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Biomedical subjects

L Edvinsson

Publications and source records attributed to L Edvinsson.

At least 19 recordsLinked to original sources

Cutaneous vascular reactivity is reduced in aging and in heart failure: association with inflammation.

In the present study, we have investigated whether changes in vascular reactivity in congestive heart failure (CHF) patients can be detected in the cutaneous microvessels and whether these changes are due to endothelial dysfunction, are affected by increasing age and related to an ongoing inflammation. The responses to local warming and iontophoretically administered endothelium-dependent and -independent vasodilators were investigated in healthy young adults, healthy elderly adults and elderly adults with CHF. The results were correlated with plasma concentrations of vascular risk factors and markers for endothelial dysfunction and inflammation. The vasorelaxant responses were reduced in the elderly groups and were attenuated further in the CHF group. This group also had increases in levels of several markers associated with inflammation, higher blood glucose and homocysteine levels, a lower low-density lipoprotein-cholesterol and a rise in the concentration of von Willebrand factor, indicating a prothrombotic endothelial function. The severity of the heart failure, measured as the plasma level of brain natriuretic peptide, correlated with the intensity of inflammation and to the changes in vascular risk factors and endothelial function. It is concluded that the reactivity of the cutaneous microvessels is reduced with age, and the presence of CHF causes a further impairment. There is endothelial dysfunction in CHF, but it is uncertain to what extent this contributes to the reduced vasodilatory capacity. The inflammatory response appears central for many of the manifestations of the CHF syndrome.

Adult↗

Enhanced vasodilator responses to calcitonin gene-related peptide (CGRP) in subcutaneous arteries in human hypertension.

Isolated segments (1-2 mm) of small subcutaneous arteries (diameter 0.1-0.9 mm) and veins (0.1-1.0 mm) from patients with hypertension (essential n = 13, renovascular n = 6) and controls (n = 17) were examined. The relaxant responses to the sensory transmitters calcitonin gene-related peptide (CGRP) and substance P, and the contractile responses to potassium and noradrenaline were studied. Enhanced dilatory responses (E(max)) but no change in sensitivity (pEC50) were demonstrated in the arteries but not in the veins to CGRP in hypertensives (P < 0.01) as compared with normotensives, and in the hypertensive subgroups (essential hypertension, P < 0.05; renovascular hypertension, P< 0.05). The relaxant responses to substance P were not altered either in arteries or in veins of hypertensives. Furthermore, there were no differences in the contractile responses to 60 mM potassium or to 10 microM noradrenaline between the groups. The results suggest that the enhanced vasodilator response to CGRP in hypertension is an adaptive reaction. The elevated blood pressure may be augmented by vasodilatory activity since different subgroups of hypertensives showed the same results. However, other common characteristics of hypertension (eg, medication, metabolic disturbances) may have also influenced the results.

Aged↗

P2Y receptor-induced EDHF vasodilatation is of primary importance for the regulation of perfusion pressure in the peripheral circulation of the rat.

Extracellular nucleotides have been shown to induce vasodilatation of conductance arteries by release of the endothelium-derived hyperpolarizing factor (EDHF). As small resistance arteries are of greater importance for blood pressure regulation, a whole rat mesenteric arterial bed preparation was used in the present study when evaluating the physiological relevance for EDHF in mediating nucleotide dilatation. Dilatory responses were examined after pre-contraction with noradrenaline in the presence of 10 mM indomethacin. Adenosine-5'-O-thiodiphosphate (ADPbetaS), adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced vasodilatation (pEC50=6.5-7 and E(max)=40-70%), while uridine diphosphate (UDP) was ineffective. Endothelium-derived hyperpolarizing factor was studied in the presence of 0.5 mM Nvarpi-nitro-L-arginine (L-NOARG). ADPbetaS and UTP induced strong and potent EDHF-dilatations, while ATP only had a weak effect (E(max)=25%). After P2X1 receptor desensitization with 10 microM alphabeta-methylene-adenosine triphosphate, the ATP response was significantly increased (E(max)=65%). Putatively, this could be because of simultaneous activation of both endothelial P2Y receptors and P2X1 receptors on smooth muscle cells, which resulted in the release of EDHF and subsequent hyperpolarization, and depolarization, respectively. Nitric oxide (NO) was studied in the presence of 60 mM K+. ADPbetaS, ATP and UTP induced weak NO dilatations, suggesting a minor role for NO as compared with EDHF. In conclusion, extracellular nucleotides stimulate dilatation by activating P2Y(1) and P2Y(2)/P2Y(4) receptors, but not P2Y(6) receptors. The dilatory responses are mediated primarily by EDHF in the peripheral vascular bed.

