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2.
Br J Pharmacol ; 170(6): 1199-209, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23941276

ABSTRACT

BACKGROUND AND PURPOSE: Endothelin (ET)-1 and ET-2 cause potent long-lasting vasoconstrictions by tight binding to smooth muscle ETA receptors. We tested the hypotheses that different mechanisms mediate initiation and maintenance of arterial contractile responses to ET-1 and ET-2 and that this differs among vascular beds. EXPERIMENTAL APPROACH: Segments of rat mesenteric resistance artery (MRA) and basilar artery (BA) were studied in wire myographs with and without functional antagonists. KEY RESULTS: Sensitivity and maximum of MRA contractile responses to ET-1 were not, or only moderately, reduced by stimulation of soluble GC, AC or K(+) -channels and by an inhibitor of receptor-operated ion channels. However, each of these reduced maintenance of ET-1 effects and relaxed ET-1-induced contractions in MRA. A calcium channel antagonist did not alter sensitivity, maximum and maintenance of ET-1 effects, but relaxed ET-1-induced contractions in MRA. A PLC inhibitor prevented contractile responses to ET-1 and ET-2 in MRA and BA, and relaxed ET-1- and ET-2-induced responses in MRA and ET-1 effects in BA. A Rho-kinase inhibitor did not modify sensitivity, maximum and maintenance of responses to both peptides in both arteries but relaxed ET-2, but not ET-1, effects in MRA and ET-1 effects in BA. CONCLUSIONS AND IMPLICATIONS: PLC played a key role in arterial contractile responses to ETs, but ET-1 and ET-2 initiated and maintained vasoconstriction through different mechanisms, and these differed between MRA and BA. Selective functional antagonism may be considered for agonist- and vascular bed selective pharmacotherapy of ET-related diseases.


Subject(s)
Cerebral Arteries/physiology , Endothelin-1/physiology , Endothelin-2/physiology , Mesenteric Arteries/physiology , Type C Phospholipases/physiology , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Animals , Cerebral Arteries/drug effects , Estrenes/pharmacology , Male , Mesenteric Arteries/drug effects , Phosphodiesterase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrrolidinones/pharmacology , Rats , Rats, Inbred WKY , Type C Phospholipases/antagonists & inhibitors , Vasoconstriction/drug effects , Vasoconstriction/physiology , rho-Associated Kinases/antagonists & inhibitors , rho-Associated Kinases/physiology
3.
Life Sci ; 91(13-14): 587-92, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22365954

ABSTRACT

AIMS: The pharmacological profile of the novel putative neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) inhibitor SOL1 was examined. MAIN METHODS: The enzyme inhibitory profile of SOL1 was established in vitro. The pharmacokinetic and pharmacodynamic profile was determined in rodents in vivo. KEY FINDINGS: In vitro, at neutral pH, 10 µM SOL1 inhibited NEP-1, NEP-2, and ECE-1 by 99%, 94% and 75%, respectively. The IC(50)s were 25, 25 and 3200 nmol/L, respectively. In anesthetized rats, SOL1 inhibited blood pressure (BP) responses to big-ET-1 and ET-1(1-31) with ED(50)s of 1.9 and 0.03 mg/kg, corresponding to plasma EC(50)s of 4.6 and 0.1 µmol/L, respectively. Pharmacokinetics of SOL1 were examined after single injections in mice and rats. In these species, the estimated clearance of SOL1 varied between 5 and 9 ml/kg.min and T(1/2) between 20 and 60 min. Steady state kinetics of SOL1 were examined after continuous s.c. infusions of SOL1 for 3 weeks at 50mg/kg.day in DOCA-salt hypertensive rats. This treatment lowered BP by 22 mmHg. Steady state concentrations of SOL1 in plasma were 3.9 µmol/L. In heart, lung, and kidney the concentrations of SOL1 were 0.4, 1.8, and 20.5 µmol/kg, respectively. About 63% of the daily dose was retrieved unaltered in the urine. SIGNIFICANCE: These data indicate that SOL1 is primarily a NEP inhibitor in vitro as well as in vivo. Given the preferential renal accumulation and renal clearance of SOL1 additional ECE-1 inhibition in the kidney may have contributed to its chronic BP lowering effects in the DOCA-salt hypertensive rat model.


Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Benzazepines/pharmacokinetics , Enzyme Inhibitors/pharmacology , Metalloendopeptidases/antagonists & inhibitors , Neprilysin/antagonists & inhibitors , Animals , Benzazepines/administration & dosage , Blood Pressure/drug effects , Desoxycorticosterone/toxicity , Disease Models, Animal , Endothelin-Converting Enzymes , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Hydrogen-Ion Concentration , Hypertension/drug therapy , Inhibitory Concentration 50 , Male , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Rats, Wistar , Sodium Chloride, Dietary/toxicity , Tissue Distribution
4.
Br J Pharmacol ; 166(6): 1833-45, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22324472

ABSTRACT

BACKGROUND AND PURPOSE Endothelin-1 (ET-1) causes long-lasting vasoconstrictions. These can be prevented by ET(A) receptor antagonists but are only poorly reversed by these drugs. We tested the hypothesis that endothelin ET(A) receptors are susceptible to allosteric modulation by endogenous agonists and exogenous ligands. EXPERIMENTAL APPROACH Rat isolated mesenteric resistance arteries were pretreated with capsaicin and studied in wire myographs, in the presence of L-NAME and indomethacin to concentrate on arterial smooth muscle responses. KEY RESULTS Endothelins caused contractions with equal maximum but differing potency (ET-1 = ET-2 > ET-3). ET-1(1-15) neither mimicked nor antagonized these effects in the absence and presence of ET(16-21). 4(Ala) ET-1 (ET(B) agonist) and BQ788 (ET(B) antagonist) were without effects. BQ123 (peptide ET(A) antagonist) reduced the sensitivity and relaxed the contractile responses to endothelins. Both effects depended on the agonist (pK(B): ET-3 = ET-1 > ET-2; % relaxation: ET-3 = ET-2 > ET-1). Also, with PD156707 (non-peptide ET(A) antagonist) agonist-dependence and a discrepancy between preventive and inhibitory effects were observed. The latter was even more marked with bulky analogues of BQ123 and PD156707. CONCLUSIONS AND IMPLICATIONS These findings indicate allosteric modulation of arterial smooth muscle ET(A) receptor function by endogenous agonists and by exogenous endothelin receptor antagonists. This may have consequences for the diagnosis and pharmacotherapy of diseases involving endothelins.


Subject(s)
Mesenteric Arteries/physiology , Muscle, Smooth, Vascular/physiology , Receptor, Endothelin A/physiology , Animals , Binding, Competitive , Carbocyanines/pharmacology , Dioxoles/pharmacology , Endothelin A Receptor Antagonists , Endothelins/pharmacology , Fluorescein-5-isothiocyanate/pharmacology , In Vitro Techniques , Mesenteric Arteries/drug effects , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Peptides, Cyclic/pharmacology , Rats , Receptor, Endothelin A/agonists
5.
Br J Pharmacol ; 166(1): 297-308, 2012 May.
Article in English | MEDLINE | ID: mdl-22074193

ABSTRACT

BACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) has been proposed to relax vascular smooth muscle cells (VSMC) via cAMP and can promote dissociation of endothelin-1 (ET-1) from ET(A) receptors. The latter is not mimicked by other stimuli of adenylate cyclases. Therefore, we evaluated the involvement of G-protein ßγ subunits (Gßγ) in the arterial effects of CGRP receptor stimulation. EXPERIMENTAL APPROACH: To test the hypothesis that instead of α subunits of G-proteins (Gαs), Gßγ mediates the effects of CGRP receptor activation, we used (i) rat isolated mesenteric resistance arteries (MRA), (ii) pharmacological modulators of cyclic nucleotides; and (iii) low molecular weight inhibitors of the functions of Gßγ, gallein and M119. To validate these tools with respect to CGRP receptor function, we performed organ bath studies with rat isolated MRA, radioligand binding on membranes from CHO cells expressing human CGRP receptors and cAMP production assays in rat cultured VSMC. KEY RESULTS: In isolated arteries contracted with K(+) or ET-1, IBMX (PDE inhibitor) increased sodium nitroprusside (SNP)- and isoprenaline (ISO)- but not CGRP-induced relaxations. While fluorescein (negative control) was without effects, gallein increased binding of [(125) I]-CGRP in the absence and presence of GTPγS. Gallein also increased CGRP-induced cAMP production in VSMC. Despite these stimulating effects, gallein and M119 selectively inhibited the relaxing and anti-endothelinergic effects of CGRP in isolated arteries while not altering contractile responses to K(+) or ET-1 or relaxing responses to ISO or SNP. CONCLUSION AND IMPLICATIONS: Activated CGRP receptors induce cyclic nucleotide-independent relaxation of VSMC and terminate arterial effects of ET-1 via Gßγ.


