Search PubMed⌕ Search

Biomedical subjects

L Edvinsson

Publications and source records attributed to L Edvinsson.

At least 109 records · Page 6Linked to original sources
PubMed1998

Regional variation in appearance of vascular contractile endothelin-B receptors following organ culture.

OBJECTIVE: The aim of this study was to investigate the appearance of contractile endothelin (ET)-B receptors following organ culture in different vascular regions. METHOD: The contractile responses of vascular smooth muscle induced by ET-1 and the selective ETB receptor agonist sarafotoxin 6c (S6c) were investigated in circular segments representing eight vascular regions in the rat (aorta, femoral artery, mesenteric artery, branch of the mesenteric artery, proximal and distal parts of the caudal artery, femoral and mesenteric veins). To allow the ETB receptor to be expressed, the segments were placed in organ culture for 1 to 5 days. Pharmacological characterisation of the ET receptors was performed in mesenteric arterial segments. All contractile responses were measured in percentage of K(+)-induced contraction. RESULTS: ET-1 induced strong concentration-dependent contractions of all fresh (not cultured) segments. S6c had negligible effects on all fresh vessels with the exception of the mesenteric vein, where a small contraction was seen. After 1 day of organ culture all tested segments, with the exception of aorta and the proximal part of the caudal artery, showed concentration-dependent contractile responses to S6c which were further augmented after 5 days of culture. The ET-1-induced responses were only slightly affected by organ culture. Contractions induced by S6c were more enhanced in small arteries and veins than in larger arteries. Furthermore, the S6c-induced response was more pronounced in the mesenteric region as compared to the hindlimb. In fresh mesenteric arterial segments FR139317 (ETA receptor antagonist) and bosentan (ETA/ETB receptor antagonist) but not IRL 2500 (ETB receptor antagonist) shifted the ET-1-induced concentration-response curve in parallel to the right. In contrast, after organ culture the S6c-induced concentration-response curves were shifted parallel to the right in the following potency order: IRL 2500 > bosentan > FR139317. CONCLUSION: During normal conditions, the ETA receptor is the dominating mediator of endothelin-induced contraction in eight different vascular regions. Furthermore, this study indicates that most of the vessels have the ability to develop contractile ETB receptors and that this plasticity differs in vascular regions.

Animals↗
PubMed1998

Innervation of the human middle meningeal artery: immunohistochemistry, ultrastructure, and role of endothelium for vasomotility.

The majority of nerve fibers in the middle meningeal artery and branching arterioles are sympathetic, storing norepinephrine and neuropeptide Y (NPY). A sparse supply of fibers contain acetylcholinesterase activity and immunoreactivity toward vasoactive intestinal peptide (VIP), peptidine histidine methionine (PHM), and calcitonin gene-related peptide (CGRP). Only few substance P and neuropeptide K immunoreactive fibers are noted. Electronmicroscopy shows axons and terminals at the adventitial medial border of the human middle meningeal artery, with a fairly large distance to the smooth muscle cells (>500 nM). Several axon profiles contain vesicles of different types, including putative sensory profiles. The perivascularly stored signal substances, norepinephrine and NPY induced vasoconstrictor. Relaxations were induced by acetylcholine and substance P, and these were significantly reduced in arteries without endothelium, while the responses to norepinephrine, NPY, VIP, PHM, and CGRP were not changed by endothelium removal. Blockade experiments showed that the vasomotor responses to norepinephrine were blocked by prazosin, to NPY by BIBP 3226, acetylcholine by atropin, substance P by RP 67580, and the human alpha-CGRP response by human alpha-CGRP(8-37).

Acetylcholine↗
PubMed1998

Effects of alpha-trinositol on peripheral circulation in diabetic patients with critical limb ischaemia. A pilot study using laser Doppler fluxmetry, transcutaneous oxygen tension measurements and dynamic capillaroscopy.