Animals↗

Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2.

In migraine and other primary headaches there is a strong vascular component. Besides the trigeminovascular components some of the associated symptoms point to the involvement of brain stem regions. The central limb of the trigeminal vascular pathway is its projection to the trigeminal nucleus caudalis (TNC) and to the C1-C2 levels of the spinal cord. The aim of the present study was to demonstrate the occurrence of some neurotransmitters in these regions in man. In both the TNC and in the Rexed's laminae I and II of the dorsal horns at the C1 and C2 levels there were numerous substance P immunoreactive fibres. Fibres containing calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) were moderately dense in number. Fibres containing vasoactive intestinal peptide (VIP) or nitric oxide synthase (NOS) were not seen in the TNC or at the C1 and C2 levels of the spinal cord.

Adult↗

An immunocytochemical investigation of human trigeminal nucleus caudalis: CGRP, substance P and 5-HT1D-receptor immunoreactivities are expressed by trigeminal sensory fibres.

5-HT1D (but not 5-HT1B)-receptor immunoreactivity (i.r.) can be detected on trigeminal fibres within the spinal trigeminal tract of the human brainstem. The present study used immunohistochemical and morphometric techniques to determine the proportions of trigeminal fibres expressing substance P, CGRP or 5-HT1D-receptor immunoreactivities. Co-localization studies between 5-HT1D-receptor and substance P- or CGRP-i.r. were also performed. Brainstem material was obtained with consent (four donors) and the total number of immunoreactive fibres within the trigeminal tract was estimated using random field sampling. A greater proportion of fibres (>1 microm diameter) expressed CGRP-i.r. (80 +/- 6%) compared with substance P-i.r. (46 +/- 7%) or 5-HT1D-receptor-i.r. (25 +/- 1%). 5-HT1D-receptor-i.r. was co-localized on some CGRP- or substance P-i.r. fibres. This suggests that 5-HT1D-receptors can regulate the release of CGRP and substance P and may be relevant to the clinical effectiveness of 5-HT1B/1D-receptor agonists in the treatment of migraine and other cranial pain syndromes.

Calcitonin Gene-Related Peptide↗

Expression of ET(A) and ET(B) receptor mRNA in human cerebral arteries.

The vascular effects of endothelins (ET) are in mammals mediated via two receptor subtypes, endothelin A (ET(A), mainly constrictive) and endothelin B (ET(B), mainly dilating) receptors. We have examined the presence of ET(A) and ET(B) receptor mRNA using the reverse transcription polymerase chain reaction (RT-PCR) in both normal human cerebral arteries and cerebral arteries from patients with cerebrovascular disease. Two vessel preparations were studied: macroscopic arteries and microvessels, the latter obtained through a sensitive separation method. In endothelial cells both ET(A) and ET(B) receptor mRNA was detected. In almost all samples from normal cerebral arteries only ET(A) receptor mRNA was detected, whereas in vessel samples from patients with cerebrovascular disease as well as cerebral neoplasms, additional ET(B) receptor mRNA was detected significantly more frequently. The pathophysiological significance of this difference is at present speculative, but does point to a vascular involvement of this receptor in cerebrovascular disease.

