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

1. 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 microM respectively. The oscillations are transiently blocked by atropine (IC50 = 8.3 microM at peak inhibition) and are not affected by 2.7 microM-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 voltage-sensitive 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.