Disease relevance of Cromakalim

• The data support the hypothesis that BRL 34915, like hypoxia, activates ATP-sensitive K+ channels in the heart [1].
• Spasms evoked by low concentrations of KCl (less than 20 mM) were inhibited by BRL 34915 but those evoked by higher concentrations (greater than 40 mM) were unaffected [2].
• 4. BRL 34915 (0.1 and 0.3 mg kg-1, i.v.) lowered blood pressure in rats dose-dependently and caused reflex tachycardia [3].
• The effects of various concentrations (1-100 microM) of BRL 34915 on the action potential characteristics were investigated in normal canine Purkinje fibers and Purkinje fibers surviving infarction [4].
• Short-term monotherapy with the potassium channel activator BRL 34915 on endocrine sodium regulation in essential hypertension [5].

High impact information on Cromakalim

• The mechanism by which the antihypertensive agent BRL 34915 (cromakalim) affects action potential duration (APD) and effective refractory period (ERP) in isolated cardiac muscle was investigated [1].
• BRL 34915 (greater than or equal to 3 microM) shortened ERP of ferret (Mustela putorius furo) and guinea pig (Cavia porcellus) papillary muscles in a concentration-dependent fashion [1].
• The actions of BRL 34915 were temperature-dependent, decreasing ERP 64% at 37 degrees C, but having no effect at 22 degrees C. The effect of BRL 34915 on K+ currents was tested directly in voltage-clamped guinea pig ventricular myocytes [1].
• Effects of K+ channel blockers and cromakalim (BRL 34915) on the mechanical activity of guinea pig detrusor smooth muscle [6].
• Apamin (0.5 microM) and crude scorpion venom (2.5 micrograms/ml) attenuated AA- but not BRL 34915-induced vasodilation [7].

Chemical compound and disease context of Cromakalim

• Glyburide, an inhibitor of ATP-sensitive K+ channels, prevented or reversed the shortening of ERP and APD produced by hypoxia and BRL 34915, respectively [1].
• 1 BRL 34915 (0.04-1.3 microM) caused concentration-dependent inhibition of spontaneous phasic spasms of the isolated uterus of the term pregnant rat and this effect was not antagonized by propranolol [2].
• Cromakalim (BRL 34915), a novel vasodilator, is used clinically to manage systemic hypertension [8].
• Tachycardia was more pronounced after BRL 34915 than after pinacidil [9].

Biological context of Cromakalim

• 6. Apamin pretreatment did not modify the blood pressure lowering activity of BRL 34915 in rats [3].
• BRL 34915 inhibited myogenic activity with an IC50 value of 12 +/- 2 nM by reducing primarily the frequency of spontaneous contractions [10].
• In the absence of these K+-channel inhibitors, BRL 34915 had no effect on resting membrane potential, membrane resistance, action potential, inward current or outward current [2].
• An i.v. injection of BRL 34915 (4, 20 and 100 micrograms/kg) caused a dose-related reduction of mean arterial pressure but there were no significant changes in renal blood flow [11].
• At 1.0 micrograms/kg/min, a dose which produced a slight reduction in mean arterial pressure, significant decreases in calculated renal vascular resistance were observed, thereby indicating that BRL 34915 has vasodilator action on the renal vasculature [11].

Anatomical context of Cromakalim

• As observed with the papillary muscles, BRL 34915 was without effect at 22 degrees C. At 36 degrees C, BRL 34915 (after a delay) increased outward currents positive to, and less so at potentials negative to, the K+ current reversal potential [1].
• It is concluded that the inhibitory actions of BRL 34915 on both aorta and portal vein result from the opening of membrane potassium channels [12].
• 5. These results provide some indirect evidence that membrane hyperpolarization may not be the only cause of the smooth muscle relaxation induced by BRL 34915 [13].
• It is proposed that the unique electrophysiological activity of BRL 34915 in canine Purkinje fibers is related to an increase in the potassium currents, ix1, ik1, and the ATP-sensitive potassium current in these fibers [4].
• Thus we have been unable to demonstrate an effect of BRL 34915 other than of increasing potassium efflux in rabbit vascular smooth muscle [14].

Associations of Cromakalim with other chemical compounds

• Effects of cromakalim (BRL 34915) and pinacidil on normal and hypertrophied rat detrusor in vitro [15].
• Studies on the anti-vasoconstrictor activity of BRL 34915 in spontaneously hypertensive rats; a comparison with nifedipine [16].
• The effects of BRL 34915 and nicorandil on electrical and mechanical activity and on 86Rb efflux in rat blood vessels [12].
• The vasodilator effect of BRL 34915 was not affected by ouabain, but abolished during perfusion with Krebs solution containing excess K+ or depleted of K+ [17].
• 7 The relaxant profile of BRL 34915 in the rat uterus is similar to that described for other smooth muscles where an action to open membrane K+-channels has been proposed [2].

Gene context of Cromakalim

• 2 In experiments using extracellular electrical recording, BRL 34915 (10 microM) selectively inhibited oxytocin-induced phasic spasms and the associated spike activity but had little effect on the tonic component of the spasms [2].
• These results indicate that short-term administration of an antihypertensive dose of BRL 34915 does not alter the renin-angiotensin-aldosterone and ANP systems [5].
• BRL 34915 also elicited dose-related relaxations of rat aorta and trachea precontracted with ET-1 [18].

Analytical, diagnostic and therapeutic context of Cromakalim

• 1. The effects of cromakalim (BRL 34915) on the smooth muscle cells of guinea-pig mesenteric artery and vein were investigated with microelectrode and tension recording methods [19].
• 2. In conscious SHR, intravenous injection of BRL 34915 (0.1, 0.3 mg kg-1) produced rapid, dose-related falls in mean arterial pressure of greater than 3 h duration [16].
• 5. In pithed SHR, both BRL 34915 and nifedipine (each at 0.3 mg kg-1 i.v.) reduced the basal blood pressure level and produced marked inhibition of frequency-dependent pressor responses evoked by electrical stimulation of the spinal cord sympathetic outflow (0.25-4.0 Hz) [16].
• The purpose of this study was to determine the response of both the mean and pulsatile pulmonary hemodynamic parameters to intravenous infusion of BRL 34915 (0.1 mg/kg/min for 10 min) in 48-hr-old open-chest Yorkshire pigs [8].

References