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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 first full description of the novel pharmacological properties of the prototype of this group of compounds, cromakalim, was in 1986.104 Cromakalim has been shown to inhibit spontaneous contractions and those induced by several spasmogens in a wide variety of isolated smooth muscles.66 It is considered that cromakalim acts by opening potassium (K+) channels in the plasmalemma (Figure 5).66 The nature of the particular K+ channel involved has remained elusive. There are data suggesting that it is an ATP-sensitive K+ channel, in part because the drugs are antagonized by glyburide, an ATP-sensitive K+ channel blocker in the pancreas.105 However, recent patch clamp data suggest that cromakalim acts on a different K+ channel with a low conductance.106 Cromakalim may also have intracellular actions to reduce free Ca2+ concentrations.107 There are other newly developed compounds (e.g., RP 49356) and substances that are in therapeutic use (pinacidil, minoxidil sulphate, nicorandil, diazoxide) that have similar profiles to cromakalim.66
Spirulina extract improves age-induced vascular dysfunction
Published in Pharmaceutical Biology, 2022
Michal Majewski, Mercedes Klett-Mingo, Carlos M. Verdasco-Martín, Cristina Otero, Mercedes Ferrer
The drugs used were hydroethidine (HE), L-noradrenaline (NA) hydrochloride, ACh chloride, potassium chloride, sodium nitroprusside (SNP), cromakalim and carbon monoxide releasing molecule (CORM) (Sigma-Aldrich). Stock solutions (10 mM) of cromakalim and CORM were prepared in absolute ethanol, and final ethanol concentration in the tissue baths never exceeded 0.1% (v/v). The remaining drugs were prepared in distilled water, except for NA which was dissolved in NaCl (0.9%)-ascorbic acid (0.01% w/v) solution. These solutions were kept at −20 °C and appropriate dilutions were made in KHS on the day of the experiment.
Mechanisms of butylidenephthalide for twitch facilitation in electrically stimulated mouse vas deferens
Published in Pharmaceutical Biology, 2018
Chung-Hung Shih, Chi-Ming Chen, Wun-Chang Ko
In the present results, Bdph-induced twitch facilitations were not influenced by atropine, dl-propranolol, atenolol, yohimbine and phenoxybenzamine (3 μM), suggesting that Bdph-induced twitch facilitations were unrelated to activation of postjunctional cholinergic or adrenergic receptors. Recently, we reported Bdph similar to 4-AP, a blocker of Kv1 family of K+ channels, to antagonize cromakalim, an ATP-dependent K+ channel opener, in guinea-pig trachea (Hsu et al. 2014). Thus, Bdph may result in depolarization on the prejunctional membrane of adrenergic nerve ending, and in more releases of NA and ATP. In the present results, at a higher concentration of phenoxybenzamine (10 μM) or prazosin (1 μM) augmented the Bdph-induced twitch facilitations. Phenoxybenzamine was reported to irreversibly block α1 and α2-adrenoceptors and prazosin has a 1000-fold greater affinity for α1- than α2-receptors (Williams and Turner 2005). However, both at a higher concentration may block prejunctional α2-autoreceptors and results in more NA and ATP release from adrenergic neurons (Cleary et al. 2003; Williams and Turner 2005). In addition, phenoxybenzamine also inhibits NA uptake into both adrenergic nerve terminals and extraneuronal tissues (Williams and Turner 2005). Thus, in this experiment, phenoxybenzamine augmented Bdph-induced twitch facilitations. This augmentation was more obvious than that induced by prazosin at low concentrations of Bdph (Figure 2(a)). In contrast, verapamil-induced twitch facilitations were inhibited by all antagonists at low concentrations, suggesting that these facilitations may be due to endogenous NA and ACh released from adrenergic and cholinergic nerve endings, respectively. Thus, Bdph and verapamil did not influence their facilitations each other (Figure 3(a)). In contrast to MVD, we recently reported Bdph or verapamil (5 µM) inhibited, but not facilitated, the twitch response in electrically stimulated guinea-pig ileum (Chen and Ko 2016). Thus, the facilitation induced by Bdph or verapamil seems dependent on tissue preparation. For example, it has been reported that paradoxical effects of verapamil in vas deferens and adrenal chromaffin cells from which transmitters are released (Bergantin et al. 2013).