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Biomedical subjects

L Edvinsson

Publications and source records attributed to L Edvinsson.

At least 19 recordsLinked to original sources
PubMed1992

Antagonism of pre- and postjunctional responses to neuropeptide Y and sympathetic stimulation by D-myo-inositol-1,2,6-trisphosphate in the anaesthetised dog.

Pre- and postjunctional responses to nerve released or exogenous neuropeptide Y (NPY) were measured in the anaesthetised dog before and after administration of D-myo-inositol-1,2,6-trisphosphate (PP56) a putative NPY antagonist. The inhibition of the increase in pulse interval evoked by vagal stimulation was used as a measure of prejunctional action of NPY and the magnitude of increase in blood pressure was used as a measure of postjunctional action of NPY (direct action or constrictor potentiating). Elevated plasma levels of PP56 were maintained throughout the course of the experiment. PP56 significantly reversed the inhibitory effect of NPY (nerve released or exogenous) on cardiac vagal action, and significantly inhibited the pressor response to exogenous NPY. PP56 did not affect the pressor response to intravenous phenylephrine, a selective alpha-adrenoceptor agonist. PP56 therefore significantly antagonises both pre- and postjunctional effects of NPY (nerve released and exogenous) and, with respect to its postjunctional antagonism, this action is selective for NPY.

Anesthesia↗
PubMed1992

A novel inositol phosphate selectively inhibits vasoconstriction evoked by the sympathetic co-transmitters neuropeptide Y (NPY) and adenosine triphosphate (ATP).

Postganglionic sympathetic nerves release norepinephrine (NE) as their primary neurotransmitter at vascular and other targets. However, much evidence supports involvement of additional messengers, co-transmitters, which are co-released with NE upon sympathetic nerve stimulation and thereby contribute to their actions, e.g., vasoconstriction. Two such putative co-transmitters, neuropeptide Y (NPY) and adenosine triphosphate (ATP) have been of particular interest since they fulfill several neurotransmitter criteria. Importantly, hitherto it has been difficult to antagonize vasoconstriction evoked by either NPY or ATP with agents that are devoid of intrinsic activity. The present study describes the ability of a novel inositol phosphate, D-myo-inositol 1,2,6-trisphosphate (Ins[1,2,6]P3; PP-56) to in vitro potently block vasoconstrictor responses elicited by NPY and ATP, but not by NE, as studied in guinea-pig isolated basilar artery. The action of Ins[1,2,6]P3 does not seem to occur through antagonism at NPY- or ATP-receptor recognition sites, labeled by 125I-peptide YY and 35S-gamma-ATP, respectively, in membranes of rat cultured vena cava vascular smooth muscle cells. However, it does involve inhibition of the influx of Ca2+ induced by either co-transmitter in these same vena cava cells. It is proposed that Ins[1,2,6]P3 may be a useful functional antagonist of non-adrenergic component(s) of the vasoconstrictor response to sympathetic nerve stimulation.

Adenosine Triphosphate↗
PubMed1992

Neuropeptide Y modulates the action of vasodilator agents in guinea-pig epicardial coronary arteries.

Recently, we have demonstrated that guinea-pig epicardial coronary arteries are supplied by numerous nerve fibres containing neuropeptide Y (NPY) immunoreactivity. However, examination of vasomotor responses revealed that NPY did not elicit a contractile response in these arteries. In contrast, acetylcholine (ACh), calcitonin gene-related peptide (CGRP), substance P and vasoactive intestinal polypeptide (VIP) all relaxed precontracted arteries. In the present study, we have used histochemical, immunohistochemical and in vitro pharmacological techniques, in order to further investigate the possible role of NPY in guinea-pig epicardial coronary arteries. A double-immunofluorescence staining technique revealed that CGRP and substance P were co-localized in nerve fibres distinct from those displaying NPY immunoreactivity. Furthermore, using a method combining immunofluorescence and histochemical techniques, we observed that putative cholinergic nerve fibres (identified by their acetylcholinesterase content) and NPY-immunoreactive nerve fibres are two different nerve populations. An in vitro pharmacological method demonstrated that NPY markedly inhibited the relaxant responses mediated by ACh, VIP, substance P and isoprenaline but had no effect on CGRP. These results suggest that NPY-containing nerves associated with guinea-pig epicardial coronary arteries may be predominantly involved in modulating the action of vasodilator agents.

