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Biomedical subjects

A P Davenport

Publications and source records attributed to A P Davenport.

At least 19 recordsLinked to original sources
PubMed2006

Characterization of the snake venom ligand [125I]-DNP binding to natriuretic peptide receptor-A in human artery and potent DNP mediated vasodilatation.

BACKGROUND AND PURPOSE: The natriuretic peptides, ANP and BNP, modulate vascular smooth muscle tone in human conduit arteries. Surprisingly, the natriuretic peptide receptor-A (NPR-A) has not been visualized using radioligand binding in these vessels. A new member of this peptide family, Dendroaspis natriuretic peptide (DNP) identified from snake venom, has been proposed to be present in human plasma and endothelial cells. Also, recently a novel radioligand, [(125)I]-DNP, has been characterized as selective for NPR-A in human heart. EXPERIMENTAL APPROACH: Our aims were to investigate expression and function of NPR-A receptors in human mammary artery using [(125)I]-DNP to quantify receptor density, immunocytochemistry to delineate the cellular distribution of the receptor and in vitro pharmacology to compare DNP induced vasodilatation to that of ANP. KEY RESULTS: Saturable, sub-nanomolar affinity [(125)I]-DNP binding was detected to smooth muscle of mammary artery, with receptor density of approximately 2 fmol mg(-1) protein, comparable to that of other vasoactive peptides. NPR-A immunoreactivity was localised to vascular smooth muscle cells and this was confirmed with fluorescence dual labelling. NPR-A expression was not detected in the endothelium. Like ANP, DNP fully reversed the constrictor response to ET-1 in endothelium intact or denuded mammary artery, with comparable nanomolar potencies. CONCLUSIONS AND IMPLICATIONS: This is the first characterization of NPR-A in human mammary artery using [(125)I]-DNP and we provide evidence for the presence of receptor protein on vascular smooth muscle cells, but not endothelial cells. This implies that the observed vasodilatation is predominantly mediated via direct activation of smooth muscle NPR-A.

Adrenomedullin↗
PubMed2006

Endothelin.

In humans, the endothelins (ETs) comprise a family of three 21-amino-acid peptides, ET-1, ET-2 and ET-3. ET-1 is synthesised from a biologically inactive precursor, Big ET-1, by an unusual hydrolysis of the Trp21 -Val22 bond by the endothelin converting enzyme (ECE-1). In humans, there are four isoforms (ECE-1a-d) derived from a single gene by the action of alternative promoters. Structurally, they differ only in the amino acid sequence of the extreme N-terminus. A second enzyme, ECE-2, also exists as four isoforms and differs from ECE-1 in requiring an acidic pH for optimal activity. Human chymase can also cleave Big ET-1 to ET-1, which is cleaved, in turn, to the mature peptide as an alternative pathway. ET-1 is the principal isoform in the human cardiovascular system and remains one of the most potent constrictors of human vessels discovered. ET-1 is unusual in being released from a dual secretory pathway. The peptide is continuously released from vascular endothelial cells by the constitutive pathway, producing intense constriction of the underlying smooth muscle and contributing to the maintenance of endogenous vascular tone. ET-1 is also released from endothelial cell-specific storage granules (Weibel-Palade bodies) in response to external stimuli. ETs mediate their action by activating two G protein-coupled receptor sub-types, ETA and ET(B). Two therapeutic strategies have emerged to oppose the actions of ET-1, namely inhibition of the synthetic enzyme by combined ECE/neutral endopeptidase inhibitors such as SLV306, and receptor antagonists such as bosentan. The ET system is up-regulated in atherosclerosis, and ET antagonists may be of benefit in reducing blood pressure in essential hypertension. Bosentan, the first ET antagonist approved for clinical use, represents a significant new therapeutic strategy in the treatment of pulmonary arterial hypertension (PAH).

Amino Acid Sequence↗
PubMed2003

Maternal dexamethasone increases endothelin-1 sensitivity and endothelin a receptor expression in ovine foetal placental arteries.

