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2.
Anesthesiology ; 121(5): 930-6, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25198173

RESUMEN

BACKGROUND: Vasopressor drugs, commonly used to treat systemic hypotension and maintain organ perfusion, may also induce regional vasoconstriction in specialized vascular beds such as the lung. An increase in pulmonary vascular tone may adversely affect patients with pulmonary hypertension or right heart failure. While sympathomimetics constrict pulmonary vessels, and vasopressin does not, a direct comparison between these drugs has not been made. This study investigated the effects of clinically used vasopressor agents on human isolated pulmonary and radial arteries. METHODS: Isolated pulmonary and radial artery ring segments, mounted in organ baths, were used to study the contractile responses of each vasopressor agent. Concentration-response curves to norepinephrine, phenylephrine, metaraminol, and vasopressin were constructed. RESULTS: The sympathomimetics norepinephrine, phenylephrine, and metaraminol caused concentration-dependent vasoconstriction in the radial (pEC50: 6.99 ± 0.06, 6.14 ± 0.09, and 5.56 ± 0.07, respectively, n = 4 to 5) and pulmonary arteries (pEC50: 6.86 ± 0.11, 5.94 ± 0.05 and 5.56 ± 0.09, respectively, n = 3 to 4). Vasopressin was a potent vasoconstrictor of the radial artery (pEC50 9.13 ± 0.20, n = 3), whereas in the pulmonary artery, it had no significant effect. CONCLUSIONS: Sympathomimetic-based vasopressor agents constrict both human radial and pulmonary arteries with similar potency in each. In contrast, vasopressin, although a potent vasoconstrictor of radial vessels, had no effect on pulmonary vascular tone. These findings provide some support for the use of vasopressin in patients with pulmonary hypertension.


Asunto(s)
Arteria Pulmonar/efectos de los fármacos , Arteria Radial/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Arginina Vasopresina/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Técnicas In Vitro , Simpatomiméticos/farmacología , Vasodilatación/efectos de los fármacos
3.
Biochem Pharmacol ; 222: 116092, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38408679

RESUMEN

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α1-adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α1-adrenoceptor antagonism by clioquinol.


Asunto(s)
Clioquinol , Ratas , Humanos , Animales , Chlorocebus aethiops , Clioquinol/farmacología , Oxiquinolina , Receptores Adrenérgicos alfa 1/metabolismo , Ionóforos , Zinc
4.
Nat Med ; 11(5): 507-14, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15834429

RESUMEN

Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.


Asunto(s)
Arterias/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Adhesividad Plaquetaria/fisiología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Transducción de Señal/fisiología , Trombosis/metabolismo , Animales , Tiempo de Sangría , Plaquetas/metabolismo , Citometría de Flujo , Isoenzimas/metabolismo , Ratones , Ratones Noqueados , Inhibidores de las Quinasa Fosfoinosítidos-3 , Reología , Serotonina/metabolismo , Trombosis/patología , Proteínas de Unión al GTP rap/metabolismo
5.
Org Biomol Chem ; 9(2): 473-9, 2011 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-21049134

RESUMEN

Benzothiophene and benzoselenophene analogues of the thiophene-containing antihypertensives milfasartan and eprosartan were prepared and tested for AT(1) receptor antagonist properties. While the sulfur-containing systems were prepared following existing methodology, the selenium-containing analogues required the development of novel, tandem free-radical chemistry involving addition of aryl radicals to alkynes, followed by intramolecular homolytic substitution at the higher heteroatom. All four compounds prepared proved to be excellent AT(1) receptor antagonists, with pK(B) estimates of 7.2-9.5.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Radicales Libres/química , Estructura Molecular
6.
Eur J Pharmacol ; 909: 174433, 2021 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-34416240

