Analysis of the beta₁ and beta₂ adrenoceptor interactions of the partial agonist, clenbuterol (NAB365), in the rat jugular vein and atria

Summary

The potent bronchodilator, clenbuterol, was compared to other beta adrenoceptor agonists with regard to affinity and efficacy for interaction with beta₁ and beta₂ adrenoceptors in the rat jugular vein and atria. Clenbuterol was a potent partial beta adrenoceptor agonist in both tissues based on the following observations: 1. Maximal relaxation of the jugular vein and increases in atrial rate to clenbuterol were less than maximal responses to other beta adrenoceptor agonists. 2. Clenbuterol antagonized responses to the stronger agonist, isoproterenol, in both tissues and 3. the equilibrium dissociation constant for clenbuterol approximated the ED₅₀ concentration for vascular relaxation and increase in atrial rate, a characteristic of some, but not all, partial agonists. Relative to other beta adrenoceptor agonists, clenbuterol showed high affinity toward both beta₁ and beta₂ adrenoceptors and selectivity toward beta₂ adrenoceptors. Equilibrium dissociation constants were 38 and 6.3 nM for beta₁ and beta₂ adrenoceptors, respectively. The high affinity of clenbuterol toward beta₁ and beta₂ adrenoceptors was coupled to a low relative efficacy of clenbuterol to activate either beta₁ or beta₂ adrenoceptors. Most beta₂ adrenoceptor agonists such as isoproterenol or salbutamol require approximately 1–3% adrenoceptor occupation for 40–50% relaxation of the jugular vein whereas clenbuterol required approximately 100% adrenoceptor occupation for a similar response. Thus, based on our analysis, the high agonist potency of clenbuterol results primarily from the high affinity toward beta adrenoceptors rather than efficient activation of the adrenoceptor as occurs with isoproterenol or salbutamol.