Despite National Institutes of Health recommendations to administer antenatal steroids as a single course to women threatening preterm delivery, repeated treatments are often given. We investigated effects of repeated dexamethasone (DM) administered to the ewe on small maternal and foetal placental arteries. We hypothesized that DM would increase responsiveness to endothelin-1 (ET-1) and norepinephrine (NE) and that foetal arteries would react differently to ET-1 and NE compared to maternal arteries. Ewes received three treatments beginning at 103, 110, and 117 days of gestation (dGA). Each treatment consisted of four IM injections of 2mg DM or saline at 12-h intervals. At 119 dGA, in vitro functional studies were performed using Mulvany wire myography and endothelin receptor (ETR) expression was quantified using real-time RTPCR and receptor ligand autoradiography. Foetal placental arteries demonstrated greater maximal contractility to ET-1 and lesser maximal contractility to NE compared to maternal arteries. DM increased the maximal contraction elicited by ET-1 and NE in foetal but not maternal placental arteries. DM also increased the abundance of type-A ETR but not type-B ETR mRNA in foetal but not maternal placental arteries. However, within the whole placentome, DM increased the abundance of type-B ETR and decreased type-A ETR mRNA, which was confirmed by similar changes in ETR binding specifically within the labyrinth region. In summary, repeated DM treatment results in agonist and vascular bed specific responses within the placenta.

Animals↗
PubMed2002

Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography.

BACKGROUND: Atherosclerotic plaque rupture is usually a consequence of inflammatory cell activity within the plaque. Current imaging techniques provide anatomic data but no indication of plaque inflammation. The glucose analogue [18F]-fluorodeoxyglucose (18FDG) can be used to image inflammatory cell activity non-invasively by PET. In this study we tested whether 18FDG-PET imaging can identify inflammation within carotid artery atherosclerotic plaques. METHODS AND RESULTS: Eight patients with symptomatic carotid atherosclerosis were imaged using 18FDG-PET and co-registered CT. Symptomatic carotid plaques were visible in 18FDG-PET images acquired 3 hours post-18FDG injection. The estimated net 18FDG accumulation rate (plaque/integral plasma) in symptomatic lesions was 27% higher than in contralateral asymptomatic lesions. There was no measurable 18FDG uptake into normal carotid arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas of the plaque. CONCLUSIONS: This study demonstrates that atherosclerotic plaque inflammation can be imaged with 18FDG-PET, and that symptomatic, unstable plaques accumulate more 18FDG than asymptomatic lesions.

Aged↗
PubMed2002

Discovery of recently adopted orphan receptors for apelin, urotensin II, and ghrelin identified using novel radioligands and functional role in the human cardiovascular system.

Using novel synthetic radioligands, we have discovered receptors for the recently paired apelin (APJ orphan receptor), ghrelin (GHS orphan receptor), and urotensin II (orphan GPR14) in the human cardiovascular system and determined their anatomical localisation. In addition, we have established functional vasoactive properties for these three peptides as potential vasoconstrictor/vasodilator mediators and provided evidence for alteration of receptor density in cardiovascular disease. We find that receptors for apelin, ghrelin, and urotensin II are widely distributed in human cardiovascular tissue, suggesting perhaps vasoactive roles for these peptides in human vascular physiology and a potential role in pathophysiology. Apelin and urotensin II are potent vasoconstrictors with low efficacy, consistent with their low receptor density. Ghrelin receptor density was increased (approximately three- to fourfold) with atherosclerosis of coronary artery disease and accelerated atherosclerosis of saphenous vein grafts, compared with normal vessels, highlighting a potentially beneficial role for this novel vasodilator peptide in human vascular disease. Our approach has demonstrated one successful strategy for translating genetic information encoding recently paired orphan receptor ligands into discovery of function. This study has the advantage of focussing on the actual disease processes, which allow the more precise identification of novel therapeutic targets.

Amino Acid Sequence↗
PubMed2001

The endothelin system in human saphenous vein graft disease.

