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NO-cGMP pathway accentuates the decrease in heart rate caused by cardiac vagal nerve stimulation
C E Sears1, J K Choate, D J Paterson
1University Laboratory of Physiology, Oxford OX1 3PT, United Kingdom. claire.sears@physiol.ox.ac.uk
Insights
Excessive nitric oxide (NO) enhances vagal nerve stimulation
Area of Science:
- Cardiovascular Physiology
- Autonomic Nervous System Regulation
- Molecular Signaling
Background:
- The precise role of the cardiac nitric oxide (NO) pathway in cholinergic control of heart rate (HR) remains debated.
- Understanding this pathway is crucial for elucidating autonomic regulation of cardiac function.
Purpose of the Study:
- To investigate how elevated nitric oxide (NO) or cyclic guanosine monophosphate (cGMP) levels influence heart rate (HR) responses to vagal nerve stimulation (VNS).
- To determine the specific mechanisms underlying NO's modulation of cholinergic cardiac control.
Main Methods:
- Experiments conducted in anesthetized rabbits (in vivo) and isolated guinea pig atria (in vitro).
- Administration of NO donors (molsidomine, sodium nitroprusside) and cGMP analog (8-bromoguanosine 3',5'-cyclic monophosphate).
- Vagal nerve stimulation (VNS) applied, with or without interventions, and HR responses measured. Specific antagonists (ZD-7288) and acetylcholine analogs (carbachol) used to probe mechanisms.
Main Results:
- In vivo, molsidomine significantly amplified the HR decrease induced by VNS.
- In vitro, sodium nitroprusside (SNP) produced a similar accentuation of VNS-induced bradycardia, even after blocking baseline HR shifts.
- The effect of SNP was replicated by 8-bromoguanosine 3',5'-cyclic monophosphate but not by carbachol, suggesting a presynaptic, cGMP-dependent mechanism.
Conclusions:
- Excessive nitric oxide (NO) potentiates the heart rate reduction elicited by vagal nerve stimulation (VNS).
- This potentiation appears to operate via a presynaptic mechanism involving the cyclic guanosine monophosphate (cGMP) pathway.
- The findings clarify the intricate interplay between NO signaling and the autonomic control of heart rate.
Abstract:
The role of the cardiac muscarinic-receptor-coupled nitric oxide (NO) pathway in the cholinergic control of heart rate (HR) is controversial. We investigated whether adding excessive NO or its intracellular messenger cGMP could significantly modulate the HR response to vagal nerve stimulation (VNS) in the anesthetized rabbit and isolated guinea pig atria. The NO donor molsidomine (0.2 mg/kg iv) significantly enhanced the decrease in HR seen with right VNS (5 Hz, 5 V, 30 s) in vivo. A qualitatively similar effect was seen with the NO donor sodium nitroprusside (SNP; 10 and 100 microM) during VNS in vitro. This effect was still present when the baseline shift in HR caused by SNP was eliminated by using the specific hyperpolarization-activated current antagonist 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)-pyrimidinium chloride (ZD-7288, 1 microM). The accentuated decrease in HR with SNP during VNS was mimicked by the stable analog of cyclic GMP, 8-bromoguanosine 3',5'-cyclic monophosphate (0.5 mM). This, however, was not seen with bath application of the stable analog of acetylcholine, carbamylcholine chloride (100 nM). We conclude that excessive NO enhances the magnitude of the decrease in HR caused by VNS. This effect appears to involve a presynaptic action via a cGMP-dependent pathway because it was not mimicked by bath-applied carbamylcholine chloride.