RESUMEN

Cannabidiol is increasingly considered for treatment of a wide range of medical conditions. Binding studies suggest that cannabidiol binds to CB1 receptors. In the rat isolated vas deferens bioassay, a single electrical pulse causes a biphasic contraction from nerve-released ATP and noradrenaline. WIN 55,212-2 acts on prejunctional CB1 receptors to inhibit release of these transmitters. In this bioassay, we tested whether cannabidiol and SR141716 were acting as competitive antagonists of this receptor. Monophasic contractions mediated by ATP or noradrenaline in the presence of prazosin or NF449 (P2X1 inhibitor), respectively, were measured to a single electrical pulse delivered every 30 min. Following treatment with cannabidiol (10-100 µM) or SR141716 (0.003-10 µM), cumulative concentrations of WIN 55,212-2 (0.001-30 µM) were applied followed by a single electrical pulse. The WIN 55,212-2 concentration-contraction curve EC50 values were applied to global regression analysis to determine the pKB. The antagonist potency of cannabidiol at the CB1 receptor in the rat vas deferens bioassay matched the reported receptor binding affinity. Cannabidiol was a competitive antagonist of WIN 55,212-2 with pKB values of 5.90 when ATP was the effector transmitter and 5.29 when it was noradrenaline. Similarly, SR141716 was a competitive antagonist with pKB values of 8.39 for ATP and 7.67 for noradrenaline as the active transmitter. Cannabidiol's low micromolar CB1 antagonist pKB values suggest that at clinical blood levels (1-3 µM) it may act as a CB1 antagonist at prejunctional neuronal sites with more potency when ATP is the effector than for noradrenaline.


Asunto(s)
Cannabidiol/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Contracción Muscular/efectos de los fármacos , Receptor Cannabinoide CB1/antagonistas & inhibidores , Conducto Deferente/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Bioensayo , Masculino , Norepinefrina/metabolismo , Ratas , Receptor Cannabinoide CB1/metabolismo , Rimonabant/farmacología , Conducto Deferente/metabolismo
7.
Eur J Pharmacol ; 891: 173767, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33275960

RESUMEN

The pharmacology of cannabidiol, the non-psychoactive major component of Cannabis sativa, is of growing interest as it becomes more widely prescribed. This study aimed to examine the effects of cannabidiol on a wide range of contractile agents in rat small resistance arteries, in comparison with large arteries, and to explore its mechanism of action. The vascular actions of cannabidiol were also contrasted with effects on the contractions of bronchial, urogenital, cardiac and skeletal muscles. Isolated small or large arteries were incubated with cannabidiol (0.3-3 µM) or vehicle and concentration-contraction response curves were completed to various agents, including endothelin-1, arginine vasopressin, methoxamine, 5-HT, α-methyl 5-HT and U46619. In small arteries, the effects of cannabidiol were tested in the presence of antagonists of CB1 or CB2 receptors, calcitonin gene-related peptide (CGRP), nitric oxide synthase, cyclooxygenase, PPARγ or a combination. The role of L-type voltage-operated calcium channels was also assessed. Cannabidiol 1-3 µM significantly inhibited the contraction of small resistance arteries to all tested agents through a combination of mechanisms that include CGRP and L-type calcium channels. However, large arteries were insensitive to cannabidiol. Cannabidiol (10-100 µM) was largely without effect in bronchi, atria and hemidiaphragm, but 100 µM attenuated maximum contractions in vasa deferentia. Cannabidiol's effects in the clinical range (1-3 µM) appear to be specific to small resistance arteries. This high sensitivity of the resistance arterial circulation to cannabidiol may offer a therapeutic opportunity in peripheral vascular disease that excludes off-target sites such as the heart and non-vascular smooth muscle.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/efectos de los fármacos , Cannabidiol/farmacología , Arterias Mesentéricas/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio , Relación Dosis-Respuesta a Droga , Masculino , Arterias Mesentéricas/metabolismo , Ratas Sprague-Dawley
8.
Nat Commun ; 12(1): 3296, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-34075043

RESUMEN

Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.


Asunto(s)
Endotelio Vascular/metabolismo , Músculo Liso Vascular/fisiología , Células Receptoras Sensoriales/metabolismo , Vasodilatación/fisiología , Zinc/metabolismo , Anciano , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Canales de Calcio Tipo N/metabolismo , Quelantes/farmacología , Citoplasma/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/inervación , Etilenodiaminas/farmacología , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Músculo Liso Vascular/efectos de los fármacos , Técnicas de Placa-Clamp , Prostaglandina-Endoperóxido Sintasas/metabolismo , Prostaglandinas/metabolismo , Ratas , Canal Catiónico TRPA1/genética , Canal Catiónico TRPA1/metabolismo , Vasodilatación/efectos de los fármacos
9.
Heliyon ; 6(4): e03810, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32368652