Subject(s)
Calcitonin Gene-Related Peptide/metabolism , GTP-Binding Protein beta Subunits/metabolism , GTP-Binding Protein gamma Subunits/metabolism , Receptors, Calcitonin Gene-Related Peptide/metabolism , 1-Methyl-3-isobutylxanthine/pharmacology , Animals , CHO Cells , Calcitonin Gene-Related Peptide/pharmacology , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Cyclohexanes/pharmacology , Humans , Isoproterenol/pharmacology , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/metabolism , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Nitroprusside/pharmacology , Rats , Rats, Inbred WKY , Vasodilation/drug effects , Xanthenes/pharmacology
6.
Thromb Haemost ; 106(6): 1179-88, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22071958

ABSTRACT

Platelet P2Y12 receptors play an important role in arterial thrombosis by stimulating thrombus growth. Both irreversibly (clopidogrel) and reversibly binding (ticagrelor, AZD6140) P2Y12 antagonists are clinically used for restricted periods, but possible differences in platelet function recovery after drug cessation have not been investigated. We treated WKY rats with a single, high dose of 200 mg/kg clopidogrel or 40 mg/kg ticagrelor. Blood was collected at different time points after treatment. Flow cytometry confirmed full platelet protection against ADP-induced αIIbß3 activation shortly after clopidogrel or ticagrelor treatment. At later time points after clopidogrel treatment, a subpopulation of juvenile platelets appeared that was fully responsive to ADP. Addition of ticagrelor to clopidogrel-treated blood reduced αIIbß3 activation of the unprotected platelets. In contrast, at later time points after ticagrelor treatment, all platelets gradually lost their protection against ADP activation. Perfusion experiments showed abolishment of thrombus formation shortly after clopidogrel or ticagrelor treatment. Thrombus formation on collagen was determined under high shear flow conditions. At later time points, large thrombi formed in the clopidogrel but not in the ticagrelor group, and unprotected, juvenile platelets preferentially incorporated into the formed thrombi. However, platelets from both groups were still similarly reduced in assays of whole blood aggregation. Conclusively, recovery of rat platelet function after ticagrelor differs mechanistically from that after clopidogrel. This difference is masked by conventional platelet aggregation methods, but is revealed by thrombus formation measurement under flow. Juvenile platelets formed at later time points after clopidogrel treatment promoted thrombus formation.


Subject(s)
Adenosine/analogs & derivatives , Blood Platelets/metabolism , Purinergic P2Y Receptor Antagonists/administration & dosage , Thrombosis/drug therapy , Ticlopidine/analogs & derivatives , Adenosine/administration & dosage , Adenosine/adverse effects , Adenosine Diphosphate/metabolism , Animals , Blood Platelets/drug effects , Blood Platelets/pathology , Clopidogrel , Cytoprotection/drug effects , Platelet Activation/drug effects , Protein Binding , Purinergic P2Y Receptor Antagonists/adverse effects , Rats , Rats, Inbred WKY , Thrombosis/metabolism , Thrombosis/pathology , Ticagrelor , Ticlopidine/administration & dosage , Ticlopidine/adverse effects
7.
J Physiol Pharmacol ; 60(1): 119-30, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19439814

ABSTRACT

Among chickens, meat-producing broiler strains are highly prone to develop severe pulmonary hypertension (PH) that is accompanied by endothelial dysfunction in the conduit extrapulmonary arteries. We hypothesized that exposure to chronic prenatal mild hypoxia would accelerate PH and endothelial dysfunction in smaller intrapulmonary arteries from broiler chickens. Fertilized broiler and layer (White Leghorn, WL) eggs were incubated under normoxic or hypoxic conditions. Endothelium-dependent (tested with acetylcholine, ACh ) and -independent (tested with sodium nitroprusside, SNP) relaxations of the caudomedial intrapulmonary artery were studied on fetal day 19 and at 2 weeks post-hatch. The response to acute hypoxia in vitro was also studied in the 2 wk-old vessels. Relaxations induced by ACh and SNP were similar in broiler and layer chickens and were unaffected by chronic mild hypoxia during incubation. However, during in vitro acute hypoxia the broiler arteries showed a markedly enhanced contraction. Chronic prenatal hypoxia did not affect the response of intrapulmonary arteries to acute hypoxia. We conclude that early endothelial dysfunction is not present in the small pulmonary arteries of fast-growing broilers after incubation under normoxic or hypoxic conditions. The higher susceptibility of the broiler pulmonary arteries to acute hypoxia might, at least partially, explain the higher susceptibility to PH.


