Relationship between atrial and ventricular rates of fibrillation and cardiac contractile tissue effective refractory periods in the dog.

1 During total cardiopulmonary bypass, acetylcholine-, isoprenaline-, ouabain- and quinidine-induced variations in the atrial and ventricular rates of fibrillation were studied and compared with the variations in effective refractory periods (ERP) of atrial and ventricular contractile tissue obtained under the same experimental conditions. 2 Acetylcholine significantly shortened the ERP and accelerated the rate of fibrillation in the atrium but did not provoke any change in ventricular tissue. A parallel decrease in atrial and ventricular ERP and a parallel increase in atrial and ventricular rates of fibrillation were observed with isoprenaline. 3 Ouabain exerted a biphasic effect on the atrium, with an initial decrease in the ERP and an initial acceleration of the rate of fibrillation. It produced only a slight decrease in the ventricular ERP and no significant variation in the ventricular rate of fibrillation. 4 Quinidine induced a greater increase in the ERP and a greater slowing of the rate of fibrillation in the atrium than in the ventricle. 5 The variations in percentage change of refractoriness and rate of fibrillation were strictly correlated: r = 0.89 (P less than 0.001); the equation of the regression line was y = --0.86 x --2.98.

Are anticholinergic effects responsible for the heterogeneous quinidine-induced modifications of heart muscle refractoriness?

Vagal tone is responsible for the heterogeneous reactivity of atrial and ventricular contractile tissues to quinidine. Acetylcholine may make atrial cells more sensitive to the effects of quinidine.

Influence of acetylcholine, isoproterenol, quinidine and ouabain on effective refractory periods of atrial and ventricular myocardium in the dog.

Acetylcholine-, isoproterenol-, quinidine- and ouabain-induced variations of the effective refractory periods (E.R.P.) of the non-specialized atrial and ventricular tissue have been explored in the dog by the extra-stimulus method during total cardiopulmonary by-pass. Acetylcholine significantly shortens the E.R.P. of atrial fibers, but does not provoke any change in the ventricular tissue, whereas a parallel decrease of atrial and ventricular E.R.P. is noted with isoproterenol. Quinidine induces a larger increase of the E.R.P. in the atrium than in the ventricle. The ouabain-induced shortening of the E.R.P. in the atrium is more marked than in the ventricle but is followed by a secondary increase which depends on both time after injection and dose. Hypotheses about the mechanisms of these effects, their importance in fibrillation and their relation to clinical uses are discussed.

Characterization of sub-peak b4.2, middle molecule.

The Middle Molecules (MM) within the molecular weight (MW) range of vitamin B12 (1355 daltons) are assumed to be partly responsible for uremic toxicity. We have isolated a solute, b4.2, the purity of which is controlled by thin layer chromatography on silica gel. It correlates with active clinical polyneuropathy. The Stockholm group is dealing with a MM they call peak 7c. After exchange of purified solutes between the Stockholm group and us, comparative analyses demonstrate that 7c and b4.2 are different. The b4.2 solute is a glucuronide but it is impossible to obtain the aglycon moiety after enzymatic or acidic hydrolysis. Desorption chemical ionization and electron-impact ionization mass spectrometry results of b4.2 after transformation in methyl ester trimethylsilyl derivative are compatible with a b4.2 MW of 568 daltons (or 526 in native form) corresponding to a glucuronoconjugate of an aglycon with a MW 392 daltons (or 350 in native form). Moreover mass spectrometry confirms that b4.2 isolated from normal human urine and from uremic RP6 hemofiltrate fluid are identical.

Technical aspects on middle molecules: separation, isolation, and identification.

For the last few years we have attempted to separate and isolate from biological fluids the uremic Middle Molecules (MM). The first step in the treatment of plasma is an ultrafiltration through AN69 membrane. The samples are fractionated by Sephadex G-15 chromatography into 9 peaks "a" to "i' under precise conditions that have been selected in order to exhibit different patterns in the MM range (peak b and c) between uremic and uremic polyneuropathic patients. Further separation of peak b is performed by ion exchange chromatography with Sephadex DEAE A-25 into 7 sub-peaks b; sub-peak b 4-2 is the only one to correlate with neuropathy. Prior to b 4-2 identification studies, specific large scale isolation procedures are necessary. The purity of the product is monitored at each step by thin-layer chromatography on silica gel.