OBJECTIVETo determine the effect of resveratrol on constrictions of isolated human intrapulmonary arteries and its mechanisms.

METHODSIntrapulmonary arteries (1-1.5 mm in diameter) were dissected and cut into rings (1.8-2.0 mm in length) under microscope, and were then mounted in a Multi Myograph system. The rings were stimulated with 100 nmol/L U46619, 30 nmol/L endothelin-1, or 60 mmol/L KCl to produce sustained contraction of the intrapulmonary arteries, after which resveratrol was applied cumulatively. Endothelium denudation, L-NAME and indomethecin were used to investigate the effect of resveratrol on constrictions of the isolated arteries, suing DMSO as the control.

RESULTSResveratrol induced concentration-dependent relaxations in endothelium-intact rings that contracted in response to stimulations with U46619, ET-1 and KCl, with pD2 of 3.82±0.20, 3.84±0.57, and 3.68±0.27, Emax of (99.58±0.83)%, 100%, and (99.65±0.98)%, respectively. Treatment of the arterial rings with the eNOS inhibitor L-NAME, but not with indomethecin or endothelium denudation, obviously affected the relaxant effects of resveratrol.

CONCLUSIONResveratrol can concentration-dependently produce relaxant effect on human intrapulmonary arteries independent of the endothelium possibly by promoting synthesis and release of NO.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; pharmacology ; Humans ; In Vitro Techniques ; Pulmonary Artery ; drug effects ; Stilbenes ; pharmacology ; Vasoconstriction ; drug effects

BACKGROUND: The goal of our study was to investigate the effects of propofol anesthesia on the pulmonary vascular response to prostacyclin during U46619 precontraction in dogs. METHODS: Eight mongrel dogs were anesthetized and instrumented to measure the left pulmonary vascular pressure-flow relation, by loosely positioning a hydraulic occluder around the right main pulmonary artery and placing an electromagnetic flow probe around the left main pulmonary artery. During slowly occlusion of the right main pulmonary artery, the pressure-flow plots were measured in the left main pulmonary artery in the control and propofol-anesthetized (5.0 mg/kg plus 0.5 mg/kg/min intravenously) states at baseline, after preconstriction with the U46619, and during the cumulative intravenous administration of prostacyclin. RESULTS: Propofol had no effect on the baseline pressure-flow relation versus the control state. A lower (P <0.05) dose of U46619 was necessary to achieve the same degree of preconstriction during propofol anesthesia. The pulmonary vasodilator response to prostacyclin was markedly attenuated (P <0.05) during propofol anesthesia compared to the control state. CONCLUSIONS: These results imply that propofol directly inhibits the pulmonary vasodilatory effects of prostacyclin. However the signal transduction pathway of cyclooxygenase-induced pulmonary vasodilation requires further investigation to determine mechanisms involved.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid* ; Administration, Intravenous ; Anesthesia ; Animals ; Dogs* ; Epoprostenol ; Magnets ; Propofol* ; Pulmonary Artery ; Pulmonary Circulation ; Signal Transduction ; Vasodilation*

BACKGROUND: Prostacyclin administered intravenously has demonstrated intermediate pulmonary specificity and its aerosol form has an even greater pulmonary selectivity. There have been few systematic analyses of the difference in response according to the route of administration and the dose of administration of prostacyclin. So we have compared prostacyclin infusion versus inhalation in various concentrations in an animal model. METHODS: Pulmonary hypertension was induced by continuous intravenous infusion of the vasoconstrictor U46619 and prostacyclin solutions of 10, 50, 100, 200 mcg/ml were inhaled using a jet nebulizer. Prostacyclin infusion was done at a rate of 100, 200, 400 ng/kg/min. RESULTS: With inhalation of 10, 50, 100, 200 mcg/ml prostacyclin, PVR fell to values of 85%, 76%, 64%, 55% of the preinhalation value and SVR fell to values of 94%, 80%, 76%, 64% of the preinhalation value, respectively (p<0.05). PVR/SVR ratios decreased significantly in all inhalation doses (p<0.05). With infusion of prostacyclin at a rate of 100, 200, 400 ng/kg/min, PVR fell to values of 73%, 60%, 50% of the preinfusion value and SVR fell to values of 68%, 54%, 38% of the preinfusion value, respectively (p<0.05). PVR/SVR ratios increased at an infusion rate of 400 ng/kg/min. CONCLUSION: Prostacyclin inhalation did not result in selective pulmonary vasodilation without causing any efects on the systemic vascular bed (absolute pulmonary selectivity). But it did cause more predominant vasodilation on the pulmonary vascular bed (relative pulmonary selectivity). By contrast, prostacyclin infusion caused more predominant vasodilation on the systemic vascular bed, creating the risk of severe systemic hypotension.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; Epoprostenol* ; Hypertension, Pulmonary* ; Hypotension ; Infusions, Intravenous ; Inhalation ; Models, Animal ; Nebulizers and Vaporizers ; Sensitivity and Specificity ; Vasodilation

