Nitric oxide donors can increase heart rate independent of autonomic activation

Administration of nitric oxide (NO) donors in vivo is accompanied by a baro reflex-mediated increase in heart rate (KR). In vitro, however, NO donors c an increase HR directly by stimulating a pathway that involves NO, cGMP, an d the hyperpolarization-activated current (I-f). The aim of this study was to assess the functional significance of this pathway in vivo by testing wh ether NO donors can increase HR in the anesthetized rabbit independent of t he autonomic nervous system. New Zealand White rabbits were vagotomized, ca rdiac sympathectomized, and treated with propranolol (0.3 mg/kg iv). The NO donor molsidomine (0.2 mg/kg iv) caused a progressive increase (Delta) in HR (Delta HR, 14 +/- 3 beats/min; P < 0.01). This effect was significantly reduced by the I-f blocker ZD-7288 (0.2 mg/kg iv; Delta HR, 2 +/- 3 beats/m in; P = not significant). Similar results were seen with sodium nitroprussi de. The positive chronotropic effect of sodium nitroprusside (50 mu M) was confirmed in the isolated working rabbit heart preparation (Delta HR, 17 +/ - 3 beats/min; P < 0.01). In conclusion, NO donors exert a small, but signi ficant, positive chronotropic effect in vivo that is independent of the aut onomic nervous system. These results are also consistent with data in sinoa trial node cells that show that NO donors increase HR by stimulating I-f.