Adolescent↗

Adenosine A1 receptor agonists inhibit trigeminovascular nociceptive transmission.

There is a considerable literature to suggest that adenosine A1 receptor agonists may have anti-nociceptive effects, and we sought to explore the role of adenosine A1 receptors in a model of trigeminovascular nociceptive transmission. Cats were anaesthetized (alpha-chloralose 60 mg/kg, intraperitoneally), and prepared for physiological monitoring. The superior sagittal sinus (SSS) was stimulated electrically, and linked units were recorded in the trigeminocervical complex. Post-stimulus histograms were constructed to analyse the responses and the effect of drug administration. Blood was sampled from the external jugular vein to determine levels of calcitonin gene-related peptide (CGRP) release before and after drug administration. Intravenous administration of the highly selective adenosine A1 receptor agonist, GR79236 (3-100 microg/kg) had a dose-dependent inhibitory effect on SSS-evoked trigeminal activity. The maximal effect (80 +/- 6% reduction in probability of firing) was seen at 100 microg/kg. The neuronal inhibitory effect of GR79236 could be inhibited by the selective adenosine A1 receptor antagonist DPCPX (300 microg/kg; P < 0.05). SSS stimulation increased cranial CGRP levels from 33 +/- 2 pmol/l (n = 6) to 64 +/- 3 pmol/l, an effect substantially reduced by pre-treatment with GR79236 (30 microg/kg; P < 0.01). The selective low efficacy adenosine A1 receptor agonist, GR190178 (30-1000 microg/kg i.v.), also inhibited SSS-evoked neuronal activity in a dose-dependent fashion. In this model of trigeminovascular nociception, adenosine A1 receptor activation leads to neuronal inhibition without concomitant vasoconstriction, suggesting a novel avenue for the treatment of migraine and cluster headache.

Adenosine↗

In depth pharmacological characterization of endothelin B receptors in the rat middle cerebral artery.

Whereas the endothelin A receptor is generally believed to mediate vasoconstriction; the endothelin B receptor seems elusive; both dilative and constrictive responses have been reported. Using the in vitro arteriograph, a method allowing compartmentalized study of vessel segments, segments of rat middle cerebral artery were cannulated with micropipettes, pressurized and luminally perfused. Vessel diameters were evaluated using a microscope equipped with an imaging system. Both intra- and extraluminal applications of endothelin-1 produced constriction. Intraluminal administration of a selective endothelin B receptor agonist sarafotoxin 6c in precontracted cerebral arteries and in the presence of the endothelin A receptor blocker FR139317 caused vasodilation in a concentration-dependent manner. Inhibition of nitric oxide synthase significantly reduced the dilation induced by sarafotoxin 6c, whereas inhibition of cyclooxygenase and endothelium-derived hyperpolarizing factor did not.

Animals↗

[Both neurogenic and vascular causes of primary headache].

The cerebral circulation is innervated by sympathetic, parasympathetic and sensory nerves which store a number of neurotransmitters. The significance of these for primary headache has been evaluated. A clear association between head pain and the release of calcitonin gene-related peptide (CGRP) was demonstrated. In cluster headache and in chronic paroxysmal hemicrania, there was additionally a release of vasoactive intestinal peptide (VIP) in association with facial symptoms (nasal congestion, rhinorrhea). Upon treatment with sumatriptan, head pain subsided and neuropeptide release normalized. These data show the involvement of sensory and parasympathetic mechanisms in the pathophysiology of primary headache.

Calcium Channels↗

5-HT(1B) and 5-HT(1D) receptors in the human trigeminal ganglion: co-localization with calcitonin gene-related peptide, substance P and nitric oxide synthase.

