Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adrenomedullin (AM) is a potent vascular wall-derived vasorelaxing peptide which induces the release of nitric oxide (NO). To explore the role of endogenous AM in vascular function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists [AM (22-52), and calcitonin gene-related peptide (CGRP) (8-37)] on the isometric tension of aortic rings isolated from AM transgenic (TG) and knockout (KO) mice and wild type littermates (WT). ACh and AM caused a dose-dependent reduction of the isometric tension of aortic rings, but the degree of vasodilatation was smaller in TG than in KO or WT (% delta tension [10(-6) mol/l ACh]: KO -69 +/- 10%, WT -39 +/- 8%, TG -29 +/- 1%, p < 0.01). On the other hand, N(G)-nitro-L-arginine methyl ester, an NO synthase inhibitor, induced greater vasoconstriction in TG (% delta tension 10(-5)mol/l: KO +78 +/- 16%, WT +99 +/- 27%, TG +184 +/- 20%, p < 0.01), whereas E-4021, a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase inhibitor, caused greater vasodilation in TG mice. Both AM antagonists increased tension in TG to a greater extent than in KO or WT mice (% delta tension [10(-6) mol/l CGRP (8-37)]: KO +24 +/- 5%, WT +51 +/- 6%, TG +75 +/- 7%, p < 0.01). Endothelial denudation of the aorta diminished the vasoconstriction caused by the AM antagonists. In conclusion, the amounts of AM expressed in the aortic endothelium influenced baseline NO release. AM antagonists increased vascular tone in WT as well as in TG, suggesting that endogenous AM plays a physiological role in the regulation of aortic tone.
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PMID:Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice. 1263 Aug 15

Our laboratory previously demonstrated that nitric oxide and natriuretic peptides can synergistically enhance cAMP elevations and vasorelaxations in rat aortic rings induced by calcitonin gene-related peptide, likely involving cyclic guanosine monophosphate (cGMP)-mediated inhibition of type-3 phosphodiesterase (PDE3). It was predicted that this cellular mechanism may also serve as a point of synergism between adrenomedullin (ADM) and brain natriuretic peptide (BNP) in aortic smooth muscle cells. The current study shows that ADM (100 nM)-induced vasorelaxations in isolated aortic rings of Sprague-Dawley rats are dependent on endothelium (34.1 +/- 4.2% relaxation with endothelium versus 3.0 +/- 0.6% relaxation without endothelium; P < 0.001). To determine interactions between ADM and BNP in smooth muscle cells without interference from endothelium-derived factors, further studies used aortic rings denuded of endothelium. Pretreatment with BNP (1 nM), which elevated cGMP levels 1.6 fold, uncovered direct vasorelaxant effects of ADM in endothelium-denuded rings, showing 5.6 +/- 1.8%, 20.9 +/- 6.1%, and 55 +/- 9.4% relaxations with ADM at 1, 10, and 100 nM, respectively (n = 6). ADM (100 nM) significantly (P < 0.05) increased cyclic adenosine monophosphate (cAMP) levels in denuded aortic rings pretreated with BNP (1 nM), but not in denuded rings without BNP. Quazinone (20 microM), a PDE3 inhibitor, caused similar enhancement of direct cAMP elevations to ADM (100 nM). The data indicate vasodilatory synergism between ADM and BNP in aorta, likely mediated by enhanced accumulation of cAMP in smooth muscle cells resulting from BNP/cGMP-induced inhibition of PDE3. This synergistic mechanism may be especially important in subjects with dysfunctional endothelium, in which BNP may uncover direct vasorelaxant effects of ADM in arteries that normally require healthy (nitric oxide-releasing) endothelium for ADM-induced vasorelaxations to occur.
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PMID:Adrenomedullin induces direct (endothelium-independent) vasorelaxations and cyclic adenosine monophosphate elevations that are synergistically enhanced by brain natriuretic peptide in isolated rings of rat thoracic aorta. 1277 61