OBJECTIVES: To evaluate whether alpha-trinositol may have an effect on the microcirculation in patients with diabetes mellitus and critical ischaemia. MATERIAL AND METHODS: Ten patients with previously known diabetes mellitus and with critical limb ischaemia were given alpha-trinositol during a 24 h infusion, resulting in a total dose of 2400 mg. Microcirculation was evaluated by means of laser doppler fluxmetry (LDF), transcutaneous oxygen tension (tcPO2) and dynamic capillaroscopy (CBV). RESULTS: Plasma concentration of alpha-trinositol reached a steady state level after 1 h following the start of the administration. There were no detectable changes in blood pressure or heart rate. Laser Doppler flux increased from 41% to 57.5% and tcPO2 changed from 116 to 91 s in "half time recovery" after occlusion. Capillary blood flow showed an increase in resting velocity from 0.1 to 0.5 mm/s at 24 h. CONCLUSIONS: The infusion of alpha-trinositol did not cause any changes in the haemodynamics in general, but resulted in changes in LDF(rest value), tcO2(half-time recovery) and CBV(rest flow) during or following the infusion suggesting improved microcirculation.

Aged↗
PubMed1998

P2U-receptor mediated endothelium-dependent but nitric oxide-independent vascular relaxation.

1. The dilator effect of extracellular adenosine triphosphate (ATP) has mainly been characterized as a direct effect on smooth muscle or as an endothelium-dependent effect mediated by nitric oxide (NO) or prostaglandins. We tested the hypothesis that endothelium-derived hyperpolarizing factor (EDHF) may also be involved. Dilator effects were studied in vitro by continuous recording of isomeric tension in cylindrical segments of rat blood vessels precontracted by noradrenaline (NA), in the presence of indomethacin (10 microM). 2. By screening different blood vessels in the rat we found that both acetylcholine (ACh) and ATP dilate mesenteric arteries with a resting tone of 1 mN by an endothelium-dependent non-NO mechanism. With an increased resting tone (4 mN) the dilatation was mediated by NO. Thus by varying the resting tension the different dilator mechanisms could be examined. However, in the carotid artery the dilatation was solely mediated by an endothelium-dependent NO mechanism, even at different resting tones (1 and 4 mN). 3. The N-nitro-L-arginine methyl ester (L-NAME)-resistant dilatation to ACh and ATP was further inhibited by the NO-scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), indicating L-NAME insensitive NO-synthesis. 4. In carotid arteries and mesenteric arteries at high resting tones (4 mN) the ATP-dilatation was totally inhibited by endothelium removal or L-NAME (10(-3) M). In mesenteric arteries at low resting tone (1 mN) the ATP, UTP (uridine-triphosphate) and 2-MeSATP (2methylthioATP)-dilatation was totally inhibited by endothelium removal. However, L-NAME in combination with indomethacin attenuated only 5% of the UTP dilatation, 70% of the ATP dilatation but all of the 2-MeSATP-dilatation. The inhibitors of Ca2+-activated K+ channels charybdotoxin (0.5 x 10(-7) M) together with apamin (10(-6) M), and the cytochrome P450 inhibitor, SKF 525A (10(-4) M), each in combination with indomethacin. L-NAME and PTIO (0.5 x 10(-3) M) totally abolished the remaining ATP and UTP-dilatation. This indicates a dilatation mediated by an endothelium-dependent non-NO factor, probably EDHF. 5. Agonist potency (UTP>ATP>>2-MeSATP), indicates that the EDHF-mediated dilatation was stimulated by a P2U-receptor, possibly by a selective pyrimidine-receptor. In contrast, a P2Y-receptor stimulated NO-mediated dilatation (2-MeSATP=ATP>UTP). 6. In conclusion, the dilator effects of ATP and especially UTP can be mediated by an endothelium-dependent non-NO-mediated mechanism, probably EDHF, mediated by a P2U-receptor, possibly a selective pyrimidine-receptor, while NO-mediated dilatation is stimulated mainly by a P2Y1-receptor. Furthermore, the EDHF-dilatation is dependent on the resting tone of the blood vessel.

Acetylcholine↗
PubMed1998

Appearance of contractile endothelin-B receptors in rat mesenteric arterial segments following organ culture.