Saphenous vein graft stenosis is a significant clinical complication for coronary artery bypass patients. Endothelin-1, a peptide synthesised by vascular endothelial cells, is the most potent known vasoconstrictor and has mitogenic properties. Recent advances in our knowledge of endothelin-1 synthesis and endothelin receptor expression and function in normal and atherosclerotic human saphenous vein imply a role for the peptide in the progression of vein graft failure. Manipulation of the endothelin system, by selective receptor antagonism or inhibition of the specific endothelin-converting enzymes may, therefore, represent a novel therapeutic target for treating vein graft disease.

Animals↗
PubMed2001

Nitric oxide-mediated modulation of the endothelin-1 signalling pathway in the human cardiovascular system.

1. We studied the ability of nitric oxide (NO) to physiologically antagonize endothelin-1 (ET-1) induced constrictions in human internal mammary artery (IMA). We also investigated the hypothesis that NO interacts directly with ET-receptor binding in human heart and aorta. 2. ET-1 potently contracted IMA (EC(50) 6.86 nM, 95% CI: 3.5 - 13.4 nM; n=12). The constrictor response to 10 nM ET-1 was fully reversed by the NO-donor diethylamine NONOate (DEA/NO; EC(50) 2.0 microM, 95% CI: 0.8 - 4.8 microM; n=5). The guanylate cyclase inhibitor ODQ (100 microM) reduced the response to DEA/NO but did not abolish it (E(MAX) 50.9+/-8.5% in the presence of ODQ; 113.0+/-8.4%, control). 3. The increase in cyclic GMP by 30 microM DEA/NO was abolished in the presence of 100 microM ODQ (n=6). 4. In saturation binding experiments the NO-donor Diethyltriamine NONOate (DETA/NO; 1 mM) caused a 90% reduction in maximum binding of [(125)I]-ET-1 in human heart, without affecting the affinity. This reduction in binding was abolished by haemoglobin. Pre-incubating either the radiolabel or the tissue with NO-donors did not reduce binding. A similar effect was observed in aortic smooth muscle. 5. We have shown that DEA/NO is able to reverse ET-1-induced contractions in the human vasculature. The binding studies suggest a direct interaction between NO and the ET receptor or receptor-ligand complex in human ventricular and aortic tissue. NO is released continuously in vivo, thus this apparent modification of ET-receptor binding may provide an additional mechanism by which NO counter-balances the effects of ET.

Adolescent↗
PubMed2001

[(125)I]-(Pyr(1))Apelin-13 is a novel radioligand for localizing the APJ orphan receptor in human and rat tissues with evidence for a vasoconstrictor role in man.

1. We have determined the binding characteristics of [(125)I]-(Pyr(1))Apelin-13, a putative ligand for the APJ orphan receptor in human cardiovascular and rat tissue and investigated the functional properties of (Pyr(1))Apelin-13 in human saphenous vein. 2. The binding of [(125)I]-(Pyr(1))Apelin-13 to sections of human heart tissue was time dependent and rapid at 23 degrees C. Data were fitted to a single site model with an association rate constant (k(obs)) of 0.115 min(-1). [(125)I]-(Pyr(1))Apelin-13 also dissociated from a single site with a dissociation rate constant of 0.0105 min(-1). 3. In saturation binding experiments [(125)I]-(Pyr(1))Apelin-13 bound to human left ventricle with a K(D) value of 0.35+/-0.08 nM, B(max) of 4.3+/-0.9 fmol mg(-1) protein with a Hill slope of 0.97+/-0.04 and to the right atria with a K(D) of 0.33+/-0.09 nM, B(max) of 3.1+/-0.6 fmol mg(-1) protein and a Hill slope of 0.93+/-0.05. 4. [(125)I]-(Pyr(1))Apelin-13 binding sites were localized using autoradiography to human cardiovascular tissue, including coronary artery, aorta and saphenous vein grafts. In rat tissue a high density of receptors were localized to the molecular layer of the rat cerebellum, rat lung, rat heart and low levels in the rat kidney cortex. 2. (Pyr(1))Apelin-13 potently contracted human saphenous vein with a pD(2) value of 8.4+/-0.2 (n=8). The maximum response elicited by the peptide was 22.6+/-6% of 100 mM KCl. 6. We provide the first evidence of APJ receptor expression, relative densities and functional properties of (Pyr(1))Apelin-13 in human cardiovascular tissue.

