Analysis of the nitric oxide-cyclic guanosine monophosphate pathway in experimental liver cirrhosis suggests phosphodiesterase-5 as potential target to treat portal hypertension

Liver cirrhosis is a frequent condition with high impact on patients’ life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.

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The efficacy of fp 736-04 in experimental liver cirrhosis

Acta Radiologica ◽

10.3109/02841859809172227 ◽

1998 ◽

Vol 39 (5) ◽

pp. 568-571

Author(s):

A. Bergman ◽

A. Magnusson ◽

K. Moore ◽

A. Sundin ◽

S. Davies ◽

...

Keyword(s):

Liver Cirrhosis ◽

Experimental Liver Cirrhosis ◽

Experimental Liver

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Cyclic Guanosine Monophosphate Modulates Locomotor Acceleration Induced by Nitric Oxide but not Serotonin in Clione limacina Central Pattern Generator Swim Interneurons

Integrative Organismal Biology ◽

10.1093/iob/obaa045 ◽

2020 ◽

Author(s):

Thomas J Pirtle ◽

Richard A Satterlie

Keyword(s):

Nitric Oxide ◽

Central Pattern Generator ◽

Guanylyl Cyclase ◽

Signal Transduction Pathway ◽

Soluble Guanylyl Cyclase ◽

Cyclic Guanosine Monophosphate ◽

Pattern Generator ◽

Guanosine Monophosphate ◽

Cellular Changes ◽

Clione Limacina

Abstract Typically, the marine mollusk, Clione limacina, exhibits a slow, hovering locomotor gait to maintain its position in the water column. However, the animal exhibits behaviorally relevant locomotor swim acceleration during escape response and feeding behavior. Both nitric oxide and serotonin mediate this behavioral swim acceleration. In this study, we examine the role that the second messenger, cGMP, plays in mediating nitric oxide and serotonin-induced swim acceleration. We observed that the application of an analog of cGMP or an activator of soluble guanylyl cyclase increased fictive locomotor speed recorded from Pd-7 interneurons of the animal’s locomotor central pattern generator. Moreover, inhibition of soluble guanylyl cyclase decreased fictive locomotor speed. These results suggest that basal levels of cGMP are important for slow swimming and that increased production of cGMP mediates swim acceleration in Clione. Because nitric oxide has its effect through cGMP signaling and because we show herein that cGMP produces cellular changes in Clione swim interneurons that are consistent with cellular changes produced by serotonin application, we hypothesize that both nitric oxide and serotonin function via a common signal transduction pathway that involves cGMP. Our results show that cGMP mediates nitric oxide-induced but not serotonin-induced swim acceleration in Clione.

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Renal effects of nitric oxide synthesis inhibition in cirrhotic rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.267.6.r1454 ◽

1994 ◽

Vol 267 (6) ◽

pp. R1454-R1460 ◽

Cited By ~ 4

Author(s):

N. M. Atucha ◽

J. Garcia-Estan ◽

A. Ramirez ◽

M. C. Perez ◽

T. Quesada ◽

...

Keyword(s):

Nitric Oxide ◽

Renal Excretion ◽

Renal Plasma Flow ◽

Tubular Reabsorption ◽

Nitric Oxide Synthesis ◽

Important Mediator ◽

Experimental Liver Cirrhosis ◽

Endogenous Nitric Oxide ◽

And Control ◽

Experimental Liver

In the present study, we have characterized the renal response to inhibition of endogenous nitric oxide (NO) synthesis [intravenous NG-nitro-L-arginine methyl ester (L-NAME) for 3 h] in anesthetized cirrhotic rats, with (ASC) and without (CIR) ascites, at doses that do not change blood pressure (BP). Administration of L-NAME induced opposite effects on water (UV) and sodium (UNaV) excretion in cirrhotic and control animals. Infusion of 1 microgram.kg-1.min-1 of L-NAME in CIR (n = 5) decreased renal plasma flow (RPF) at the end of the 3-h period, whereas UV, UNaV, and glomerular filtration rate (GFR) were unaltered. In contrast, infusion of L-NAME at 10 micrograms.kg-1.min-1 in six more CIR increased UV and UNaV significantly by the 1st h, without changes in BP or GFR, and these parameters remained elevated throughout the experiment. Infusion of 1 microgram.kg-1.min-1 in ASC (n = 6) did not change BP or GFR but significantly enhanced UV and UNaV after the 1st h. These effects were prevented by pretreatment with L-arginine (0.1 mg.kg-1.min-1) in another group of ASC infused with 1 microgram.kg-1.min-1 of L-NAME. These results indicate that, in ASC and CIR cirrhotic rats, inhibition of NO synthesis at nonpressor does improves renal excretion of sodium and water via a decrease in tubular reabsorption. NO is an important mediator of the renal excretory and hemodynamic alterations of experimental liver cirrhosis.

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The nitric oxide–cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y10-109 ◽

2011 ◽

Vol 89 (2) ◽

pp. 89-95 ◽

Cited By ~ 22

Author(s):

Ercan Ozdemir ◽

Ihsan Bagcivan ◽

Nedim Durmus ◽

Ahmet Altun ◽

Sinan Gursoy

Keyword(s):

Nitric Oxide ◽

Analgesic Effect ◽

Soluble Guanylate Cyclase ◽

Morphine Tolerance ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Albino Rats ◽

Tail Flick ◽

Analgesic Effects ◽

Cgmp Signaling

Although the phenomenon of opioid tolerance has been widely investigated, neither opioid nor nonopioid mechanisms are completely understood. The aim of the present study was to investigate the role of the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) pathway in the development of morphine-induced analgesia tolerance. The study was carried out on male Wistar albino rats (weighing 180–210 g; n = 126). To develop morphine tolerance, animals were given morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), BAY 41-2272, S-nitroso-N-acetylpenicillamine (SNAP), NG-nitro-l-arginine methyl ester (L-NAME), and morphine were considered at 15 or 30 min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests (n = 6 in each study group). The results showed that YC-1 and BAY 41-2272, a NO-independent activator of soluble guanylate cyclase (sGC), significantly increased the development and expression of morphine tolerance, and L-NAME, a NO synthase (NOS) inhibitor, significantly decreased the development of morphine tolerance. In conclusion, these data demonstrate that the nitric oxide–cGMP signal pathway plays a pivotal role in developing tolerance to the analgesic effect of morphine.

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