Subject(s)
Endothelium, Vascular/metabolism , Hypertension, Pulmonary/etiology , Hypoxia , Pulmonary Artery/metabolism , Acetylcholine/pharmacology , Animals , Chick Embryo , Chickens , Disease Models, Animal , Endothelium, Vascular/drug effects , Female , Hypertension, Pulmonary/physiopathology , Nitroprusside/pharmacology , Pulmonary Artery/drug effects , Vasoconstriction , Vasodilation/drug effects
8.
Br J Pharmacol ; 156(8): 1239-47, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19302591

ABSTRACT

BACKGROUND AND PURPOSE: We tested the hypothesis that activated arterial smooth muscle (ASM) stimulates endothelial vasomotor influences via gap junctions and that the significance of this myoendothelial coupling increases with decreasing arterial diameter. EXPERIMENTAL APPROACH: From WKY rats, first-, second-, third- and fourth-order branches of the superior mesenteric artery (MA1, MA2, MA3 and MA4 respectively) were isolated and mounted in wire-myographs to record vasomotor responses to 0.16-20 micromol x L(-1) phenylephrine. KEY RESULTS: Removal of endothelium increased the sensitivity (pEC(50)) to phenylephrine in all arteries. The nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (100 micromol x L(-1)) did not modify pEC(50) to phenylephrine in all denuded arteries, and increased it in intact MA1, MA2 and MA3 to the same extent as denudation. However, in intact MA4, the effect of L-NAME was significantly larger (DeltapEC(50) 0.57 +/- 0.02) than the effect of endothelium removal (DeltapEC(50) 0.20 +/- 0.06). This endothelium-dependent effect of L-NAME in MA4 was inhibited by (i) steroidal and peptidergic uncouplers of gap junctions; (ii) a low concentration of the NO donor sodium nitroprusside; and (iii) by the endothelin-receptor antagonist bosentan. It was also observed during contractions induced by (i) calcium channel activation (BayK 8644, 0.001-1 micromol x L(-1)); (ii) depolarization (10-40 mmol x L(-1) K(+)); and (iii) sympathetic nerve stimulation (0.25-32 Hz). CONCLUSIONS AND IMPLICATIONS: These pharmacological observations indicated feedback control by endothelium of ASM reactivity involving gap junctions and a balance between endothelium-derived NO and endothelin-1. This myoendothelial coupling was most prominent in distal resistance arteries.


Subject(s)
Endothelin-1/metabolism , Endothelium, Vascular/metabolism , Gap Junctions/metabolism , Muscle, Smooth, Vascular/metabolism , Nitric Oxide/metabolism , Paracrine Communication , Vasoconstriction , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Animals , Bosentan , Calcium Channel Agonists/pharmacology , Dose-Response Relationship, Drug , Electric Stimulation , Endothelin Receptor Antagonists , Endothelium, Vascular/drug effects , Enzyme Inhibitors/pharmacology , Gap Junctions/drug effects , Hydroxyeicosatetraenoic Acids/metabolism , In Vitro Techniques , Mesenteric Arteries/metabolism , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/innervation , Myography , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Donors/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolism , Nitroprusside/pharmacology , Paracrine Communication/drug effects , Phenylephrine/pharmacology , Rats , Rats, Inbred WKY , Receptors, Endothelin/metabolism , Sulfonamides/pharmacology , Sympathetic Nervous System/physiology , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology
9.
J Physiol Pharmacol ; 59(1): 55-76, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18441388

ABSTRACT

We tested the hypothesis that endothelium-dependent relaxation in the chicken ductus arteriosus (DA) is developmentally regulated. Isolated DA rings from 15-, 19- and 21-day-old (externally pipped) chicken embryos relaxed to acetylcholine (ACh). This relaxation was unaffected by indomethacin but impaired by endothelium removal, by the NO synthase inhibitor L-NAME, and by the soluble guanylate cyclase inhibitor ODQ, suggesting the involvement of NO. This NO production was confirmed with the fluorescent probe DAF-2DA. The combination of apamin and charybdotoxin with L-NAME produced a further inhibition of ACh-induced relaxation, suggesting the participation of a putative EDHF. In the 21-day DA, the relaxations induced by ACh and sodium nitroprusside (SNP) were markedly reduced and scanning electron microscopy demonstrated an irregular endothelial lining with protrusion and detachment of endothelial cells. The relaxations induced by BAY 41-2272 and 8-Br cGMP were not affected by age. When compared with 5%, lower (0%) and higher (21, 95%) O(2) concentrations impaired ACh-induced relaxation. In summary, we found that ACh induces endothelium-dependent relaxation of the chicken DA and that NO and EDHF are involved in this response. During chicken DA closure, endothelial cells undergo morphologic and functional alterations that result in the lack of endothelium-dependent relaxation.