Adult↗
PubMed2001

Depressor and regionally-selective vasodilator effects of human and rat urotensin II in conscious rats.

The regional haemodynamic effects of rat or human urotensin II (U-II) 3, 30, 300 and 3000 pmol kg(-1), i.v.) were assessed in separate groups of conscious, unrestrained, male, Sprague-Dawley rats (n=8 in each). Rat and human U-II had similar effects. At a dose of 3 pmol kg(-1), neither peptide had any significant action, while at a dose of 30 pmol kg(-1), there was a transient mesenteric vasodilatation (significant only for rat U-II). At doses of 300 and 3000 pmol kg(-1), there were dose-dependent tachycardias, and mesenteric and hindquarters hyperaemic vasodilatations. Thus, in conscious rats, the predominant cardiovascular action of rat and human U-II is vasodilatation. This is in contrast to recent findings with human U-II in non-human primates, but is consistent with effects on human isolated resistance vessels.

Animals↗
PubMed2001

Physiological antagonism of endothelin-1 in human conductance and resistance coronary artery.

The ability of four endogenous vasodilators, nitric oxide (NO; 0.01 - 30 microM), atrial (ANP), brain (BNP) and C-type (CNP) natriuretic peptide (0.1 - 300 nM), to reverse endothelin-1 (ET-1; 10 nM) constrictions in human resistance and conductance coronary arteries (CA) in vitro was investigated. ET-1 (0.1 - 300 nM) constricted resistance CA more potently than conductance CA (P<0.05; EC(50) values 2.98 nM (95% CI: 1.49 - 5.95 nM and 8.58 (4.72 - 15.6 nM) respectively)). The NO-donor diethylamine NONOate fully reversed the ET-1 constriction in conductance CA (E(MAX) 127+/-9.16%), however only partial reversal was observed in resistance CA (E(MAX) 78.8+/-8.13; P<0.05). The soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (100 microM) reduced the maximum response to diethylamine NONOate to 76.9+/-14.4% in conductance CA (P<0.05), but had no effect on resistance CA (E(MAX) 77.2+/-18.4%). There was no difference between responses to ANP in conductance and resistance CA (EC(50) values 4.25 nM (0.84 - 21.4 nM) and 18.4 nM (2.92 - 116 nM), E(MAX) 53.1+/-14.7% and 48.6+/-11.8% respectively). BNP was a more potent vasodilator of conductance than resistance CA. In conductance CA the mean EC(50) value was 2.4 nM (0.74 - 7.75 nM), E(MAX) 54.5+/-14.9%. Concentration-response curves to BNP were incomplete in resistance CA. Concentration-response curves to CNP were incomplete in both conductance and resistance CA. The greater potency of ET-1 in resistance vessels may exacerbate the effects of increased circulating levels of the peptide in disease. Only NO could fully reverse ET-1 mediated constrictions in conductance CA, and none of the dilators tested could completely counteract constrictions in resistance CA.

Adolescent↗
PubMed2001

[125I-His(9)]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis.

