Nitric oxide synthases in vagal neurons are crucial for the regulation of heart rate in awake dogs

Abstract

Nitric oxide synthase (NOS) inhibitors elicit bradycardias independent of the endothelium (e-NOS) or increases in blood pressure. Therefore, this bradycardia could be mediated by other NOS isoforms, most likely that of the nervous system (n-NOS). If so, heart rate variability (HRV) as a measure of vagal activity should be an indicator of the activity of n-NOS in vagal neurons. To test this, we studied the dose-effect relations of L-NAME (0.3 – 50 mg·kg⁻¹) on heart rate (HR), HRV and systemic vascular resistance (SVR) in seven awake dogs. HRV was analyzed in the time domain as standard deviation of the RR-intervals (SDNN) and in the frequency domain as power in the high (0.15 – 0.5 Hz) and low (0.04 – 0.15 Hz) frequency range. The effects of HR and SDNN reached their maxima at a dose of 3 mg·kg⁻¹ and had their ED₅₀ at 0.27 ± 0.03 mg·kg⁻¹ and 0.43 ± 0.1 mg·kg⁻¹, respectively, whereas SVR had its maximum at 10 mg·kg⁻¹ and ED₅₀ at 0.86 ± 0.11 mg·kg⁻¹ (p < 0.05). HF-power (vagal activity) predominated compared to LF-power (mainly sympathetic activity) during baseline as well as after L-NAME. The effects on HR and HRV were absent after ganglionic blockade (hexamethonium), whereas the effects on SVR remained unchanged. Thus, NO exerts a powerful restraining activity on vagal neurons and plays a key role in the adjustment of heart rate in awake resting animals with prevailing vagal activity.