Subject(s)
Ductus Arteriosus/embryology , Endothelium, Vascular/metabolism , Vasodilation/physiology , Acetylcholine/pharmacology , Animals , Chick Embryo , Ductus Arteriosus/metabolism , Embryonic Development , Endothelium, Vascular/embryology , Fluorescein , Indomethacin/pharmacology , Microscopy, Electron, Scanning , Nitric Oxide/metabolism , Oxygen/metabolism , Vasodilation/drug effects
10.
J Vasc Res ; 45(4): 350-6, 2008.
Article in English | MEDLINE | ID: mdl-18332633

ABSTRACT

The objective of this study was to explore the mechanism responsible for the higher relaxing responses of mesenteric arteries to calcitonin-gene-related peptide (CGRP) in pregnancy. We performed myograph and ligand binding studies to determine the role of matrix metalloproteinase-2 (MMP-2) and CGRP receptor density. MMP activity was manipulated in isolated arteries by exposing them to the blocking effects of doxycycline. Vascular activity of MMP-2 was studied by gelatin zymography, and CGRP receptor density was determined by ligand binding analysis. Compared to nonpregnant rats, CGRP elicited stronger arterial relaxation in pregnant rats. The latter effect was neither accompanied by a change in relaxing responses to direct activation of adenylyl cyclase by forskolin nor by a change in the response to stimulation of G-protein-coupled adrenergic receptors by isoproterenol. Doxycycline did not affect the stronger arterial relaxation in pregnancy in spite of the observed more than threefold higher arterial MMP-2 activity. Density of binding sites for [(125)I]CGRP in arteries from pregnant rats (64 +/- 14 fmol/mg protein) and from virgin rats (54 +/- 5 fmol/mg protein) were comparable. The results of this study provide evidence for increased coupling of CGRP receptors to adenylyl cyclase in early pregnancy.


Subject(s)
Calcitonin Gene-Related Peptide/physiology , Matrix Metalloproteinase 2/physiology , Mesenteric Arteries/physiology , Pregnancy/physiology , Receptors, Calcitonin Gene-Related Peptide/physiology , Vasodilation , Adenylyl Cyclases , Animals , Doxycycline/pharmacology , Female , Rats
11.
Reprod Sci ; 14(8): 771-9, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18089595

ABSTRACT

The objective of this study is to determine whether the vascular response to adrenomedullin is modulated by pregnancy. To this end, the authors study the effect of adrenomedullin on different contractile responses of mesenteric, uterine, renal, and saphenous arteries of 10-day pregnant and nonpregnant rats in myographs. Adrenomedullin inhibited contractile responses induced by electrical field stimulation in only the mesenteric and uterine arteries. This effect was more pronounced during pregnancy than in the nonpregnant state. Adrenomedullin did not modify concentration response curves to noradrenaline. The reduction of contractile responses to 40 mmol/L K(+) by adrenomedullin was similar in arteries of pregnant and nonpregnant rats. However, after incubation with capsaicin, this effect was significantly increased in mesenteric arteries of the pregnant group. The authors conclude that pregnancy is associated with a rise in the prejunctional inhibitory effect of adrenomedullin in some regions of the arterial system.


Subject(s)
Adrenomedullin/pharmacology , Arteries/drug effects , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Animals , Arteries/physiology , Female , In Vitro Techniques , Kidney/blood supply , Mesenteric Arteries/drug effects , Mesenteric Arteries/physiology , Myography , Pregnancy , Rats , Rats, Wistar , Uterus/blood supply , Vasodilation/physiology
12.
J Vasc Res ; 44(2): 87-98, 2007.
Article in English | MEDLINE | ID: mdl-17192719