Hypoxic pulmonary vasoconstriction (HPV) is physiologically important response for preventing mismatching between ventilation and perfusion in lungs. The HPV of isolated pulmonary arteries (HPV-PA) usually require a partial pretone by thromboxane agonist (U46619). Because the HPV of ventilated/perfused lungs (HPV-lung) can be triggered without pretone conditioning, we suspected that a putative tissue factor might be responsible for the pretone of HPV. Here we investigated whether HPV can be also observed in precision-cut lung slices (PCLS) from rats. The HPV in PCLS also required partial contraction by U46619. In addition, K+ channel blockers (4AP and TEA) required U46619-pretone to induce significant contraction of PA in PCLS. In contrast, the airways in PCLS showed reversible contraction in response to the K+ channel blockers without pretone conditioning. Also, the airways showed no hypoxic constriction but a relaxation under the partial pretone by U46619. The airways in PCLS showed reliable, concentration-dependent contraction by metacholine (EC50, ~210 nM). In summary, the HPV in PCLS is more similar to isolated PA than V/P lungs. The metacholine-induced constriction of bronchioles suggested that the PLCS might be also useful for studying airway physiology in situ.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; Animals ; Bronchioles ; Constriction ; Contracts ; Lung ; Perfusion ; Pulmonary Artery ; Rats ; Relaxation ; Thromboplastin ; Thromboxane A2 ; Vasoconstriction ; Ventilation

BACKGREOUND: The ideal drug for treatment of pulmonary hypertension would be a vasodilator which acts preferentially on the pulmonary vascular bed. The aim of this study was to compare the effects of prostaglandin I2 (PGI2) on central hemodynamics and right ventricular function with the more widely used vasodilators, prostaglandin E1 (PGE1) and nitroglycerin (NTG) and to investigate whether PGI2 is more selective to the pulmonary vascular bed compared with PGE1 and NTG in dogs. METHODS: We have used a method for producing sustained pulmonary hypertension in vivo by continuous infusion of U46619 adjusting the infusion rate until a mean pulmonary artery pressure (PAP) exceeded 25 mmHg. And the pulmonary and systemic effects of the three pulmonary vasodilators were compared at doses producing equivalent, lowered approximately 20% of mean arterial pressures (MAP) or mean PAP returned to baseline. RESULTS: After infusion of the three vasodilators, heart rate, cardiac output, and mean PAP/MAP ratio were significantly increased, but there was no statistical significant differences among the three vasodilators. PGI2 and PGE1 significantly increased (worsened) the PVR/SVR ratio, but NTG decreased. However there was no significant difference among the three vasodilators. After infusion of the three vasodilators, the arterial oxygen tension (PaO2), mixed venous oxygen tension (PO2), O2 deliver, and O2 uptake were increased, and shunt ratio (s/t(%)) were significantly decreased, but there were no significant differences among three vasodilators. CONCLUSIONS: PGI2, PGE1, and NTG all decreased both PVR and SVR. None of these vasodilatorswere more selective to the pulmonary vascular bed, myocardial performance, and improved gas exchange.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; Alprostadil* ; Animals ; Arterial Pressure ; Cardiac Output ; Dogs* ; Epoprostenol* ; Heart Rate ; Hemodynamics* ; Hypertension, Pulmonary* ; Nitroglycerin* ; Oxygen ; Pulmonary Artery ; Vasodilator Agents ; Ventricular Function, Right

OBJECTIVETo investigate the reactivity of intrapulmonary arterial rings to vasoactive substances as thromboxane A2 and endothelin-1 in patients with chronic obstructive pulmonary disease (COPD).