5-Hydroxytryptamine (5-HT) is implicated in migraine and agonist directed against 5-HT(1B) and 5-HT(1D) receptors are commonly used as effective therapies. The antimigraine mechanisms involve the inhibition of intracranial sensory neuropeptide release. In order to determine which 5-HT(1) receptor subtypes are involved we have by immunocytochemistry examined the distribution of 5-HT(1B) and 5-HT(1D) receptors in the human trigeminal ganglia, and addressed which of them colocalize with calcitonin gene-related peptide (CGRP), substance P (SP) or nitric oxide synthase (NOS). We detected that 5-HT(1D) receptor immunoreactivity (i.r.) was predominantly expressed in medium-sized cells (86% of positive cells, 30-60 microm). About 9% of the 5-HT(1D) receptor i.r. cells were large in size (> 60 microm) and 5% were small in size (< 30 microm). In a similar pattern, 5-HT(1B) receptor i.r. was mainly expressed in medium-sized cells (81% in 30-60 microm, 15% in > 60 microm and 4% in < 30 microm). Double immunostaining was used to determine whether the 5-HT(1B) or 5-HT(1D) receptor immunoreactive cells co-localized with either CGRP, SP or NOS. Thus, 89% of the CGRP i.r. cells expressed 5-HT(1D) receptor i.r. and 65% of the CGRP positive cells were 5-HT(1B) receptor positive. Most of the 5-HT(1D) (95%) and the 5-HT(1B) (94%) receptor i.r. cells showed SP immunostaining and 83% of 5-HT(1D) receptor and 86% of 5-HT(1B) receptor i.r. cells contained NOS. In conclusion, both 5-HT(1B) and 5-HT(1D) receptors are expressed in the human trigeminal ganglion and they are mainly localized in medium-sized cells and they seem to colocalize with CGRP, SP and NOS.

Aged↗

Selective up-regulation of 5-HT(1B/1D) receptors during organ culture of cerebral arteries.

5-Hydroxytryptamine (5-HT) is thought to be involved in migraine headache and the pathophysiology of cerebrovascular diseases. Previous data show that organ culture induces a phenotypic change in cerebral vessels. Therefore we investigated if these changes also applied for the vasoconstrictive 5-HT receptors. Rat cerebral arteries express 5-HT2 receptors. Using organ culture we observed a phenotypic change with a selective up-regulation of 5-HT(1B/1D) receptors. This was revealed by an increased sensitivity to the selective 5-HT(1B/1D) agonist 5-CT after organ culture (pEC50(fresh) 5.6+/-0.2 and pEC50(cultured) 6.8+/-0.4). The response was inhibited by the 5-HT(1B/1D) selective antagonist GR55562 (pEC50(fresh) 5.1+/-0.2 and pEC50(cultured) 6.0+/-0.3). The organ model might mimic the phenotypic changes during cerebrovascular diseases.

Animals↗

The role of cGMP hydrolysing phosphodiesterases 1 and 5 in cerebral artery dilatation.

The aim was to investigate the presence and activity of cGMP hydrolysing phosphodiesterases in guinea pig basilar arteries and the effect of selective and non-selective phosphodiesterase inhibitors on cerebral artery dilatation involving the nitric oxide (NO)-guanosine cyclic 3'5-monophosphate (cGMP) pathway. Immunoreactivity to phosphodiesterases 1A, 1B and 5, but not phosphodiesterase 1C was found in fractions of homogenised cerebral arteries eluted by high-pressure liquid chromatography (HPLC). Both the phosphodiesterase 1 inhibitor 8-methoxymethyl-1-methyl-3-(2methylpropyl)-xanthine (8-MM-IBMX) and the phosphodiesterase 5 inhibitors zaprinast and dipyridamole induced dilatation of cerebral arteries. The dilatory response to 8-MM-IBMX was reduced by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 microM) and endothelial removal and restored by sodium nitroprusside (0.1 microM) pretreatment, indicating a close relation to the nitric oxide-cGMP pathway. The responses to zaprinast and dipyridamole, however, were not only moderately affected, but also restored by sodium nitroprusside (0.1 microM) pretreatment. At high concentrations, the dilatory effects of zaprinast and dipyridamole were partly caused by cGMP-independent mechanisms. Targeting the phosphodiesterases present in cerebral arteries, with selective inhibitors or activators of phosphodiesterase, may be a possible new way of treating cerebrovascular disease.

