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Publication Record


A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition.
Shibao CA, Celedonio JE, Ramirez CE, Love-Gregory L, Arnold AC, Choi L, Okamoto LE, Gamboa A, Biaggioni I, Abumrad NN, Abumrad NA
(2016) J Clin Endocrinol Metab 101: 2751-8
MeSH Terms: Adult, CD36 Antigens, Cardiovascular Diseases, Case-Control Studies, Drug Resistance, Endothelium, Vascular, Female, Genetic Predisposition to Disease, Humans, Insulin Resistance, Metabolic Syndrome, Middle Aged, Obesity, Phosphodiesterase 5 Inhibitors, Polymorphism, Single Nucleotide, Sildenafil Citrate, Treatment Outcome, Vasodilation
Show Abstract · Added March 14, 2018
CONTEXT - The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction.
OBJECTIVE - To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil.
DESIGN - IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2).
SETTING - Two-center study.
PARTICIPANTS - Obese AA women.
INTERVENTION - A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks.
RESULTS - G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], -0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, -0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, -2.6 (95% CI, -5.1 to -0.1; P = .04).
CONCLUSIONS - The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial.
Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, Brown NJ, Shibao CA
(2015) J Clin Endocrinol Metab 100: 4533-40
MeSH Terms: Adult, Albuminuria, Double-Blind Method, Endothelium, Vascular, Female, Fibrinolysis, Glucose, Glucose Clamp Technique, Glucose Tolerance Test, Hemodynamics, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Overweight, Phosphodiesterase 5 Inhibitors, Plasminogen Activator Inhibitor 1, Prediabetic State, Sildenafil Citrate
Show Abstract · Added November 30, 2015
CONTEXT - Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance.
OBJECTIVE - The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function.
DESIGN - This was a randomized, double-blind, placebo-controlled study.
SETTING - This trial was conducted at Vanderbilt Clinical Research Center.
PARTICIPANTS - Participants included overweight individuals with prediabetes.
INTERVENTIONS - Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment.
MAIN OUTCOME MEASURES - The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion.
RESULT - Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per μU/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per μU/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3-month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P > .30). Sildenafil decreased plasminogen activator inhibitor-1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 ± 14.67 to 6.84 ± 4.86 μg/mg Cr. This effect persisted 3 months after sildenafil discontinuation.
CONCLUSIONS - Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.
0 Communities
3 Members
0 Resources
20 MeSH Terms
Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice.
Kang L, Ayala JE, Lee-Young RS, Zhang Z, James FD, Neufer PD, Pozzi A, Zutter MM, Wasserman DH
(2011) Diabetes 60: 416-26
MeSH Terms: Analysis of Variance, Animals, Blotting, Western, Collagen Type III, Collagen Type V, Diet, Extracellular Matrix, Glucose Clamp Technique, Immunohistochemistry, Insulin, Insulin Resistance, Integrin alpha2beta1, Matrix Metalloproteinase 9, Mice, Mice, Knockout, Muscle, Skeletal, Phosphodiesterase 5 Inhibitors, Piperazines, Purines, Reverse Transcriptase Polymerase Chain Reaction, Sildenafil Citrate, Sulfones
Show Abstract · Added February 24, 2014
OBJECTIVE - The hypothesis that high-fat (HF) feeding causes skeletal muscle extracellular matrix (ECM) remodeling in C57BL/6J mice and that this remodeling contributes to diet-induced muscle insulin resistance (IR) through the collagen receptor integrin α(2)β(1) was tested.
RESEARCH DESIGN AND METHODS - The association between IR and ECM remodeling was studied in mice fed chow or HF diet. Specific genetic and pharmacological murine models were used to study effects of HF feeding on ECM in the absence of IR. The role of ECM-integrin interaction in IR was studied using hyperinsulinemic-euglycemic clamps on integrin α(2)β(1)-null (itga2(-/-)), integrin α(1)β(1)-null (itga1(-/-)), and wild-type littermate mice fed chow or HF. Integrin α(2)β(1) and integrin α(1)β(1) signaling pathways have opposing actions.