RESUMEN

OBJECTIVES: The vascular amplifier in hypertension is a result of structural changes in resistance arteries. We estimated the vascular amplifier hypertensive:normotensive (H:N) ratio in the renal bed compared with the total peripheral bed in conscious rabbits during infusion of vasoconstrictor and vasodilator stimuli. METHODS: Rabbits were subjected to bilateral renal cellophane wrap or sham operation. A perivascular ultrasonic flow probe was implanted on the left renal artery to measure renal blood flow. A catheter was inserted into the thoracic aorta for agonist administration. Blood pressure, heart rate and renal blood flow were measured on three separate days in conscious rabbits with intact effectors, ganglionic block or neurohumoral block. Dose-response curves were constructed to intra-arterial infusion of noradrenaline, angiotensin II, adenosine and acetylcholine. RESULTS: Resting renal vascular resistance in hypertensive rabbits was markedly decreased by ganglionic block and further by neurohumoral block. With effectors intact, ganglionic block or neurohumoral block, the H:N ratio for renal vascular resistance was 2.32, 1.72 or 1.72, respectively. The ratio was generally maintained during the infusion of constrictor and dilator drugs although distortions occurred at higher concentrations of constrictor or dilator drugs. CONCLUSIONS: Estimation of the renal resistance amplifier in renal wrap hypertension with neurohumoral block accords with our earlier estimates of the total peripheral resistance amplifier (1.79). This vascular resistance amplifier is consistent with a decrease in internal radius through structural remodelling in the renal vascular bed as is reflected in the total arterial circulation in hypertension.

10.
Eur J Pharmacol ; 882: 173304, 2020 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-32592771

RESUMEN

Recently, the ß2-adrenoceptor agonist terbutaline was shown to have α1-adrenolytic activity in mouse isolated pulmonary arteries in vitro and to lower pulmonary artery pressure in anaesthetised mice. The aim of our study was to determine the α1-adrenoceptor antagonist activity of terbutaline and its structurally close resorcinol, orciprenaline, in rat isolated small mesenteric arteries set up for myography. Their α1-adrenoceptor antagonist potency was then compared with their potency as ß2-adrenoceptor agonists. Concentration-response curves to methoxamine were competitively antagonised by terbutaline (30-300 µM) or orciprenaline (30-300 µM) with a pKB of 4.70 ± 0.09 or 4.79 ± 0.17, respectively. Both terbutaline and orciprenaline fulfilled the criteria for simple, silent competitive antagonism. Terbutaline (30-300 µM) had no effect on endothelin-1 concentration-contraction curves. Our findings suggest that after oral dosing of terbutaline, the maximum plasma levels would NOT reach levels to show α1-adrenoceptor antagonist activity. In conclusion, our work has provided additional quantitative evidence that terbutaline and orciprenaline are weak competitive α1-adrenoceptor antagonists, but this additional property is probably not therapeutically important in the clinical treatment of asthma or pulmonary artery hypertension with these more potent ß2-adrenoceptor agonists.


Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Broncodilatadores/farmacología , Arterias Mesentéricas/efectos de los fármacos , Metaproterenol/farmacología , Terbutalina/farmacología , Animales , Masculino , Arterias Mesentéricas/fisiología , Ratas Sprague-Dawley
11.
J Vasc Res ; 46(1): 45-54, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-18552506

RESUMEN

AIMS: To assess fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor-B (VEGF-B) effects on flow reserve and morphological adaptation in the rabbit ischemic hind limb. METHODS: Following bilateral femoral artery ligation, calf blood pressure (C(BP)), flow reserve, collateral artery numbers and capillary numbers were assessed. Treatment consisted of rabbit serum albumin (RSA), FGF-2, VEGF-B or FGF-2 + VEGF-B. RESULTS: Ligation decreased C(BP); on day 14, a 48% deficit remained in the RSA group compared with a deficit of only 22% in FGF-2 and VEGF-B groups. On day 3, flow reserve was attenuated 60%, but recovered by day 14 (with no treatment effects). Collateral artery numbers increased with RSA (+28%), FGF-2 (+53%), VEGF-B (+47%) and FGF-2 + VEGF-B (+59%). Rectus femoris muscle total capillary profiles and fibers per cross-section were alike across groups. Tibialis anterior muscle cross-sectional area was lower with ligation and total capillary number was less in RSA and FGF-2 groups, providing evidence for angiogenesis with VEGF-B. Capillary/muscle fiber ratio was similar in each group. CONCLUSIONS: FGF-2 and VEGF-B enhanced lower limb perfusion as indicated by improved C(BP) and combined treatment increased collateral artery number. Flow reserve recovery was not enhanced by cytokine treatment. VEGF-B, but not FGF-2, caused angiogenesis in the tibialis anterior muscle. Overall, VEGF-B may have advantages over FGF-2 in this setting; however, their combination may further improve arteriogenesis.


Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/uso terapéutico , Miembro Posterior/irrigación sanguínea , Isquemia/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Factor B de Crecimiento Endotelial Vascular/uso terapéutico , Inductores de la Angiogénesis/farmacología , Animales , Arteria Femoral , Isquemia/patología , Ligadura , Conejos
12.
Eur J Pharmacol ; 855: 124-136, 2019 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-31063771

RESUMEN

In the pulmonary vasculature there is clearance of endothelin-1 from the circulation mediated by endothelin ETB receptors. This study explored the haemodynamic effects of endothelin-1 and its clearance in the pulmonary and hindquarter vasculature in anaesthetised rats. Carotid and pulmonary artery pressures and pulmonary and hindquarter blood flows were measured. In each rat, a single endothelin-1 or sarafotoxin S6C cumulative dose-response curve was generated with or without antagonist pretreatment (i.v.). Endothelin-1 caused an acute fall in MAP and rise in hindquarter vascular conductance (HVC) followed by a marked increase in MAP at 5 min with falls in HVC and pulmonary vascular conductance (PVC). Bosentan (10, 20 & 30 mg/kg) pretreatment caused dose-dependent inhibition of the MAP increase as well as PVC and HVC decreases to endothelin-1. Similarly, macitentan (30 mg/kg) or ambrisentan (10 mg/kg) caused significant block of responses to endothelin-1. Sarafotoxin S6C caused acute falls in MAP and increases in HVC and then small falls in PVC and HVC, all prevented by pretreatment with ETB antagonist BQ788 (1 mg/kg). Pretreatment with BQ788 enhanced endothelin-1 potency by 2.5-fold in PVC and 2.4-fold in HVC. With BQ788 and bosentan, the fall in HVC response was completely blocked, but there were residual MAP rises and PVC falls at the highest endothelin-1 dose. Our work confirms the role of ETB receptors in the pulmonary vasculature that decrease the circulating levels of endothelin-1. This has important consequences in selecting an appropriate ETA and ETB dual receptor antagonist to effectively block endothelin-1-mediated pulmonary vasoconstriction.


Asunto(s)
Endotelina-1/farmacología , Hemodinámica/efectos de los fármacos , Pulmón/irrigación sanguínea , Neovascularización Fisiológica/efectos de los fármacos , Anestesia , Animales , Bosentán/farmacología , Interacciones Farmacológicas , Femenino , Masculino , NG-Nitroarginina Metil Éster/farmacología , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Sulfonamidas/farmacología , Venenos de Víboras/farmacología
13.
Auton Neurosci ; 222: 102588, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31669796

RESUMEN

The vas deferens responds to a single electrical pulse with a biphasic contraction caused by cotransmitters ATP and noradrenaline. Removing Mg2+ (normally 1.2 mM) from the physiological salt solution (PSS) enhances the contraction. This study aimed to determine the effect of Mg2+ concentration on nerve cotransmitter-mediated contractions. Rat vasa deferentia were sequentially bathed in increasing (0, 1.2, 3 mM) or decreasing (3, 1.2, 0 mM) Mg2+ concentrations. At each concentration a single field pulse was applied, and the biphasic contraction recorded. Contractions to exogenous noradrenaline 10 µM and ATP 100 µM were also determined. The biphasic nerve-mediated contraction was elicited by ATP and noradrenaline as NF449 (10 µM) and prazosin (100 nM) completely prevented the respective peaks. Taking the contractions in normal PSS (Mg2+ 1.2 mM) as 100%, lowering Mg2+ to 0 mM enhanced the ATP peak to 170 ±â€¯7% and raising Mg2+ to 3 mM decreased it to 39 ±â€¯3%; the noradrenaline peak was not affected by lowering Mg2+ to 0 mM (97 ±â€¯3%) but was decreased to 63 ±â€¯4% in high Mg2+ (3 mM). Contractions to exogenous ATP, but not noradrenaline, were increased in Mg2+ 0 mM and both were inhibited with Mg2+ 3 mM. Changing Mg2+ concentration affects the contractions elicited by the cotransmitters ATP and noradrenaline. The greatest effects were to potentiate the contraction to ATP in Mg2+ 0 mM and to inhibit the contraction to both ATP and noradrenaline in high Mg2+. Future publications should clearly justify any decision to vary the magnesium concentration from normal (1.2 mM) values.


