Effects of para-substituted beta-adrenoceptor blocking agents and methyl-substituted phenoxypropanolamine derivatives on maximum upstroke velocity of action potential in guinea-pig papillary muscles

Abstract

The effects of atenolol (2-5 mmol/l), sotalol (1-2 mmol/l) and pamatolol (0.1-1 mmol/l), together with N-tertiary butyl phenoxypropanolamines with o-methyl (D-2T: 50-100 mumol/l) m-methyl (D-3T: 50-100 mumol/l) and p-methyl (D-4T: 100-200 mumol/l) group as well as with o,p-methyl groups (D-24T) (50-100 mumol/l) on action potentials (APs) were investigated in isolated guinea-pig papillary muscles. All the drugs in these concentrations produced a concentration-dependent reduction of the maximum upstroke velocity (Vmax). The reduction of Vmax in premature APs induced by stimuli interpolated between the basic driving rate of 0.25, 0.1 or 0.027 Hz decayed exponentially during diastolic intervals. The time constants of these decay processes tau for atenolol, pamatolol and sotalol ranged between 260-541 ms, those for D-3T and D-4T between 655-1,166 ms, and D-2T and D-24T between 1,565-1,931 ms. A drug which provided larger tau values caused the reduction of Vmax in a wider range of the frequency.(ABSTRACT TRUNCATED AT 250 WORDS)

Modelling of Frequency‐dependent Effects of Lignocaine Homologues on the Maximum Upstroke Velocity of Action Potentials in Guinea‐pig Papillary Muscles

“…This implies that the correction term of at most 0.151 should be added to or subtracted from the difference of log P (Alog P Table 1). A significant correlation was found between Alog P and log &T. The results are consistent with previous studies that demonstrated the correlation between lipid solubility of drug molecules and the resting or tonic block (Sada & Ban 1981;Sada et al 1983;Ban et al 1985;Ichiyama et al 1986). However, a more significant factor than these physicochemical ones is the presence of the substituents on both sides of the ortho position in the present series.…”

“…1983;Campbell 1983;Ban et al 1985;Ichiyama et al 1986;Courtney 1987). The pK, values for most of the agents used here were not available, but it can be presumed that the differences are small among them as inferred from the pK, values of 7.7 (Ehring ef al.…”

Different Ability of Clenbuterol and Salbutamol to Block Sodium Channels Predicts Their Therapeutic Use in Muscle Excitability Disorders

“…Interestingly, it should be noted that most of the ␤ 2 -agonists present two hydroxyl groups on their aromatic moieties, and that the atypical clenbuterol may be the unique ␤ 2 -agonist able to block sodium channels. On the other hand, nadolol is the unique ␤-adrenoceptor antagonists with two hydroxyl groups on the aromatic moiety, suggesting that sodium channel blocking activity may be shared by many ␤-antagonists, as suggested by previous studies (Matthews and Baker, 1982;Ban et al, 1985;Courtney, 1990;Chidlow et al, 2000).…”

“…Indeed direct interaction of ␤-adrenoceptor antagonists, including propranolol, with sodium channels was proposed on the basis of 22 Na ϩ uptake measure in rat brain membrane (Matthews and Baker, 1982), cardiac action potential modulation (Ban et al, 1985;Courtney, 1990), and 3 H-batrachotoxin-A 20-␣-benzoate binding studies to rat cerebrocortical synaptosomes Fig. 8.…”

“…Using the K R value and the IC 50 value calculated for depolarized channels, a value of K I was estimated from the modulated receptor model equation: 1/IC 50 ϭ h/K R ϩ (1 Ϫ h)/K I , where the terms h and (1 Ϫ h) are the proportions of closed and inactivated channels at the potential considered (Bean et al, 1983). The value for h in the cells used for IC 50 determination at Ϫ70 mV was 0.25, which gives a K I value of ϳ23 M. Direct interaction of ␤-adrenoceptor antagonists, including propranolol, with cardiac sodium channels was proposed on the basis of their effect on the maximum upstroke velocity of action potential (Ban et al, 1985;Courtney, 1990). Although we failed to find an effect of nadolol on hSkM1 channels, the previous studies suggested that other ␤-antagonists may block I Na .…”