RESULTS - HF-fed mice had IR and increased muscle collagen (Col) III and ColIV protein; the former was associated with increased transcript, whereas the latter was associated with reduced matrix metalloproteinase 9 activity. Rescue of muscle IR by genetic muscle-specific mitochondria-targeted catalase overexpression or by the phosphodiesterase 5a inhibitor, sildenafil, reversed HF feeding effects on ECM remodeling and increased muscle vascularity. Collagen remained elevated in HF-fed itga2(-/-) mice. Nevertheless, muscle insulin action and vascularity were increased. Muscle IR in HF-fed itga1(-/-) mice was unchanged. Insulin sensitivity in chow-fed itga1(-/-) and itga2(-/-) mice was not different from wild-type littermates.
CONCLUSIONS - ECM collagen expansion is tightly associated with muscle IR. Studies with itga2(-/-) mice provide mechanistic insight for this association by showing that the link between muscle IR and increased collagen can be uncoupled by the absence of collagen-integrin α(2)β(1) interaction.
2 Communities
4 Members
0 Resources
22 MeSH Terms
Safety of sapropterin dihydrochloride (6r-bh4) in patients with pulmonary hypertension.
Robbins IM, Hemnes AR, Gibbs JS, Christman BW, Howard L, Meehan S, Cabrita I, Gonzalez R, Oyler T, Zhao L, Du RH, Mendes LA, Wilkins MR
(2011) Exp Lung Res 37: 26-34
MeSH Terms: Administration, Oral, Adult, Antihypertensive Agents, Biomarkers, Biopterin, Chemokine CCL2, Drug Therapy, Combination, Endothelin Receptor Antagonists, Exercise Test, Exercise Tolerance, Female, Humans, Hypertension, Pulmonary, London, Male, Middle Aged, Natriuretic Peptide, Brain, Nitric Oxide, Oxidative Stress, Peptide Fragments, Phosphodiesterase 5 Inhibitors, Piperazines, Purines, Recovery of Function, Sildenafil Citrate, Sulfones, Tennessee, Time Factors, Treatment Outcome, Walking
Show Abstract · Added February 19, 2015
The authors investigated the safety of oral tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthesis, as a novel treatment for pulmonary hypertension (PH). Eighteen patients with pulmonary arterial hypertension or inoperable chronic thromboembolic PH received sapropterin dihydrochloride (6R-BH4), the optically active form of BH4, in addition to treatment with sildenafil and/or endothelin receptor antagonists in an open-label, dose-escalation study. 6R-BH4 was administered starting at a dose of 2.5 mg/kg and increasing to 20 mg/kg over 8 weeks. Changes in markers of nitric oxide synthesis, inflammation and oxidant stress, as well as exercise capacity and cardiac function were measured. 6R-BH4 was well tolerated at all doses without systemic hypotension, even when given in combination with sildenafil. There was a small but significant reduction in plasma monocyte chemoattractant protein (MCP)-1 levels on 5 mg/kg. No significant changes in measures of nitric oxide synthesis or oxidant stress were observed. There was improvement in 6-minute walk distance, most significant at a dose of 5 mg/kg, from 379 ± 61 to 413 ± 57 m 414 ± 57 m (P = .002). Oral 6R-BH4 can be administered safely in doses up to 20 mg/kg daily to patients with PH. Further studies are needed to explore its therapeutic potential.
0 Communities
1 Members
0 Resources
30 MeSH Terms
Excessive nitric oxide function and blood pressure regulation in patients with autonomic failure.
