Summary
Potassium channel opener's (KCOs) were originally thought of as nonselective smooth muscle relaxants. However, recent investigations in animal models of both peripheral vascular disease (PVD) and asthma have revealed interesting effects of these drugs at unexpectedly low doses. Hemodynamically, KCOs are interesting in PVD since they have little effect on blood supply to normally perfused skeletal muscle, but enhance perfusion to chronically ligated ischemic tissue. In animal PVD models, SDZ PCO-400 and cromakalim have been shown to improve recovery of muscle energy stores from ischemia or to preserve performance under conditions of ischemic contracture. Beneficial effects in rat PVD models were manifest at doses below those affecting systemic blood pressure and may be attributable to a selective dilatation of collateral vessels. With regard to the airways, the apparent efficacy of KCOs as antiasthmatic drugs seems not to be attributable solely to their bronchodilator activity. Although KCOs elicit no antiinflammatory effect in animal models, studies with SDZ PCO-400 in guinea pigs sensitized to antigen or treated with immune complexes have revealed that expression of airway hyperreactivity is significantly inhibited at drug doses exhibiting only modest bronchodilator activity. At least part of this action can be attributed to inhibition at the level of neural innervation of the airways, possibly through attenuation of nonadrenergic noncholinergic (NANC) transmission. Thus, based on results generated in animal models of asthma and PVD, clinical evaluation of the KCOs in these indications would seem warranted, with the hope that (due to their “selective” actions) beneficial therapeutic effects can be achieved at doses devoid of unwanted systemic actions.
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References
Cook NS, Quast U. Potassium channel pharmacology. In: Cook NS, ed.Potassium Channels: Structure, Classification, Function and Therapeutic Potential. Chichester: Ellis Horwood, 1990:181–255.
Radack K, Wyderski RJ. Conservative management of intermittent claudication.Am Coll Phys 1990;113:135–146.
Duprez D, Clement DL. Medical treatment of peripheral vascular disease: Good or bad?Eur Heart J 1992;13:149–151.
Creager MA, Roddy MA. The effect of nifedipine on calf blood flow and exercise capacity in patients with intermittent claudication.J Vasc Med Biol 1990;2:94–99.
Cook NS, Hof RP. Cardiovascular effects of apamin and BRL 34915 in rats and rabbits.Br J Pharmacol 1988;93:121–131.
Buckingham RE, Clapham JC, Hamilton TC, et al. BRL 34915, a novel antihypertensive agent: Comparison of effects on blood pressure and other haemodynamic parameters with those of nifedipine in animal models.J Cardiovasc Pharmacol 1986;8:798–804.
Angersbach D, Nicholson CD. Enhancement of muscle blood cell flux andpO2 by cromakalim (BRL 34915) and other compounds enhancing membrane K+ conductance, but not by Ca2+ antagonists or hydralazine, in an animal model of occlusive arterial disease.Naunyn-Schmiedebergs Arch Pharmacol 1988;337:341–346.
Hof RP. Modification of vasopressin- and angiotensin II-induced changes by calcium antagonists in the peripheral circulation of anaesthetized rabbits.Br J Pharmacol 1985;85:75–87.
Hof RP, Hof A, Takiguchi Y. Comparative haemodynamic studies of isradipine and dihydralazine in atherosclerotic and normal rabbits.J Cardiovasc Pharmacol 1990;15(Suppl 1):S13-S22.
Richer C, Pratz J, Mulder P, et al. Cardiovascular and biological effects of K+ channel openers, a class of drugs with vasorelaxant and cardioprotective properties.Life Sci 1990;47:1693–1705.
Cook NS, Weir SW, Danzeisen MC. Anti-vasoconstrictor effect of the K+ channel opener cromakalim on the rabbit aorta—comparison with the calcium antagonist isradipine.Br J Pharmacol 1988;95:741–752.
Cook NS, Rudin M, Pally C, et al. Effects of the potassium channel openers SDZ PCO-400 and cromakalim in an in vivo rat model of occlusive arterial disease assessed by31P-NMR spectroscopy.J Vasc Med Biol 1993;4:14–22.