Acetylcholine↗
PubMed1992

Redistribution of blood flow in the cerebral cortex of normal subjects during head-up postural change.

Regional cerebral blood flow was measured in 21 normotensive subjects during supine rest and during head-up tilt to 70 degrees. The results showed significant and consistent regional cerebral blood flow changes in the frontal areas with lower relative flow distribution values (percentage of mean flow) during head-up tilt than during supine rest. The lower frontal flow distribution values during tilt were not related to habituation, to repeated measurements, or to the estimated level of arterial CO2 which was derived from expired end-tidal CO2 levels. None of the subjects had orthostatic hypotension and there was no significant difference in mean hemispheric blood flow between lying down and standing up. There was no significant gender difference in regional cerebral blood flow, although female subjects tended to have higher mean hemispheric flow than males in both postures. It remains to be established whether the flow decreases in the frontal cortex are caused by cerebral functional factors or by haemodynamic mechanisms.

Adult↗
PubMed1992

Yohimbine pharmacokinetics and interaction with the sympathetic nervous system in normal volunteers.

The pharmacokinetics of yohimbine and its effects on sympathoadrenal function were studied in 13 young, healthy, male volunteers after an IV bolus dose of 0.25 or 0.5 mg.kg-1. Pharmacokinetic analysis showed that distribution was rapid, with a half life between 0.4 and 18 min, and the elimination half life ranged between 0.25 and 2.5 h. The volume of distribution (Vss) was 74 l, (range 26 to 127 l). Only 0.5 to 1% of unchanged yohimbine was found in the urine, indicating that the major part of the drug was eliminated by hepatic clearance. Total plasma clearance was 117 l.h-1, which exceeds the hepatic plasma flow. This means that yohimbine is a high extraction drug with considerable extra-hepatic metabolism. Fractional urine sampling revealed that 0.5-1% of unchanged yohimbine was excreted in urine in a biphasic manner. The data also suggested the existence of a slower elimination phase, with a half life of 13 h. The venous plasma concentration of noradrenaline (NA) increased 3-fold within 15 min after the yohimbine injection while plasma adrenaline (A) and neuropeptide Y-like immunoreactivity (NPY-LI) remained unchanged. The plasma concentration-effect relationship of the changes in circulating NA followed counter-clockwise hysteresis. The results show that the hyperadrenergic state elicited by therapeutic doses of the alpha 2-adrenergic autoreceptor antagonist, yohimbine, is due to an interaction with NA but not to release of A or NPY in man.

Adult↗
PubMed1992

Mutual modification of vasoactivity by calcitonin gene-related peptide and endothelin-1 in isolated porcine ophthalmic artery.

Vasodilation has been implicated in the pathophysiology of some headaches, but the mechanisms behind such abnormalities remain unknown. Calcitonin gene related peptide (CGRP), a peptide present in sensory trigeminal fibres, induces strong and long lasting vasodilation in cranial vessels, and has been found to be increased in jugular blood during migraine attacks. Endothelin (ET) is a recently identified potent vasoconstrictor peptide, which also induces long-lasting responses. ET-CGRP interactions may be of importance in vascular beds putatively involved in pain development in the head, and were therefore studied in isolated porcine ophthalmic arteries. Both peptides were found to induce strong and long-lasting reactions in this artery. CGRP decreased ET-induced contractions and ET decreased CGRP-induced relaxations. These effects were additive rather than synergistic.