Gamboa A, Shibao C, Diedrich A, Paranjape SY, Farley G, Christman B, Raj SR, Robertson D, Biaggioni I
(2008) Hypertension 51: 1531-6
MeSH Terms: Aged, Blood Pressure, Cross-Over Studies, Enzyme Inhibitors, Female, Humans, Hypertension, Male, Middle Aged, Nitric Oxide, Nitric Oxide Synthase, Piperazines, Purines, Shy-Drager Syndrome, Sildenafil Citrate, Sulfones, Supine Position, Vasodilator Agents, omega-N-Methylarginine
Show Abstract · Added December 10, 2013
Approximately 50% of patients with autonomic failure (AF) suffer from supine hypertension, even those with very low plasma norepinephrine and renin. Because NO is arguably the most potent metabolic modulator of blood pressure, we hypothesized that impaired NO function contributes to supine hypertension in AF. However, we found that AF patients (n=14) were more sensitive to the pressor effects of the NO synthase inhibitor N(G)-monomethyl-l-arginine, suggesting increased NO function rather than deficiency; a lower dose of N(G)-monomethyl-l-arginine was needed to produce a similar increase in blood pressure in AF patients, as in healthy control subjects in whom AF was induced with the ganglionic blocker trimethaphan (171+/-37 mg versus 512+/-81 mg, respectively; P=0.001). Furthermore, potentiation of the actions of endogenous NO with the phosphodiesterase inhibitor sildenafil (25 mg PO) decreased nighttime supine systolic blood pressure from 182+/-11 to 138+/-4 mm Hg in 8 AF patients with supine hypertension (P=0.012 compared with placebo). Finally, AF patients tolerated a greater degree of upright tilt during infusion of N(G)-monomethyl-l-arginine (56+/-6 degrees versus 41+/-4 degrees with placebo; n=7; P=0.014), an improvement in orthostatic tolerance similar to that obtained with equipressor doses of phenylephrine. In conclusion, AF patients do not have NO deficiency contributing to supine hypertension. Instead, they have increased NO function contributing to their orthostatic hypotension. Potentiation of NO could be used in the treatment of supine hypertension, and its inhibition offers a novel approach to improve orthostatic hypotension.
0 Communities
5 Members
0 Resources
19 MeSH Terms
Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice.
Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, Wasserman DH
(2007) Diabetes 56: 1025-33
MeSH Terms: Animal Feed, Animals, Arginine, Blood Glucose, Blood Pressure, Body Composition, Dietary Fats, Echocardiography, Energy Metabolism, Feeding Behavior, Glucose Clamp Technique, Insulin, Male, Mice, Mice, Inbred C57BL, Mitochondria, Muscle, Piperazines, Purines, Sildenafil Citrate, Sulfones, Vasodilator Agents
Show Abstract · Added December 22, 2010
Stimulation of nitric oxide-cGMP signaling results in vascular relaxation and increased muscle glucose uptake. We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 inhibitor sildenafil improves energy balance and enhances in vivo insulin action in a mouse model of diet-induced insulin resistance. High-fat-fed mice treated with sildenafil plus L-arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, uncoupling protein-1 levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil plus L-arginine or sildenafil alone increased arterial cGMP levels but did not adversely affect blood pressure or cardiac morphology. Sildenafil treatment, with or without l-arginine, resulted in lower fasting insulin and glucose levels and enhanced rates of glucose infusion, disappearance, and muscle glucose uptake during a hyperinsulinemic (4 mU x kg(-1) x min(-1))-euglycemic clamp in conscious mice. These effects occurred without an increase in activation of muscle insulin signaling. An acute treatment of high fat-fed mice with sildenafil plus l-arginine did not improve insulin action. These results show that phosphodiesterase-5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance.
0 Communities
2 Members
0 Resources
21 MeSH Terms
cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism.
Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA
(2005) Circ Res 96: 100-9
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Adenoviridae, Adrenergic beta-Agonists, Animals, Carbolines, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 5, Fluorescence Resonance Energy Transfer, Genetic Vectors, Guanylate Cyclase, Isoproterenol, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Contraction, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Phosphodiesterase Inhibitors, Piperazines, Purines, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, beta, Receptors, Cytoplasmic and Nuclear, Recombinant Fusion Proteins, Second Messenger Systems, Sildenafil Citrate, Soluble Guanylyl Cyclase, Sulfones, Tadalafil
Show Abstract · Added March 4, 2015
Beta-adrenergic agonists stimulate cardiac contractility and simultaneously blunt this response by coactivating NO synthase (NOS3) to enhance cGMP synthesis and activate protein kinase G (PKG-1). cGMP is also catabolically regulated by phosphodiesterase 5A (PDE5A). PDE5A inhibition by sildenafil (Viagra) increases cGMP and is used widely to treat erectile dysfunction; however, its role in the heart and its interaction with beta-adrenergic and NOS3/cGMP stimulation is largely unknown. In nontransgenic (control) murine in vivo hearts and isolated myocytes, PDE5A inhibition (sildenafil) minimally altered rest function. However, when the hearts or isolated myocytes were stimulated with isoproterenol, PDE5A inhibition was associated with a suppression of contractility that was coupled to elevated cGMP and increased PKG-1 activity. In contrast, NOS3-null hearts or controls with NOS inhibited by N(G)-nitro-L-arginine methyl ester, or soluble guanylate cyclase (sGC) inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one, showed no effect of PDE5A inhibition on beta-stimulated contractility or PKG-1 activation. This lack of response was not attributable to altered PDE5A gene or protein expression or in vitro PDE5A activity, but rather to an absence of sGC-generated cGMP specifically targeted to PDE5A catabolism and to a loss of PDE5A localization to z-bands. Re-expression of active NOS3 in NOS3-null hearts by adenoviral gene transfer restored PDE5A z-band localization and the antiadrenergic efficacy of PDE5A inhibition. These data support a novel regulatory role of PDE5A in hearts under adrenergic stimulation and highlight specific coupling of PDE5A catabolic regulation with NOS3-derived cGMP attributable to protein subcellular localization and targeted synthetic/catabolic coupling.