The aim of this study was to examine how different procedures for organ culture affect the expression of contractile endothelin(ET)-B receptors in a branch of the rat mesenteric artery. In fresh segments, ET-1 and ET-3 induced similar strong contractions, ET-1 being 20-fold more potent, whereas neither of the selective ETB receptor agonists, sarafotoxin 6c (S6c) nor IRL 1620, induced significant contractions. In segments cultured for 1 day, ET-3 was only 3-fold less potent as ET-1, and S6c and IRL 1620 induced concentration-dependent contractions which were about 60% of the ET-1 induced contraction. The maximum contractile response to S6c was not altered in segments cultured with foetal calf serum or in buffer solution, but was reduced to about 20% of the control value when cultured in glucose-free buffer solution. The contraction to S6c was abolished in segments placed in cold (4 degrees C) buffer solution. Removal of the endothelium had no effect on the S6c-induced contractions. Arteries cultured at isometric tension (at 2 mN) for 1 day achieved the same contractile response for ETB agonists as resting segments. Pressurized arteries (60 mmHg) did not constrict to S6c when mounted as a fresh segment but demonstrated a strong contraction after 1 day at this transmural pressure. This study suggests that the appearance of ETB receptor mediated contraction following organ culture is not dependent on specific nutrients, endothelial factors or absence of intrinsic tension, but is a metabolically active process.

Animals↗
PubMed1998

Increased endothelin ETB contractile activity in cultured segments of human temporal artery.

Contractions induced by endothelin-1, endothelin-3 and the selective ETB agonist, sarafotoxin S6c, were studied in segments of human temporal artery. The results in fresh arteries were compared with those obtained after 1 or 4 days in organ culture, and with the specific ETA antagonist FR 139,317, the specific, mixed antagonist bosentan, or the specific ETB antagonist, BQ 788. Sarafotoxin S6c induced no contractile activity in fresh artery segments, but elicited marked contractions after culture. This contraction was only slightly inhibited by FR 139,317, but was abolished by BQ 788. Contractions induced by endothelin-1 were antagonized by FR 139,317 and bosentan, but not by BQ 788. Organ culture did not change the overall pattern, but all concentration-response curves were shifted leftwards. Contractions induced by endothelin-3 were abolished by all antagonists in fresh arteries, but some activity was restored after organ culture. Sensitivity to endothelin-3 was markedly increased. The results suggest a change in endothelin receptors during organ culture, resulting in a marked increase in contractile ETB activity, and possibly some increase in ETA activity. Such changes illustrate the complexity of endothelin responses in this vascular bed.

Azepines↗
PubMed1998

Inhibition of angiotensin II-induced contraction by losartan in human coronary arteries.

The in vitro effects of angiotensin II (Ang II) in human vessels are not well studied. The development of specific Ang II-receptor antagonists has made it possible to delineate more carefully the receptor mechanisms involved. The objective of this study was twofold: to investigate the effect of Ang II on human coronary arteries and to study the effects of angiotensin II type 1 receptor blockade with losartan. The setting was contractile experiments with ring segments of coronary arteries. We observed that Ang II is a vasoconstrictor of human coronary arteries, with a pEC50 value of 9.26 +/- 0.22 and Emax of 68.7 +/- 9.61% of potassium-induced contraction. Losartan (10-100 nM) shifted the concentration-response curve of Ang II to the right, with pEC50 values of 7.64 +/- 0.10 and 7.00 +/- 0.15, respectively (p = 0.001), demonstrating the antagonistic properties of losartan. We also noted a decreased maximal response to Ang II after incubation of losartan, with Emax of 51.1 +/- 7.08% and 41.9 +/- 4.70% (p = 0.05), respectively. In conclusion, this is the first report describing the contractile effect of Ang II and the antagonizing effects of losartan in isolated human coronary arteries.

Angiotensin II↗
PubMed1998

Increased levels of endothelin ETB receptor mRNA in human omental arteries after organ culture: quantification by competitive reverse transcription-polymerase chain reaction.

