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Biomedical subjects

L Edvinsson

Publications and source records attributed to L Edvinsson.

At least 163 records · Page 9Linked to original sources
PubMed1995

Selective attenuation of neuropeptide-Y-mediated contractile responses in blood vessels from patients with diabetes mellitus.

Vascular smooth muscle contractile responses to neuropeptide Y, alpha,beta-methyleneATP and noradrenaline were studied in circular segments of isolated vessels with intact endothelium in vitro from 12 patients with diabetes mellitus type 2 (NIDDM) and 12 control subjects. The dilatory effect of acetylcholine was used to test the function of the endothelium. Subcutaneous arteries and veins (diameter 0.1-1.1 mm) were obtained during surgery. There was no difference in contractile responses to noradrenaline or alpha,beta-methyleneATP between diabetic and control vessels. The contractile response to neuropeptide Y, however, was markedly reduced in the diabetic group. The maximal contractile effect (46.0 +/- 14.0%, p < 0.05) but not the sensitivity to neuropeptide Y was significantly less in diabetic veins compared to control (107.5 +/- 19.6%). Thus, the attenuation of neuropeptide Y responses was present in humans as previously observed in alloxan-induced diabetes mellitus in rabbits. There was no difference in the dilator effect of acetylcholine between the diabetic and the control group in any of the vessel types, indicating that the difference in vascular reactivity to neuropeptide Y was not endothelium-dependent. In conclusion, the present study has shown that the postjunctional effects of neuropeptide Y, a co-transmitter of the peripheral sympathetic nervous system, is selectively attenuated in diabetes mellitus.

Acetylcholine↗
PubMed1995

Innervation of human epicardial coronary veins: immunohistochemistry and vasomotility.

OBJECTIVE: The aim was to investigate the innervation and vasomotor responses to classical and putative transmitters of the coronary venous bed. METHODS: The innervation of human epicardial coronary veins was investigated using acetylcholinesterase histochemistry and immunofluorescence staining, together with antisera against the general neuronal marker protein gene product 9.5 (PGP 9.5), the catecholamine synthesising enzyme tyrosine hydroxylase, and neuropeptides [neuropeptide Y, vasoactive intestinal peptide (VIP), substance P, and calcitonin gene related peptide (CGRP)]. The vasomotor responses to noradrenaline, acetylcholine, neuropeptide Y, substance P, human alpha calcitonin gene related peptide (alpha CGRP), and VIP were tested on isolated circular human epicardial coronary vein segments. RESULTS: A network of nerve fibres was shown in the major epicardial coronary veins by means of an antiserum to PGP 9.5. The majority of the perivascular nerve fibres possessed neuropeptide Y and tyrosine hydroxylase immunoreactivity. Only a few nerve fibres displayed substance P, CGRP, and VIP immunoreactivity and acetylcholinesterase activity. Noradrenaline and acetylcholine induced powerful contractions of all the tested segments, whereas no contraction was induced by neuropeptide Y, alpha CGRP, substance P, or VIP. All segments precontracted with U46619 responded with potent relaxation to alpha CGRP, substance P, and VIP, whereas noradrenaline and acetylcholine only in low concentrations induced weak relaxation of a few of the segments. No relaxation was induced by neuropeptide Y. CONCLUSIONS: This is the first study to demonstrate comprehensively the perivascular innervation of human coronary veins and corresponding vasomotor effects, suggesting a role in regulation of the coronary venous circulation.

Acetylcholine↗
PubMed1995

Cardiovascular and renal effects of alpha-trinositol in ischemic heart failure rats.