1. Ghrelin is the recently identified endogenous ligand for the cloned growth hormone secretagogue receptor (GHS-R). We have characterized for the first time the binding of human [125I-His(9)]-ghrelin to normal human and rat tissue and demonstrated expression of this 'orphan' receptor that has previously been predicted to exist from mRNA. Furthermore, we have discovered that [125I-His(9)]-ghrelin density is significantly increased in atherosclerosis. 2. [125I-His(9)]-Ghrelin bound to non-diseased human heart (left ventricle) with an association rate constant (k(obs)) of 0.16+/-0.004 min(-1), a dissociation rate constant of 0.068+/-0.0005 min(-1) (kinetically derived K(D) of 0.1 nM; n=5 individuals+/-s.e.mean), a K(D) of 0.43+/-0.08 nM and B(max) of 7.8+/-0.9 fmol mg(-1) protein (n=6 individual+/-s.e.mean). 3. Specific [125I-His(9)]-ghrelin binding was to the human vasculature including aorta, coronary, pulmonary, arcuate arteries in the kidney and saphenous veins. In rat tissues, binding sites were also localized to the vasculature in peripheral tissues as well as the granular layer of the cerebellum in the CNS. 4. [125I-His(9)]-Ghrelin binding was significantly up-regulated (3 - 4 fold) in both atherosclerotic coronary arteries and saphenous vein grafts with advanced intimal thickening, compared with normal vessels (P<0.05). 5. Our results suggest that the native receptor for [125I-His(9)]-ghrelin may be widely distributed in the human cardiovascular system. Furthermore, changes in the density of this proposed ghrelin receptor implicates this new transmitter system in the development of atherosclerosis and may therefore represent a novel therapeutic target in the treatment of cardiovascular disease.

Adult↗
PubMed2001

Vasoconstrictor activity of novel endothelin peptide, ET-1(1 - 31), in human mammary and coronary arteries in vitro.

1. The ability of the putative chymase product of big endothelin-1 (big ET-1), ET-1(1 - 31), to constrict isolated endothelium-denuded preparations of human coronary and internal mammary artery was determined. 2. pD2 values in coronary and mammary artery respectively were 8.21+/-0.12 (n=14) and 8.55+/-0.11 (n=12) for ET-1, 6.74+/-0.11 (n=16) and 7.10+/-0.08 (n=16) for ET-1(1 - 31) and 6.92+/-0.10 (n=15) and 7.23+/-0.11 (n=12) for big ET-1. ET-1(1 - 31) was significantly less potent than ET-1 (P<0.001, Student's t-test) and equipotent with big ET-1. 3. Vasoconstrictor responses to 100 - 700 nM ET-1(1 - 31) were significantly (P<0.05, Student's paired t-test) attenuated by the ET(A) antagonist PD156707 (100 nM). 4. There was no effect of the ECE inhibitor PD159790 (30 microM), the ECE/NEP inhibitor phosphoramidon (100 microM) or the serine protease inhibitor chymostatin (100 microM) on ET-1(1 - 31) responses in either artery. 5. Radioimmunoassay detected significant levels of mature ET in the bathing medium of coronary (1.6+/-0.5 nM, n=14) and mammary (2.1+/-0.6 nM, n=14) arteries, suggesting that conversion of ET-1(1 - 31) to ET-1 contributed to the observed vasoconstriction. 6. ET-1(1 - 31) competed for specific [(125)I]-ET-1 binding to ET(A) and ET(B) receptors in human left ventricle with a pooled K(D) of 71.6+/-7.0 nM (n=3). 7. Therefore, in human arteries the novel peptide ET-1(1 - 31) mediated vasoconstriction via activation of the ET(A) receptor. The conversion of ET-1(1 - 31) to ET-1, by an as yet unidentified protease, must contribute wholly or partly to the observed constrictor response. Chymase generated ET-1(1 - 31) may therefore represent an alternative precursor for ET-1 production in the human vasculature.

Adult↗
PubMed2001

Thromboxane receptor density is increased in human cardiovascular disease with evidence for inhibition at therapeutic concentrations by the AT(1) receptor antagonist losartan.