1. Using competitive reverse transcription-polymerase chain reaction (RT-PCR) and in vitro pharmacology, smooth muscle endothelin ETB receptor expression was studied in segments of human omental artery, fresh and after organ culture for 1 and 5 days. 2. The competitive RT-PCR assay used in the present study uses an internal RNA standard bearing a 69 b.p. deletion in order to control all steps of the reaction, including the RT step. Control experiments showed linearity over five subsequent 1:10 dilutions and a wide range of cycle numbers. The assay was able to quantify subattomolar concentrations in samples under 1 microgram total RNA, making it possible to measure mRNA expression even in small tissue biopsies. 3. In fresh arteries, ETB mRNA levels were 0.19 +/- 0.05 amol/microgram total RNA (range 0.03-0.42 amol/microgram; n = 8). After organ culture, an increase in ETB mRNA levels by 317 +/- 28 and 288 +/- 12% was found at days 1 and 5, compared with fresh arteries, respectively. 4. In vitro pharmacology showed that endothelin (ET)-1 induced a strong and potent contraction in fresh arteries, whereas the selective ETB receptor agonist IRL 1620 failed to induce a significant contraction. The ET-1-induced contraction was not altered in potency or Emax after organ culture for 1 and 5 days. In contrast, IRL 1620 induced a clear contraction after 1 day, which increased further in both Emax and potency after 5 days organ culture. 5. Our results indicate that a massive new transcription of ETB receptor mRNA is induced by organ culture, resulting in functional contractile ETB receptors on the smooth muscle layer.

Arteries↗
PubMed1998

Mechanism of nicotine-induced relaxation in the porcine basilar artery.

The present experiment was designed to examine possible influence of adrenergic nerves on nicotine-induced neurogenic vasodilation in porcine basilar arteries denuded of endothelium. Nicotine and transmural nerve stimulation (TNS) induced relaxation of basilar arteries. Tetrodotoxin (TTX) abolished the relaxation elicited by TNS, but only partially blocked that induced by nicotine. Relaxation induced by both nicotine and TNS was abolished by N-nitro-L-arginine. The N-nitro-L-arginine inhibition of both TNS- and nicotine-induced relaxation was reversed by L-arginine but not by D-arginine. Hexamethonium abolished the relaxation induced by nicotine, but did not affect that elicited by TNS. Relaxation induced by nicotine was diminished by guanethidine, which did not affect the relaxation induced by TNS, suggesting that guanethidine blockade of nicotine-induced relaxation is not due to its local anesthetic effect. Results from histochemical studies indicated that catecholamine fluorescence and NADPH-diaphorase fibers were not appreciably affected by guanethidine. Following incubation with 6-hydroxydopamine for 1 hr, the catecholamine fluorescence fibers in the basilar arteries completely disappeared, although the NADPH-diaphorase fibers were not affected. In these adrenergically denervated arteries, nicotine-induced relaxation was abolished, while the TNS-elicited relaxation was not affected. Furthermore, norepinephrine-induced relaxation in basilar arteries was blocked by N-nitro-L-arginine, but was not affected by N-nitro-D-arginine or hexamethonium. These results suggest that in porcine cerebral arteries nicotine-induced nitric oxide-mediated relaxation is dependent on an intact adrenergic innervation. Nicotine appears to act on nicotinic receptors on the presynaptic adrenergic nerve terminals to release norepinephrine or a related substance, which then stimulates release of nitric oxide from the neighboring nitric oxidergic nerves. The TNS-elicited nitric oxide-mediated relaxation, however, is resulted from direct depolarization of nitric oxidergic nerves.

Animals↗
PubMed1997

Neuropeptide Y Y1 receptor blockade does not alter adrenergic nerve responses of the rat tail artery.

Using the selective neuropeptide Y Y1 receptor antagonist, BIBP3226 [(N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-argininamide], the role of endogenous neuropeptide Y in mediating vasoconstrictor responses to adrenergic nerve stimulation was investigated by recording isometric force from isolated rat tail artery segments. BIBP3226 had no effect on contractile responses to adrenergic nerve stimulation (10 pulses; 0.5-2 Hz), but it completely blocked the enhancement of contraction produced by exogenous neuropeptide Y. When frequency and train length of the transmural nerve stimulation were increased (100 pulses; 1-16 Hz), contractile responses were still unaffected by BIBP3226. A peptidase inhibitor mixture known to increase responses to exogenous neuropeptide Y was added; however, BIBP3226 still did not influence contractile responses to adrenergic nerve stimulation. Thus, contractile responses to adrenergic nerve stimulation in the rat tail artery do not appear to involve the release and postjunctional action of endogenous neuropeptide Y; however, exogenous neuropeptide Y does potentiate these responses by acting on Y1 receptors.

Animals↗
PubMed1997

Cholinergic, nitric oxidergic innervation in cerebral arteries of the cat.

