Baroreflex responses in neuronal nitric oxide synthase knoukout mice (nNOS)

Carvalho, Tais; Lopes, Oswaldo Ubrı́aco; Tolentino-Silva, Fatima Rosaria Paulino

doi:10.1016/j.autneu.2006.03.001

Cited by 15 publications

(5 citation statements)

References 31 publications

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“…Thus, the reversion of this response by both fluoxetine and 7-NI may constitute a negative effect. Baroreflex analysis through the pharmacological approach also demonstrated that 7-NI reduced reflex bradycardia in unstressed rats, which is in line with evidence showing that nNOS is critical for the transmission of baroreflex signals (Carvalho et al, 2006). Impairment of baroreflex activity is associated with a negative prognosis in a variety of cardiovascular diseases (La Rovere et al, 2008).…”

Section: Discussionsupporting

confidence: 74%

Effects of nitric oxide synthesis inhibitor or fluoxetine treatment on depression-like state and cardiovascular changes induced by chronic variable stress in rats

Almeida

Duarte

Oliveira

et al. 2015

Stress

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Comorbidity between mood disorders and cardiovascular disease has been described extensively. However, available antidepressants can have cardiovascular side effects. Treatment with selective inhibitors of neuronal nitric oxide synthase (nNOS) induces antidepressant effects, but whether the antidepressant-like effects of these drugs are followed by cardiovascular changes has not been previously investigated. Here, we tested in male rats exposed to chronic variable stress (CVS) the hypothesis that nNOS blockers are advantageous compared with conventional antidepressants in terms of cardiovascular side effects. We compared the effects of chronic treatment with the preferential nNOS inhibitor 7-nitroindazole (7-NI) with those evoked by the conventional antidepressant fluoxetine on alterations that are considered as markers of depression (immobility in the forced swimming test, FST, decreased body weight gain and increased plasma corticosterone concentration) and cardiovascular changes caused by CVS. Rats were exposed to a 14-day CVS protocol, while being concurrently treated daily with either 7-NI (30 mg/kg) or fluoxetine (10 mg/kg). Fluoxetine and 7-NI prevented the increase in immobility in the FST induced by CVS and reduced plasma corticosterone concentration in stressed rats. Both these treatments also prevented the CVS-evoked reduction of the depressor response to vasodilator agents and baroreflex changes. Fluoxetine and 7-NI-induced cardiovascular changes independent of stress exposure, including cardiac autonomic imbalance, increased intrinsic heart rate and vascular sympathetic modulation, a reduction of the pressor response to vasoconstrictor agents, and impairment of baroreflex activity. Altogether, these findings provide evidence that fluoxetine and 7-NI have similar effects on the depression-like state induced by CVS and on cardiovascular function.

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Section: Discussionsupporting

confidence: 74%

Effects of nitric oxide synthesis inhibitor or fluoxetine treatment on depression-like state and cardiovascular changes induced by chronic variable stress in rats

Almeida

Duarte

Oliveira

et al. 2015

Stress

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“…In part this has been due to skepticism about selectivity of the nNOS inhibitors used in earlier pharmacological studies. In keeping with an effort to study the contribution of nNOS to baroreflex transmission, others (Carvalho et al 2006) have studied nNOS knockout mice and reported that there was a significant reduction of baroreflex responses when compared with wild‐type mice. However, as used, the knockout mouse model did not allow one to assess nNOS specifically in the NTS or any other select site in the CNS.…”

Section: Introductionmentioning

confidence: 99%

Decreased expression of neuronal nitric oxide synthase in the nucleus tractus solitarii inhibits sympathetically mediated baroreflex responses in rat

