Cromakalim (INN) is a potassium channel-opening vasodilator. The active isomer is levcromakalim. It acts on ATP-sensitive potassium channels and so causes membrane hyperpolarization. It can be used to treat hypertension as it will relax vascular smooth muscle to lower blood pressure. Hyperpolarisation of smooth muscle cell membranes pulls their membrane potential away from the threshold, so making it more difficult to excite them and thereby cause contraction. Reaction of 4-cyanophenol (4-Hydroxybenzonitrile) with 2-hydroxy-2-methyl-3-butyne under PTC probably proceeds to initial formation of a propargyl carbocation. The course of the reaction can be envisaged by assuming that this then attacks the aromatic ring; the resulting allylic cation can then capture the adjacent phenol oxygen and thus form the observed product (3). Treatment of that product with aqueous NBS leads to the addition of the elements of hypobromous acid and formation of the bromohydrin (4) as a mixture of the trans ...

The invention provides methods for determining the ability of compounds to regulate lipogenesis and lipolysis by acting as a sulfonylurea-1 (SUR 1) potassium channel activator, an adipocyte potassium channel activator, an SUR 1 antagonist, and an adipocyte specific SUR 1 antagonist. The present invention recognizes the presence of the sulfonylurea receptor in adipocytes and its utility in identifying compounds and in regulating lipogenesis and lipolysis.

Toxins that block voltage-dependent K(+) channels and those that modify Na(+) channel gating exhibit positive inotropic effect on skeletal muscle. We compared the effect of the venom of Tityus cambridgei (Tc) and Tityus serrulatus (Ts) scorpions on mouse diaphragm force, in vitro. In indirect and direct (using D-tubocurarine 7.3 mu M) stimulation, Tc, 10 mu g/mL increased the contractile force, an effect prevented by tetrodotoxin (TTX) while Ts, 0.5 mu g/mL, potentiated only indirectly stimulated diaphragm, thus indicating its activity is mainly mediated through acetylcholine release from nerve terminal. This effect is prevented by TTX and attenuated by the K(+) channel opener cromakalim. In conclusion, our data show that while the positive inotropic effect of both venoms appears associated to the activity of Na(+) and K(+) channels, only Tc venom acts also directly on skeletal muscle. This finding call for further studies on Tc venom to identify the toxin responsible for its direct inotropic ...

Purpose : To evaluate the pharmacologic and safety parameters of CKLP1 following topical application in hound dog eyes. Methods : Optimal concentration of CKLP1 for reduction of IOP was established in female hound dogs (n=5) by topical application to the eye with CKLP1 (5-20 mM). Following washout (14 days), the dogs were treated with the optimal dose once daily for 60 consecutive days. IOP was measured 3 times daily (1, 4 and 23 hours post treatment), 3-7 times per week. Blood pressure measurements were recorded using a tail cuff, once daily, 3-5 times per week. For pharmacokinetic studies, both eyes were treated with CKLP1 for 8 consecutive days. Blood samples were collected on days 1, 4 and 8 and concentration of CKLP1 and its parent compound levcromakalim were evaluated in the plasma by LC MS/MS. Necropsy was performed on all animals and systemic effects of drug administration were histologically evaluated in 40 different tissue samples from each animal. Results : The 10 mM topical dose of ...

Experimental and clinical studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid‑onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance. Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L‑calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra‑rapid potassium channel‑operated current. Testosterone improves cardiac output, functional exercise capacity, VO2max and vagally mediated arterial baroreceptor cardiac reflex sensitivity in chronic heart failure. Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance ...

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The present invention describes novel nitrosated and/or nitrosylated potassium channel activators, and novel compositions comprising at least one nitrosated and/or nitrosylated potassium channel activator, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent. The present invention also provides novel compositions comprising at least one potassium channel activator, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent. The present invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses

The present invention describes novel nitrosated and/or nitrosylated potassium channel activators, and novel compositions comprising at least one nitrosated and/or nitrosylated potassium channel activator, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent. The present invention also provides novel compositions comprising at least one potassium channel activator, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent. The present invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses

(2015) Sun et al. Frontiers in Neurology. High dose sodium salicylate causes moderate, reversible hearing loss and tinnitus. Salicylate-induced hearing loss is believed to arise from a reduction in the electromotile response of outer hair cells (OHCs) and/or reduction of KCNQ4 potassium currents ...

Effects of KRN4884 (5-amino-,i,N,/i,-[2-(2-chlorophenyl)ethyl]-,i,N,/i,-cyano-3-pyridinecarboxamidine), a novel K,sup,+,/sup, channel opener, on ionic currents were examined in rabbit femoral arterial myocytes (RFAMs). Under whole-cell clamp conditions where cells were superfused with 5.9 mM K,sup,+,/sup, bathing solution, KRN4884 elicited an outward current at −30 mV. KRN4884-induced current had a reversal potential of −78 mV and was abolished by application of glibenclamide (glib). KRN4884 was approximately 43 times more potent than levcromakalim in activating an ATP-sensitive K,sup,+,/sup, current (I,sub,K-ATP,/sub,). On the other hand, KRN4884 affected neither voltage-dependent Ca,sup,2+,/sup, nor delayed rectifier K,sup,+,/sup, channel currents. In the inside-out patch clamp configuration where cells were superfused with the symmetrical 140 mM K,sup,+,/sup, solution, KRN4884 activated 47 pS K,sup,+,/sup, channels in the presence of adenosine diphosphate. Similar 47 pS K,sup,+,/sup, ...