Previous studies have demonstrated that alpha-trinositol (D-myo-inositol-1.2.6-trisphosphate; PP56) may act as a functional neuropeptide Y (NPY) inhibitor. Because NPY is known to be a potent vasoconstrictor, the effects of alpha-trinositol on renal function, vascular responses and the potentiating effects of NPY were investigated in rats with congestive heart failure (CHF) induced by ligation of the left coronary artery. Incremental doses of alpha-trinositol were given to conscious rats (bolus 2, 4 or 10 mg/kg i.v. followed by a 15-minute infusion 20, 40 and 100 mg/kg/h, respectively). Urinary volume, sodium and potassium excretions were significantly increased in both CHF and sham-operated control animals after alpha-trinositol administration compared with saline. Diuresis and natriuresis were observed also during co-administration of alpha-trinositol with NPY but not with norepinephrine (NE). In the pithed CHF rats, threshold doses of NPY potentiated the pressor effects of endothelin-1 (ET-1) and angiotensin II (AII), but not preganglionic nerve stimulation or phenylephrine administration. Alpha-trinositol antagonized both the pressor response to NPY and the potentiation by NPY of pressor responses to effects of ET-1 and AII. Our data show that alpha-trinositol exhibis diuretic and natriuretic effects as well as vascular antagonistic effects on NPY in normal and CHF rats. These effects of alpha-trinositol may be due to an interaction with NPY mediated antidiuresis and antinatriuresis.

Animals↗
PubMed1995

The peptidergic innervation of the human superficial temporal artery: immunohistochemistry, ultrastructure, and vasomotility.

The peptidergic innervation of the human superficial temporal artery was investigated by means of immunohistochemical, ultrastructural, and in vitro pharmacological techniques. A dense network of nerve fibers was found in the adventitia. The majority of the nerve fibers displayed immunoreactivity for tyrosine hydroxylase and neuropeptide Y (NPY). A moderate supply of perivascular nerve fibers displayed either acetylcholinesterase activity or immunoreactivity for vasoactive intestinal peptide (VIP), peptide histidine methionine-27 (PHM), and calcitonin gene-related peptide (CGRP). Only a few nerve fibers displayed substance P (SP), neurokinin A (NKA), and neuropeptide K (NPK) immunoreactivity. In double immunostained preparations, SP immunoreactivity was co-localized with NPK and CGRP in the same nerve fibers. Ultrastructural studies revealed the presence of numerous axon variocosities at the adventitial--medial border. NPY, VIP, and CGRP immunoreactivities occurred in the same type of large granular vesicles, but in morphological distinct nerve profiles. NPY had, in general, no direct vasoconstrictor effect. However, at a low concentration of NPY contractile response induced by NA (10(-7)-10(-6)M) was 9-15 times enhanced. The NPY-induced potentiation of the NA-induced contraction was not dependent on the presence of an intact endothelium. No significant difference was found between acetylcholine, VIP, and PHM in either potency or degree of relaxation. SP, NKA, and CGRP also acted as vasodilatory agents, with CGRP being more potent than the tachykinins. The response to SP, but not CGRP, was dependent on an intact endothelium. Pretreatment of the vessels with a low concentration of NPY did not change the responses to ACh, VIP, SP, or CGRP.

Acetylcholinesterase↗
PubMed1995

Regional study of the co-localization of neuronal nitric oxide synthase with muscarinic receptors in the rat cerebral cortex.

