Peripheral pre-synaptic pathway reduces the heart rate response to sympathetic activation following exercise training: role of NO

Objectives: We tested the hypothesis that the attenuated heart rate (HR) re sponse to sympathetic activation following swim training in the guinea pig (Cavia porcellus) results from a peripheral modulation of pacemaking by nit ric oxide (NO). Methods: Nitric oxide synthase (NOS) inhibition on the incr ease in heart rate with sympathetic nerve stimulation (SNS) was investigate d in the isolated guinea pig double atrial/right stellate ganglion preparat ion from exercise trained (6-weeks swimming, n=20) and sedentary animals (n =20). Western blot analysis for neuronal nitric oxide synthase (nNOS) was p erformed on the stellate ganglion from both groups. Results: Relative to th e control group, the exercise group demonstrated typical exercise adaptatio ns of increased ventricular weight/body weight ratio, enhanced skeletal mus cle citrate synthase activity and higher concentrations of [H-3]ouabain bin ding sites in both skeletal and cardiac tissue (P<0.05). The increase in he art rate (bpm) with SNS significantly decreased in the exercise group (n=16 ) compared to the sedentary group (n=16) from 30+/-5 to 17+/-3 bpm at 1 Hz; 67+/-7 to 47+/-4 bpm at 3 Hz; 85+/-9 to 63+/-4 bpm at 5 Hz and 101+/-9 to 78+/-5 bpm at 7 Hz stimulation (P<0.05). The increase in heart rate with cu mulative doses (0.1-10 mu M) or a single dose (0.1 mu M) of bath-applied no repinephrine expressed as the effective doses at which the HR response was 50% of the maximum response (EC,,) were similar in both exercise (EC50 -6.0 8+/-0.16 M, n=8) and sedentary groups (EC50 -6.18+/-0.07 M, n=7). Trained a nimals had significantly more nNOS protein in left stellate ganglion compar ed to the sedentary group. In the exercise group, the non-isoform selective NOS inhibitor, N-omega nitro-L-arginine (L-NA,100 mu M) caused a small but significant increase in the heart rate response to SNS. However, the posit ive chronotropic response to sympathetic nerve stimulation remained signifi cantly attenuated in the exercise group compared to the sedentary group dur ing NOS inhibition (P<0.05). Conclusions: Our results indicate that there i s a significant peripheral pre-synaptic component reducing the HR response to sympathetic activation following training, although NO does nor play a d ominant role in this response. (C) 2000 Elsevier Science B.V. All rights re served.