With the advent of phosphodiesterase type-5 inhibition as oral therapy, intracavernous injection of vasoactive agents has been relegated to second-line therapy for most patients with erectile dysfunction. However, the future of this category of agents remains bright as an ever-expanding number and combination of agents in use and under investigation will likely make intracavernous injection more appealing as greater efficacy, tolerability, and more rapid onset is attained. In this article, functional anatomy and physiology of human penile erection is reviewed, as are current clinical vasoactive agents including prostaglandin E-1, papaverine, and phentolamine. Emerging therapies discussed include guanylate cyclase activators, potassium channel openers, nitric oxide donors, vasoactive intestinal polypeptide, calcitonin gene-related peptide, selective alpha-1 receptor antagonists, and gene therapy. Ongoing research continues to define new roles for this effective and safe technique, which has withstood the test of time, restoring erectile function among patients with diverse ED etiologies and a variety of co-morbidities.
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PMID:Intracavernous pharmacotherapy for erectile dysfunction. 1514 94

Capacitation in vitro in mammalian spermatozoa can be regulated by a number of first messengers, including fertilization promoting peptide, adenosine, calcitonin and angiotensin II, all of which are found in seminal plasma. The responses appear to involve several separate signal transduction pathways that have a common end point. These seminal-plasma derived first messengers can bind to specific receptors and directly or indirectly modulate the activity of membrane-associated adenylyl cyclase isoforms and production of the second messenger cAMP. Responses to all of these except angiotensin II involve initial acceleration of cAMP production and capacitation followed by inhibition of both cAMP production and spontaneous acrosome loss, resulting in maintenance of fertilizing potential. Appropriate G proteins and various phosphodiesterase isoforms also appear to be involved. The transition from stimulatory to inhibitory responses involves loss of decapacitation factors (DF) from receptors (DF-R) on the external surface; a DF-R present on both mouse and human spermatozoa has recently been identified as phosphatidylethanolamine-binding protein 1. The presence/absence of DF appears to cause changes in the plasma membrane that then alter the functionality of various membrane-associated proteins, including receptors. Since spermatozoa contact these first messengers at ejaculation, it is plausible that their actions observed in vitro also occur in vivo, allowing these molecules to play a pivotal role in enhancing the chances of successful fertilization.
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PMID:Regulation of mammalian sperm capacitation by endogenous molecules. 1636 43

Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. ED is a highly prevalent health problem with considerable impact on the quality of life of men and their partners. Although the treatment of ED with oral phosphodiesterase type V (PDE5) inhibitors is effective in a wide range of individuals, it is not efficacious in all patients. The failure of PDE5 inhibitors happens mainly in men with diabetes, non-nerve sparing radical prostatectomy, and high disease severity. Therefore, improved therapies based on a better understanding of the fundamental issues in erectile physiology and pathophysiology have recently been proposed. Here, we summarize studies on ED treatment using gene and stem cell therapies. Adenoviral-mediated intracavernosal transfer of therapeutic genes, such as endothelial nitric oxide synthase (eNOS), calcitonin gene-related peptide (CGRP), superoxide dismutase (SOD), and RhoA/Rho kinase and mesenchymal stem cell-based cell and gene therapy strategy for the treatment of age- and diabetes-related ED are the focus of this review.
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PMID:Gene and stem cell therapy for erectile dysfunction. 1639 45

