The proconvulsant effect of sildenafil in mice: role of nitric oxide-cGMP pathway

Background In the central nervous system neurotransmitters, drugs or conditions that excite increase cyclic guanosine 3',5'-monophosphate (cGMP), an effect mediated by the neuromodulator nitric oxide, whereas those that sedate decrease cGMP. Volatile anesthetics were shown to decrease cerebellar cGMP, an effect that correlates with their anesthetic and anticonvulsant effect. Because alpha-2 adrenoceptor agonists have anesthetic properties, the role of the nitric oxide-cGMP pathway in the action of the alpha-2 adrenoceptor agonists clonidine and dexmedetomidine was investigated. Methods Groups of mice were given, intraperitoneally, one dose of either 30-600 micrograms/kg clonidine, or 3-300 micrograms/kg D-medetomidine (dexmedetomidine) or L-medetomidine. The alpha-2 adrenoceptor antagonists, 0.3-5 mg/kg yohimbine or 1 mg/kg atipamezole, 1 mg/kg of the alpha-1 antagonist prazosin, and 10-300 mg/kg of the nitric oxide synthase inhibitors, N omega-nitro-1-arginine methylester and N omega-nitro-1-arginine, were given 10-20 min before the agonist. The mice were killed by microwave radiation focused to the head. Cyclic GMP was measured by radioimmunoassay in deproteinized extracts from different brain areas. Results Clonidine and dexmedetomidine, at sedative doses, dose-dependently decreased cerebellar cGMP (ED50: 100 and 50 micrograms/kg for clonidine and dexmedetomidine, respectively). This effect was inhibited by yohimbine and atipamezole, but not by prazosin, confirming the alpha-2 nature of the response to the agonists. L-medetomidine, which has no sedative/hypnotic effect, did not decrease cGMP. Pretreatment of the mice with a maximum dose of 100 mg/kg of a nitric oxide synthase antagonist abolished the cGMP response to the agonists. Similar results were obtained in the cerebral cortex, hippocampus and caudate nucleus. Conclusions The results suggest that the nitric oxide-cGMP pathway is an effector system coupled to the alpha-2 adrenoceptor mediating sedation.

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ROLE OF TESTOSTERONE ON T-TYPE (ALPHA1-G) LOW VOLTAGE-ACTIVATED CALCIUM CHANNEL AND INTERACTIONS WITH NITRIC OXIDE-CGMP PATHWAY IN HUMAN CAVERNOSAL SMOOTH MUSCLE CELLS

The Journal of Urology ◽

10.1016/s0022-5347(09)60856-9 ◽

2009 ◽

Vol 181 (4S) ◽

pp. 300-301

Author(s):

Suresh C Sikka ◽

Ming Li ◽

Wayne JG Hellstrom

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Calcium Channel ◽

Low Voltage ◽

Muscle Cells ◽

Cgmp Pathway

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Insulin sensitivity is mediated by the activation of the ACh/NO/cGMP pathway in rat liver

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00085.2004 ◽

2004 ◽

Vol 287 (3) ◽

pp. G527-G532 ◽

Cited By ~ 34

Author(s):

Maria P. Guarino ◽

Nina C. Correia ◽

W. Wayne Lautt ◽

M. Paula Macedo

Keyword(s):

