Analysis of the beta 1 and beta 2 adrenoceptor interactions of the partial agonist, clenbuterol (NAB365), in the rat jugular vein and atria.

The potent bronchodilator, clenbuterol, was compared to other beta adrenoceptor agonists with regard to affinity and efficacy for interaction with beta 1, and beta 2 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 increases in atrial rate, a characteristic of some, but not all, partial agonists. Relative to other beta adrenoceptor agonists, clenbuterol showed high affinity toward both beta 1 and beta 2 adrenoceptors and selectively toward beta 2 adrenoceptors. Equilibrium dissociation constants were 38 and 6.3 nM for beta 1 and beta 2 adrenoceptors, respectively. The high affinity of clenbuterol toward beta 1 and beta 2 adrenoceptors was coupled to a low relative efficacy of clenbuterol to activate either beta 1 or beta 2 adrenoceptors. Most beta 2 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.