Animals↗
PubMed1992

Diminished contractile responses to neuropeptide Y of arteries from diabetic rabbits.

The vascular smooth muscle contractile response to neuropeptide Y (NPY), potassium, noradrenaline, histamine and serotonin was studied in circular segments of isolated vessels in vitro from rabbits with alloxan-induced diabetes mellitus. The injection of alloxan resulted in a marked and maintained increase in serum glucose as early as 1 week after treatment. Four vessel types were examined: abdominal aorta, and renal, left anterior descending coronary and middle cerebral arteries. There was no difference in the contractile response to histamine or serotonin between control and diabetic vessels. However, in the cerebral artery the contractile response to noradrenaline was reduced in the diabetic group, while in the aorta and the renal artery no significant differences were seen. Noradrenaline failed to evoke any contractile response in the coronary arteries in either group. NPY induced strong, concentration-dependent contractions of coronary and cerebral arteries, but did not have any contractile effect per se in aorta or renal arteries, either in control or in alloxan-treated rabbits. The maximal contractile effect and the sensitivity to NPY was significantly less in diabetic coronary and cerebral vessels as compared to control. There was no difference in dilator effect of acetylcholine and substance P between the diabetic animals and the control group in any of the vessel types, indicating that the changed vascular responses to NPY and noradrenaline were not endothelium-dependent. In conclusion, the present study has shown that the postjunctional effects of NPY and noradrenaline in the peripheral sympathetic nervous system are selectively attenuated in this model of chronic diabetes.

Animals↗
PubMed1992

Cutaneous sensory stimulation leading to facial flushing and release of calcitonin gene-related peptide.

A patient is described with a 17-year history of intractable left-sided facial pain. The pain occurred daily in 5 sec spasms to a maximum of one every 2-3 min and was restricted to the left upper face. It was associated with rhinorrhoea on the left and often with ipsilateral facial flushing. Conventional therapy, including carbamazepine, baclofen and three posterior fossa explorations, had not provided lasting relief. Local facial stimulation by tapping a painful trigger point led to both pain and flushing of the face ipsilaterally. During this flushing, blood was collected and assayed using sensitive radioimmunoassays for several neuropeptides (neuropeptide Y, substance P, vasoactive intestinal polypeptide and calcitonin gene-related peptide). A marked (119%) increase in calcitonin gene-related peptide was noted in the external jugular vein blood ipsilaterally during the flushing with no change in the other peptides measured. To quantitate the effect of calcitonin gene-related peptide on human extracranial vessels, standard pharmacological procedures were used to examine the potency of the peptide as a vasodilator of human facial artery. The IC50 of calcitonin gene-related peptide for the prostaglandin F2 alpha-precontracted human facial artery was 10(-9) mol/l. The relevance of these observations to the clinical problem of migraine is considered.

Calcitonin Gene-Related Peptide↗
PubMed1992

Sumatriptan is a potent vasoconstrictor of human dural arteries via a 5-HT1-like receptor.

The action of sumatriptan, putatively a selective 5-HT1D or 5-HT1-like receptor agonist which is effective in the treatment of migraine, has been studied on fresh human dural (middle meningeal) arteries. In low concentrations (10(-8)-10(-7) M) it was found to be a significantly stronger vasoconstrictor of dural arteries compared to cerebral and temporal arteries. However, its potency was less than that of 5-HT. The sumatriptan-induced vasoconstriction was antagonized by methiothepin (10(-9)-10(-8) M), but not by ketanserin (10(-7) M). The observations suggest that the sumatriptan-induced contraction of the dural artery is mediated via activation of 5-HT1D or 5-HT1-like receptors, whereas it does not appear to activate the 5-HT2 receptors.

Cerebral Arteries↗
PubMed1992

Reduction of calcitonin gene-related peptide in jugular blood following electrical stimulation of rat greater occipital nerve.

