KAtp channel blockers

The approach discussed to use VolSurf derived in silica models to understand structure-PK relationships for pharmacokinetic properties was also applied to one series of selective cardiac KATP channel blockers [160]. It was found that compounds fulfilling the predefined selectivity profile exhibit only less-optimal pharmacokinetic properties because of a short plasma mean residential time (MRT). Consequently, the MRT for 28 compounds from rabbit iv studies for one series was used as dependent variable to derive a VolSurf PLS model in addition to ligand affinity SAR data. The chemical... 

Ikeda et al., 2000 Narita et al., 2000). KAtp channels have been shown to be opened by Gj/0-proteins (Edwards and Weston, 1993) and could thus mediate the inhibitory effect of morphine at the cellular level. Furthermore, such an interaction would also explain the antagonism and potentiation of morphine analgesia by Katp channel blockers and openers, respectively (see above). However, a recent electrophysiological study demonstrated that Katp channels do not mediate the effect of morphine in ventrolateral PAG neurones (Chiou and How, 2001). 

Again, as is the case for KAtp channels involved in supraspinal analgesia those participating in spinal antinociception are not tonically activated since none of the Katp channel blockers exerted any effect per se. 

Indeed, using the same experimental approach (i.e. i.c.v. administration of KAtp channel openers and blockers) it was shown that supraspinal KAtp channels are also involved in producing antinociceptive effects of several other classes of analgesic substances (Table 1). The KAtp channels involved in supraspinal antinociception are not... 

A final series of experiments were performed in our laboratory to determine the role of the sarcolemmal KATP (sarcKATP) channel and the mitoKATP channel in TAN-67-induced cardioprotection in the intact rat heart [60]. Administration of the selective sarcKATP inhibitor HMR 1098 prior to TAN-67 did not significantly block the cardioprotection produced by TAN-67. Elowever, pretreatment with 5HD, the selective mitoKATP channel blocker, completely abolished TAN-67-induced cardioprotection. These data clearly suggest that delta, opioid receptor-induced infarct size reduction is mediated by the mito KATP channel in rats. A summary of the major signaling components involved in acute opioid-induced preconditioning is schematically depicted in Figure 2. 

PKG and cyclic nucleotide phosphodiesterases (PDEs) (reviewed by Baxter37). A rapid release of natriuretic peptides and induction of their de novo synthesis occurs in myocardial ischemia. Natriuretic peptides may have a cardioprotective role. BNP-32 administration in perfused rat hearts prior to left main coronary artery occlusion and until 30 min of reperfusion resulted in limitation of infarct size in a concentration dependent manner. Furthermore, this effect was abolished by 5-hydroxydecanoate (presumed to be a selective blocker of mitochondrial KATp channels), L-NAME, an inhibitor of NOS and ODQ, a specific soluble guanyl cyclase inhibitor.38 Similarly, human recombinant ANP limited infarct size and reperfusion arrhythmias in a canine model of coronary occlusion and reperfusion.39... 

Pharmacological rescue of disease phenotype by a Wang et al. calcium channel blocker, nifedipine, and a KATP (2014a)... 

Figure 3 Effects of various stimuli and mitochondrial inhibitors on the resting membrane potential of quiescent chromaffin cells. A typical example of hypoxia-induced membrane depolarization is shown in (a), using nystatin perforated-patch whole-cell recording. In (b), bicuculline (100 pM), a reversible inhibitor of small-conductance Ca +-dependent K+ channels (SK), also caused membrane depolarization similar to hypoxia. The mitochondrial inhibitors 2,4-drnitrophenol (DNP) and cyanide (CN) did not mimic the h poxia-mduced membrane depolarization seen in (c) and (d), respectively in fact, in (d), CN caused membrane h3q)erpolarization, though in most cases no change in membrane potential was observed. Both DNP and CN were usually without effect even after perfusing the drug for >10 min. In (e), the hyperpolarizing effect of CN was reversed in the presence of 200 pM glibenclamide, a blocker of Katp channels.

---