0 Communities
1 Members
0 Resources
34 MeSH Terms
Stimulation of serotonin transport by the cyclic GMP phosphodiesterase-5 inhibitor sildenafil.
Zhu CB, Hewlett WA, Francis SH, Corbin JD, Blakely RD
(2004) Eur J Pharmacol 504: 1-6
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Animals, CHO Cells, Cricetinae, Cyclic Nucleotide Phosphodiesterases, Type 5, Membrane Glycoproteins, Membrane Transport Proteins, Nerve Tissue Proteins, Phosphodiesterase Inhibitors, Piperazines, Protein Binding, Purines, Rats, Serotonin, Serotonin Plasma Membrane Transport Proteins, Sildenafil Citrate, Sulfones
Show Abstract · Added July 10, 2013
The serotonin (5-hydroxtryptamine, 5-HT) transporter (SERT) plays a critical role in the inactivation of synaptic 5-HT and has been implicated in multiple psychiatric and peripheral disorders. SERT regulation studies demonstrate that activation of cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-linked pathways can increase SERT activity. As cGMP actions are limited by cGMP-specific phosphodiesterase (PDEs), we investigated whether the cGMP-specific PDE5 inhibitor sildenafil (Viagra) can stimulate 5-HT uptake and potentiate cGMP-mediated regulation. In RBL-2H3 cells, SERT activity was stimulated by sildenafil in a concentration- and time-dependent manner. Sildenafil also enhanced the stimulation of SERT triggered by the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), effects blocked by the PKG inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8). Sildenafil stimulation of 5-HT uptake arises from an increase in 5-HT transport Vmax and is paralleled by elevated SERT surface antagonist binding, also H8-sensitive. These findings implicate cGMP-targeted PDEs in limiting the regulation of antidepressant-sensitive 5-HT transport.
1 Communities
1 Members
0 Resources
17 MeSH Terms
Adenosine receptor, protein kinase G, and p38 mitogen-activated protein kinase-dependent up-regulation of serotonin transporters involves both transporter trafficking and activation.
Zhu CB, Hewlett WA, Feoktistov I, Biaggioni I, Blakely RD
(2004) Mol Pharmacol 65: 1462-74
MeSH Terms: Adenosine-5'-(N-ethylcarboxamide), Animals, Biological Transport, CHO Cells, Calcium, Carrier Proteins, Cells, Cultured, Cricetinae, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Female, Guanylate Cyclase, Membrane Glycoproteins, Membrane Transport Proteins, Mitogen-Activated Protein Kinases, Nerve Tissue Proteins, Phosphodiesterase Inhibitors, Piperazines, Purines, Rats, Receptors, Purinergic P1, Serotonin, Serotonin Plasma Membrane Transport Proteins, Sildenafil Citrate, Sulfones, Type C Phospholipases, Up-Regulation, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added December 10, 2013
Serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) are critical determinants of synaptic 5-HT inactivation and the targets for multiple drugs used to treat psychiatric disorders. In support of prior studies, we found that short-term (5-30 min) application of the adenosine receptor (AR) agonist 5'-N-ethylcarboxamidoadenosine (NECA) induces an increase in 5-HT uptake Vmax in rat basophilic leukemia 2H3 cells that is enhanced by pretreatment with the cGMP phosphodiesterase inhibitor sildenafil. NECA stimulation is blocked by the A3 AR antagonist 3-ethyl-5-benzyl-2-methyl-phenylethynyl-6-phenyl-1,4(+/-)dihydropyridine-3,5-dicarboxylate (MRS1191), by the phospholipase C inhibitor 1-(6-[[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl] amino]hexyl)-1H-pyrrole-2,5-dione (U73122), by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, and by the guanyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Hydroxylamine, a nitric-oxide donor, and 8-bromo-cGMP, a membrane-permeant analog of