There is increasing evidence that nitric oxide is an important molecular messenger involved in a wide variety of biological processes including the regulation of the cerebral circulation. For instance, it has been implicated in the vascular response to nucleus basalis magnocellularis stimulation, a structure which is widely recognized as the predominant source of cholinergic fibres projecting to the neocortex. The present investigation was carried out to determine if muscarinic receptors are present on cortical neurons expressing neuronal nitric oxide synthase (nitric oxide-producing enzyme). To this aim, double labelling of both neuronal nitric oxide synthase/vessels and neuronal nitric oxide synthase/muscarinic receptors was performed on free-floating cryosections obtained from rat brain. The observations were made by confocal laser scanning microscopy. The double labelling of neuronal nitric oxide synthase with the arterioles demonstrated the presence of nitroxidergic fibres in the wall of intraparenchymal vessels. A rich network of nitroxidergic fibres independent of the vessels was also seen in the parenchyma. Since the maximal surface of a square of tissue without any nitroxidergic fibres corresponded to 1400 +/- 105 microns2, the distance separating any cortical point from its closest neuronal nitric oxide synthase-positive fibre was never higher than 25 microns (half diagonal of square). According to models of the diffusional spread of nitric oxide, it is likely that nitric oxide can reach the whole cortical volume. Our results on the regional study of neuronal nitric oxide synthase/muscarinic receptors showed a high density of neuronal nitric oxide synthase-positive neurons principally in the frontal and perirhinal cortices and a low density in the occipital cortex. These data fit well with the known pattern of cortical projections from the nucleus basalis magnocellularis as revealed by anterogradely transported markers. The double labelling showed that about 10% of neuronal nitric oxide synthase-positive neurons were co-localized with muscarinic receptors in the frontoparietal cortex. In agreement with previous papers, the vascular innervation by nitroxidergic neuronal processes was often found to lie near the branching points of arterioles. Such localization allows neuronal nitric oxide synthase-positive neurons an extensive control of the vascular tree without requiring a large number of neuronal commands. Therefore, despite the low level of neuronal nitric oxide synthase/muscarinic receptor co-localization, this neuronal subpopulation could represent a possible relay implicated in the vascular effects of the nucleus basalis magnocellularis.

Animals↗
PubMed1995

Neuropeptides in the cerebral circulation: relevance to headache.

The article briefly describe the innervation of the human cerebral circulation by nerve fibers containing neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP). The neuropeptides in human cerebral arteries were characterized by radioimmunoassay in combination with HPLC. These neuropeptides mediate contraction (NPY) and dilation (VIP, SP, CGRP). In conjunction with spontaneous attacks of migraine or cluster headache, release of CGRP is seen. With the associated symptoms of nasal congestion and rhinorrhea, VIP is released. Successful treatment may abort the peptide release in parallel with disappearance of headache.

Cerebral Arteries↗
PubMed1995

Modification of vasoconstrictor responses in cerebral blood vessels by lesioning of the trigeminal nerve: possible involvement of CGRP.

The functional role of the trigeminal system has been addressed in experiments on the cortical surface of alpha-chloralose anaesthetized cats. Application of calcitonin gene-related peptide (CGRP) caused a concentration-dependent increase in arteriolar calibre by 38 +/- 5% (n = 8) with an IC50 of 2 nM. Cerebral veins did not relax upon CGRP administration (n = 12). Substance P (SP) was less potent but showed dilatation of both arterioles (21 +/- 4%) and veins (16 +/- 4%). The cerebrovascular trigeminal system was investigated after chronic (14 days) surgical lesion of the trigeminal nerve with the concomitant disappearance of perivascular CGRP/SP immunoreactive nerves. The cortical arteriolar responses to subarachnoid microinjections of acidic (pH 6.8) and basic CSF (pH 7.6) as well as noradrenaline (10(-4) M), neuropeptide Y (10(-7) M), prostaglandin F2x (10(-6 M), barium chloride (10(-4) M), and autologous blood (5 microl) were examined in anaesthetized cats with lesions of the trigeminal nerve, and were compared with their effects in sham-operated animals. The magnitude of the vasodilator and vasoconstrictor responses to these agents was unaffected by trigeminal lesions. However, duration of the vasoconstriction produced by basic CSF, but not the vasodilitation to acidic CSF, was markedly prolonged by trigeminal lesions (from 0.8 +/- 0.1 min to 2.2 +/- 0.3 min, p < 0.01). Also, the vasoconstrictor responses to noradrenaline, prostaglandin F2x, barium chloride, and autologous blood were significantly prolonged, while the maximum contractile effect to each agent was similar in lesioned as in sham-operated controls. The effects of CGRP, SP, and neurokinin A (NKA) have been examined on isolated cerebral arteries in vitro. Different CGRP analogues induced a strong relaxation with no difference in Imax (85-96%) or pD2 values (8.65 - 9.12). NKA induced a stronger relaxation than SP (Imax: 33% and 13%, respectively). SP was more potent than NKA (pD2:8.7 and 7.7, respectively). Capsaicin, a substance which selectively causes the release of stored sensory neuropeptides (CGRP, SP, NKA), caused in vitro relaxation of precontracted arteries. This relaxation was not affected by the neurokinin blocker spantide, but shifted towards higher capsaicin concentrations by the CGRP antagonist (CGRP 8-37. Thus, in this preparation CGRP rather than a neurokinin (SP/NKA) is responsible for the capsaicin-induced dilatations.