METHODSIntrapulmonary arterial rings isolated from patients with normal lung function and COPD were mounted in a Multi Myograph system to determine the reactivity of the intrapulmonary arterial rings to 60 mmol/L KCl, thromboxane A2 analogue U46619 and endothelin-1 before and after preconditioning with the COX synthase inhibitor indomethacin.

RESULTSThe reactivity of intrapulmonary arterial rings to U46619 and endothelin-1 was significantly decreased in patients with COPD. The reactivity to U46619 was dramatically decreased in patients with normal lung function after application of indomethacin.

CONCLUSIONThe reactivity of intrapulmonary arterial rings is significantly decreased in patients with COPD.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; pharmacology ; Aged ; Endothelin-1 ; metabolism ; Female ; Humans ; In Vitro Techniques ; Indomethacin ; pharmacology ; Male ; Middle Aged ; Pulmonary Artery ; metabolism ; Pulmonary Disease, Chronic Obstructive ; metabolism ; Thromboxane A2 ; metabolism

BACKGROUND: Vasoconstrictor-induced reduction in arterial graft diameter can cause significant flow deprivation. The aim of this study was to evaluate the effect of vasodilator pretreatment on vasoconstrictor-induced blood vessel spasm in vitro. MATERIAL AND METHOD: Rabbit brachial arteries (BA) and celiac arteries (CA) were cut into rings (3~4 mm) and suspended with a force displacement transducer (TSD 125C(R), Biopac Inc. USA) in a tissue bath filled with 5 mL modified Krebs solution bubbled with 5% CO2 and 95% O2 at 38degrees C. The rings were contracted with vasoconstrictors, and the developed tension changes were considered control values. The rings were then pretreated with 30micrometer nitroglycerin, nicardipine, verapamil, and papaverine, respectively, for 40 minutes and rinsed with the physiologic buffered salt solution three times every 15 min. The vasoconstrictor-induced tension changes after the previous procedure were considered experimental values. Data are expressed as the percentage tension induced by vasoconstrictors before and after pretreatment with vasodilators. RESULT: Nicardipine depressed vasoconstriction induced by norepinephrine, angiotensin II (AII), and U46619 in both the BA and the CA more significantly than did nitroglycerin (p<0.01) and verapamil (p<0.05). Verapamil depressed vasoconstriction induced by 5-hydroxytryptamine (5HT), AII, and U46619 in the BA and by 5HT in the CA more significantly than did nitroglycerin (p<0.01). CONCLUSION: These findings suggest that both nicardipine and verapamil effectively depressed vasoconstrictor action. Nicardipine is thought to be more effective than verapamil for the prevention of vasoconstrictor action.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; Angiotensin II ; Baths ; Blood Vessels ; Brachial Artery ; Celiac Artery ; Contracts ; Displacement (Psychology) ; Glycosaminoglycans ; Isotonic Solutions ; Nicardipine ; Nitroglycerin ; Norepinephrine ; Papaverine ; Serotonin ; Spasm ; Transducers ; Transplants ; Vasoconstriction ; Vasoconstrictor Agents ; Vasodilator Agents ; Verapamil

