Table 1

Antagonistic effects against the negative inotropic action of oxotremorine in isolated paced guinea pig left atria as induced by the indicated antagonists and by W84, as well as by combinations of W84 with the antagonists

AntagonistpKBAntagonist concentrationDRantW84 concentrationDRW84DRexpDRabsFαMean α
μm μm
AF-DX 3848.5  ± 0.033100254  ± 451,4771,162  ± 810.8338
1,224  ± 120444
31,000350  ± 511,573882  ± 910.6550
Dexetimide9.8  ± 0.170.3100223  ± 829714,556  ± 1,3014.7109
749  ± 9492
0.31,000211  ± 89597,980  ± 1,7518.374
Atropine9.1  ± 0.051992  ± 169100295  ± 332,23511,094  ± 1,4335.026
19
11,796  ± 3021,000269  ± 152,64730,622  ± 3,90811.612
(−)-Scopolamine9.1  ± 0.020.3372  ± 13100219  ± 185903,634  ± 3646.225
37
0.3306  ± 301,000197  ± 255022,651  ± 3935.348
(−)-NMS9.9  ± 0.070.11,064  ± 93100335  ± 851,3988,133  ± 1,8405.813
18
0.11,164  ± 1231,000195  ± 111,35818,238  ± 3,22613.423
(−)-NBS7.2  ± 0.0830499  ± 27100234  ± 187324,082  ± 565.628
33
30332  ± 551,000204  ± 55354,135  ± 3687.737
Methoctramine7.9  ± 0.043198  ± 321,000226  ± 28423217  ± 200.5N.D.

pK B-values, presented as mean ± standard error, denote the respective dissociation constants for the antagonists at the cardiac muscarinic receptor derived from Schild analyses (Arunlakshana and Schild, 1959) as illustrated in Fig. 2 for NMS and AF-DX 384. DRant and DRW84 quantify the rightward shift of the oxotremorine concentration-effect-curve as induced at the indicated concentrations by the antagonists and by W84, respectively. DRexp is the oxotremorine curve shift to be expected if two competitive antagonists were combined. DRobs indicates the experimentally observed shift induced by the combination of antagonist plus W84. F = DRobs/DRexp and indicates the deviation of the observed antagonistic effect from the expected effect. α is the cooperativity factor for the interaction of W84 with the respective orthosteric antagonist according to the cooperativity model. Given are means ± standard error of four to six experiments in separate atria.

    • N.D., Not determinable; the experimental data set yielded a negative value for α.