Although it is known that pain in the forehead may be induced by neck abnormalities, the actual neck-head connections responsible for development of pain in trigeminal areas are poorly understood. Vasoactive neuropeptides released from sensory fibres, such as substance P (SP) and calcitonin gene-related peptide (CGRP), have been considered as important elements in headache pathophysiology. The levels of CGRP-like immunoreactivity (LI) were measured bilaterally in the jugular blood (52 rats) and intraocular aspirates (66 rats) following electrical stimulation of the left greater occipital nerve, and in the jugular blood of 13 control animals. One-third of the stimulated rats had varying combinations of conjunctival injection, tearing, diminished eye aperture and miosis or mydriasis on the stimulated side. The other two-thirds exhibited no ocular signs. Significantly lower levels of CGRP-LI were present in the jugular blood on the stimulated side in comparison with control rats. There was comparatively lower CGRP-LI on the non-stimulated side as well, but to a lesser extent. Significant differences between the stimulated and the non-stimulated side were present, particularly in the tearing/diminished eye cleft group. It is proposed that stimulation of the rat GON inhibits the trigeminal system (reduction of CGRP-LI) and possibly activates parasympathetic fibres (ocular changes).

Animals↗
PubMed1992

Effects of vasoconstrictors on isolated rabbit coronary arteries exposed to isotonic iohexol. Potassium chloride-, histamine-, endothelin-, and prostaglandin-F2 alpha-induced contractions on arteries exposed to iohexol without and with osmotic additions (sodium chloride or glucose).

RATIONALE AND OBJECTIVES: A major effect of contrast media (CM) on coronary vessels is vasodilatation, but occasionally, both ionic and nonionic media may cause coronary artery spasm. The influence of CM on the actions of vasoactive substances is not well known. To investigate the effects on rabbit coronary arteries of an iso-osmolar nonionic CM, iohexol (140 mg I/mL) the vasoconstrictors potassium chloride (KCl), histamine, endothelin, and prostaglandin-F2 alpha (PGF2 alpha) were used. The effects of iohexol with 30 to 150 mM sodium chloride (NaCl) or with 25-50 g/L glucose also were investigated. METHODS: Coronary artery segments were mounted between two L-shaped prongs in tissue baths with buffer solution. Before each investigation, buffer was exchanged with iohexol solution. Increasing concentrations of a vasoconstrictor were added, and the constriction of the vessels was recorded. RESULTS: Iohexol caused a comparatively small inhibition of the contractile effects of histamine and endothelin. This meant little reduction in maximal contraction (Emax), and the concentration of constrictory substance resulting in half maximal contraction (EC50) compared with buffer solution. Iohexol also caused a small reduction in Emax of KCl, but EC50 was significantly lower. Adding NaCl or glucose to iohexol decreased Emax and increased EC50. Iohexol inhibited most of the contractile effect of PGF2 alpha, but adding NaCl increased Emax slightly. CONCLUSIONS: The effects caused by a nonionic CM on coronary arteries cannot be attributed to osmolality alone. The CM influenced the effects of vasoconstrictors to differing degrees, but the inhibition of the CM per se was usually small.

Animals↗
PubMed1992

Neuropeptide Y-like immunoreactivity and hypertension.