Asunto(s)
Adenosina Trifosfato/metabolismo , Sistema Nervioso Autónomo/fisiología , Fenómenos Electrofisiológicos/fisiología , Magnesio/farmacología , Contracción Muscular/fisiología , Norepinefrina/metabolismo , Conducto Deferente/fisiología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Animales , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/metabolismo , Bencenosulfonatos/farmacología , Cationes Bivalentes/farmacología , Fenómenos Electrofisiológicos/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Prazosina/farmacología , Ratas , Ratas Sprague-Dawley , Conducto Deferente/efectos de los fármacos , Conducto Deferente/inervación
14.
Circulation ; 115(3): 353-60, 2007 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-17200440

RESUMEN

BACKGROUND: Cardiac tissue engineering offers the prospect of a novel treatment for acquired or congenital heart defects. We have created vascularized pieces of beating cardiac muscle in the rat that are as thick as the adult rat right ventricle wall. METHOD AND RESULTS: Neonatal rat cardiomyocytes in Matrigel were implanted with an arteriovenous blood vessel loop into a 0.5-mL patented tissue-engineering chamber, located subcutaneously in the groin. Chambers were harvested 1, 4, and 10 weeks after insertion. At 4 and 10 weeks, all constructs that grew in the chambers contracted spontaneously. Immunostaining for alpha-sarcomeric actin, troponin, and desmin showed that differentiated cardiomyocytes present in tissue at all time points formed a network of interconnected cells within a collagenous extracellular matrix. Constructs at 4 and 10 weeks were extensively vascularized. The maximum thickness of cardiac tissue generated was 1983 microm. Cardiomyocytes increased in size from 1 to 10 weeks and were positive for the proliferation markers Ki67 and PCNA. Connexin-43 stain indicated that gap junctions were present between cardiomyocytes at 4 and 10 weeks. Echocardiograms performed between 4 and 10 weeks showed that the tissue construct contracted spontaneously in vivo. In vitro organ bath experiments showed a typical cardiac muscle length-tension relationship, the ability to be paced from electrical field pulses up to 3 Hz, positive chronotropy to norepinephrine, and positive inotropy in response to calcium. CONCLUSIONS: In summary, the use of a vascularized tissue-engineering chamber allowed generation of a spontaneously beating 3-dimensional mass of cardiac tissue from neonatal rat cardiomyocytes. Further development of this vascularized model will increase the potential of cardiac tissue engineering to provide suitable replacement tissues for acquired and congenital defects.


Asunto(s)
Cámaras de Difusión de Cultivos/métodos , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Neovascularización Fisiológica/fisiología , Ingeniería de Tejidos/instrumentación , Ingeniería de Tejidos/métodos , Actinas/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Animales , Animales Recién Nacidos , Vasos Sanguíneos/citología , Vasos Sanguíneos/metabolismo , Calcio/farmacología , Proliferación Celular , Células Cultivadas , Conexina 43/metabolismo , Desmina/metabolismo , Antígeno Ki-67/metabolismo , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Norepinefrina/farmacología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ratas Sprague-Dawley , Troponina/metabolismo
15.
J Vasc Res ; 45(4): 279-94, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18212510

RESUMEN

AIMS: The effects of ischemia and hypercholesterolemia on the function and morphological adaptation of the rabbit hindlimb were assessed. METHODS: In rabbits on normal or cholesterol diet, experiments were performed on days 0-28 following bilateral femoral artery ligation. Calf blood pressure (C(BP)), exercise tolerance, flow reserve, agonist vasodilatation, angiography and capillary density were examined and modeled. RESULTS: C(BP) decreased markedly post-ligation and returned to 41 and 68% of baseline by days 7 and 28. Exercise tolerance was attenuated 40% and flow reserve 50-60% on day 7, with recovery by day 28. Ligation caused decreases in 5-hydroxytryptamine-induced dilatation, while adenosine and acetylcholine responses were unaffected. Hypercholesterolemia attenuated acetylcholine-elicited dilatation. There was marked loss of adenosine dilatation on days 7-14 in the ligation plus hypercholesterolemia group. Ligation caused a doubling in the number of medium-sized collateral arteries. Hypercholesterolemia, either alone or combined with ligation, greatly augmented small vessel density. Capillary density was unaltered by any treatment. CONCLUSIONS: The rabbit hindlimb shows a remarkable ability to recover its muscle function through vascular adaptation and remodeling 4 weeks following ligation, with or without hypercholesterolemia. Exercise tolerance, flow reserve and vascular reactivity were mainly restored 28 days post-ligation.