NO-responsive, cGMP-producing structures are abundantly present in the cervical spinal cord. NO-mediated cGMP synthesis has been implicated in nociceptive signaling and it has been demonstrated that cGMP has a role establishing synaptic connections in the spinal cord during development. As cGMP levels are controlled by the activity of soluble guanylyl cyclase (synthesis) and the phosphodiesterase (PDE) activity (breakdown), we studied the influence of PDE activity on NO-stimulated cGMP levels in the rat cervical spinal cord. cGMP-immunoreactivity (cGMP-IR) was localized in sections prepared from slices incubated in vitro. A number of reported PDE isoform-selective PDE inhibitors was studied in combination with diethylamineNONOate (DEANO) as a NO-donor including isobutyl-methylxanthine (IBMX) as a non-selective PDE inhibitor. We studied 8-methoxy-IBMX as a selective PDE1 inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and BAY 60-7550 as selective PDE2 inhibitors, sildenafil as a selective PDE5 inhibitor, dipyridamole as a mixed type PDE5 and PDE10 inhibitor, rolipram as a PDE4 inhibitor, and SCH 81566 as a selective PDE9 inhibitor. cGMP-IR structures (nerve fibers, axons, and terminals) were characterized using the following neurochemical markers: vesicular transporter molecules for acetylcholine, GABA, and glutamate (type 1 and type 2), parvalbumin, glutamate transporter molecule EAAT3, synaptophysin, substance P, calcitonin gene-related peptide, and isolectin B4. Most intense cGMP-IR was observed in the dorsal lamina. Ventral motor neurons were devoid of cGMP-IR. cGMP-IR was observed in GABAergic, and glutamatergic terminals in all gray matter laminae. cGMP-IR was abundantly colocalized with anti-vesicular glutamate transporter 2 (vGLUT2), however not with the anti-vesicular glutamate transporter 1 (vGLUT1), suggesting a functional difference between structures expressing vGLUT1 or vGLUT2. cGMP-IR did not colocalize with substance P- or calcitonin-gene related peptide-IR structures, however did partially colocalize with isolectin B4 in the dorsal horn. cGMP-IR in cholinergic structures was observed in dorsal root fibers entering the spinal cord, occasionally in laminae 1-3, in laminae 8 and 9 in isolated boutons and in the C-type terminals, and in small cells and varicosities in lamina 10. This latter observation suggests that the proprioceptive interneurons arising in lamina 10 are also NO-responsive. No region-specific nor a constant co-expression of cGMP-IR with various neuronal markers was observed after incubation of the slices with one of the selected PDE inhibitors. Expression of the mRNA of PDE2, 5, and 9 was observed in all lamina. The ventral motor neurons and the ependymal cells lining the central canal expressed all three PDE isoforms. Incubation of the slices in the presence of IBMX, DEANO in combination with BAY 41-2272, a NO-independent activator of soluble guanylyl cyclase, provided evidence for endogenous NO synthesis in the slice preparations and enhanced cGMP-IR in all lamina. Under these conditions cGMP-IR colocalized with substance P in a subpopulation of substance P-IR fibers. It is concluded that NO functions as a retrograde neurotransmitter in the spinal cord but that also postsynaptic structures are NO-responsive by producing cGMP. cGMP-IR in a subpopulation of isolectin B4 positive fibers and boutons is indicative for a role of NO-cGMP signaling in nociceptive processing. cGMP levels in the spinal cord are controlled by the concerted action of a number of PDE isoforms, which can be present in the same cell.
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PMID:The role of phosphodiesterase isoforms 2, 5, and 9 in the regulation of NO-dependent and NO-independent cGMP production in the rat cervical spinal cord. 1662 45

To assess the combination effect of calcitonin and the phosphodiesterase 4 inhibitor rolipram on osteoclastogenesis, adherent cell-depleted bone marrow cells from mouse tibia and femur (ACD-BMCs), which were cultured in the presence of 25 ng/ml colony-stimulating factor 1 (CSF-1) and 100 ng/ml soluble receptor activator of NF-kappaB ligand (sRANKL), were utilized. Calcitonin inhibited formation of tartrate-resistant acid phosphatase-positive multinucleated cells, as mature osteoclasts, by 70% even at 20 pM, whereas rolipram (10 microM) scarcely affected osteoclast formation; in contrast, the combination of both agents led to significant inhibition of multinucleation and pit formation ability of osteoclasts. The combined administration of calcitonin and rolipram attenuated calcitonin receptor mRNA expression in comparison to treatment with either agent alone, whereas expression of RANK and CSF-1 receptor mRNAs was unchanged. Alone, these agents scarcely elevated intracellular cyclic AMP (cAMP) concentration; however, combination treatment with both agents significantly increased cAMP concentration in osteoclast progenitors and osteoclasts. The combination effect was abolished by H-89, an inhibitor of protein kinase A. It appears that rolipram inhibited hydrolysis of cAMP formed by calcitonin in cells and potentiated the inhibitory effect of calcitonin on osteoclastogenesis. The escape phenomenon following calcitonin treatment may also be prevented by concomitant treatment with the phosphodiesterase 4 inhibitor.
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PMID:Phosphodiesterase 4 inhibitor rolipram potentiates the inhibitory effect of calcitonin on osteoclastogenesis. 1681 19