Lee Sang Eok , Han Ji Young , Kim Hyun Woo , Yang In Jun , Xu Wen-Xie , Lee Sang Jin , Kim Young Chul , Yun Hyo-Yung , Kim Dae Hoon , Son Seung Myeung , Choi Song-Yi , You Ra Young , Kim Chan Hyung , Choi Woong , Kim Hun Sik , Lim Yung Ji … channel opener, suppressed contractions to 30% (basal tone to −0.2 g) of the control. … The inhibitory effect of pinacidil on contraction was reversed to 59% of the control by glibenclamide (20 μM), a K,sub,ATP,/sub, … Pinacidil also inhibited the acetylcholine (ACh)-induced tonic and phasic contractions in a glibenclamide-sensitive manner (42% and 6% of the control, respectively). … Journal of Smooth Muscle Research 56(0), 29-45, 2020 J-STAGE ...

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TY - JOUR. T1 - The energetic state within hibernating myocardium is normal during dobutamine despite inhibition of ATP-dependent potassium channel opening with glibenclamide. AU - McFalls, Edward O.. AU - Kelly, Rosemary F.. AU - Hu, Qingsong. AU - Mansoor, Abdul. AU - Lee, Joseph. AU - Kuskowski, Michael. AU - Sikora, Joseph. AU - Ward, Herbert B.. AU - Zhang, Jianyi. PY - 2007/11. Y1 - 2007/11. N2 - Within hibernating myocardium, it is uncertain whether a normal energetic state is present at baseline and whether maintaining that energy state during a catecholamine challenge is dependent on ATP-dependent potassium channel opening. In this study, 16 swine underwent a thoracotomy with placement of an external constrictor on the left anterior descending coronary artery (LAD) (hibernation model). Seven additional swine underwent a sham operation. At 10 wk, the myocardial energetic state in the LAD region was assessed by 31P-NMR spectroscopy, and the ratio of phosphocreatine to ATP (PCr/ATP) was ...

There has been much recent interest in the roles played by smooth-muscle K+ channels in protecting cells against ischemic and anoxic insults and in therapeutic vaso- and bronchodilation (Buckingham 1990; Longmore & Weston 1990). A K+ channel, which is uniquely sensitive to cytoplasmic ATP (KATP), has been identified as a likely candidate for mediating these important functions (Standen et al. 1989). We now show, by using electrophysiological techniques in three different types of smooth muscle, that a large-conductance voltage and Ca2+ -sensitive channel, otherwise indistinguishable from the large-conductance Ca2+ -activated K+ channel (BK channel), is also sensitive to cytoplasmic ATP and cromakalim. ATP, in a dose-dependent manner, decreased the probability of channel opening (P0) of rabbit aortic, rabbit tracheal and pig coronary artery BK channels with a K1 of 0.2-0.6mM. Cromakalim, 10 μM, partially reversed the ATP induced inhibition and increased P0. Our observations raise the possibility ...

McCloskey, Conor, Bailey, Elizabeth H., Zhang, J. (Jie), Shmygol, Anatoly, Thornton, Steven, Catalano, Roberto D., England, Sarah, Rada, Cara and Blanks, Andrew M. (2011) The novel potassium channel Kir7.1 is a critical component of uterine quiescence in mice and human. Reproductive Sciences, Vol.18 (No.3). 159A-159A ...

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Synopsis Nicorandil belongs to the class of compounds known as potassium channel activators which are characterised by their arterial vasodilator properties. In addition, nicorandil has venodilating...

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Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segreg …

Hydrogen peroxide and peroxynitrite induce relaxations via ATP-sensitive K+ channels, indicating that oxygen-derived free radicals may activate these channels. Levels of free radicals are increased throughout the arterial wall in animal models of atherosclerosis, and therefore, vasorelaxation via ATP-sensitive K+ channels may be augmented in chronic hypertension. The present study was designed to determine whether relaxations to an ATP-sensitive K+ channel opener, levcromakalim, are increased in the aorta from spontaneously hypertensive rats (SHR) and whether free radical scavengers reduce these relaxations. Rings of aortas without endothelium taken from age-matched Wistar-Kyoto rats (WKY) and SHR were suspended for isometric force recording. Relaxations to levcromakalim (10(-8) to 10(-5) M), which are abolished by glibenclamide (10(-5) M), were augmented in the aorta from SHR, compared to those in the aorta from WKY. In the aorta from SHR, catalase (1200 U/ml), but neither superoxide dismutase (150 U

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Iptakalim was unable to open pancreatic β-cell KATP channels, perhaps due to the presence of the SUR1, instead of the SUR2, subunit in these cells. Moreover, an intriguing finding was that iptakalim closed pancreatic β-cell-type KATP channels. It has been reported that PNU-99963, a nonsulfonylurea-based KATP channel inhibitor that has a structure similar to the KATP channel opener pinacidil, inhibits β-cell KATP channels (Cui et al., 2003). Structurally, iptakalim is also similar to the core portion of pinacidil; therefore, it is possible that KATP channel opener analogs with such a structure can inhibit KATP channels. Iptakalim may directly block β-cell KATP channels by acting on the Kir6.2 subunit (or some closely associated regulatory proteins). It is well documented that some KATP channel modulators, such as nicorandil, pinacidil, and glibenclamide, regulate KATP channel activity by targeting the regulating subunit SUR (Gribble and Ashcroft, 2000a; Hansen, 2006), whereas others (e.g., ...

The family of potassium channel openers regroups drugs that share the property of activating adenosine triphosphate-sensitive potassium (K(ATP)) channels, metabolic sensors responsible for adjusting membrane potential-dependent functions to match cellular energetic demands. K(ATP) channels, widely r …

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