Biomedical subjects

L Schilling

Publications and source records attributed to L Schilling.

At least 55 records · Page 3Linked to original sources

PubMed1998

ET(A) and ET(B) specific ligands synergistically antagonize endothelin-1 binding to an atypical endothelin receptor in primary rat astrocytes.

Using a whole-cell binding procedure with long incubations at low temperature and subsequent acid stripping, we have characterized an atypical endothelin (ET) receptor in primary rat cortical astrocyte cultures. We found the following: (a) no competition for 125I-ET-1 binding by the ET(A) antagonists BQ-123 and LU 135252 or the ET(B) agonist IRL 1620; (b) weak competition by the ET(B) antagonist BQ-788 and by the predominant ET(B) ligand ET-3; (c) potent synergistic competition of ET(A) and ET(B) ligands in combination for 125I-ET-1 binding; (d) potent competition of ET-1 with any of the radioligands used, 125I-ET-1, 125I-IRL 1620, and [3H]BQ-123; (e) lack of competition of IRL 1620 and BQ-123 with the respective other radioligand; (f) shifting of the amount of acid-strippable 125I-ET-1 binding from 20 to 80% by ET(B) ligands and to 4% by ET(A) ligands; and (g) as a control, typical ET(A) and ET(B) binding characteristics of the RAT-1 fibroblast and the U373MG astrocytoma cell line, respectively, under our assay conditions. The unusual binding properties of astrocytic ET receptors described in this study appear to be the result of several binding sites in the receptor for different ET ligands or ligand epitopes.

Animals↗

PubMed1998

Characterization of angiogenesis and microcirculation of high-grade glioma: an intravital multifluorescence microscopic approach in the athymic nude mouse.

The current study follows angiogenesis and microcirculatory changes associated with malignant glioma growth by means of an intravital fluorescence microscopic approach, which allows for the direct and continuous visualization of the glioma microvasculature and its quantitative analysis. Fluorescently labeled C6 rat glioma cells (5 x 10(5)) were implanted into dorsal skinfold chamber preparations of athymic nude mice. Glioma growth, vascularization, microhemodynamics, vascular permeability, and leukocyte-endothelial cell interactions were simultaneously followed over a 22-day observation period using intravital epiillumination microscopy and a multifluorescent labeling technique. Analysis of the process of glioma vascularization revealed three stages with distinct microvascular characteristics: avascular stage (days 0 to 6), lag of glioma growth but initial glioma-induced angiogenesis within the host tissue in peritumoral areas; early vascular stage (days 6 to 14), glioma cell proliferation associated with a spatially homogeneous development of a glioma microvasculature; and late vascular stage (days 14 to 22), exponential tumor growth and expansion (> 400 mm3) with high vascular densities in the peritumoral region and reduced vascularization (microvascular perfusion) in the glioma center. Within the center, the functional vessel length per area correlated inversely with glioma size (P < 0.01). In the peritumoral region, functional vessel length per area was independent of glioma size, indicating persistent, high angiogenic activity throughout the observation period. Thus, the microvasculature of mature gliomas revealed a microvascular zonal division with a progressive reduction of the functional vessel length per area within the tumor center. The perfusion failure of individual microvessels within the glioma center was partly compensated by an increase of diameters (P < 0.05), and thus by an increase of blood flow in these functional microvessels (P < 0.05) over time. Histologic analysis demonstrated both expanding and infiltrating growth patterns, as well as focal necroses on day 22. These are the first data from repeated in vivo analysis of glioma growth, vascularization, and microcirculation.

Animals↗

PubMed1998

Delayed loss of ETB receptor-mediated vasorelaxation after cold lesion of the rat parietal cortex.

