneously hype ...[more]

PMID: 36313372

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Project description:1. In this study, intracellular Ca(2+) was measured as the Fura-2 ratio (R) of fluorescence excited at 340 and 380 nm (F(340)/F(380)) in nonpressurized rat mesenteric small arterioles ( (lumen diameter) 10-25 microm). 2. The response to depolarization using 75 mm KCl was an increase in R from a baseline of 0.96+/-0.01 ([Ca(2+)](i) approximately 74 nm) to 1.04+/-0.01 ( approximately 128 nm) (n=80). The response to 75 mm K(+) was reversibly abolished in Ca(2+)-free physiological saline solution, whereas phentolamine (10 microm) or tetrodotoxin (1 microm) had no effects. LaCl(3) (200 microm) inhibited 61+/-9% of the response. 3. A [K(+)]-response curve indicated that the Ca(2+) response was activated between 15 and 25 mm K(+). The data suggest that the Ca(2+) response was caused by the activation of voltage-dependent Ca(2+) channels. 4. Mibefradil use dependently inhibited the Ca(2+) response to 75 mm K(+) by 29+/-2% (100 nm), 73+/-7% (1 microm) or 89+/-7% (10 microm). Pimozide (500 nm) use dependently inhibited the Ca(2+) response by 85+/-1%. 5. Nifedipine (1 microm) inhibited the Ca(2+) response to 75 mm K(+) by 41+/-12%. The response was not inhibited by calciseptine (500 nm), omega-agatoxin IVA (100 nm), omega-conotoxin MVIIA (500 nm), or SNX-482 (100 nm). 6. Using reverse transcriptase-polymerase chain reaction, it was shown that neither Ca(V)2.1a (P-type) nor Ca(V)2.1b (Q-type) voltage-dependent Ca(2+) channels were expressed in mesenteric arterioles, whereas the Ca(V)3.1 (T-type) channel was expressed. Furthermore, no amplification products were detected when using specific primers for the beta(1b), beta(2), or beta(3) auxiliary subunits of high-voltage-activated Ca(2+) channels. 7. The results suggest that the voltage-dependent Ca(2+) channel activated by sustained depolarization in mesenteric arterioles does not classify as any of the high-voltage-activated channels (L-, P/Q-, N-, or R-type), but is likely to be a T-type channel. The possibility that the sustained Ca(2+) influx observed was the result of a T-type window current is discussed.

Dataset Information

Thromboxane-induced contractile response of mesenteric arterioles is diminished in the older rats and the older hypertensive rats.

Publications

Thromboxane-induced contractile response of mesenteric arterioles is diminished in the older rats and the older hypertensive rats.

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