Induction of haemodynamic oscillations in the perfused rat liver by K+ channel blockers.

Abstract

SUMMARY1. Exposure of the isolated perfused (constant flow) rat liver to the K+ channel blockers 4-aminopyridine (4-AP) or Cs+ causes the appearance of oscillations in portal pressure and oxygen uptake. The oscillations have a mean frequency of 0 035 Hz (2-1 cycles/min) and are fully reversible upon perfusion with blocker-free saline. Tetraethylammonium (0-17-24-7 mM) does not induce oscillatory behaviour.2. Reversible block of the 4-AP-induced oscillations is caused by 2 mM-EGTA, or verapamil, chlorpheniramine, phentolamine or propranolol with IC50 values of 0-42, 13-5, 15 or 11-5 /M respectively. The oscillations are transiently blocked by atropine (IC50 = 8-3 /M at peak inhibition) and are not affected by 2-7 tM-tetrodotoxin. 3. Endothelium-dependent vasorelaxants, Kupffer cell activity modifiers, retrograde perfusion, or removal of the portal vein from the circuit do not modify the oscillation parameters.4. Oscillations are also caused by infusion of physiological concentrations of adrenaline or phenylephrine, but not isoprenaline.5. The results provide new evidence for the existence of intrahepatic voltagesensitive Ca2+, and 4-AP-and Cs+-sensitive K+ channels. We propose that the K+ channel blockers reveal an intrinsic oscillator in the liver, and that phasic vasoactivity may involve a minor contribution from neurotransmitter and/or hormonal substances.

Involvement of intrahepatic innervation in caesium‐induced haemodynamic oscillations in the rat liver.

“…In an earlier report we showed that 4-aminopyridine (4-AP) causes the appearance of oscillations in portal pressure and effluent 02 concentration of 0-6 mmHg and 6 AM 0 within 5 min of infusion, and having a frequency of 0-035 Hz (Hill & Ajikobi, 1992). The differences between the 4-AP-and Cs+-induced oscillations are discussed in terms of tetrodotoxin (TTX) sensitivity, and waveform and frequency, with the aim of differentiating between the primary mechanism and site of action of these two K+ channel blockers.…”

“…First, the fast Na+ channel blocker TTX reversibly blocks the Cs+-induced oscillations but not those caused by 4-AP (Hill & Ajikobi, 1992). TTX-sensitive Na+ channels are not present in endothelial cells derived from different tissues (Adams, Barakeh, Laskey & Van Breeman, 1989), or smooth muscle cells from the portal vein (Hume & LeBlanc, 1989) and other vascular sources (Van Breeman & Saida, 1989).…”

“…The concentration ranges used were previously shown to affect the oscillatory response of the perfused rat liver to 4-aminopyridine- (Hill & Ajikobi, 1992), histamine-or acetylcholineinduced mechanical activity of the portal vein (Brown, Anuras & Heistad, 1982), and x-or ,-adrenergic responses of the liver (for example see Ulken, Puschel & Jungermann, 1991). Figure 5 shows the effects of concentrations of antagonists that result in maximum inhibition.…”

“…We have observed earlier that equimolar replacement of perfusate KCl with CsCl (5-9 mM) causes the appearance of oscillations having lower amplitude (0-6 mmnHg) and higher frequency (0 04 Hz) oscillations that were not significantly different in magnitude to those seen with 5 mm 4-AP (Hill & Ajikobi, 1992). To determine the dependence of oscillation parameters on the concentration of Cs+ the portal pressure responses of the livers to different concentrations of perfusate Cs+ were measured.…”

“…causes periodic fluctuations in portal pressure in the isolated portally perfused rat liver (Hill & Ajikobi, 1992). Qualitatively these oscillations resemble the myogenic activity observed in a variety of capillary systems (Holstein-Rathlou, 1987; Riva, Pournaras, Poitry-Yamate & Petrig, 1990) and in isolated segments of rat and rabbit portal vein (Leander, Arner & Johansson, 1977;Hara, Kitamura & Kuriyama, 1980).…”