1-Methyl-3-isobutylxanthine↗

Origin and Co-localization of nitric oxide synthase, CGRP, PACAP, and VIP in the cerebral circulation of the rat.

The origin of perivascular nerve fibres storing nitric oxide synthase (NOS) and co-localisation with perivascular neuropeptides were examined in the rat middle cerebral artery (MCA) by retrograde tracing with True Blue (TB) in combination with immunocytochemistry. Application of TB to the proximal part of the middle cerebral artery labelled nerve cell bodies ipsilaterally in the trigeminal, sphenopalatine, otic, and superior cervical ganglia. A few labelled cell bodies were seen contralaterally, suggesting bilateral innervation. In the parasympathetic sphenopalatine and otic ganglia, numerous TB-labelled cell bodies contained neuronal NOS (C- and N-terminal), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase activating peptide (PACAP). In the trigeminal ganglion, almost all TB-labelled cell bodies contained calcitonin gene-related peptide (CGRP) but only a few cells contained NOS. In the superior cervical ganglion, the majority of the TB-labelled nerve cells contained neuropeptide Y (NPY) but none of them contained NOS. Removal of the ipsilateral sphenopalatine ganglion caused a slight reduction in the number of perivascular VIP-, PACAP-, and NOS-containing fibres after 3 days in the MCA while there was no difference at 2 and 4 weeks after the denervation as compared to control. This indicates that the parasympathetic VIP-, PACAP-, and NOS-immunoreactive nerve fibres in the rat MCA originate from several sources.

Animals↗

Amylin: localization, effects on cerebral arteries and on local cerebral blood flow in the cat.

Amylin and adrenomedullin are two peptides structurally related to calcitonin gene-related peptide (CGRP). We studied the occurrence of amylin in trigeminal ganglia and cerebral blood vessels of the cat with immunocytochemistry and evaluated the role of amylin and adrenomedullin in the cerebral circulation by in vitro and in vivo pharmacology. Immunocytochemistry revealed that numerous nerve cell bodies in the trigeminal ganglion contained CGRP immunoreactivity (-ir); some of these also expressed amylin-ir but none adrenomedullin-ir. There were numerous nerve fibres surrounding cerebral blood vessels that contained CGRP-ir. Occasional fibres contained amylin-ir while we observed no adrenomedullin-ir in the vessel walls. With RT-PCR and Real-Time-PCR we revealed the presence of mRNA for calcitonin receptor-like receptor (CLRL) and receptor-activity-modifying proteins (RAMPs) in cat cerebral arteries. In vitro studies revealed that amylin, adrenomedullin, and CGRP relaxed ring segments of the cat middle cerebral artery. CGRP and amylin caused concentration-dependent relaxations at low concentrations of PGF 2alpha-precontracted segment (with or without endothelium) whereas only at high concentration did adrenomedullin cause relaxation. CGRP8-37 blocked the CGRP and amylin induced relaxations in a parallel fashion. In vivo studies of amylin, adrenomedullin, and CGRP showed a brisk reproducible increase in local cerebral blood flow as examined using laser Doppler flowmetry applied to the cerebral cortex of the alpha-chloralose-anesthetized cat. The responses to amylin and CGRP were blocked by CGRP8-37. The studies suggest that there is a functional sub-set of amylin-containing trigeminal neurons which probably act via CGRP receptors.

Adrenomedullin↗

Characterisation of the effects of a non-peptide CGRP receptor antagonist in SK-N-MC cells and isolated human cerebral arteries.