Using immunoperoxidase labeling (IPL) and immunofluorescence labeling (IFL) methods, and each followed by NADPH diaphorase (NADPHd) histochemical staining in the same specimen, colocalization of choline acetyltransferase (ChAT) and NADPHd, indicative of nitric oxide synthase (NOS), in cerebral pial arteries and the sphenopalatine ganglia (SPG) of the cat was examined. In addition, retrograde axonal tracing using true blue was performed to determine if cerebral perivascular nerves containing ChAT and NADPHd originate in the SPG. Consistent results were obtained from IPL and IFL methods, indicating that the middle cerebral artery (MCA) and the circle of Willis received dense ChAT-immunoreactive (I) and NADPHd bundles and fine fibers. Almost all ChAT-I fibers and NADPHd fibers were found to be coincident in the arteries examined. A few fine fibers exhibited only NADPHd staining. In the SPG, approximately half of the ganglionic cells were both ChAT-I and NADPHd positive, while the remaining cells were positively only for NADPHd staining. One week after application of true blue on the middle cerebral arteries (MCA), the fluorescent true blue was found in the ganglionic cells of the SPG. Some of the true blue-positive cells contained both ChAT-immunoreactivity and NADPHd staining. These results provide morphological evidence indicating that all ChAT-I fibers in the MCA and the circle of Willis contain NOS, and that these fibers originate in the SPG, although not all NOS-I ganglionic cells in the SPG send fibers to pial vessels. These results also support the hypothesis that acetylcholine (ACh) and nitric oxide (NO) are synthesized and co-released in the same neurons in cerebral perivascular nerves. Based on the reported findings that NO mediates a major component of neurogenic vasodilation, and that ACh acts as a modulator, the present results demonstrate the presence of a cholinergic, nitric oxidergic innervation in cerebral arteries of the cat.

Animals↗
PubMed1997

Expression of calcitonin gene-related peptide1 receptor mRNA in human trigeminal ganglia and cerebral arteries.

Reverse transcriptase polymerase chain reaction (RT-PCR) using primers for the recently cloned human CGRP1 receptor detected mRNA expression of CGRP1 receptors in trigeminal ganglia and cerebral vessels, obtained at autopsy or during neurosurgical tumor resections. An RT-PCR product of the expected size (339 bp) was seen in cerebral arteries, both in the presence and in the absence of endothelium and in trigeminal ganglia. Sequence analysis of the RT-PCR product of the published sequence showed 100% homology with the human CGRP1 receptor. The presence of the CGRP1 receptor mRNA in human trigeminal ganglia and cerebral blood vessels, indicates the occurrence of both prejunctional (trigeminal) and postjunctional location (blood vessels) of the CGRP1 receptor.

Antisense Elements (Genetics)↗
PubMed1997

Transcriptional regulated plasticity of vascular contractile endothelin ET(B) receptors after organ culture.

The aim of the present study was to investigate the level of regulation of the contractile endothelin ET(B) receptor which appears spontaneously after organ culture of vascular segments. Endothelin-1 elicited a strong contraction while the selective endothelin ET(B) receptor agonist, sarafotoxin 6c, had a negligible effect on fresh ring segments of rat mesenteric artery. After organ culture in serum-free Dulbecco's modified Eagle's medium at 37 degrees C (for 1 or 2 days) the endothelin-1-induced contraction was unchanged, whereas sarafotoxin 6c induced, after 1 day, a marked contraction which was further increased at day 2. The contraction induced by sarafotoxin 6c was significantly attenuated by the transcriptional inhibitor, actinomycin D, or the translational inhibitor, cyclohexamide, while the endothelin-1-induced contraction was much less affected. mRNA for endothelin ET(A) and endothelin ET(B) receptors was present in fresh human omental arteries denuded of endothelium. However, after organ culture, endothelin ET(B) mRNA was more prominent than endothelin ET(A) mRNA. Furthermore, the mRNA for both receptors was decreased after treatment with actinomycin D but not with cyclohexamide. This suggests that the endothelin ET(A) receptor is the dominating contractile receptor in fresh arteries while organ culture induces transcription and subsequent translation of contractile endothelin ET(B) receptors.

