Zaprinast increases cyclic GMP levels in plasma and in aortic tissue of rats

Dundore, Ronald L.; Clas, Dawn; Wheeler, Lynn T.; Habeeb, Peter; Bode, Donald C.; Buchholz, Richard; Silver, Paul J.; Pagani, Edward D.

doi:10.1016/0014-2999(93)90525-m

Cited by 60 publications

(39 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As both cAMP and cGMP are known vasodilators (Dundore et al, 1993;Dundore et al, 1992;Fertel and Weiss 1976;Paterno et al, 1996), it is possible that the cognitive enhancement evident in our studies following treatment with PDE inhibitors could be explained by increased delivery of energy substrates to the brain as a consequence of decrease cerebrovascular resistance. Certainly, rolipram did increase blood flow in the perirhinal cortex, although it had no effect in hippocampus.…”

Section: Discussionmentioning

confidence: 89%

“…However, PDE4 and PDE5 inhibitors also cause peripheral vasodilatation by elevating cAMP and cGMP, respectively (Dundore et al, 1993;Dundore et al, 1992;Paterno et al, 1996). Therefore, an alternative explanation could be that these drugs improve memory performance by enhancing cerebral blood flow and the delivery of glucose and oxygen to the brain, although such a mechanism is more likely to be important when the cognitive impairment arises from vascular insufficiency in the first place (eg, vascular dementia).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Rutten

Donkelaar

Ferrington

et al. 2009

Neuropsychopharmacol

113

View full text Add to dashboard Cite

Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), and are currently studied as possible targets for cognitive enhancement. Earlier studies indicated beneficial effects of PDE inhibitors in object recognition. In this study we tested the effects of three PDE inhibitors on spatial memory as assessed in a place and object recognition task. Furthermore, as both cAMP and cGMP are known vasodilators, the effects of PDE inhibition on cognitive functions could be explained by enhancement of cerebrovascular function. We examined this possibility by measuring the effects of PDE5 and PDE4 inhibitor treatment on local cerebral blood flow and glucose utilization in rats using [ 14 C]-iodoantipyrine and [ 14 C]-2-deoxyglucose quantitative autoradiography, respectively. In the spatial location task, PDE5 inhibition (cGMP) with vardenafil enhanced only early phase consolidation, PDE4 inhibition (cAMP) with rolipram enhanced only late phase consolidation, and PDE2 inhibition (cAMP and cGMP) with Bay 60-7550 enhanced both consolidation processes. Furthermore, PDE5 inhibition had no cerebrovascular effects in hippocampal or rhinal areas. PDE4 inhibition increased rhinal, but not hippocampal blood flow, whereas it decreased glucose utilization in both areas. In general, PDE5 inhibition decreased the ratio between blood flow and glucose utilization, indicative of general oligaemia; whereas PDE4 inhibition increased this ratio, indicative of general hyperemia. Both oligaemic and hyperemic conditions are detrimental for brain function and do not explain memory enhancement. These results underscore the specific effects of cAMP and cGMP on memory consolidation (object and spatial memory) and provide evidence that the underlying mechanisms of PDE inhibition on cognition are independent of cerebrovascular effects.

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Rutten

Donkelaar

Ferrington

et al. 2009

Neuropsychopharmacol

113

View full text Add to dashboard Cite

show abstract

“…Rather than performing cell culture and intracellular cGMP measurement, we chose to assess plasma cGMP concentration as a baseline comparison of genotype groups. This decision is supported by evidence that in other species, plasma cGMP concentration is significantly correlated with aortic tissue concentrations of cGMP in and changes in cGMP after pharmacologic phosphodiesterase inhibition continue to correlate well 23. Additionally, the study was performed in healthy dogs and no medical intervention with phoshpodiesterase inhibiting drugs, additional diagnostic tests or investigation into disease states was performed.…”

Section: Discussionmentioning

confidence: 97%

Identification of PDE5A:E90K: A Polymorphism in the Canine Phosphodiesterase 5A Gene Affecting Basal cGMP Concentrations of Healthy Dogs

Stern

Reina-Doreste

Chdid

et al. 2013

Veterinary Internal Medicne

View full text Add to dashboard Cite

BackgroundCyclic guanosine monophosphate (cGMP)‐specific phosphodiesterase (PDE5A) is the target of phosphodiesterase inhibitors such as sildenafil. Polymorphisms in the PDE5A gene that may predict response to therapy with sildenafil and nitric oxide, be linked to disease progression, and aid in risk assessment have been identified in human beings. Identification of polymorphisms in PDE5A could affect the physiologic actions of PDE5A and the effects of phosphodiestrase type 5 inhibitor drugs.Hypothesis/ObjectiveFunctional polymorphisms exist in the canine PDE5A gene. Specific objectives were to identify PDE5A polymorphisms and evaluate their functional relevance.AnimalsSeventy healthy dogs.MethodsThe exonic, splice‐site, 3′ and 5′ untranslated regions of the canine PDE5A gene were sequenced in 15 dogs and aligned with the canine reference sequence. Identified polymorphisms were evaluated in 55 additional, healthy, unrelated dogs of 20 breeds. Plasma was collected from 51 of these dogs and cGMP was measured. An unpaired t‐test and one‐way ANOVA with Dunnett's test of multiple comparisons were used to evaluate the effect of genotype on cGMP.ResultsA common exonic polymorphism was identified that changed glutamic acid to lysine and resulted in significantly lower cGMP concentrations in the group with polymorphism versus the wild type group (P = .014). Additionally, 6 linked single nucleotide polymorphisms in the 3′ untranslated region were identified that did not alter cGMP concentrations.Conclusions and Clinical ImportanceA polymorphism exists in the canine PDE5A gene that is associated with variable circulating cGMP concentrations in healthy dogs and warrants investigation in diseases such as pulmonary hypertension.

show abstract

“…48,96,97 Since cGMP/cAMP have vasodilator effects, increased blood flow and glucose metabolism may also contribute to the effects of PDE inhibitors on memory. 98,99 3. PDE INHIBITORS IN THE TREATMENT OF ALZHEIMER'S DISEASE To evaluate the therapeutic value of PDEs in AD, it is important to determine the expression of the different enzymes in the human brain, both in normal and pathological conditions.…”

Section: 54mentioning

confidence: 99%

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

García‐Osta¹,

Cuadrado‐Tejedor²,

García‐Barroso³

et al. 2012

ACS Chem. Neurosci.

233

179

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.

show abstract

Zaprinast increases cyclic GMP levels in plasma and in aortic tissue of rats

Cited by 60 publications

References 9 publications

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Identification of PDE5A:E90K: A Polymorphism in the Canine Phosphodiesterase 5A Gene Affecting Basal cGMP Concentrations of Healthy Dogs

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

Contact Info

Product

Resources

About