1. The aim of this study was to establish how thromboxane receptors (TP) respond to the increase in levels of plasma thromboxane observed in both cardiac (cardiomyopathy, ischaemic heart disease and pulmonary hypertension) and vascular disease (atherosclerosis of coronary artery disease and accelerated atherosclerosis of saphenous vein grafts). 2. The agonist radioligand [(125)I]-BOP, bound rapidly to TP receptors in normal human cardiovascular tissue, displaying high affinity in left ventricle (K(D) 0.23 +/- 0.06 nM, B(max) 28.4 +/- 5.7 fmol mg(-1) protein) and reversibility with a t(1/2) of 10 min (n = five individuals +/- s.e.mean). 3. In the heart, TP receptor density in the right ventricle of primary pulmonary hypertensive patients were significantly increased (66.6 +/- 6 fmol mg(-1) protein) compared to non-diseased right ventricle (37.9 +/- 4.1 fmol mg(-1) protein, n = six individuals +/- s.e.mean, P<0.05). 4. In diseased vessels, TP receptor densities were significantly increased (3 fold in the intimal layer) in atherosclerotic coronary arteries, saphenous vein grafts with severe intimal thickening (n = 8-12 individuals, P<0.05) and aortic tissue (n=5 - 6 individuals, P<0.05), compared with normal vessels. 5. Losartan, tested at therapeutic doses, competed for [(125)I]-BOP binding to human vascular tissue, suggesting that some of the anti-hypertensive effects of this AT(1) receptor antagonist could also be mediated by blocking human TP receptors. 6. The differential distribution of TP receptors in the human cardiovascular system and the alteration of receptor density, accompanying the increase in endogenous thromboxane levels in cardiovascular disease, suggest that TP receptors represent a significant target for therapeutic interventions and highlights the importance for the development of novel selective antagonist for use in humans.

Adult↗
PubMed2001

Effect of in vivo fetal infusion of dexamethasone at 0.75 GA on fetal ovine resistance artery responses to ET-1.

At 110-111 days gestation, instrumented fetal sheep were administered saline or dexamethasone (2.2 microgram. kg(-1). h(-1) iv) for 48 h. Measurement of fetal blood pressure showed a greater increase in dexamethasone-treated (n = 6) compared with control (n = 5) fetuses (7.3 +/- 2.3 vs. 0.6 +/- 2.3 mmHg, P < 0.05). Fetuses were delivered by cesarean section, and the femoral muscle and brain were obtained under halothane anesthesia. Femoral and middle cerebral arteries (approximately 320-micrometer internal diameter) were evaluated using wire myography. Sensitivity to KCl (2.5-125 mM) and the magnitude of the maximal vasoconstriction to 125 mM K(+) were similar in femoral and middle cerebral arteries from dexamethasone-treated vs. control fetuses. Acetylcholine-induced vasorelaxation was similar in femoral arteries from control and dexamethasone-treated fetuses. Middle cerebral arteries did not relax to acetylcholine. Sensitivity to endothelin-1 (ET-1; 0.1 pM-0.1 microM) and magnitude of the ET-1-induced vasoconstriction were greater in femoral arteries from dexamethasone-treated vs. control fetuses (P < 0.05). Autoradiographical studies with receptor-specific ligands demonstrated increased ET(A)-receptor binding, the principal receptor subtype, in femoral muscle vessels (P < 0.001) but decreased ET(A)-receptor binding in middle cerebral arteries (P < 0.01) from dexamethasone-treated compared with control fetuses. Relatively little ET(B)-receptor binding was evident in all tissues examined. We conclude that hyperreactivity to ET-1, due to increased ET(A)-receptor binding, may be involved in the dexamethasone-induced increase in peripheral vascular resistance in fetal sheep in vivo.

Acetylcholine↗
PubMed2000

Endothelin receptor antagonism in patients with chronic heart failure.