The aim of this study was to investigate the involvement of endothelins (ET) in brain injury. The effect of ET was studied in the isolated basilar artery (BA) taken from control, sham-operated, and cold-lesioned rats. Cold lesion was induced by application of a precooled (-78 degrees C) copper cylinder (outer diameter 5 mm) for 60 seconds to the intact dura over the parietal cortex. After precontraction with prostaglandin (PG) F2alpha, ET-3 (10(-10) to 10(-8) mol/L) dilated BA with a pD2 (negative log of the half-maximal concentration) of 9.06+/-0.031 (mean +/- SD) and a maximal effect (Emax) of 1.64+/-1.0 mN at 3 x 10(-9) mol/L in sham-operated animals. This dilation was reduced 24 and 48 hours after cold lesion by 33% and 73%, respectively, at 3 x 10(-9) mol/L. The effects of acetylcholine (10(-8) to 10(-4) mol/L) and sodium nitroprusside (10(-3) mol/L) were unaltered. Activation of the ETB receptor in thoracic aorta by the specific agonist IRL 1620 also resulted in a reduced dilation (51% by 48 hours after cold lesion). Reverse transcriptase-polymerase chain reaction of the BA showed unaltered expression of mRNA for the ETB receptor after cold lesion whereas ETB immunoreactivity in BA and in its intraparenchymal arteries was reduced at 24 and 48 hours. In contrast to the reduction of ET-3-induced dilation, the constrictor effects of ET-1 and ET-3 were retained after cold lesion. Endothelin-1 (10(-12) to 10(-6) mol/L) dose-dependently contracted segments of untreated control BA segments under resting conditions with a pD2 of 8.03+/-0.22 and an Emax of 6.35+/-0.70 mN. Further evidence that the constrictor ability of BA was not influenced by cold lesion is given by the unaltered response to 124 mmol/L K+ and 10(-6) mol/L serotonin. We conclude that the ETB receptor of BA after cold lesion is downregulated specifically, apparently at the posttranscriptional level. Because the ETB-mediated dilation in thoracic aorta was also reduced, downregulation of the ETB receptor apparently is not restricted to cerebral arteries. The nitric oxide-cyclic guanosine monophosphate system in BA is, however, intact.

Animals↗

PubMed1998

Evidence for functional endothelin-converting enzyme activity in isolated rat basilar artery: effect of inhibitors.

Endothelin-1 (ET-1) may be involved in the upregulation of cerebroarterial resistance under pathologic conditions, most notably in the development of vasospasm after subarachnoid hemorrhage. Therefore, blocking the contractile action of ET-1 by receptor antagonists may prove to be a new and worthwhile approach. However, decreasing synthesis and release of ET-1 by blocking the endothelin-converting enzyme (ECE) activity may also prove worthwhile. In this study we have therefore investigated the effect of several putative ECE inhibitors in isolated rat basilar artery by measuring isometric contraction after application of big ET-1, the precursor peptide which is not vasoactive in itself. In the presence of phosphoramidon (10(-4) M in segments with an intact endothelium or 5 x 10(-4) M in de-endothelialized segments), there was only a small shift to the right of the concentration-effect curve for big ET-1. Similarly, 10(-3) M thiorphan (a selective inhibitor of the neutral endopeptidase) did not affect big ET-1-induced contraction, both alone and in combination with phosphoramidon (10(-3) M). When the big ET-1 analogue [22Phe]big ET-1[19-37] was applied, an increase in resting tension occurred irrespective of whether or not the endothelium was present. Furthermore, in the presence of 10(-5) M [22Phe]big ET-1[19-37], contraction induced by big ET-1 was not affected in de-endothelialized segments but rather was enhanced in endothelium-intact segments. These results suggest the presence of functional ECE activity in the rat basilar artery wall. However, such activity could not be markedly inhibited with different putative enzyme inhibitors. Therefore, the chemical nature of the cerebroarterial ECE activity must be further elucidated before rational development of efficient ECE inhibitors for treatment of cerebral vasospasm becomes possible.

Animals↗

PubMed1997

Assessment of the CAMINO intracranial pressure device in clinical practice.