Animals↗
PubMed1995

Calcium antagonistic effects of an angiographic contrast medium in vitro. A comparison of the effects of iohexol with the effects of nifedipine in isolated arteries.

RATIONALE AND OBJECTIVES: Vasodilatation is a well-known side effect of contrast media. Contrast media inhibit the action of vasoconstrictors. The nonionic contrast medium, iohexol, inhibits vasoactive substances to a lesser extent than ionic contrast media. Iohexol inhibited the action of vasoconstrictors in a way that raised suspicion of a calcium antagonistic effect of the medium. The authors test this hypothesis by comparing the inhibitory effect of iohexol with the inhibitory effect of a calcium antagonist (nifedipine). The vasoconstrictors were KCl, which depends on potential-operated calcium channels, and histamine, endothelin-1, and prostaglandin F2 alpha (PGF2 alpha), which depend on receptor-operated calcium channels. METHODS: Segments of rabbit coronary arteries were mounted between two L-shaped prongs in tissue baths containing calcium-free buffer, calcium-free buffer with 10(-8) M nifedipine, or iohexol. One of the vasoconstrictors, KCl, histamine, endothelin-1, or PGF2 alpha, was added to induce a level of activation. Thereafter, increasing concentrations of CaCl2 were added in a stepwise manner, and the contractile responses of the vessel segments were recorded. RESULTS: Addition of CaCl2 caused concentration-dependent vasoconstrictions in the buffer. The effect of adding CaCl2 was inhibited in the buffer with nifedipine and in iohexol when the vessels were activated with histamine, endothelin-1, or PGF2 alpha. When the vessels were activated with the potential-operated calcium channel-dependent vasoconstrictor, KCl, the effect of adding CaCl2 was inhibited in the buffer with nifedipine but not in iohexol. CONCLUSIONS: In vitro, iohexol had the same effect as the calcium antagonist nifedipine on the action of receptor-operated calcium channel-dependent vasoconstrictors. This suggests a calcium antagonistic effect of iohexol on the action of the ROC.

Animals↗
PubMed1995

Effects of some novel D-myo-inositol-phosphate derivatives on binding and sympathetic transmission.

The vascular effects of myo-inositol and a series of D-myo-inositol phosphate derivatives: D-myo inositol-1-monophosphate (Ins[1]P1), D-myo-inositol-2-monophosphate (Ins[2]P1), D-myo-inositol-1, 2-biphosphate (Ins[1,2,6]P2), D-myo-inositol-1,2,6-trisphosphate (Ins[1,2,6]P3, alpha-trinositol; PP56), D-myo-inositol-1,2,5,6-tetraphosphate (Ins[1,2,5,6]P4), and D-myo-inositol-1,2,3,4,5,6-hexa-phosphate (InsP6, phytic acid) were studied in binding assays in rat heart membranes, in vitro in isolated guinea pig basilar artery, and in vivo in pithed rats. In binding assays in rat heart membranes, Ins[1,2,6]P3, Ins[1,2,5,6]P4, and InsP6 displaced the binding of [3H] alpha-trinositol [3H]Ins[1,2,6]P3). In the isolated guinea pig basilar artery, Ins[1,2]P2 and Ins[1,2,6]P3 inhibited the contractile effects of exogenous neuropeptide Y (NPY) in the concentration range of 10(-8)-10(-6) M. In pithed Sprague-Dawley rats, Ins[1,2,6]P3 inhibited the NPY-induced pressor response in the dose range [2 mg/kg (3.8 mumol/kg) combined with an infusion of 20 mg/kg/h (38 mumol/kg/h) for 30 min] in which no inhibitory effects on the pressor responses were elicited by preganglionic nerve stimulation (PNS) or a bolus injection of phenylephrine (Phe). Ins[1,2]P2 had only slight NPY inhibitory effects in vivo. We conclude that selected inositol derivatives may inhibit the vasopressor effects to NPY in vitro and in vivo. In particular, Ins[1,2,6]P3, which most readily inhibited the NPY-induced pressor response in vivo, may represent a new class of synthetic nonpeptide drugs, which may inhibit the vascular effects of NPY without binding to the NPY receptor itself.

