Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice

Pitayadet Jumrussirikul, Jay Dinerman, Ted M. Dawson, Valina L. Dawson, Ulf Ekelund, Dimitrios Georgakopoulos, Lawrence P. Schramm, Hugh Calkins, Solomon H. Snyder, Joshua Hare, Ronald D. Berger

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Nitric oxide (NO) synthesized within mammalian sinoatrial cells has been shown to participate in cholinergic control of heart rate (HR). However, it is not known whether NO synthesized within neurons plays a role in HR regulation. HR dynamics were measured in 24 wild-type (WT) mice and 24 mice in which the gene for neuronal NO synthase (nNOS) was absent (nNOS(-/-) mice). Mean HR and HR variability were compared in subsets of these animals at baseline, after parasympathetic blockade with atropine (0.5 mg/kg i.p.), after β-adrenergic blockade with propranolol (1 mg/kg i.p.), and after combined autonomic blockade. Other animals underwent pressor challenge with phenylephrine (3 mg/kg i.p.) after β-adrenergic blockade to test for a baroreflex-mediated cardioinhibitory response. The latter experiments were then repeated after inactivation of inhibitory G proteins with pertussis toxin (PTX) (30 μg/kg i.p.). At baseline, nNOS(-/-) mice had higher mean HR (711±8 vs. 650±8 bpm, P = 0.0004) and lower HR variance (424±70 vs. 1,112±174 bpm2, P = 0.001) compared with WT mice. In nNOS(-/-) mice, atropine administration led to a much smaller change in mean HR (-2±9 vs. 49±5 bpm, P = 0.0008) and in HR variance (64±24 vs. -903±295 bpm2, P = 0.02) than in WT mice. In contrast, propranolol administration and combined autonomic blockade led to similar changes in mean HR between the two groups. After β-adrenergic blockade, phenylephrine injection elicited a fall in mean HR and rise in HR variance in WT mice that was partially attenuated after treatment with PTX. The response to pressor challenge in nNOS(-/-) mice before PTX administration was similar to that in WT mice. However, PTX- treated nNOS(-/-) mice had a dramatically attenuated response to phenylephrine. These findings suggest that the absence of nNOS activity leads to reduced baseline parasympathetic tone, but does not prevent baroreflex- mediated cardioinhibition unless inhibitory G proteins are also inactivated. Thus, neuronally derived NO and cardiac inhibitory G protein activity serve as parallel pathways to mediate autonomic slowing of heart rate in the mouse.

Original languageEnglish
Pages (from-to)1279-1285
Number of pages7
JournalJournal of Clinical Investigation
Volume102
Issue number7
StatePublished - Oct 1 1998
Externally publishedYes

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Nitric Oxide Synthase Type I
GTP-Binding Proteins
Heart Rate
Nitric Oxide Synthase
Pertussis Toxin
Phenylephrine
Adrenergic Agents
Nitric Oxide
Baroreflex
Atropine
Propranolol
Cholinergic Agents

Keywords

  • Autonomic nervous system
  • Baroreflex
  • G protein
  • Nitric oxide
  • Parasympathetic

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Jumrussirikul, P., Dinerman, J., Dawson, T. M., Dawson, V. L., Ekelund, U., Georgakopoulos, D., ... Berger, R. D. (1998). Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice. Journal of Clinical Investigation, 102(7), 1279-1285.

Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice. / Jumrussirikul, Pitayadet; Dinerman, Jay; Dawson, Ted M.; Dawson, Valina L.; Ekelund, Ulf; Georgakopoulos, Dimitrios; Schramm, Lawrence P.; Calkins, Hugh; Snyder, Solomon H.; Hare, Joshua; Berger, Ronald D.

In: Journal of Clinical Investigation, Vol. 102, No. 7, 01.10.1998, p. 1279-1285.

Research output: Contribution to journalArticle

Jumrussirikul, P, Dinerman, J, Dawson, TM, Dawson, VL, Ekelund, U, Georgakopoulos, D, Schramm, LP, Calkins, H, Snyder, SH, Hare, J & Berger, RD 1998, 'Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice', Journal of Clinical Investigation, vol. 102, no. 7, pp. 1279-1285.
Jumrussirikul P, Dinerman J, Dawson TM, Dawson VL, Ekelund U, Georgakopoulos D et al. Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice. Journal of Clinical Investigation. 1998 Oct 1;102(7):1279-1285.
Jumrussirikul, Pitayadet ; Dinerman, Jay ; Dawson, Ted M. ; Dawson, Valina L. ; Ekelund, Ulf ; Georgakopoulos, Dimitrios ; Schramm, Lawrence P. ; Calkins, Hugh ; Snyder, Solomon H. ; Hare, Joshua ; Berger, Ronald D. / Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice. In: Journal of Clinical Investigation. 1998 ; Vol. 102, No. 7. pp. 1279-1285.
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abstract = "Nitric oxide (NO) synthesized within mammalian sinoatrial cells has been shown to participate in cholinergic control of heart rate (HR). However, it is not known whether NO synthesized within neurons plays a role in HR regulation. HR dynamics were measured in 24 wild-type (WT) mice and 24 mice in which the gene for neuronal NO synthase (nNOS) was absent (nNOS(-/-) mice). Mean HR and HR variability were compared in subsets of these animals at baseline, after parasympathetic blockade with atropine (0.5 mg/kg i.p.), after β-adrenergic blockade with propranolol (1 mg/kg i.p.), and after combined autonomic blockade. Other animals underwent pressor challenge with phenylephrine (3 mg/kg i.p.) after β-adrenergic blockade to test for a baroreflex-mediated cardioinhibitory response. The latter experiments were then repeated after inactivation of inhibitory G proteins with pertussis toxin (PTX) (30 μg/kg i.p.). At baseline, nNOS(-/-) mice had higher mean HR (711±8 vs. 650±8 bpm, P = 0.0004) and lower HR variance (424±70 vs. 1,112±174 bpm2, P = 0.001) compared with WT mice. In nNOS(-/-) mice, atropine administration led to a much smaller change in mean HR (-2±9 vs. 49±5 bpm, P = 0.0008) and in HR variance (64±24 vs. -903±295 bpm2, P = 0.02) than in WT mice. In contrast, propranolol administration and combined autonomic blockade led to similar changes in mean HR between the two groups. After β-adrenergic blockade, phenylephrine injection elicited a fall in mean HR and rise in HR variance in WT mice that was partially attenuated after treatment with PTX. The response to pressor challenge in nNOS(-/-) mice before PTX administration was similar to that in WT mice. However, PTX- treated nNOS(-/-) mice had a dramatically attenuated response to phenylephrine. These findings suggest that the absence of nNOS activity leads to reduced baseline parasympathetic tone, but does not prevent baroreflex- mediated cardioinhibition unless inhibitory G proteins are also inactivated. Thus, neuronally derived NO and cardiac inhibitory G protein activity serve as parallel pathways to mediate autonomic slowing of heart rate in the mouse.",
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