We investigated modulation of excitation-contraction (EC) coupling by calcitonin gene-related peptide (CGRP), which is released by motorneurons during neuromuscular transmission. Mouse skeletal myotubes were cultured either under control conditions or in the presence of 100 nm CGRP ( approximately 4-72 h). T- and L-type Ca(2+) currents, immobilization resistant charge movement, and intracellular Ca(2+) transients were characterized in whole-cell patch-clamp experiments. CGRP treatment increased the amplitude of voltage-gated Ca(2+) release ((DeltaF/F)(max)) approximately 75-350% and moderately increased both maximal L-current conductance (G(max)) and charge movement (Q(max)). In contrast, CGRP treatment did not affect their corresponding voltage dependence of activation (V(1/2) and k) or T-current density. CGRP treatment enhanced voltage-gated Ca(2+) release in approximately 4 h, whereas the effect on L-channel magnitude took longer to develop ( approximately 24 h), suggesting that short-term potentiation of EC coupling may lead to subsequent long-term up-regulation of DHPR expression. CGRP treatment also drastically increased caffeine-induced Ca(2+) release in approximately 4 h ( approximately 400%). Thus, short-term potentiation of EC coupling is due to an increase in sarcoplasmic reticulum Ca(2+) content. Both application of a phosphodiesterase inhibitor (papaverine) and a membrane-permeant cAMP analogue (Db-cAMP) produced a similar potentiation of EC coupling. Conversely, this potentiation was prevented by pretreatment with either CGRP1 receptor antagonist (CGRP(8-37)) or a PKA inhibitor (H-89). Thus, CGRP acts through CGRP1 receptors and the cAMP/PKA signalling pathway to enhance voltage-gated Ca(2+) release. Effects of CGRP on both EC coupling and L-channels were attenuated at later times during myotube differentiation. Therefore, we conclude that CGRP accelerates maturation of EC coupling.
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PMID:Sustained CGRP1 receptor stimulation modulates development of EC coupling by cAMP/PKA signalling pathway in mouse skeletal myotubes. 1765 31

Previous studies have shown that the development of tolerance to nitroglycerin is related to reduction of endogenous calcitonin gene-related peptide (CGRP) release. In the present study, Nitroglycerin caused a concentration-dependent relaxation concomitantly with a significant increase in the release of CGRP in the isolated rat thoracic aorta, an effect that was reduced by preincubation with capsaicin. Pretreatment with nitroglycerin significantly decreased its vasodilation and depressor effect and the release of CGRP, which was restored in the presence of vinpocetine, an inhibitor of phosphodiesterase. The present results suggest that reversal of tolerance to nitroglycerin with vinpocetine is related to the increased release of CGRP in the rat.
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PMID:Reversal of tolerance to nitroglycerin with vinpocetine: a role of calcitonin gene-related peptide. 1780 99

It has been shown that calcitonin gene-relate peptide plays an extensive role in cardiovascular system. CGRP is a potent vasodilator and plays an important role in mediation of nitroglycerin-induced vascular relaxation. Recently, calcitonin gene-relate peptide is emerging as a potential player in nitroglycerin tolerance. There is increasing evidence that the decreased depressor effect of nitroglycerin in tolerant states is closely related to a decrease in calcitonin gene-relate peptide release. The reduced release of calcitonin gene-relate peptide in nitroglycerin tolerance is associated with the decreased nitroglycerin biotransformation due to the mitochondrial dysfunction. Recent work has been shown that the inhibited activity of mitochondrial isoform of aldehyde dehydrogenase and the upregulation of phosphodiesterase 1A1 are the key factors that lead to the decreased nitroglycerin biotransformation in nitroglycerin tolerance, with a subsequently reduced release of calcitonin gene-relate peptide.
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PMID:New insights into nitroglycerin effects and tolerance: role of calcitonin gene-related peptide. 1836 69


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