Animals↗
PubMed1997

Mechanical properties and effects of sympathetic co-transmitters on human coronary arteries and veins.

Active isometric wall tension was studied at different levels of passive wall tension in isolated circular 2 mm long segments of human epicardial coronary arteries and veins, and maximum active wall tension was calculated to 6.60 mN/ mm for arteries and 0.86 mN/mm for veins. Vasomotor responses to sympathetic co-transmitters were studied at resting tension and after precontraction with U46619. Noradrenaline (NA) and adenosine 5'-triphosphate (ATP) induced strong contractions of veins, whereas relaxant responses dominated in arteries. Isoprenaline potently relaxed all arteries and veins. Prazosin and rauwolscine in a concentration of 10(-7) M both competitively antagonized NA-induced contraction of arteries and veins. For uridine 5'-triphosphate (UTP), relaxant responses were demonstrated in most arteries but only some veins. Neuropeptide Y (NPY) elicited no observable vasomotor responses in either arteries or veins. Mechanical removal of the arterial endothelium did not significantly alter relaxant responses to NA, ATP, UTP or isoprenaline. In conclusion, alpha 1- and alpha 2-adrenoceptors mediating contraction and beta-adrenoceptors mediating relaxation seem to be present in both human epicardial coronary arteries and veins. When applied to isolated epicardial coronary vessels, NA and ATP had a stronger influence on vasomotor tone than NPY and UTP, mediating strong contraction of veins but mainly relaxation of coronary arteries, that was independent of an intact endothelium.

Adult↗
PubMed1997

Attenuation of contractile responses to sympathetic co-transmitters in veins from subjects with essential hypertension.

Neuropeptide Y (NPY), noradrenaline (NA) and ATP are cotransmitters of the sympathetic nervous system and exert vasocontractile effects. The aim of this study was to determine the role of these sympathetic co-transmitters in human hypertension. Subcutaneous vessels from 12 patients with essential hypertension and 12 matched controls were studied in vitro. Vascular contractile responses to NPY, NA, alpha,beta-methylene ATP (alpha,beta-mATP) and potassium were studied in isolated arteries and veins (diameter 0.1-1.1 mm) with intact endothelium. The dilatory effect of acetylcholine was used to test the endothelial function. There was no difference in potency (pD2) or contractile response to NPY, NA or alpha,beta-mATP between hypertensive and control arteries. In veins, however, the contractile response to NPY was significantly reduced in hypertensives and the responses to NA were unchanged. Furthermore, the sensitivity (pD2) to alpha,beta-mATP was significantly reduced in veins from hypertensives. There was no difference in the dilatory response to acetylcholine between the hypertensives and the controls, neither in the arteries nor in the veins, indicating that the observed changes in vascular reactivity to NPY, NA and alpha,beta-mATP were not endothelium-dependent. In conclusion, the postjunctional contractile effect of NPY and sensitivity (pD2) to alpha,beta-mATP, co-transmitters of the peripheral sympathetic nervous system, are attenuated in veins in essential hypertension.

Acetylcholine↗
PubMed1997

Blockade of nitric oxide decreases the renal vasodilatory effect of neuropeptide Y in the insulin-treated diabetic rat.

The effect of 50 days of streptozotocine-induced diabetes mellitus (blood glucose 20 mmol/l) on contraction and relaxation of isolated renal and intrarenal arteries in rats were examined. Strong and similar contractions were induced by potassium (60 mM), 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) in renal and intrarenal arteries in diabetic and control rats. The vasodilatory reactivity, after precontraction with 5-HT, of neuropeptide Y (NPY) was similar to that of acetylcholine (ACh), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and was similar in diabetic and control rats. The relaxing effect of NPY was decreased (40%) only in the diabetic group by blockade of nitric oxide synthase with NG-nitro-L-arginine methyl ester (10(-4) M) and by blockade (50%) of NPY with alpha-trinositol (10(-6) M). In conclusion, the present study showed that diabetes mellitus in the rat is associated with normal vasoconstrictive and vasodilatory capacities. However, the vasodilatory response to NPY was largely eliminated by blockade of nitric oxide synthesis only in the diabetic animals. This indicates that the vasodilatory effect of NPY in diabetes mellitus may be dependent on nitric oxide synthesis.

Animals↗