We sought to explore new strategies targeting SUR2B/Kir6.1, a subtype of adenosine triphosphate (ATP)-sensitive potassium channels (KATP), against pressure overload-induced heart failure. The effects of natakalim, a SUR2B/Kir6.1 selective channel opener, on progression of cardiac remodeling were investigated. Pressure overload-induced heart failure was induced in Wistar rats by abdominal aortic banding. The effects of natakalim (1, 3, and 9 mg·kg⁻¹·d⁻¹ for 10 weeks) on myocardial hypertrophy and heart failure, cardiac histology, vasoactive compounds, and gene expression were assessed. Ten weeks after the onset of pressure overload, natakalim treatment potently inhibited cardiac hypertrophy and prevented heart failure. Natakalim remarkably inhibited the changes of left ventricular hemodynamic parameters and reversed the increase of heart mass index, left ventricular weight index, and lung weight index. Histological examination demonstrated that there was no significant hypertrophy or fibrosis in pressure-overloaded hearts of natakalim-treated rats. Ultrastructural examination of hearts revealed well-organized myofibrils with mitochondria grouped along the periphery of longitudinally oriented fibers in rats from the natakalim group. The content of serum nitric oxide and plasma prostacyclin was increased, whereas that of plasma endothelin-1 and cardiac tissue hydroxyproline and atrial and B-type natriuretic peptide messenger RNA was downregulated in natakalim-treated rats. Natakalim at 0.01-100 µM had no effects on isolated working hearts derived from Wistar rats; however, natakalim had endothelium-dependent vasodilatory effects on the isolated tail artery helical strips precontracted with norepinephrine. These results indicate that natakalim reduces heart failure caused by pressure overloading by activating the SUR2B/Kir6.1 KATP channel subtype and protecting against endothelial dysfunction.
Aim: To determine whether administration of choline could attenuate brain injury in a rat model of ischemic stroke and the underlying mechanisms.Methods: A rat model of ischemic stroke was established through permanent middle cerebral artery occlusion (pMCAO). After the surgery, the rats were treated with choline or choline plus the specific α7 nAChR antagonist methyllycaconitine (MLA), or with the control drug nimodipine for 10 days. The neurological deficits, brain-infarct volume, pial vessel density and the number of microvessels in the cortex were assessed. Rat brain microvascular endothelial cells (rBMECs) cultured under hypoxic conditions were used in in vitro experiments. Results: Oral administration of choline (100 or 200 mg·kg -1 ·d -1 ) or nimodipine (20 mg·kg -1 ·d -1 ) significantly improved neurological deficits, and reduced infarct volume and nerve cell loss in the ischemic cerebral cortices in pMCAO rats. Furthermore, oral administration of choline, but not nimodipine, promoted the pial arteriogenesis and cerebral-cortical capillary angiogenesis in the ischemic regions. Moreover, oral administration of choline significantly augmented pMCAO-induced increases in the expression levels of α7 nAChR, HIF-1α and VEGF in the ischemic cerebral cortices as well as in the serum levels of VEGF. Choline-induced protective effects were prevented by co-treatment with MLA (1 mg·kg -1 ·d -1, ip). Treatment of rBMECs cultured under hypoxic conditions in vitro with choline (1, 10 and 100 μmol/L) dose-dependently promoted the endothelial-cell proliferation, migration and tube formation, as well as VEGF secretion, which were prevented by co-treatment with MLA (1 μmol/L) or by transfection with HIF-1α siRNA. Conclusion: Choline effectively attenuates brain ischemic injury in pMCAO rats, possibly by facilitating pial arteriogenesis and cerebralcortical capillary angiogenesis via upregulating α7 nAChR levels and inducing the expression of HIF-1α and VEGF.
These results demonstrate that iptakalim could protect against IR-induced endothelial dysfunction, and ameliorate IR associated with hypertension, possibly via restoring the balance between NO and ET-1 signaling.
Non-steroidal anti-inflammatory drugs (NSAIDs) are effective for relieving pain but undesirable side effects limit their clinical usefulness. Choline is a α7 nicotinic receptor agonist that has antinociceptive effects in a variety of pain models. Drug combination is a strategy in the management of pain to reduce side effects. The aim of the study was to evaluate the nature of the interaction between choline and aspirin in two distinct inflammatory pain models. The analgesic mechanism of choline was also investigated. In the writhing test, intravenous administration of choline or aspirin showed dose-dependent antinociceptive activity, and isobolographic analysis revealed a synergistic nature of the interaction between choline and aspirin. More importantly, coadministration choline with aspirin could significantly shorten the antinociceptive latency of aspirin and prolong the antinociceptive duration of aspirin in the writhing test. In the carrageenan test, single administration of choline or aspirin significantly attenuated carrageenan-induced thermal hyperalgesia in a dose-dependent relationship. Coadministration of non-analgesic doses of aspirin with choline significantly suppressed the thermal hyperalgesia, with a longer duration efficacy. Furthermore, we found that α7 nicotinic, muscarinic, and opioid-receptors are involved in the antinociceptive effect of choline in the writhing test and the antinociceptive effect produced by systemically administered choline may be via a peripheral mechanism. In conclusion, coadministration of choline and aspirin holds promise for development as a safe analgesic drug combination for inflammatory pain, with a higher potency and longer duration than either aspirin or choline alone.
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