ABSTRACT

Understanding vascular pathologies requires insight in the structure and function, and, hence, an imaging technique combining subcellular resolution, large penetration depth, and optical sectioning. We evaluated the applicability of two-photon laser-scanning microscopy (TPLSM) in large elastic and small muscular arteries under physiological conditions. Elastic (carotid) and muscular (uterine, mesenteric) arteries of C57BL/6 mice were mounted in a perfusion chamber. TPLSM was used to assess the viability of arteries and to visualize the structural components elastin, collagen, nuclei, and endothelial glycocalyx (EG). Functionality was determined using diameter changes in response to noradrenaline and acetylcholine. Viability and functionality were maintained up to 4 h, enabling the assessment of structure-function relationships. Structural vessel wall components differed between elastic and muscular arteries: size (1.3 vs. 2.1 microm) and density (0.045 vs. 0.57 microm(-2)) of internal elastic lamina fenestrae, smooth muscle cell density (3.50 vs. 1.53 microm(-3)), number of elastic laminae (3 vs. 2), and adventitial collagen structure (tortuous vs. straight). EG in elastic arteries was 4.5 microm thick, covering 66% of the endothelial surface. TPLSM enables visualization and quantification of subcellular structures in vital and functional elastic and muscular murine arteries, allowing unraveling of structure-function relationships in healthy and diseased arteries.


Subject(s)
Carotid Arteries/cytology , Carotid Arteries/physiology , Mesenteric Arteries/cytology , Mesenteric Arteries/physiology , Microscopy, Fluorescence, Multiphoton/methods , Acetylcholine/pharmacology , Animals , Cell Nucleus , Collagen/metabolism , Elasticity , Elastin/metabolism , Female , Glycocalyx/metabolism , Mice , Mice, Inbred C57BL , Microscopy, Fluorescence, Multiphoton/instrumentation , Norepinephrine/pharmacology , Uterus/blood supply , Vasoconstriction/drug effects , Vasoconstriction/physiology , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilation/physiology , Vasodilator Agents/pharmacology
13.
Kidney Int ; 69(5): 864-8, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16518347

ABSTRACT

Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) both exhibit natriuretic activity within the human kidney. Furthermore, they both act partly through activation of the endothelial nitric oxide pathway. Since ET-1 may cause vasodilation and natriuresis via stimulation of the ET-B receptor, the aim of the present study was to investigate whether renal ET-B receptors participate in the renal actions of BNP. In this placebo-controlled, crossover study, we infused BNP (4 pmol/kg/min) or placebo (i.v.) for 1 h, with or without co-infusion of the ET-B receptor antagonist BQ-788 (50 nmol/min) for 15 min on 4 separate days, in 10 healthy subjects (mean age 54+/-6 years.). During infusion, we measured effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) using PAH/inulin clearance. Cardiac output was measured before and after infusion, using echocardiography. Blood pressure and heart rate (HR) were monitored as well. Urine and plasma samples were taken every hour to measure diuresis, natriuresis, cyclic 3',5' guanosine monophosphate, and ET-1 levels. BNP with or without ET-B receptor blockade increased natriuresis and diuresis. In addition, BNP alone increased GFR and filtered load, without changing ERPF. BQ-788 infusion did not affect renal hemodynamics or natriuresis. Neither BNP nor BQ-788 altered cardiac output, blood pressure, and heart rate. In conclusion, the present study shows that selective ET-B receptor blockade has no effect on the BNP-induced natriuresis and glomerular filtration rate.


Subject(s)
Endothelin B Receptor Antagonists , Natriuresis/drug effects , Natriuresis/physiology , Natriuretic Peptide, Brain/pharmacology , Cross-Over Studies , Cyclic GMP/blood , Cyclic GMP/urine , Double-Blind Method , Endothelin-1/blood , Endothelin-1/urine , Female , Hemodynamics/drug effects , Humans , Infusions, Intravenous , Kidney/drug effects , Kidney/physiology , Male , Middle Aged , Natriuretic Peptide, Brain/administration & dosage , Oligopeptides/pharmacology , Piperidines/pharmacology
14.
J Vasc Res ; 41(1): 18-27, 2004.
Article in English | MEDLINE | ID: mdl-14726629