Analysis of Variance↗
PubMed1995

Neuropeptide Y (NPY) in the orbital arteries of the rabbit. Immunocytochemistry and vasomotor activity.

The purpose of the present study was to investigate the presence and vascular effects of neuropeptide Y in the rabbit orbital arteries. Neuropeptide Y-containing nerve fibers were demonstrated, using an indirect immunofluorescence method with a neuropeptide Y antiserum raised in goat against porcine neuropeptide Y. Isometric responses in isolated circular segments of the orbital arteries were measured following application of neuropeptide Y, different contracting agonists, and the neuropeptide Y blocker alpha-trinositol. A rich supply of neuropeptide Y-containing nerve fibers was seen around the orbital arteries. Neuropeptide Y (10(-10)-10(-6) M) did not induce any contractions in resting arterial segments. Noradrenaline and histamine evoked concentration dependent constrictions which were potentiated by neuropeptide Y (3 x 10(-7) M). This potentiation was completely blocked by alpha-trinositol (3 x 10(7) M). The contractile effects of endothelin-1, endothelin-3, prostaglandin F2 alpha, and 5-hydroxytryptamine were not modified by neuropeptide Y.

Animals↗
PubMed1995

Relation between cyclic GMP generation and cerebrovascular reactivity: modulation by NPY and alpha-trinositol.

It is considered that cyclic guanosine monophosphate (cGMP) plays a pivotal role in mediating the relaxation of vascular and nonvascular smooth muscles. cGMP steady state levels are regulated by guanylyl cyclase, cGMP phosphodiesterases and its flux from cells. The present study examines the possible relation between cerebrovascular vasodilator agents and generation of cGMP in guinea pig cerebral vessels. Acetylcholine, substance P, nitroglycerine and sodium nitroprusside significantly increased the generation of cGMP. The application of acetylcholine, substance P, nitroglycerine and sodium nitroprusside elicited concentration-dependent relaxation of basilar artery segments. Neuropeptide Y increased the generation of cGMP by 2%-46% of control levels (at 10(-7)-10(-6)M of neuropeptide Y; *P < 0.05). In addition, neuropeptide Y (10(-6)M) induced a transient relaxation of the precontracted guinea pig basilar arteries with endothelium. This transient relaxation was blocked by nitro-L-arginine (10(-4)M). alpha-Trinositol does not alter the formation of cGMP nor the neuropeptide Y-induced relaxation. In the presence of alpha-trinositol neuropeptide Y (10(-7)-10(-6)M) did not significantly elevate the production of cGMP as compared with controls. The rise in cGMP induced by acetylcholine, substance P and nitroglycerine was slightly increased by the addition of neuropeptide Y (3 x 10(-7) M). Acetylcholine and substance P induced an endothelium-dependent relaxation of the precontracted guinea pig basilar arteries, while sodium nitroprusside and nitroglycerine induced an endothelium-independent relaxation. Acetylcholine, substance P and nitroglycerine induced concentration-dependent relaxations of basilar artery, respectively. The relaxation elicited by acetylcholine or substance P, but not nitroglycerine, was markedly attenuated by neuropeptide Y (3 x 10(-7) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

Modulation of vascular contractile responses to alpha 1- and alpha 2-adrenergic and neuropeptide Y receptor stimulation in rats with ischaemic heart failure.

