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Pharmacological Strategies for Uterine Relaxation
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Michael Hollingsworth, Sandra J. Downing, Josephine M. S. Cheuk, Ian T. Piper, Sarah J. Hughes
The KCOs pinacidil, nicorandil, and minoxidil are in clinical use in essential hypertension by virtue of their peripheral vasodilator properties.66 Hence, a KCO used to inhibit uterine contractions could be anticipated to produce a fall in blood pressure and some reflex tachycardia and to be relaxants of other smooth muscles. This comment might suggest that any KCO would lack selectivity for the uterus but it would appear that inhibition of uterine contractions can be achieved at doses which do not produce marked vasodilation (Figure 7). What is required is a truly uterine selective KCO.
Dihydromyricetin improves vascular hyporesponsiveness in experimental sepsis via attenuating the over-excited MaxiK and KATP channels
Published in Pharmaceutical Biology, 2018
Jin Peng, Jian Zhang, Li Zhang, Yonggang Tian, Yahong Li, Lujun Qiao
ASMCs were isolated from the thoracic aorta by using enzymatic digestion to obtain highly purified acute isolated ASMCs. Figure 3(A) illustrated that under the same experimental conditions, the whole-cell MaxiK currents density in LPS + DMY was smaller than that in LPS rats. The statistical analysis was shown in Figure 3(C) (0.2 ± 0.02 vs. 0.1 ± 0.02 nA/pF, p < 0.01). The whole cell recordings were carried out in a symmetrical 140 mM K+ solution to optimize the recordings, and the cells were held at a holding potential of −60 mV. Raising the extracellular K+ to 140 mM induced small KATP currents. Pinacidil (10 μM) was applied to increase an inward current in cells from LPS and LPS + DMY rats for enhancing the KATP currents (Figure 3(B)) and glibenclamide (a KATP channel inhibitor) could revert it in both cell types. Then pinacidil-induced KATP currents in isolated ASMCs from both LPS and LPS + DMY models were obtained. The magnitude of the KATP current in ASMCs from LPS + DMY rats was significantly lower than those from LPS rats (−26.7 ± 3.0 vs. −16.9 ± 3.7 pA/pF, Figure 3(D), p < 0.05).
The ATP-sensitive potassium channel: a therapeutic target for neurodegeneration?
Published in Expert Opinion on Therapeutic Targets, 2023
Xue Xiao, Mingxia Bi, Xixun Du, Hong Jiang
Previously, some evidences have suggested that neurodegenerative diseases usually accompanied by metabolic disorders, cell necrosis, ischemia, hypoxia, etc., however, KATP channels play an important role in regulating metabolism, neuronal excitability and neurotransmitter release [3]. Therefore, whether the KATP channels could play a therapeutic role in neurodegenerative diseases by regulating its opening state? In this review by Lv et al., the author discussed and further summarized the forms and functional characteristics of two types of KATP channels, sarcolemmal KATP (sarcKATP) channels and mitochondrial KATP (mitoKATP) channels, at the same time, the double-edged effect of KATP channel openers (KCOs) and inhibitors in Alzheimer’s disease (AD), Parkinson’s disease (PD), vascular dementia and Huntington’s disease were explained in detail [2]. Openers of KATP channels, such as diazoxide, pinacidil and KATP channels inhibitors sulfonylureas, have been widely used in clinical practice, playing a very significant effect in the treatment of metabolic diseases, angina pectoris and hypertension (Table 1) [4,5]. Using the existing drugs correctly is a very effective way to treat diseases, because drug’s pharmacodynamic and pharmacokinetic profiles have been established, which can greatly improve efficiency and clarify the toxic side effects of drugs in humans. If we can fully grasp the advantages and disadvantages of KCOs and inhibitors in neurodegenerative diseases, it will be a very clear direction for the treatment of neurodegenerative diseases. Based on the extensive application of KCOs and inhibitors in the above-mentioned diseases, this article summarizes the application prospects of KATP channels in neurodegenerative diseases.
Emerging therapeutic targets in the short QT syndrome
Published in Expert Opinion on Therapeutic Targets, 2018
Jules C Hancox, Dominic G Whittaker, Chunyun Du, A. Graham Stuart, Henggui Zhang
There are no genotypically accurate mammalian models of the SQTS. Information on underlying arrhythmia mechanisms in the syndrome has been gleaned from studies using in vitro preparations and potassium channel activators and also from computer modeling based on changes to ion channel properties seen in recombinant channel experiments. The KATP channel activator pinacidil produces a short QT phenotype when applied to canine left ventricular wedge preparations or to intact rabbit hearts [78–80]. Pinacidil was seen to produce heterogeneous APD abbreviation across the canine left ventricular wall and thus augment transmural dispersion of repolarization (TDR) and increase susceptibility to provoked polymorphic VT [78]. In intact rabbit hearts, pinacidil abbreviated QT interval and ERP, which was associated with increased susceptibility to VF [79,80]. Application of the hERG/IKr activator PD118057 to canine left ventricular wedge preparations to mimic SQT1 abbreviated QT interval and ERP and augmented TDR and arrhythmia susceptibility [81]. Enhanced TDR has been seen in SQTS patients [82]. Multilevel modeling of N588K-linked SQT1 has shown reductions in APD and ERP, with localized increases in maximal ventricular transmural voltage heterogeneity (δV) in the SQT1 setting, increasing vulnerability to unidirectional conduction block [45]. A reduced ventricular substrate size needed to sustain re-entry facilitated spiral and scroll wave lifespan/stability in 2D and 3D simulations [45]. Parallel observations have been made in simulations of SQT2 [58,59]. Biophysical modeling has also confirmed the ventricular proarrhythmic nature of KCNJ2 SQTS mutations [65,68,70]. For example, D172N Kir2.1 leads to abbreviated APD and ERP and to steeper restitution curves for these parameters [68]. The D172N mutation reduces tissue excitability at slow rates but increases it at higher ones, also increasing temporal vulnerability to initiation of re-entry whilst reducing the substrate size required to maintain re-entry [68].