cGMP, mimic the effects of NECA on 5-HT uptake, whereas the protein kinase G (PKG) inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8) blocks NECA, hydroxylamine, and 8-bromo-cGMP effects. NECA stimulation activates p38 mitogen-activated protein kinase (MAPK), whereas p38 MAPK inhibitors block NECA stimulation of SERT activity, as does the protein phosphatase 2A (PP2A) inhibitor calyculin A. 5-HT-displaceable [125I]3beta-(4-iodophenyl)-tropane-2beta-carboxylic acid methylester tartrate (RTI-55) whole-cell binding is increased by NECA or sildenafil, and both surface binding and cell surface SERT protein are elevated after NECA or sildenafil stimulation of AR/SERT-cotransfected Chinese hamster ovary cells. Whereas p38 MAPK inhibition blocks NECA stimulation of 5-HT activity, it fails to blunt stimulation of SERT surface density. Moreover, inactivation of existing surface SERTs fails to eliminate NECA stimulation of SERT. Together, these results reveal two PKG-dependent pathways supporting rapid SERT regulation by A3 ARs, one leading to enhanced SERT surface trafficking, and a separate, p38 MAPK-dependent process augmenting SERT intrinsic activity.
1 Communities
3 Members
0 Resources
28 MeSH Terms
Sildenafil-induced vasorelaxation is associated with increases in the phosphorylation of the heat shock-related protein 20 (HSP20).
Tessier DJ, Komalavilas P, McLemore E, Thresher J, Brophy CM
(2004) J Surg Res 118: 21-5
MeSH Terms: Animals, Arteries, Coronary Vessels, Dose-Response Relationship, Drug, HSP20 Heat-Shock Proteins, Heat-Shock Proteins, In Vitro Techniques, Phosphoproteins, Phosphorylation, Piperazines, Purines, Sildenafil Citrate, Sulfones, Swine, Vasoconstriction, Vasodilation, Vasodilator Agents
Show Abstract · Added March 11, 2015
PURPOSE - Sildenafil is an oral phosphodiesterase type 5 inhibitor that is a vasodilator used in the treatment of erectile dysfunction. Cyclic nucleotide-dependent vasorelaxation is associated with increases in the phosphorylation of the heat shock related protein 20 (HSP20). The purpose of this study was to determine if sildenafil-induced vasorelaxation is associated with increases in the phosphorylation of HSP20.
MATERIALS AND METHODS - Peptides containing an 11 amino acid enhanced protein transduction domain (PTD) and the functional 13 amino acid sequence of HSP20 with a phosphoserine (PTD-pHSP20) were synthesized using F-MOC technology. Rings of porcine coronary artery were suspended in a muscle bath and sub-maximally contracted with serotonin. Increasing concentrations of sodium nitroprusside (SNP; 0.01-10 microM), sildenafil (0.01-100 microM), or PTD-pHSP20 (0.1-1.0 mM) were added to the baths and the percent relaxation was recorded. To determine if sildenafil-induced vasorelaxation was associated with increases in the phosphorylation of HSP20, rings of porcine coronary artery were untreated (control) or treated with SNP (10 microM) or sildenafil (100 microM) for 2, 5, and 10 min and then snap frozen. Extracted proteins were then separated using two-dimensional SDS-PAGE, transferred to a membrane, and probed for HSP20.
RESULTS - Sildenafil induced vasorelaxation of pre-contracted coronary artery in a dose-dependent manner. Sildenafil-induced vasorelaxation was associated with an increase in the phosphorylation of HSP20. Transduction of peptide analogues of pHSP20 led to a dose-dependent relaxation of pre-contracted porcine coronary artery.
CONCLUSIONS - These findings suggest that sildenafil-induced vasorelaxation is associated with increases in the phosphorylation of HSP20 and that transduction of phosphopeptide analogues of HSP20 is sufficient for relaxation of vascular smooth muscle.
0 Communities
1 Members
0 Resources
17 MeSH Terms