ABSTRACT

Changes in arterial stiffness and structure occur during cardiovascular diseases and can be modified by angiotensin-converting enzyme (ACE) inhibitors. In the present study we investigated the role of membrane-bound ACE (t-ACE) in the regulation of arterial structure and mechanics. Large and small arteries of t-ACE-/- mice were isolated to determine the passive pressure-diameter relationship. We observed that t-ACE-/- mice exhibit a reduced arterial distensibility compared to t-ACE+/+ mice. This reduced arterial distensibility was also observed after 9 weeks of captopril treatment (80 mg/kg/ day). We hypothesized that bradykinin type 2 receptor (BK(2)) stimulation might be involved in the regulation of arterial stiffness. t-ACE-/- and t-ACE+/+ mice were treated with Hoe 140 (1 mg/kg/day) for 14 days. After Hoe 140 treatment, both the structural and mechanical changes observed in the t-ACE-/- carotid artery were abolished. Although Hoe 140 administration increased blood pressure in both groups by approximately 10 mm Hg, the pressure difference between the two groups did not change. Thus, t-ACE is involved in the regulation of arterial distensibility. The changes observed in t-ACE-/- mice are not caused by an altered fetal development. Moreover, it is likely that the regulation of arterial distensibility by ACE involves stimulation of the BK(2) receptor.


Subject(s)
Arteries/physiology , Blood Pressure , Bradykinin/analogs & derivatives , Peptidyl-Dipeptidase A/genetics , Receptor, Bradykinin B2/physiology , Adrenergic beta-Antagonists/pharmacology , Animals , Aorta/physiology , Bradykinin/pharmacology , Bradykinin B2 Receptor Antagonists , Carotid Arteries/physiology , Female , Male , Mesenteric Arteries/physiology , Mice , Mice, Inbred C57BL , Mice, Mutant Strains
15.
J Vasc Res ; 40(6): 531-7, 2003.
Article in English | MEDLINE | ID: mdl-14654717

ABSTRACT

The effects of vitamin K (phylloquinone: K1 and menaquinone-4: MK-4) on vascular calcification and their utilization in the arterial vessel wall were compared in the warfarin-treated rat model for arterial calcification. Warfarin-treated rats were fed diets containing K1, MK-4, or both. Both K1 and MK-4 are cofactors for the endoplasmic reticulum enzyme gamma-glutamyl carboxylase but have a structurally different aliphatic side chain. Despite their similar in vitro cofactor activity we show that MK-4 and not K1 inhibits warfarin-induced arterial calcification. The total hepatic K1 accumulation was threefold higher than that of MK-4, whereas aortic MK-4 was three times that of K1. The utilization of K1 and MK-4 in various tissues was estimated by calculating the ratios between accumulated quinone and epoxide species. K1 and MK-4 were both equally utilized in the liver, but the aorta showed a more efficient utilization of MK-4. Therefore, the observed differences between K1 and MK-4 with respect to inhibition of arterial calcification may be explained by both differences in their tissue bioavailability and cofactor utilization in the reductase/carboxylase reaction. An alternative explanation may come from an as yet hypothetical function of the geranylgeranyl side chain of MK-4, which is a structural analogue of geranylgeranyl pyrophosphate and could interfere with a critical step in the mevalonate pathway.


Subject(s)
Anticoagulants , Calcinosis/prevention & control , Hemostatics/pharmacokinetics , Vitamin K 2/analogs & derivatives , Vitamin K 2/pharmacokinetics , Warfarin , Animals , Antifibrinolytic Agents/pharmacokinetics , Aorta/metabolism , Aorta/pathology , Arteriosclerosis/drug therapy , Arteriosclerosis/pathology , Arteriosclerosis/prevention & control , Calcinosis/drug therapy , Calcinosis/pathology , Drug Therapy, Combination , Epoxy Compounds/metabolism , Liver/metabolism , Male , Rats , Rats, Inbred WKY , Tissue Distribution , Vitamin K 1/pharmacokinetics
16.
J Vasc Res ; 40(4): 344-50, 2003.
Article in English | MEDLINE | ID: mdl-12891003

ABSTRACT

The objective of the present study was to determine the effect of early pregnancy on the sensitivity to, and endogenous production of calcitonin gene-related peptide (CGRP). Contractile responses of arteries of 10-day pregnant and nonpregnant rats were studied in myographs. During contractions induced by 40 mmol/l K(+), exogenous CGRP elicited an approximately 30% stronger relaxation in mesenteric arteries in pregnancy, an effect not seen in renal and uterine arteries. Capsaicin treatment during K(+)-induced contractions caused a persistent potentiation of the contractile response in mesenteric arteries, indicating that K(+) stimulates the endogenous release of CGRP. This potentiation was similar in the pregnant and nonpregnant state (+81 +/- 23% and +82 +/- 23%, respectively), suggesting no effect of pregnancy on the endogenous CGRP release. The latter was paralleled by comparable CGRP content in the arteries of both groups, indicating similar tissue CGRP availability. The results of this study support the concept that early pregnancy is associated with a rise in the vascular sensitivity to CGRP in selected areas of the vascular bed without concomitant increase in the vascular CGRP production and release.