Nitric Oxide ◽

Insulin Sensitivity ◽

Muscarinic Receptors ◽

Wistar Rats ◽

No Donor ◽

Parasympathetic Nerves ◽

Cgmp Pathway ◽

Male Wistar Rats ◽

Oxide Synthase

The hepatic parasympathetic nerves and hepatic nitric oxide synthase (NOS) are involved in the secretion of a hepatic insulin sensitizing substance (HISS), which mediates peripheral insulin sensitivity. We tested whether binding of ACh to hepatic muscarinic receptors is an upstream event to the synthesis of nitric oxide (NO), which, along with the activation of hepatic guanylate cyclase (GC), permits HISS release. Male Wistar rats (8–9 wk) were anesthetized with pentobarbital sodium (65 mg/kg). Insulin sensitivity was assessed using a euglycemic clamp [the rapid insulin sensitivity test (RIST)]. HISS inhibition was induced by antagonism of muscarinic receptors (atropine, 3 mg/kg iv) or by blockade of NOS [ NG-nitro-l-arginine methyl ester (l-NAME), 1 mg/kg intraportally (ipv)]. After the blockade, HISS action was tentatively restored using a NO donor [3-morpholynosydnonimine (SIN-1), 5–10 mg/kg ipv] or ACh (2.5–5 μg·kg−1·min−1 ipv). SIN-1 (10 mg/kg) reversed the inhibition caused by atropine (RIST postatropine 137.7 ± 8.3 mg glucose/kg; reversed to 288.3 ± 15.5 mg glucose/kg, n = 6) and by l-NAME (RIST post-l-NAME 152.2 ± 21.3 mg glucose/kg; reversed to 321.7 ± 44.7 mg glucose/kg, n = 5). ACh did not reverse HISS inhibition induced by l-NAME. The role of GC in HISS release was assessed using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 nmol/kg ipv), a GC inhibitor that decreased HISS action (control RIST 237.6 ± 18.6 mg glucose/kg; RIST post-ODQ 111.7 ± 6.2 mg glucose/kg, n = 5). We propose that hepatic parasympathetic nerves release ACh, leading to hepatic NO synthesis, which activates GC, triggering HISS action.

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Exploring the regulatory role of nitric oxide (NO) and the NO-p38MAPK/cGMP pathway in larval settlement of the bryozoan Bugula neritina

Biofouling ◽

10.1080/08927014.2018.1470240 ◽

2018 ◽

Vol 34 (5) ◽

pp. 545-556 ◽

Cited By ~ 5

Author(s):

Xiao-Xue Yang ◽

Yue Him Wong ◽

Yu Zhang ◽

Gen Zhang ◽

Pei-Yuan Qian

Keyword(s):

Nitric Oxide ◽

Larval Settlement ◽

Regulatory Role ◽

Bugula Neritina ◽

Cgmp Pathway

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Venlafaxine Attenuates the Development of Morphine Tolerance and Dependence: Role of L-Arginine/Nitric Oxide/cGMP Pathway

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530318666171213153920 ◽

2018 ◽

Vol 18 (4) ◽

pp. 362-370 ◽

Cited By ~ 6

Author(s):

Mohammad Taghi Mansouri ◽

Bahareh Naghizadeh ◽

Behnam Ghorbanzadeh ◽

Soheila Alboghobeish ◽

Gholamreza Houshmand ◽

...

Keyword(s):

Nitric Oxide ◽

Morphine Tolerance ◽

Cgmp Pathway

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Endocardial endothelium in the avascular heart of the frog: morphology and role of nitric oxide.

Journal of Experimental Biology ◽

10.1242/jeb.200.24.3109 ◽

1997 ◽

Vol 200 (24) ◽

pp. 3109-3118 ◽

Cited By ~ 3

Author(s):

S U Sys ◽

D Pellegrino ◽

R Mazza ◽

A Gattuso ◽

L J Andries ◽

...

Keyword(s):

Nitric Oxide ◽

Stroke Volume ◽

Systolic Function ◽

Rana Esculenta ◽

Confocal Scanning Laser Microscopy ◽

Stroke Work ◽

Ventricular Performance ◽

Cgmp Pathway ◽

Endocardial Endothelium

Endocardial endothelial morphology and the physiological modulatory role of nitric oxide (NO) were studied in an in vitro preparation of the working intact heart of the frog Rana esculenta, which lacks coronary vasculature and is thus devoid of a coronary vascular endothelium. En face confocal scanning laser microscopy of samples of perfused fixed hearts demonstrated the presence of NO synthase as a cytoplasmic constituent of the endocardial endothelial cells. Stroke volume (as a measure of performance in paced frog hearts) and stroke work (as an index of systolic function) increased by approximately 5 % after inhibition of the NO-cGMP pathway with 10(-4 )mol l-1 NG-nitro-l-arginine methyl ester and by approximately 8 % after inhibition with 10(-6 )mol l-1 Methylene Blue. In contrast, stroke volume and stroke work decreased by approximately 22 % after activation of the NO-cGMP pathway with sodium nitroprusside (10(-4 )mol l-1), while 3-morpholinosydnonimine (5x10(-8) to 10(-5 )mol l-1) caused a decrease of between 15 and 30 % and 8-bromo-cGMP (10(-6 )mol l-1) a decrease of approximately 8 %. These responses were significantly attenuated after exposure of the ventricular luminal to Triton X-100 (0.05 %, 0.1 ml), which itself increased performance (by over 10 %) without detectable morphological changes. These results show that the endocardial endothelium of Rana esculenta produces amounts of NO sufficient to modulate ventricular performance.

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