OBJECTIVE: The relative importance of ETA and ETB receptors in mediating the constrictor effects of endogenous endothelin-1 in patients with chronic heart failure is not known. The primary purpose of this study was to compare the acute effects of selective ETA and ETB receptor antagonists in vivo in healthy subjects and patients with chronic heart failure. Our secondary aim was to examine more closely the effect of chronic heart failure on endothelin biosynthesis. METHODS: We studied the effects of BQ-123 (a selective ETA antagonist) and BQ-788 (a selective ETB antagonist) in ten healthy subjects and ten patients with chronic heart failure. Locally active doses of each antagonist were infused into the non-dominant brachial artery for 90 min on separate days at least 1 week apart. Changes in forearm blood flow were measured by venous occlusion plethysmography. Venous blood samples were obtained prior to antagonist infusion for assay of total endothelin, big endothelin-1 and C-terminal fragment immunoreactivity. RESULTS: BQ-123 (100 nmol/min) increased blood flow by 54+/-10% (P<0.001) and 30+/-5% (P<0.001) in controls and heart failure patients, respectively. BQ-788 (1 nmol/min) reduced blood flow by 15+/-5% (P=0. 036) and 9+/-4% (P=0.001) in controls and heart failure patients, respectively. Total endothelin immunoreactivity was non significantly greater in heart failure patients than controls (6. 8+/-1.4 vs. 4.6+/-0.5 pM; P=0.13). Big endothelin-1 (2.6+/-0.4 vs. 1. 7+/-0.1 pM; P=0.04) and C-terminal fragment immunoreactivity (2. 1+/-0.3 vs. 0.6+/-0.1 pM; P<0.0001) were each significantly greater in heart failure patients than controls. CONCLUSIONS: Selective ETA receptor antagonism caused vasodilatation in the peripheral circulation of healthy subjects and patients with chronic heart failure while selective ETB receptor antagonism caused vasoconstriction in each group. ETB receptor antagonism may therefore cause potentially deleterious vasoconstriction in chronic heart failure. Chronic heart failure is associated with a significant increase in plasma big endothelin-1 and C-terminal fragment immunoreactivity.

Case-Control Studies↗
PubMed2000

Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1.

We have determined the distribution of receptors for human urotensin-II (U-II) in human and rat CNS and peripheral tissues. In rat, [(125)I]-U-II binding density was highest in the abducens nucleus of brainstem (139.6+/-14 amol mm(-2)). Moderate levels were detected in dorsal horn of spinal cord and lower levels in aorta (22. 5+/-6 amol mm(-2)). In human tissues density was highest in skeletal muscle and cerebral cortex ( approximately 30 amol mm(-2)), with lower levels (<15 amol mm(-2)) in kidney cortex and left ventricle. Little binding was identified in atria, conducting system of the heart and lung parenchyma. Receptor density was less in human coronary artery smooth muscle (14.6+/-3 amol mm(-2), n=10) than rat aorta with no significant difference between normal and atherosclerotic vessels. In human skeletal muscle [(125)I]-U-II bound to a single receptor population with K(D)=0.24+/-0.17 nM and B(max)=1.97+/-1.1 fmol mg(-1) protein (n=4). U-II contracted human coronary, mammary and radial arteries, saphenous and umbilical veins with sub-nanomolar EC(50) values. U-II was 50 times more potent in arteries and <10 times more potent in veins than endothelin-1 (ET-1). The maximum response to U-II ( approximately 20% of control KCl) was significantly less than to ET-1 ( approximately 80% KCl). In contrast, in rat aorta, U-II and ET-1 were equipotent with similar maximum responses. This is the first report of high affinity receptors for [(125)I]-U-II in human CNS and peripheral tissues. This peptide produces potent, low efficacy, vasoconstriction in human arteries and veins. These data suggest a potential role for U-II in human physiology.

Animals↗
PubMed2000

Syntheses of the first endothelin-A- and -B-selective radioligands for positron emission tomography.

We have synthesized two potential positron emission tomography (PET) radioligands for the endothelin (ET) receptor. [11C]-PD156707 was produced by O-methylation of PD169390 using [11C]iodomethane. Radiochemical conversions of the order of 74 +/- 3.2% (n = 8) were obtained. The radiochemical purity of the isolated [11C]-PD156707 was 99% and the specific activity was 538 mCi/micromol. [18F]-BQ3020 was produced from [18F]fluoride in a total radiochemical yield of 2.7 +/- 0.4% (n = 10) in 238 +/- 5 min. The radiochemical purity was 95% and specific activities of the order of 670-930 mCi/micromol were obtained.

Amino Acid Sequence↗