Subject(s)
Calcitonin Gene-Related Peptide/metabolism , Calcitonin Gene-Related Peptide/pharmacology , Mesenteric Arteries/physiology , Pregnancy, Animal/physiology , Vasodilation/drug effects , Vasodilation/physiology , Animals , Female , Immunohistochemistry , Mesenteric Arteries/drug effects , Mesenteric Arteries/innervation , Motor Neurons/metabolism , Neurons, Afferent/metabolism , Potassium/pharmacology , Pregnancy , Rats , Rats, Wistar , Renal Artery/drug effects , Renal Artery/innervation , Renal Artery/physiology , Uterus/blood supply
18.
Am J Physiol Regul Integr Comp Physiol ; 283(2): R331-8, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12121844

ABSTRACT

In the chicken embryo, acute hypoxemia results in cardiovascular responses, including an increased peripheral resistance. We investigated whether local direct effects of decreased oxygen tension might participate in the arterial response to hypoxemia in the chicken embryo. Femoral arteries of chicken embryos were isolated at 0.9 of incubation time, and the effects of acute hypoxia on contraction and relaxation were determined in vitro. While hypoxia reduced contraction induced by high K(+) to a small extent (-21.8 +/- 5.7%), contractile responses to exogenous norepinephrine (NE) were markedly reduced (-51.1 +/- 3.2%) in 80% of the arterial segments. This effect of hypoxia was not altered by removal of the endothelium, inhibition of NO synthase or cyclooxygenase, or by depolarization plus Ca(2+) channel blockade. When arteries were simultaneously exposed to NE and ACh, hypoxia resulted in contraction (+49.8 +/- 9.3%). Also, relaxing responses to ACh were abolished during acute hypoxia, while the vessels became more sensitive to the relaxing effect of the NO donor sodium nitroprusside (pD(2): 5.81 +/- 0.21 vs. 5.31 +/- 0.27). Thus, in chicken embryo femoral arteries, acute hypoxia blunts agonist-induced contraction of the smooth muscle and inhibits stimulated endothelium-derived relaxation factor release. The consequences of this for in vivo fetal hemodynamics during acute hypoxemia depend on the balance between vasomotor influences of circulating catecholamines and those of the endothelium.


Subject(s)
Embryo, Nonmammalian/blood supply , Femoral Artery/physiopathology , Hypoxia/physiopathology , Vasomotor System/physiopathology , Acute Disease , Animals , Biological Factors/physiology , Chick Embryo , Cyclooxygenase Inhibitors/pharmacology , Endothelium, Vascular/physiology , Enzyme Inhibitors/pharmacology , Femoral Artery/embryology , In Vitro Techniques , Nitric Oxide Synthase/antagonists & inhibitors , Vasoconstrictor Agents/pharmacology , Vasodilator Agents/pharmacology , Vasomotor System/drug effects
19.
Am J Physiol Regul Integr Comp Physiol ; 282(4): R1156-63, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11893621

ABSTRACT

In response to an acute hypoxemic insult, the mammalian fetus shows a redistribution of the cardiac output in favor of the heart and brain. Peripheral vasoconstriction contributes to this response and is partly mediated by the release of catecholamines. Two mechanisms of catecholamine release in the fetus are reported: 1) neurogenic sympathetic stimulation and 2) a nonneurogenic mechanism via a direct effect of hypoxemia on chromaffin tissues. In the present study, the effects of sympathetic blockade on plasma catecholamine release and cardiac output distribution in response to acute hypoxemia were studied in the chick embryo at different stages of incubation. Only at the end of the incubation period, sympathetic blockade markedly attenuated the increase in plasma catecholamine concentrations and resulted in a greater fraction of the cardiac output distributed to the carcass. However, these effects did not prevent a significant increase in cardiac output to the brain and heart during acute hypoxemia. These data imply that in the chick embryo the contribution of neurogenic mechanisms to the catecholaminergic response to acute hypoxemia becomes greater by the end of the incubation period.


Subject(s)
Cardiac Output/physiology , Hypoxia/physiopathology , Sympathetic Nervous System/physiology , Acute Disease , Animals , Cardiac Output/drug effects , Chick Embryo , Epinephrine/blood , Ganglionic Blockers/pharmacology , Hexamethonium/pharmacology , Norepinephrine/blood , Sympathetic Nervous System/drug effects
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