Keller U, Oberhänsli R, Huber P, et al. Phosphocreatine content and intracellular pH of calf muscle measured by phosphorous NMR spectroscopy in occlusive arterial disease of the legs.Eur J Clin Invest 1985;15:382–388.
Hatton R, Heys C, Todd MH, et al. Cromakalim reverses ischaemic depression of skeletal muscle contractions in rat hind limb.Br J Pharmacol 1991;102:280P.
Quast U, Cook NS. Moving together: K+ channel openers and ATP-sensitive K+ channels.Trends Pharmacol Sci 1989;10:431–435.
Richer C, Mulder P, Doussau MP, et al. Systemic and regional haemodynamic interactions between K+ channel openers and the sympathetic nervous system in the pithed SHR.Br J Pharmacol 1990;100:557–563.
Chapman ID, Kristersson A, Mathelin G, et al. Effects of a potassium channel opener (SDZ PCO-400) on guinea-pig and human pulmonary airways.Br J Pharmacol 1992;106:423–429.
Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma and after bronchial provocation.Am Rev Resp Dis 1989;139:806–817.
Weinberger M, Hendeles L. In: Weiss EB, Segal MS, Stein M, eds.Bronchial Asthma: Mechanisms and Therapeutics. Boston, Little Brown, 1976:646–674.
Allen SL, Boyle JP, Cortijo J, et al. Electrical and mechanical effects of BRL 34915 in guinea-pig isolated trachealis.Br J Pharmacol 1986;89:395–405.
Arch JRS, Buckle DR, Bumstead J, et al. Evaluation of the potassium channel activator cromakalim (BRL 34915) as a bronchodilator in the guinea-pig: Comparison with nifedipine.Br J Pharmacol 1988;95:763–770.
Owen S, Stone P, Church S, et al. A randomised double-blind crossover trial of a potassium channel activator in nocturnal asthma.Thorax 1989;44:852P.
Baird A, Hamilton TC, Richards D, et al. Cromakalim, a potassium channel activator, inhibits histamine-induced bronchoconstriction in healthy volunteers.Br J Clin Pharmacol 1985;25:114P.
Sanjar S, Aoki S, Kristersson A, et al. Antigen challenge induces pulmonary airway eosinophil accumulation and airway hyperreactivity in sensitized guinea-pigs: The effect of anti-asthma drugs.Br J Pharmacol 1990;99:679–686.
Buckle DR, Taylor JF. The effects of BRL 38227 on antigen-induced extravasation and cellular infiltration into the peritoneal cavity of actively sensitised rats.Agents Actions 1991;34(Supp):47–52.
Ichinose M, Barnes PJ. A potassium channel activator modulates both excitatory noncholinergic and cholinergic neurotransmission in guinea-pig airways.J PharmacoL Exp Ther 1990;252:1207–1212.
Leff AR, Stimler NP, Munoz NM, et al. Augmentation of respiratory mast cell secretion of histamine caused by vagus nerve stimulation during antigen challenge.J Immunol 1986;136:1066–1073.
Nagai H, Kitagaki K, Goto S, et al. Effect of three novel K+ channel openers, cromakalim, pinacidil and nicorandil on allergic reaction and experimental asthma.Jpn J Pharmacol 1991;56:13–21.
Chapman ID, Kristersson A, Mazzoni L, et al. Reversal of induced airway hyperreactivity by potassium channel openers: PCO-400 and cromakalim.Br J Pharmacol 1991;102:335P.
Morley J. New drug developments for asthma. In: Morley J, ed.Preventive Therapy in Asthma. London: Academic Press, 1991:253–273.
Chapman ID, Foster A, Morley J. The relationship between inflammation and hyperreactivity of the airways in asthma.Clin Exp Allergy 1993;23:168–171.
Lewis SA, Raeburn D. Preferential pre-junctional site of inhibition of non-cholinergic bronchospasm by potassium channel openers (KCOs).Br J Pharmacol 1990:100:474P.
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Cook, N.S., Chapman, I.D. Therapeutic potential of potassium channel openers in peripheral vascular disease and asthma. Cardiovasc Drug Ther 7 (Suppl 3), 555–563 (1993). https://doi.org/10.1007/BF00877621
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DOI: https://doi.org/10.1007/BF00877621