Effect of varenicline and nicotine as agonists on nicotinic currents and evoked exocytosis and on the ACh-evoked currents in rat chromaffin cells
In order to determine whether the increased exocytosis observed might be due to the agonist effect of the drugs, they were applied in 500 ms pulses in chromaffin cells obtained from six rats. Representative original recordings of the currents elicited by each agonist are shown in Fig. 5A. ACh triggered a current of 671.1 ± 127.3 pA (n=11), while varenicline elicited currents that amounted to 316.8 ± 143.6 pA (n=11; *p), nicotine to 70.5 ± 24.5 pA (n=9; *p), and varenicline in the presence of nicotine to 81.5 ± 33.7 pA (n=9; *p) (Fig. 5B). Thus, varenicline, nicotine and both drugs applied together evoked smaller currents with respect to ACh. In order to diminish the variability among data, values were normalized, being 0.1 ± 0.9 (*p), 0.4 ± 1.3 (*p) and 0.1 ± 0.02 (*p) fold with respect to the matched control condition for each value in the presence of both drugs perfused together, and varenicline and nicotine alone, respectively.
These currents elicited exocytosis as shown by the Cmrecordings of Fig. 5C. ACh evoked 121.3 ± 34 fF (n=11), varenicline triggered 147.5 ± 51.1 fF (n=11), nicotine evoked 114 ± 46.6 fF (n=9) and both together elicited 54.6 ± 20.2 fF (n=9) (Fig. 5D). These values were normalized with respect to the corresponding matched control, amounting to 1.5 ± 0.5 and 1 ± 0.1- fold for varenicline and nicotine perfused separately, and 0.4 ± 0.2- fold (*p) for varenicline and nicotine perfused together, respectively.
Finally, the ACh-elicited currents obtained from ten rats were recorded while perfusing varenicline or/and nicotine. Drugs inhibited nicotinic currents as shown in the representative recordings displayed in Fig. 5E. ACh evoked a current of 1242 ± 141.7 pA (n=20), that was reduced to 653.7 ± 164.6 pA in the presence of varenicline (n=13, *p), to 639.7 ± 131.6 pA with nicotine (n=18, *p) and to 729.8 ± 127.4 pA when both drugs were applied together (n=19, *p) (Fig. 5F). These values represented 0.6 ± 0.1 (*p), 0.5 ± 0.1 (*p) and 0.6 ± 0.1 (*p) fold with respect to their control matched currents, respectively.