Pharmacological impact on loop gain properties to prevent irregular breathing.
Theory predicts respiratory instabilities at elevated system loop gain (G), determined by such factors as ventilatory CO(2) sensitivity, set-point PCO(2), and metabolic rate. In anesthetized rabbits, the effects on G of carbonic anhydrase (CA) inhibitors and of different sodium/proton exchanger type 3 (NHE3) inhibitors were studied. Acetazolamide significantly reduced G by 42.0 +/- 9.3% and methazolamide by 35.0 +/- 9.5% (each n = 7, P<0.01). Irrespective of the substance, NHE3 inhibition reduced G by 33.0 +/- 7.8% (n = 10, P<0.01) at 35.5 +/- 1.6 mmHg PaCO(2) (mean +/-SE), but not at lower arterial CO(2) levels (n=5). Since high baseline PCO(2) coincides with elevated brainstem NHE3 mRNA expression, this may also account for a higher risk of sleep apnea (or even occurrence of sudden infant death). Therefore, NHE3 inhibitors may gain similar therapeutic importance in the treatment of irregular breathing as CA inhibitors. Generally, effective treatment should aim at a low system loop gain, by reducing respiratory chemosensitivity, improving blood gases and preventing low metabolic rates.
Kiwull-Schöne
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H
Department of Physiology, Ruhr-University Bochum, Germany. Heidrun.Kiwull-Schoene@rub.de
Teppema
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L
Wiemann
M
M
Kalhoff
H
H
Kiwull
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P
D000086:Acetazolamide / Q000494:pharmacology*; D000818:Animals; D001784:Blood Gas Analysis; D001933:Brain Stem / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D008297:Male; D008704:Methazolamide / Q000494:pharmacology*; D010313:Partial Pressure; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D015656:Respiratory Mechanics / Q000187:drug effects*; D012891:Sleep Apnea Syndromes / Q000503:physiopathology; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism
D002257:Carbonic Anhydrase Inhibitors; D012333:RNA, Messenger; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D002245:Carbon Dioxide; D000086:Acetazolamide; D008704:Methazolamide