The cerebral circulation is innervated by calcitonin gene-related peptide (CGRP) containing fibers originating in the trigeminal ganglion. During a migraine attack, there is a release of CGRP in conjunction with the head pain, and triptan administration abolishes both the CGRP release and the pain at the same time. In the search for a novel treatment of migraine, a non-peptide CGRP antagonist has long been sought. Here, we present data on a human cell line and human and guinea-pig isolated cranial arteries for such an antagonist, Compound 1 (4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid [1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-amide). On SK-N-MC cell membranes, radiolabelled CGRP binding was displaced by both CGRP-(8-37) and Compound 1, yielding pK(i) values of 8.9 and 7.8, respectively. Functional studies with SK-N-MC cells showed that CGRP-induced cAMP production was antagonised by both CGRP-(8-37) and Compound 1 with pA(2) values of 7.8 and 7.7, respectively. Isolated human and guinea pig cerebral arteries were studied with a sensitive myograph technique. CGRP induced a concentration-dependent relaxation in human cerebral arteries which was antagonized by both CGRP-(8-37) and Compound 1 in a competitive manner. In guinea pig basilar arteries, CGRP-(8-37) antagonised the CGRP-induced relaxation while Compound 1 had a weak blocking effect. The clinical studies of non-peptide CGRP antagonists are awaited with great interest.

Animals↗

Characterization of CGRP(1) receptors in the guinea pig basilar artery.

The purpose of the present study was to characterise receptors mediating calcitonin gene-related peptide (CGRP)-induced relaxation of guinea pig basilar artery. This was done by investigating vasomotor responses in vitro and performing autoradiographic binding studies. We also intended to study the importance of an intact endothelium. Agonist studies showed that peptides of the CGRP family induced relaxation of the guinea pig basilar artery with the following order of potency: human beta-CGRP=human alpha-CGRP>>adrenomedullin=[acetamidomethyl-Cys(2,7)]alpha-human CGRP ([Cys(ACM)(2,7)]CGRP)=amylin. These data are in concord with those of the autoradiographic binding studies that showed displacement of [125I] human alpha-CGRP binding with the following order of potency: human alpha-CGRP=human beta-CGRP>>adrenomedullin=human alpha-CGRP-(8-37)>>Cys(ACM)(2,7)]CGRP. In blockade experiments, the relaxant responses to human alpha- and human beta-CGRP were competitively blocked by the CGRP(1) receptor antagonist human alpha-CGRP-(8-37), while those of adrenomedullin and amylin were blocked non-competitively. In order to examine whether amylin induced relaxation via amylin or CGRP receptors, we studied the antagonistic effect of amylin-(8-37) on the weak relaxant response to amylin and found that it was not blocked by amylin-(8-37). These findings, together with the finding that the CGRP(2) receptor agonist [Cys(ACM)(2,7)]CGRP only induced a weak relaxation in the highest concentrations examined, suggest that the CGRP family of peptides mediate relaxation by CGRP(1)-type receptors. Removal of the endothelium, the addition of N(G)-nitro-L-arginine methyl ester (L-NAME), methylene blue or indomethacin did not affect the concentration-response curves of the CGRP analogues, neither in the presence nor in the absence of human CGRP-(8-37). The study shows the presence of a relaxant CGRP(1) receptor on the smooth muscle cells of guinea pig basilar artery. Various endothelial factors did not influence relaxant responses.

Adrenomedullin↗

Pathophysiology of primary headaches.

The cerebral circulation is innervated by sympathetic, parasympathetic, and sensory nerves, which store a considerable number of neurotransmitters. The role of these has been evaluated in primary headaches. A clear association between head pain and the release of calcitonin gene-related peptide was demonstrated. In cluster headache and in a case of chronic paroxysmal headache there was in addition the release of vasoactive intestinal peptide, which was associated with the facial symptoms (nasal congestion, rhinorrhea). In parallel with sumatriptan treatment, head pain subsided and neuropeptide release normalized. These data show the involvement of sensory and parasympathetic mechanisms in the pathophysiology of primary headaches.

Blood Vessels↗