BACKGROUND: Milrinone, phosphodiesterase III inhibitor, has been used effectively in patients with right heart failure, especially resulted from pulmonary hypertension. However, milrinone is often used with alpha- and beta-adrenergic receptor agonist to prevent severe systemic vasodilation and unfavorable hypotension. Furthermore, structural and functional vasacular changes are associated with aging and are greatest in the aorta. We evaluated the vasodilatory effects of milrinone and sodium nitroprusside (SNP) on young and old rat aortic rings preconstricted with various catecholamines. METHODS: Aortic rings of young and old rat were placed in 25 ml organ chamber and preconstricted with epinephrine (EPI, 10(-6) M), norepinephrine (NE, 10(-7) M) , phenylephrine 10(-7) M) , and U46619 (10(-8) M). Cummulative dose-responses to milrinone (10(-9)-10(-5) M) and SNP (10(-9)-10(-5) M) were obtained to characterize vasodilatory effects. RESULTS: Relaxation response to milrinone was markedly enhanced in both young and old aortic rings preconstricted with U46619 compared with other vasoconstrictors. The maximal response of the young rat aortic rings preconstricted with NE is significantly reduced, compared with that of EPI. The maximal vasorelaxant response of SNP in young and old aortic rings are nearly identical. CONCLUSIONS: We conclude that combined use of milrinone and epinephrine may be more useful in prevention and treatment of systemic hypotension.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; Adrenergic beta-Agonists ; Aging ; Animals ; Aorta ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Epinephrine ; Heart Failure ; Humans ; Hypertension, Pulmonary ; Hypotension ; Milrinone ; Nitroprusside ; Norepinephrine ; Phenylephrine ; Rats ; Relaxation ; Vasoconstrictor Agents ; Vasodilation

BACKGROUND AND OBJECTIVES: Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play an important role in myocardial protection. We examined the effects of thromboxane A₂ on the regulation of K(ATP) channel activity in single ventricular myocytes. SUBJECTS AND METHODS: Single ventricular myocytes were isolated from the hearts of adult Institute of Cancer Research (ICR) mice by enzymatic digestion. Single channel activity was recorded by excised inside-out and cell-attached patch clamp configurations at -60 mV holding potential during the perfusion of an ATP-free K-5 solution. RESULTS: In the excised inside-out patches, the thromboxane A₂ analog, U46619, decreased the K(ATP) channel activity in a dose-dependent manner; however, the thromboxane A₂ receptor antagonist, SQ29548, did not significantly attenuate the inhibitory effect of U46619. In the cell-attached patches, U46619 inhibited dinitrophenol (DNP)-induced K(ATP) channel activity in a dose-dependent manner, and SQ29548 attenuated the inhibitory effects of U46619 on DNP-induced K(ATP) channel activity. CONCLUSION: Thromboxane A₂ may inhibit K(ATP) channel activity, and may have a harmful effect on ischemic myocardium.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; Adenosine Triphosphate ; Adenosine* ; Adult ; Animals ; Digestion ; Heart ; Humans ; KATP Channels ; Mice* ; Muscle Cells* ; Myocardium ; Perfusion ; Potassium Channels* ; Potassium*

BACKGROUND AND OBJECTIVES: Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play an important role in myocardial protection. We examined the effects of thromboxane A₂ on the regulation of K(ATP) channel activity in single ventricular myocytes. SUBJECTS AND METHODS: Single ventricular myocytes were isolated from the hearts of adult Institute of Cancer Research (ICR) mice by enzymatic digestion. Single channel activity was recorded by excised inside-out and cell-attached patch clamp configurations at -60 mV holding potential during the perfusion of an ATP-free K-5 solution. RESULTS: In the excised inside-out patches, the thromboxane A₂ analog, U46619, decreased the K(ATP) channel activity in a dose-dependent manner; however, the thromboxane A₂ receptor antagonist, SQ29548, did not significantly attenuate the inhibitory effect of U46619. In the cell-attached patches, U46619 inhibited dinitrophenol (DNP)-induced K(ATP) channel activity in a dose-dependent manner, and SQ29548 attenuated the inhibitory effects of U46619 on DNP-induced K(ATP) channel activity. CONCLUSION: Thromboxane A₂ may inhibit K(ATP) channel activity, and may have a harmful effect on ischemic myocardium.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; Adenosine Triphosphate ; Adenosine* ; Adult ; Animals ; Digestion ; Heart ; Humans ; KATP Channels ; Mice* ; Muscle Cells* ; Myocardium ; Perfusion ; Potassium Channels* ; Potassium*