The purpose of this study was to investigate reliability, handling characteristics and complication rate of the CAMINO-ICP-monitor-system in clinical routine. In a case controlled study 82 patients with intracranial pathology necessitating ICP-monitoring received either a ventricular or a parenchymal CAMINO-device. Clinical assessment of curve shape and apparent reliability of the measurement was documented. Probe position and presence of hematoma was evaluated in all patients with a CT after probe insertion. Handling complications, i.e. dislocation were recorded. At the end of the measuring period the drift of the probe was checked ex vivo and a two point calibration was performed using a water column. During one year 82 patients received 95 probes (parench, 73. ventric. 22). The average measuring period was 91.3 +/- 70.6 hrs. Catheter position was verified by CCT for 67 (70.5%) probes. 92.5% of the devices were placed correctly. Clinically 88.4% of the measurements were assessed plausible, in 8.2% the displayed ICP-values were judged to be too high, in 2.1% too low. Probe drift after explanation was -0.21 mmHg/24 hrs. The mean value of the recalibrated probes in the water column corresponding to 15.8 mmHg was 14.7 +/- 1.9 mmHg. There was no correlation between neither drift nor function in the water column and the duration of the measurement. Technical complications exclusively related to the construction of the CAMINO-system like kinking of the cable, dislocation (probe pulled out) or dislocated fixation screw were too high (25.3%).

Adolescent↗

PubMed1997

Endothelium-dependent relaxation counteracting the contractile action of endothelin-1 is partly due to ETB receptor activation.

The vasomotor effects of the endothelins (ETs) are mediated by activation of receptor subtypes termed ETA and ETB. The present study aimed to characterize the interaction of ETA and ETB receptor activation in the cerebral circulation. Ring segments obtained from rat basilar artery were used for measurement of isometric force under resting tension or following precontraction with prostaglandin F2 alpha. In some segments, the endothelium was removed mechanically. In precontracted arteries, ET-1 elicited contraction only. In the presence of the ETA receptor antagonist, BQ-123 (10(-5) M), however, ET-1 induced a concentration-related relaxation with a pD2 value of 8.93 +/- 0.16 (mean +/- SEM, n = 15). The relaxant action was abolished following preincubation with an ETB receptor antagonist, IRL-1038 (3 x 10(-6) M), or with a nitric oxide synthase inhibitor, NG-nitro-L-arginine (10(-5) M). These results indicate that the relaxation was mediated by ETB receptor activation coupled to the release of nitric oxide. Under resting tension, ET-1 elicited concentration-related contraction (pD2: 8.03 +/- 0.04, n = 37). In arteries devoid of a functional endothelium, the concentration-effect curve was shifted to the left yielding a pD2 value of 8.88 +/- 0.11 (n = 31). Similarly, in endothelium-intact arteries contraction to ET-1 was augmented following nitric oxide synthase inhibition or ETB receptor blockade with 3 x 10(-6) M BQ-788 (pD2: 8.94 +/- 0.18, n = 19). The results suggested that, in the isolated rat basilar artery, ET-1 induced coactivation of the contraction-mediating ETA receptor and the relaxation-mediating ETB receptor. The coactivation resulted in opposing vasomotor effects, but the contraction covered relaxation under normal conditions. However, force development by ET-1 was suppressed by its endothelium-dependent relaxant action.

Animals↗

PubMed1997

Sustained elevation of vasopressin plasma levels in healthy young men, but not in abstinent alcoholics, upon expectation of novelty.

The role of vasopressin (AVP) as a stress hormone in man is still a matter of controversy. Thus, the response of plasma AVP, among other hormones, to either intravenously injected human corticotropin releasing factor (hCRF, in the absence or presence of the opioid antagonist naloxone) or a combined 5-minute stress test was compared in healthy men (n = 10) and short-term abstinent alcoholics (n = 11), a group with recognized abnormalities of humoral stress parameters. Stimuli were applied blindly and in random order, one per day, in a 3-day experimental block. A second block using the same standardized protocol was carried out 12 weeks later. Alcoholics entered block I 8 days after the last ethanol ingestion. Up to block II, they were strictly controlled for abstinence. On each experimental day, subjects remained supine from 0700h until 1500h. Stimuli were applied alternatively at 1030h each day. Fourteen blood samples were drawn per day with simultaneous fluid substitution. There were no significant changes in plasma AVP as an acute response to any of the stimuli in either group or block. However, unexpectedly, controls had significantly higher basal AVP levels throughout block I as compared with block II without concomitant changes in plasma osmolality or blood pressure. Further analysis of the data revealed that the dramatically increased AVP levels of the five younger control subjects accounted for this difference. In fact, AVP levels in the five older healthy subjects and in all alcoholics remained low throughout the two blocks. Our data suggest that plasma AVP is continuously elevated in healthy young men upon anticipation of novelty. In contrast, healthy men of the older age group and early abstinent alcoholics seem to lack such a sustained AVP response.