In order to evaluate adaptational changes in vascular function in congestive heart failure (CHF), we studied the contractile responses of isolated arterial and venous blood vessels from rats suffering from CHF induced by coronary artery ligature, resulting in a myocardial infarction. The contractile responses of the basilar, femoral and renal arteries and of the iliac vein were examined in relation to adrenergic and neuropeptide Y (NPY) receptor function by the action of the alpha 1 agonist phenylephrine, the alpha 2 agonist clonidine and NPY. The contractile force was measured (in mN) and in % of K(+)-induced contraction as well as pD2 to each agonist. When stimulated by a 60 mM K(+)-buffer solution, the femoral and renal arteries from CHF rats responded with a stronger contraction (Emax; 9.4 +/- 0.6 and 9.8 +/- 0.6 mN) than the corresponding Sham vessels (Emax; 6.2 +/- 0.7 and 5.6 +/- 0.4 mN respectively, P < 0.001). On the contrary, the iliac vein of CHF responded less to K+ than the Sham iliac vein (Emax 2.5 +/- 0.2 and 3.7 +/- 0.5 mN, P < 0.01). The CHF iliac vein responded with a weaker contraction when stimulated with phenylephrine (Emax 1.9 +/- 0.4 mN) and showed a lower sensitivity (pD2 5.6 +/- 0.1) than the corresponding sham vessel (Emax 5.7 +/- 2.3 mN and pD2 6.3 +/- 0.5, P < 0.05). The CHF renal artery was less sensitive to clonidine (pD2 6.4 +/- 0.6) than the Sham renal artery (pD2 7.2 +/- 0.1, P < 0.05). The results indicate differences between CHF and Sham vessel segments according to both contractile capacity induced by K(+)-depolarization and to agonist induced contractile capacity and sensitivity. The differences are not of general nature but vary according to the vascular bed examined.

Animals↗
PubMed1995

The peptidergic innervation of human coronary and cerebral vessels.

It is now well established that in addition to nerves containing classical transmitters, the mammalian vascular system is also supplied by nerve fibre subpopulations containing several vasoactive peptides. The precise function of these peptides (neuropeptide Y, calcitonin gene-related peptide, vasoactive intestinal polypeptide, somatostatin and the tachykinins) is still unknown, however, their widespread occurrence in perivascular nerves indicates that they are likely candidates for a role in the neurogenic regulation of the vascular system. It has been suggested that they may exert a direct vasomotor action via their own receptors and/or modulate the release and action of other vascular transmitters. Recently, several studies have focused on the supply of nerve fibres storing neuropeptides in the coronary and cerebral vasculature of laboratory animals, however, little is known on the distribution of these putative transmitters in human coronary and cerebral vessels. In this paper, the immunocytochemical evidence that several neuropeptides are localized in subpopulations of afferent and efferent nerve fibres supplying the human coronary and cerebral vasculature is focused.

Autonomic Pathways↗
PubMed1995

Contrast medium-induced vasoconstrictions. An investigation of the vasoconstrictive action of iohexol in isolated rabbit coronary arteries.

Angiographic contrast media (CM) may cause both vasodilatation and vasoconstriction. This study evaluates a contrast medium-induced vasoconstriction that occurs when isolated arteries are exposed directly to a CM. Segments of rabbit coronary arteries were mounted in tissue baths containing buffer solution. During the experiments the buffer solution was exchanged with iohexol iso-osmolar with plasma, which caused a temporary vasoconstriction of the vessel segments. The constriction did not depend on the degree of oxygenation of iohexol. The endothelium was not involved in the vasoconstriction. Prazosin slightly decreased the vasoconstriction and a small part of the constriction might thus depend on liberation of norepinephrine by iohexol. The constriction was totally inhibited by the calcium antagonist nifedipine, while it was augmented by addition of low concentrations of KCl to ihoexol. It is concluded that the otherwise safe CM iohexol causes vasoconstriction in vitro by depolarizing the smooth muscle cells and the nerve terminals in the vessel wall.