Asunto(s)
Adaptación Fisiológica , Vasos Sanguíneos/fisiología , Arteria Femoral/fisiología , Hemodinámica , Hipercolesterolemia/fisiopatología , Ligadura , Animales , Miembro Posterior , Isquemia , Conejos
16.
Anesthesiology ; 108(1): 87-93, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18156886

RESUMEN

BACKGROUND: Propofol, sevoflurane, and desflurane may cause hemodynamic compromise during anesthesia and critical care management. The aim of the study was to compare these anesthetics during increased dose and recovery to maintenance level. METHODS: Anesthetized, open-chest New Zealand White rabbits were used to acquire dose-response curves with sevoflurane, desflurane, and propofol, followed by reduction to baseline infusion. Simultaneous high-fidelity left ventricular pressure and volume data were acquired during caval occlusion with a dual-field conductance catheter inserted via an apical stab. The preload recruitable stroke work and the end-diastolic pressure-volume relationship were used as the primary measures of contractility and diastolic function. RESULTS: The time-matched controls were stable over time. Propofol and desflurane but not sevoflurane caused dose-dependent reductions in myocardial contractility, although sevoflurane reduced contractility more at 1 minimal alveolar concentration. All anesthetics reduced mean arterial pressure, and significant recovery occurred for sevoflurane and desflurane but not for propofol. The end-diastolic pressure-volume relationship was increased by sevoflurane. Ejection fraction decreased with sevoflurane only. All anesthetics caused dose-dependent vasodilation, with recovery for desflurane and sevoflurane but not propofol. Heart rate was decreased with propofol without significant recovery. Propofol plasma concentrations remained elevated after dose return to baseline infusion rate, suggestive of distribution compartment saturation. CONCLUSION: All three anesthetics caused dose-dependent decreases in cardiovascular function. Recovery of cardiovascular function occurred rapidly with sevoflurane and desflurane, but persistent depression of contractility, vasodilation, mean arterial pressure, and heart rate occurred with propofol during a 30-min recovery period.


Asunto(s)
Anestésicos Intravenosos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Desflurano , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Isoflurano/análogos & derivados , Éteres Metílicos , Contracción Miocárdica/efectos de los fármacos , Propofol , Conejos , Sevoflurano , Vasoconstricción/fisiología , Vasodilatación/fisiología
17.
Eur J Pharmacol ; 587(1-3): 209-15, 2008 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-18455722

RESUMEN

Phosphoinositide 3-kinase (PI3K) beta has been shown to play a critical role in shear-induced arterial thrombosis. The anti-thrombotic effects of a beta isoform selective PI3K inhibitor, TGX221, were compared to the effects of non-selective PI3K inhibitors (LY294002 and wortmannin) and a PI3K delta inhibitor (IC87114) in the rat. TGX221 (2.5 mg/kg i.v.) abolished cyclic flow reductions in a Folts-like carotid artery stenosis preparation of thrombosis while not changing bleeding time, heart rate, blood pressure or carotid vascular conductance. In contrast, the PI3K non-selective isoform inhibitor, wortmannin (5 mg/kg i.v.) was as effective in abolishing cyclic flow reductions, but caused marked hypotension and carotid vasodilatation. In isolated mesenteric arteries, wortmannin was the most potent relaxant of K+-precontracted vessels (pEC(50)=6.6), while LY294002 and TGX221 were 40-60 fold less potent and IC87114 was without effect. These findings suggest that of the subclass of PI3K isoforms, the beta isoform is critical for the selective development of arterial thrombosis in vivo. The multiple actions of wortmannin are consistent with inhibition of the PI3K-C2alpha and beta isoforms and possibly other actions. Thus, a selective inhibitor of the beta isoform of PI3K offers advantages as a potential therapeutic target for the treatment of thrombosis without unwanted extension of bleeding time or adverse cardiovascular sequelae.