Adult↗

PubMed1997

Mediation of endothelium-dependent relaxation: different response patterns in rat and rabbit basilar artery.

The endothelial lining of blood vessels plays an important role in the control of arterial tone by releasing a number of vasoactive factors. Among these, nitric oxide (NO) or a NO containing moiety, some cyclooxygenase products such as prostacyclin (PGl2) and a still hypothetical hyperpolarizing factor may induce dilatation/relaxation. In the present study, the functional importance of these factors in mediating endothelium-dependent relaxation has been investigated in isolated cerebral arteries. Acetylcholine (ACh) was used to induce endothelium-dependent relaxation of ring segments obtained from rat and rabbit basilar artery (BA). Glibenclamide (10(-6) M) which acts as an inhibitor of ATP-sensitive K+ channel activation did not affect the relaxant action of ACh. With the cyclooxygenase blocked by indomethacin (10(-6) M) ACh-induced relaxation was unaffected in rat BA and only slightly attenuated in rabbit BA. The NO synthase inhibitor NG-nitro-L-arginine (L-NNA, 10(-6) and 10(-5) M) completely abolished ACh-induced relaxation in rat BA and resulted in a moderate inhibition in rabbit BA (10(-5) and 10(-4) M). However, ACh-induced relaxation of rabbit BA was abolished in the presence of both indomethacin and L-NNA. These results indicate that endothelium-dependent relaxation of large cerebral arteries is mediated by NO acting alone or in concert with a relaxant cyclooxygenase product. In addition, there is no indication for the action of an endothelium-derived hyperpolarizing factor different from NO or a prostanoid.

Acetylcholine↗

PubMed1997

Brain edema: pathogenesis and therapy.

In the brain intravascular and interstitial spaces are separated by a highly specialized endothelial lining, which is the morphological substrate of the blood-brain barrier (BBB). Under physiological conditions the BBB exerts rigid control of water soluble compounds moving from blood into brain and from brain into blood, respectively. Under pathological conditions such as trauma or ischemia, an increase in BBB permeability may occur that allows plasma constituents to escape into the brain tissue. This "opening" of the BBB may, at least in part, be due to a massive release of autacoids, which thus act as mediators of vasogenic brain edema. Five criteria have to be fulfilled by a given autacoid to be considered a mediator candidate: (i) a permeability-enhancing action under physiological conditions; (ii) a vasodilatory action; (iii) the ability of inducing vasogenic brain edema; (iv) an increase of concentration in tissue or interstitial fluid under pathological conditions; and (v) a decrease of brain edema by inhibiting the release or action of a given autacoid. Among the mediator candidates discussed, only bradykinin fulfills all these criteria. Histamine, arachidonic acid and free radicals, including nitric oxide, may also be considered mediator candidates of brain edema, but for each of these compounds evidence is less clear than for bradykinin. Although the concept of autacoids mediating brain edema is well established and supported by experimental data, it has not yet gained entrance into the clinics. Treatment of patients suffering from vasogenic brain edema is symptomatic and mainly concentrated on the control of intracranial pressure.

Arachidonic Acid↗

PubMed1997

Endocrine and hemodynamic effects of stress versus systemic CRF in alcoholics during early and medium term abstinence.

