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Nitric oxide donors can increase heart rate independent of autonomic activation
N Hogan1, B Casadei, D J Paterson
1University Laboratory of Physiology, Oxford OX1 3PT, United Kingdom.
Insights
Nitric oxide (NO) donors can directly increase heart rate (HR) in vivo by stimulating a specific pathway, independent of the nervous system. This effect involves the hyperpolarization-activated current (I(f)) and cGMP.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Autonomic Nervous System Research
Background:
- Nitric oxide (NO) donors typically increase heart rate (HR) via baroreflex mechanisms in vivo.
- In vitro studies suggest NO donors can directly increase HR through a pathway involving NO, cyclic guanosine monophosphate (cGMP), and the hyperpolarization-activated current (I(f)).
Purpose of the Study:
- To investigate the in vivo functional significance of the NO-cGMP-I(f) pathway in mediating heart rate increases.
- To determine if NO donors can elevate HR independently of autonomic nervous system control.
Main Methods:
- Anesthetized New Zealand White rabbits underwent vagotomy and cardiac sympathectomy, followed by propranolol administration.
- The NO donor molsidomine was administered, and its effect on HR was assessed with and without the I(f) blocker ZD-7288.
- Experiments were also conducted using sodium nitroprusside in vivo and in an isolated working rabbit heart preparation.
Main Results:
- Molsidomine administration resulted in a significant increase in HR (14 ± 3 beats/min).
- The I(f) blocker ZD-7288 significantly reduced this NO-donor-induced HR increase (2 ± 3 beats/min).
- Sodium nitroprusside demonstrated similar positive chronotropic effects, confirmed in both in vivo and isolated heart preparations.
Conclusions:
- Nitric oxide donors exert a small but significant positive chronotropic effect in vivo.
- This effect is independent of the autonomic nervous system and is mediated by the stimulation of the hyperpolarization-activated current (I(f)).
Abstract:
Administration of nitric oxide (NO) donors in vivo is accompanied by a baroreflex-mediated increase in heart rate (HR). In vitro, however, NO donors can increase HR directly by stimulating a pathway that involves NO, cGMP, and the hyperpolarization-activated current (I(f)). The aim of this study was to assess the functional significance of this pathway in vivo by testing whether NO donors can increase HR in the anesthetized rabbit independent of the autonomic nervous system. New Zealand White rabbits were vagotomized, cardiac 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 (DeltaHR, 14 +/- 3 beats/min; P < 0.01). This effect was significantly reduced by the I(f) blocker ZD-7288 (0.2 mg/kg iv; DeltaHR, 2 +/- 3 beats/min; P = not significant). Similar results were seen with sodium nitroprusside. The positive chronotropic effect of sodium nitroprusside (50 microM) was confirmed in the isolated working rabbit heart preparation (DeltaHR, 17 +/- 3 beats/min; P < 0.01). In conclusion, NO donors exert a small, but significant, positive chronotropic effect in vivo that is independent of the autonomic nervous system. These results are also consistent with data in sinoatrial node cells that show that NO donors increase HR by stimulating I(f).