Mechanisms for the Inhibition of Genital Vascular Responses by Antidepressants in a Female Rabbit Model

Angulo, Javier; Cuevas, Pedro; Cuevas, B.; Gupta, Sandeep; Tejada, Iñigo Sáenz de

doi:10.1124/jpet.103.063362

“…215 Fluoxetine, 216 -220 clomipramine, 220 paroxetine, 218 and citalopram 218 have inhibited apoptosis in neoplastic models. Duloxetine inhibits nitric oxide synthase 237 and, hence, free radical generation. 221 Selective NERIs block free radical generation including intramitochondrial radicals, mitochondrial permeability transition pore development, and several types of apoptosis in various cell lines.…”

Section: Modafinilmentioning

confidence: 99%

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Heuristic Clinical Applications

Lauterbach

¹

,

Shillcutt²,

Victoroff³

et al. 2010

JNP

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In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.

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“…However, in a previous study, we demonstrated that the effects of these molecules on GVR in female rabbits are not related to the inhibition of serotonin reuptake [7]. Based on the specific effects of the NOS substrate, l ‐arginine, and the α‐blocker, phentolamine, we reported that paroxetine exerted its inhibitory effect on GVR by reducing NO production, and venlafaxine‐induced inhibition of GVR in female rabbits was due to its ability to increase norepinephrine availability, whereas both reduction of NO generation and potentiation of adrenergic system are contributing to the inhibitory action of duloxetine [7]. In addition to these acute effects, more prolonged administration of these type of antidepressants has been shown to interfere with NO and adrenergic pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the mechanisms responsible for the inhibition of GVR induced by the antidepressants depend on the specific molecule administered. Disruption of the nitric oxide (NO) pathway would be responsible for the inhibitory effect of paroxetine and, partially, for that of duloxetine, whereas the increase in adrenergic input would cause the inhibitory effects of venlafaxine and, partially, those of duloxetine [7].…”

Section: Introductionmentioning

confidence: 99%

“…The frequency of sexual side effects varies among the different SRI and SNRI antidepressants [6]. We have previously reported that acute administration of the selective SRI, paroxetine, as well as the mixed SNRIs, venlafaxine and duloxetine, causes inhibition of genital vascular responses (GVR) to pelvic nerve electrical stimulation (PNES) in female rabbits [7]. Interestingly, the mechanisms responsible for the inhibition of GVR induced by the antidepressants depend on the specific molecule administered.…”

Section: Introductionmentioning

confidence: 99%

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Antidepressant-Induced Inhibition of Genital Vascular Responses is Reversed by Vardenafil in Female Rabbits

Angulo¹,

Cuevas

²

,

Cuevas

³

et al. 2006

The Journal of Sexual Medicine

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Introduction Administration of serotonin reuptake inhibitors (SRI) or serotonin and norepinephrine reuptake inhibitors (SNRI) relieves depressive symptoms but may cause sexual dysfunction in women and men. Aim The aim of the present study was to evaluate the effects of the phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, on inhibition of genital vascular responses (GVR) induced by SRI or SNRI administration in female rabbits. Methods Vaginal and clitoral vasodilatory responses to pelvic nerve electrical stimulation were measured by laser Doppler flow needle probes. Results GVR were significantly potentiated by vardenafil even at the low dose of 0.1 mg/kg, in clitoris and vagina (181 ± 22% and 180 ± 31% of control, in vagina and clitoris, respectively, at 8 Hz). The selective SRI, paroxetine (5 mg/kg), significantly inhibited GVR in female rabbits (54 ± 5% and 48 ± 6% of control). GVR were also significantly inhibited by the SNRIs, venlafaxine (5 mg/kg) (57 ± 3% and 32 ± 11%) and duloxetine (1 mg/kg) (40 ± 7% and 28 ± 5%). Treatment with vardenafil (0.1 and 0.3 mg/kg) completely reversed the inhibition of GVR induced by paroxetine, venlafaxine, or duloxetine. Conclusions Potentiation of the nitric oxide (NO) pathway by vardenafil improves vascular sexual responses in female rabbits and overcomes the inhibitory effects of acutely administered antidepressants on GVR, irrespective of the underlying pathophysiologic mechanism, i.e., disruption of the NO pathway or enhancement of α-adrenergic mechanisms. PDE5 inhibition may represent a reasonable approach to treat SRI- or SRNI-induced female sexual dysfunction, in particular, arousal disorders.

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“…235,236 SNRIs like duloxetine inhibit GSK-3␤, nitric oxide synthase, mitochondrial permeability transition pore opening, and several types of apoptosis in various cell lines. Duloxetine inhibits nitric oxide synthase 237 and, hence, free radical generation. The SNRI nortriptyline blocked glutamate-induced mitochondrial permeability transition pore opening and apoptosis in a transgenic mouse Huntington's disease model.…”

Section: Methodsmentioning

confidence: 99%

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Heuristic Clinical Applications

Lauterbach¹,

Shillcutt²,

Victoroff³

et al. 2010

Journal of Neuropsychiatry

View full text Add to dashboard Cite

In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.

show abstract

Mechanisms for the Inhibition of Genital Vascular Responses by Antidepressants in a Female Rabbit Model

Cited by 9 publications

References 38 publications

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Heuristic Clinical Applications

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Heuristic Clinical Applications

Antidepressant-Induced Inhibition of Genital Vascular Responses is Reversed by Vardenafil in Female Rabbits

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Heuristic Clinical Applications

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