In alcoholics, disturbances of the autonomic nervous system as well as of the hypothalamic-pituitary-adrenal axis (HPA) are known. However, these two systems have never been analyzed, under stimulated conditions, in parallel in the same patients. Moreover, studies using intravenous (i.v.) corticotropin releasing factor (CRF) to assess neuroendocrine function bypass the hypothalamic component of the HPA axis. Therefore, i.v. human (h) CRF (pituitary stimulation/exogenous CRF) and a multifaceted stress test (hypothalamic activation/endogenous CRF) were compared with respect to their effects on hemodynamics as well as plasma norepinephrine (NE), epinephrine (E), ACTH, and cortisol in abstinent alcoholics (n = 11) versus healthy men (n = 10). Each stimulus was tested twice, 12 weeks apart, in two separate experimental blocks (I and II). Alcoholics entered block 18 days after the last ethanol ingestion and were controlled for abstinence up to block II. hCRF caused a fall in mean arterial pressure (MAP), most pronounced in alcoholics, particularly in block II. In contrast, stress testing raised MAP in both groups and blocks. A sustained increase in ACTH, cortisol, and NE occurred after hCRF, although the ACTH response in alcoholics was blunted in both blocks. Stress testing elevated NE in both groups and blocks, while raising plasma ACTH and cortisol during block I only in controls. However, unlike the persistently blunted ACTH response to i.v. CRF, a normalization of the stress-induced ACTH output occurred in alcoholics after 12 weeks of abstinence. During block I, basal E levels were elevated in alcoholics whereas NE levels tended to be lower than in controls, resulting in a significantly decreased NE/E ratio that returned to near control values in block II. Neither CRF nor stress had any effect on circulating E in either group or block. To conclude: (1) Normalization of the ACTH response to stress, but not to i.v. CRF, after 12 weeks of abstinence, suggests that other ACTH secretagogues may be compensating for CRF dysfunction in alcoholics. (2) Despite the dramatically lowered plasma NE/E ratio in alcoholics, the NE response to stimuli was unaffected. (3) The exaggerated hypotensive reaction and blunted ACTH response to i.v. CRF may reveal a long-term dissociative dysregulation of CRF actions in alcoholics.

Adrenocorticotropic Hormone↗

PubMed1996

A novelty-related sustained elevation of vasopressin plasma levels in young men is not associated with an enhanced response of adrenocorticotropic hormone (ACTH) to human corticotropin releasing factor (hCRF).

A comparative study of the effects of intravenously administered corticotropin releasing factor (i.e. exogenous CRF), in the absence or presence of simultaneous opioid receptor blockade, versus stress (i.e. endogenous CRF) on plasma adrenocorticotropic hormone (ACTH), cortisol and vasopressin (AVP) was carried out in ten healthy men (mean age 35.6 +/- 9.5 years) using an intra-individual repeat setting. Three different stimuli were applied blindly and in random order, one per day, in a 3-day experimental block: (1) human (h) CRF; (2) hCRF/naloxone; and (3) a combined multifaceted 5-min stress test. A second block, following the same protocol, was carried out 12 weeks later. Each experimental day lasted from 0700 to 1500 hours, with subjects remaining supine throughout. ACTH and cortisol levels each responded with significant peaks to all three stimulating conditions in both blocks while AVP levels remained unaffected by any of these stimuli. Unexpectedly, in five of the ten subjects significantly elevated AVP basal concentrations were measured throughout the first block. This phenomenon appeared to be age-related, being observed in younger men only (29.6 +/- 5.2 vs 41.6 +/- 9.2 years; p = 0.03) and was not paralleled by changes in plasma osmolality or blood pressure. In the second block, AVP levels were low and no longer different between younger and older subjects. ACTH and cortisol curves did not differ among subgroups nor between blocks. In conclusion, plasma AVP, in contrast to ACTH, is not acutely influenced by either endogenous or exogenous CRF. However, anticipation of novelty seems to be a human-specific, stress-related stimulus for a sustained elevation of plasma AVP in young men. This novelty-related continuous elevation of AVP levels reported here neither affected basal plasma ACTH nor acted synergistically with exogenous hCRF to increase circulating ACTH.

Adrenocorticotropic Hormone↗

PubMed1996

Vasomotor and permeability effects of bradykinin in the cerebral microcirculation.