Lin

Dragon

Jin

et al. 2012

The Journal of Physiology

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Key points• Arteries send nerve signals to the brain in response to changes in blood pressure.• Nerves carrying these signals release chemical transmitters onto other neurons in the nucleus tractus solitarii, a nucleus in the brainstem.• One chemical that has been considered such a transmitter is nitric oxide, but there has been debate over the action of nitric oxide in brainstem influences on responses to changes blood pressure.• We show that use of a molecular tool that allows us to prevent the normal production of nitric oxide by nerve cells leads to altered reflex regulation of heart rate in rats.• Our findings, which clarify the role of neuronally derived nitric oxide in control of the cardiovascular system by the brain, could lead to better control of blood pressure in individuals with either high or low blood pressure.Abstract Despite numerous studies it remains controversial whether nitric oxide (NO·) synthesized by neuronal NOS (nNOS) plays an excitatory or inhibitory role in transmission of baroreflex signals in the nucleus tractus solitarii (NTS). In the current studies we sought to test the hypothesis that nNOS is involved in excitation of baroreflex pathways in NTS while excluding pharmacological interventions in assessing the influence of nNOS. We therefore developed, validated and utilized a short hairpin RNA (shRNA) to reduce expression of nNOS in the NTS of rats whose baroreflex activity was then studied. We demonstrate downregulation of nNOS through transduction with adeno-associated virus type 2 (AAV2) carrying shRNA for nNOS. When injected bilaterally into NTS AAV2nNOSshRNA significantly reduced reflex tachycardic responses to acute hypotension while not affecting reflex bradycardic responses to acute increases of arterial pressure. Control animals treated with intravenous propranolol to block sympathetically mediated chronotropic responses manifested the same baroreflex responses as animals that had been treated with AAV2nNOSshRNA. Neither AAV2 eGFP nor AAV2nNOScDNA affected baroreflex responses. Blocking cardiac vagal influences with atropine similarly reduced baroreflex-mediated bradycardic responses to increases in arterial pressure both in control animals and in those treated with AAV2nNOSshRNA. We conclude that NO· synthesized by nNOS in the NTS is integral to excitation of baroreflex pathways involved in reflex tachycardia, a largely sympathetically mediated response, but not reflex bradycardia, a largely parasympathetically mediated response. We suggest

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“…Interestingly, the atrial frequency observed in eNOS −/− mice is significantly reduced when compared to that observed in atria obtained from control animals, whereas that observed in atria obtained from nNOS −/− mice is unaltered. In addition, eNOS −/− mice have a lower heart rate as compared to control animals ( 70 ), whereas no difference in vivo in the basal heart frequency from nNOS −/− and wild type has been observed ( 71 ). Thus eNOS-derived 6-ND is apparently the major endogenous modulator of heart chronotropism.…”

Section: Actions Of 6-nitrodopamine In the Heartmentioning

confidence: 99%

Endothelium-Derived Dopamine and 6-Nitrodopamine in the Cardiovascular System

Zatz,

De Nucci

2024

Physiology

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The review deals with the release of endothelium-derived dopamine and 6-nitrodopamine (6-ND) and its effects on isolated vascular tissues and isolated heart. Human isolated umbilical cord vessels, human popliteal vessels, non-human primate vessels, and reptilia aortae, present basal release of both dopamine and 6-ND. The 6-ND basal release was significantly reduced when the tissues were treated with L-NAME and virtually abolished when the endothelium was mechanically removed. 6-Nitrodopamine is a potent vasodilator, and the mechanism of action responsible for this effect is the antagonism on dopamine D2-like receptor. As a vasodilator, 6-ND constitutes a novel mechanism by which NO modulates vascular tone. The basal release of 6-ND was substantially decreased in eNOS-/- mice and not altered in nNOS-/- mice, indicating a non-neurogenic source for 6-ND in the heart. Indeed, in rat isolated right atrium, the release of 6-ND was not affected when the atria were treated with tetrodotoxin. In the rat isolated right atrium, 6-ND is the most potent endogenous positive chronotropic agent, and in Langendorff's heart preparation, it is the most potent endogenous positive inotropic agent. The positive chronotropic and inotropic effects of 6-ND are antagonized by β1-adrenoceptor antagonists at concentrations that do not affect the effects induced by noradrenaline, adrenaline, and dopamine, indicating that blockade of 6-ND receptor is the major modulator of heart chronotropism and inotropism. The review proposes that endothelium-derived catecholamines may constitute a major mechanism for control of vascular tone and heart functions, in contrast to the overrated role attributed to the autonomic nervous system.

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Baroreflex responses in neuronal nitric oxide synthase knoukout mice (nNOS)

Cited by 15 publications

References 31 publications

Effects of nitric oxide synthesis inhibitor or fluoxetine treatment on depression-like state and cardiovascular changes induced by chronic variable stress in rats

Effects of nitric oxide synthesis inhibitor or fluoxetine treatment on depression-like state and cardiovascular changes induced by chronic variable stress in rats

Decreased expression of neuronal nitric oxide synthase in the nucleus tractus solitarii inhibits sympathetically mediated baroreflex responses in rat

Endothelium-Derived Dopamine and 6-Nitrodopamine in the Cardiovascular System

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