Animals↗
PubMed1995

Vasoconstriction of isolated arteries induced by angiographic contrast media. A comparison of ionic and non-ionic contrast media iso-osmolar with plasma.

Angiographic contrast media (CM) may cause both vasodilatation and vasoconstriction, effects that can only be partly be explained by the media's hyperosmolality. The present study describes a CM-induced vasoconstriction of isolated rabbit coronary arteries that depends on chemotoxicity and ion content of the CM. Rings of arteries were mounted in tissue baths and the constrictions induced by different CM were measured. Iotrolan and iodixanol (non-ionic dimers) caused the most powerful constrictions followed by iohexol (non-ionic monomer) and mannitol. Ioxaglate (ionic dimer) and diatrizoate (ionic monomer) caused no or weak constrictions. By comparing these findings with previous studies, it is concluded that non-ionic media cause vasoconstriction due to depolarization of the smooth muscle cells, an effect that for iohexol can be counteracted by addition of 30 mM NaCl. The ionic media seem to cause hyperpolarization of the cells. This difference between non-ionic and ionic CM might be one of the reasons for the lower tendency of non-ionic CM to cause vasodilatation clinically.

Angiography↗
PubMed1995

Effects of the combined ETA and ETB receptor antagonist PD145065 on arteries, arterioles, and veins in the cat hindlimb.

The aim of this study was to describe in quantitative terms the effects of ETA and ETB receptor blockade on vascular tone (resistance) in large-bore arterial resistance vessels (> 25 microns), small arterioles (< 25 microns), and veins in the cat gastrocnemius muscle in vivo. In the muscle vascular bed, the combined ETA and ETB receptor antagonist PD145065 (1 mg/kg/min, intra-arterially) abolished the biphasic vascular responses (dilatation followed by constriction) to both ET-1 (0.4 microgram/kg/min, intra-arterially) and to the selective ETB receptor agonist IRL1620 (3.2 micrograms/kg/min, intra-arterially). In the cat femoral artery and vein in vitro, PD145065 competitively inhibited the contractile responses to both ET-1 and IRL1620. The contractile response to the latter agonist could be evoked only after long-term incubation of the vessels (37 degrees C for 5 days). These results indicate that PD145065 is a potent antagonist at both ETA and ETB receptors in vivo and in vitro. Therefore, this antagonist may prove useful for elucidating the possible physiologic and/or pathophysiologic roles of the endothelins. For example, it was shown that PD145065 had no effect on vascular tone in the resting state, indicating no role for the endothelins in the regulation of basal vascular tone in cat skeletal muscle.

Animals↗
PubMed1995

Upregulation of a non-ETA receptor in human arteries in vitro.

Receptor turnover may be a crucial part in the physiology of endothelin (ET). Incubation of vessel segments could be a possible method to demonstrate this. The aim was to study contractile responses of human omental arteries to different ET agonists at various periods after incubation at 37 degrees C in 5% CO2 and air. The maximum effect (Emax; percentage of contraction to 60 mM K+ buffer solution) and the potency of ET-1 were unaltered (pD2 = 8.82 +/- 0.06). The selective ETB agonist IRL 1620 demonstrated a negligible Emax in nonincubated segments (2.4 +/- 0.9%). After only 1 day of incubation the Emax was 51 +/- 23%, and it reached 114 +/- 53% after 5 days. The pD2 of IRL 1620 was stable throughout the incubation time (7.23 +/- 0.08). ET-3 showed a moderate Emax in nonincubated segments (55 +/- 18%), with a pD2 of 6.68 +/- 0.24. However, subsequent incubation revealed an increase of pD2 to 8.60 +/- 0.20 on the fifth day. The maximum contraction increased to 206 +/- 44%; this is equal to the contraction obtained in paired experiments with ET-1 (215 +/- 18%). These findings indicate modulation of endothelin receptor expression after incubation of vessel segments, and suggest the gradual appearance of a non-ETA receptor.

Aged↗