All components of an intracerebral kallikrein-kinin system have been described. Thus, bradykinin (BK) acting from the parenchymal site as well as from the blood site may influence cerebral microcirculation. BK is a potent dilator of extra- and intraparenchymal cerebral arteries when acting from the perivascular site. The vasomotor effect of BK is mediated by B2 receptors which appear to be located at the abluminal membrane of the endothelial cell. The effect of BK is mediated by NO. prostanoids, free radicals, H2O2 or leukotrienes depending on the animal species and on the location of the artery. Selective opening of the blood-brain barrier for small tracers (Na(+)-fluorescein; MW, 376) has been found in cats during cortical superfusion or intraarterial application of BK. This leakage is mediated by B2 receptors located at the luminal and abluminal membrane of the endothelial cells. Formation of brain edema has been found after ventriculo-cisternal perfusion or interstitial infusion of BK. This can be explained by increase of vascular permeability and cerebral blood flow due to arterial dilation thus enhancing driving forces for the extravasation. An increase of the BK concentration in the interstitial space of the brain up to concentrations which induce extravasation, dilatation and oedema formation has been found under several pathological conditions. Thus, BK may be involved in oedema formation after cold lesion, concussive brain injury, traumatic spinal cord and ischemic brain injury. The mediator role of BK in brain edema is further supported by therapeutic results. Brain swelling due to cold lesion or ischemia could be diminished by treatment with kallikrein-inhibitors. Similarly, dilatation of cerebral arterioles after concussive brain injury was reduced by blockade of B2 receptors. Thus, all criteria favour BK as one mediator of vasogenic oedema.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Cerebrovascular effects of endothelin-3: modulation of contraction by nitric oxide is independent of endothelin B receptor activation.

In cerebral arteries, endothelin (ET)-3 induces relaxation in a low concentration range by activating ETB receptors located on the endothelium and, at higher concentrations, contraction by activating ETA receptors located on smooth muscle cells. The interaction of these receptors has been investigated in the present study by measuring isometric force in ring segments of basilar arteries obtained from male normotensive rats. In precontracted arteries, the ETA receptor antagonist BQ-123 markedly enhanced the relaxant effect of ET-3, while the ETB receptor antagonist BQ-788 appeared to exert a competitive antagonism. Under resting tension, the contractile action of ET-3 was enhanced following nitric oxide synthase inhibition and endothelium denudation but not in the presence of ETB receptor antagonists. These results suggest i. the relaxant effect of ET-3 is decreased by ETA receptor activation, ii. a functionally intact endothelium shifts the contractile action of ET-3 towards higher concentrations, and iii. the inhibitory effect of the endothelium on ET-3 induced contraction is independent of ETB receptor activation. The main action of ET-3 in the cerebral circulation thus appears to be relaxant, and blockade of this effect may not be desirable in pathological conditions in which the release of ET-3 is increased.

Animals↗

PubMed1995

Endothelin-3-induced relaxation of isolated rat basilar artery is mediated by an endothelial ETB-type endothelin receptor.

The endothelin (ET) receptor mediating relaxation of cerebral arteries was characterized using ring segments obtained from the rat basilar artery. Under resting tension, ET-3 (> 10(-8) M) but not the specific ETB receptor agonist IRL 1620 induced contraction. In ring segments precontracted with 3 x 10(-6) M prostaglandin (PG) F2 alpha, ET-3 (10(-12) - 10(-8) M) and IRL 1620 (10(-14) - 10(-6) M) induced concentration-related relaxation. IRL 1620 was more potent than ET-3, the pD2 (-log10EC50) values being 10.002 +/- 0.751 (mean +/- SD) for IRL 1620 and 8.836 +/- 0.415 for ET-3. Relaxation was abolished after preincubation with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (10(-5) M) as well as in segments devoid of a functionally intact endothelium. At a concentration above 10(-8) M, ET-3 resulted in a further increase of PGF2 alpha-induced contraction that was not observed with IRL 1620. The presumably specific ETB receptor antagonist IRL 1038 (10(-7) - 3 x 10(-6) M) diminished or even abolished (3 x 10(-6) M) the relaxation induced by ET-3 or IRL 1620. IRL 1038 did not exert any vasomotor effect by itself, and it did not significantly affect ET-3-induced contraction. These results indicate that in the rat isolated basilar artery, the ET-3-induced relaxation is probably due to activation of an ETB-type receptor located on the endothelial cells and mediated by release of nitric oxide.

Acetylcholine↗

PubMed1995

Effects of potassium channel activators on isolated cerebral arteries of large and small diameter in the cat.