OBJECTIVE: Neuropeptide Y is a co-transmitter with noradrenaline in sympathetic neurons supplying arteries and veins with potent contractile effects. To investigate the role of neuropeptide Y in hypertension, we measured the circulating levels of neuropeptide Y and noradrenaline in patients with severe hypertension. DESIGN: Samples were collected from patients with untreated, severe hypertension (diastolic blood pressure > 120 mmHg) and in age- and sex-matched controls. After treatment with beta-adrenoceptor blockers, diuretics, angiotensin converting enzyme inhibitors of calcium antagonists, samples were taken from the patients during 12 months. METHODS: The circulating levels of neuropeptide Y-like immunoreactivity (NPY-LI) were measured with a radioimmunoassay using a rabbit antiserum. Catecholamines were measured using high-performance liquid chromatography and electrochemical detection. RESULTS: There was a significantly higher level of NPY-LI in the patients when they were compared with the controls. However, there was no correlation either in the controls or in the hypertensives between systolic blood pressure, diastolic blood pressure and NPY-LI or noradrenaline. The increased level of NPY-LI in plasma remained elevated for up to 12 months despite reduction in blood pressure to acceptable levels. The noradrenaline level was not increased before treatment, after 2-4 weeks or after 2-12 months treatment. CONCLUSION: The high level of NPY-LI may represent a marker for higher activity of the sympathetic nervous system which is not controlled by the treatment of blood pressure to normotension.

Acute Disease↗
PubMed1992

Neuropeptide Y inhibits relaxation of guinea pig cerebral, coronary, and uterine arteries: blockade by D-myo-inositol-1,2,6-triphosphate.

Interactions between neuropeptide Y and perivascular vasodilator agents were studied in guinea pig cerebral, coronary, and uterine arteries. In all three types of arteries, vessel segments precontracted with prostaglandin F2 alpha or histamine relaxed concentration dependently upon application of acetylcholine (ACh), substance P (SP), and vasoactive intestinal peptide (VIP). Neuropeptide Y (NPY: 10(-8)-10(-7) M) caused inhibition of relaxations produced by ACh, SP, and VIP in all three types of segments; however, the effective concentration varied between vessel type. Thus, cerebral and uterine arteries were approximately 10 times more sensitive to NPY than the coronary artery. D-myo-inositol-1,2,6-triphosphate (PP56) was a potent inhibitor of the NPY effect in all three vessel types. Thus, NPY, which is colocalized not only with norepinephrine in sympathetic perivascular fibers but also with VIP and ACh in some parasympathetic neurons, can greatly reduce the vasodilatory effect of ACh and VIP, as well as of the sensory peptide SP. This further illustrates the complex interactions NPY has with perivascular neuroeffector mechanisms.

Animals↗
PubMed1992

Plasma atrial natriuretic peptide (ANP) in relation to blood pressure in severe hypertension.

Atrial natriuretic peptide-like immunoreactivity in plasma (ANP-LI) was studied in patients with severe hypertension (n = 21) and in matched healthy control subjects. There was no correlation between ANP-LI and blood pressure, and the distribution of ANP-LI values did not differ between the two groups. These results are consistent with the assumption that an increase in ANP is not caused by elevated blood pressure, although elevated ANP-LI may be found in subgroups of hypertensive subjects with increased atrial pressures due to, for example, cardiac failure.

Atrial Natriuretic Factor↗
PubMed1992

Inhibition of neuropeptide Y-induced potentiation of noradrenaline-induced vasoconstriction by PP56 (D-myo-inositol 1,2,6-tris-phosphate).

1. Although neuropeptide Y (NPY) is a potent vasoconstrictor in many vascular beds, nanomolar concentrations of this peptide potentiate the noradrenaline-induced contractions in rabbit gastroepiploic and femoral arteries, and guinea-pig mesenteric and uterine arteries. 2. The potentiating effect of NPY on noradrenaline-induced contraction was present in endothelium-denuded femoral arteries. 3. The potentiating effect of NPY on noradrenaline-induced contraction was antagonized by PP56 (D-myo-inositol 1,2,6-trisphosphate) in low concentrations (down to 0.1 nM). This antagonistic effect was observed in all four types of vessels studied. Contractions induced by noradrenaline, histamine, endothelin-1 and potassium were not altered by PP56 in concentrations upto 1 microM in femoral artery of rabbit. 4. We provide evidence that a non-peptide (PP56) can selectively antagonize NPY-induced effects in rabbit and guinea-pig peripheral arteries without affecting the vasoconstrictor response to noradrenaline.

Animals↗