Asunto(s)
Fármacos Cardiovasculares , Inhibidores Enzimáticos/farmacología , Fibrinolíticos/farmacología , Morfolinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirimidinonas/farmacología , Animales , Anticoagulantes/farmacología , Tiempo de Sangría , Presión Sanguínea/efectos de los fármacos , Enoxaparina/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Arterias Mesentéricas/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Estrés Fisiológico/sangre , Especificidad por Sustrato , Resistencia Vascular/efectos de los fármacos
18.
Bioorg Med Chem Lett ; 18(3): 1241-4, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18191398

RESUMEN

A series of selenophene analogues of the thiophene-containing antihypertensives milfasartan and eprosartan were prepared and tested for AT(1) receptor antagonist properties. All four selenophene compounds proved to be potent AT(1) receptor antagonists, with pK(B) estimates indicating that these selenides are at least as effective as the thiophene parent compounds at blocking AT(1) receptor mediated responses. These results reveal that replacement of sulfur with selenium in thiophene-containing sartans does not interfere with sartan activity.


Asunto(s)
Acrilatos/síntesis química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/síntesis química , Antihipertensivos/síntesis química , Imidazoles/síntesis química , Compuestos de Organoselenio/síntesis química , Receptor de Angiotensina Tipo 1/metabolismo , Tiofenos/síntesis química , Acrilatos/química , Acrilatos/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Cricetinae , Femenino , Imidazoles/química , Imidazoles/farmacología , Estructura Molecular , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacocinética , Ovario/citología , Estereoisomerismo , Relación Estructura-Actividad , Azufre/química , Azufre/farmacocinética , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/farmacología
19.
Eur J Med Chem ; 43(3): 513-39, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17582659

RESUMEN

An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB(1) agonists. It is hoped that compounds of this type will have clinical utility in pain control, and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of a series of 1-substituted-indole-3-oxadiazoles as potential CB(1) agonists.


Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Cannabinoides/metabolismo , Indoles/síntesis química , Indoles/farmacología , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Receptor Cannabinoide CB1/agonistas , Analgésicos/química , Analgésicos/metabolismo , Animales , Sitios de Unión , Diseño de Fármacos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Indoles/química , Indoles/metabolismo , Concentración 50 Inhibidora , Ratones , Oxadiazoles/química , Oxadiazoles/metabolismo , Ratas , Receptor Cannabinoide CB1/química , Receptor Cannabinoide CB1/metabolismo , Especificidad por Sustrato
20.
J Clin Invest ; 114(1): 112-20, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15232618

RESUMEN

Angiotensin I-converting enzyme (ACE) inhibitors are thought to lower blood pressure in hypertensive patients, mainly by decreasing angiotensin II (Ang II) formation. Chymase, a human mast cell protease, has recently been proposed to play a role in blood pressure regulation because of its Ang II-forming activity. Here we show that the predominant chymase mRNA species in the mouse aorta are those for types 4 and 5 isoforms, and that both are efficient Ang II-forming enzymes. Evaluation of ACE-dependent and ACE-independent Ang II-forming pathways in mast cell-deficient (Kit(w)/Kit(w-v)) mice and their mast cell-sufficient littermate (MC(+/+)) controls revealed that, in contrast to the latter, Kit(w)/Kit(w-v) mice fail to express chymase mRNAs in the vasculature and have almost no ACE-independent Ang II-forming activity in either isolated blood vessels or homogenates. Moreover, in MC(+/+) but not in Kit(w)/Kit(w-v) mice, a contribution of ACE-independent Ang II generation to blood pressure regulation was evident by a 1.6-fold greater maximal reduction in mean arterial pressure with acute ACE inhibition plus AT(1) receptor blockade than with ACE inhibition alone. Thus, mast cells are the source of the vascular ACE-independent pathway, and the antihypertensive benefit of combining ACE inhibitor therapy with AT(1) receptor antagonist therapy is most likely due to negation of chymase-catalyzed Ang II generation.


Asunto(s)
Angiotensina II/biosíntesis , Presión Sanguínea/fisiología , Serina Endopeptidasas/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Aorta/enzimología , Presión Sanguínea/efectos de los fármacos , Quimasas , Heterocigoto , Homeostasis , Mastocitos/enzimología , Mastocitos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/genética , Receptor de Angiotensina Tipo 1/fisiología , Serina Endopeptidasas/deficiencia , Serina Endopeptidasas/genética
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