The smooth-muscle relaxant action of adenosine 5'-triphosphate (ATP)-sensitive potassium (KATP) channels in cerebral arteries of large diameter has been confirmed in a number of in vitro studies, but there is still debate about the presence of KATP channels in small cerebral arteries. In the present study, the authors compare the effects of cromakalim and bimakalim, two putative KATP channel activators, in different parts of the feline isolated middle cerebral artery (MCA) designated proximal, intermediate, and distal. The latter corresponds to those small pial arteries that are usually studied in vivo. In ring segments precontracted with 10(-5) M of uridine-5-triphosphate (UTP), both cromakalim and bimakalim induced concentration-related relaxation, with bimakalim being more potent than cromakalim, and no significant differences noted among segments obtained from the different regions of the MCA. In vessels precontracted by adding 30 mM KCl the potency of cromakalim and bimakalim was reduced compared with that obtained after UTP precontraction. In the presence of 10(-6) M glibenclamide, an antagonist of KATP channel activators, the concentration-effect curve to bimakalim was shifted to the right in the proximal and distal MCA, indicating a similar route of action for bimakalim and cromakalim in these arteries. The present study therefore indicates the presence of KATP channels in isolated small cerebral arteries according to results obtained in vivo. Activators of KATP channesl may prove helpful in the treatment of vasospasm, which may occur in large and small cerebral arteries after subarachnoid hemorrhage.

Animals↗

PubMed1995

Endothelin-1-induced contraction and relaxation of isolated rat basilar artery: effect of the endothelium.

In rat basilar artery ring segments precontracted with prostaglandin (PG)F2a, endothelin (ET)-3 induced a concentration-related relaxation at doses of 3 x 10(-10) to 1 x 10(-8) M, whereas contraction occurred at higher concentrations. In contrast, relaxation by ET-1 was observed only in the presence of an ETA receptor antagonist. The ET-induced relaxation could be blocked by an ETB receptor antagonist and by a nitric oxide (NO) synthase inhibitor, suggesting activation of an ETB receptor. This receptor, which may be located on the endothelium, is apparently coupled to release of NO. Under resting tension, ET-1 and ET-3 induced concentration-related contractions, which were enhanced after NO synthase inhibition or after de-endothelialization. These results suggest simultaneous induction of contraction and relaxation by the ETs. With ET-1, this occurs in the same concentration range, with the relaxing effect being masked by the contraction.

Animals↗

PubMed1994

Opening of the blood-brain barrier during cortical superfusion with histamine.

Histamine may influence cerebral microcirculation from the intravascular and parenchymal side. The latter route can be simulated by cortical superfusion. The effect of cortical superfusion with histamine (10(-9)-10(-3) M) on blood-brain barrier (BBB) permeability was studied in the cat by measuring extravasation of the tracers Na(+)-fluorescein (MW 376) or fluorescein isothiocyanate (FITC) labelled dextran (MW 62,000 or 145,000) by intravital fluorescence microscopy. Histamine induced an opening of BBB resulting in extravasation of small and large molecular weight tracers with threshold concentrations of 10(-9), 10(-8) and 10(-6) M for Na(+)-fluorescein, FITC-dextran 62,000 and 145,000, respectively. Once tracer extravasation had started the degree of extravasation increased with increasing concentrations of histamine in the superfusion fluid. Similar to histamine the H2 agonist impromidine (3 x 10(-12)-3 x 10(-9) M) induced a concentration dependent extravasation of Na(+)-fluorescein. 2-Pyridylethylamine which is 3-4 times more selective for H1 than for H2 receptors also induced an extravasation of Na(+)-fluorescein. Cortical superfusion with mepyramine (10(-7) M) or cimetidine (10(-4) M), which block the H1 and H2 receptors, respectively, already induced significant extravasation of Na(+)-fluorescein by themselves. These compounds could thus not be used as competitive antagonists to block histamine-induced extravasation. However, our data are in accord with data obtained during intravascular and topical application of histamine and support the hypothesis that H2 receptors at the luminal and abluminal membrane of the endothelium mediate the opening of the BBB.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation elicited by cortical spreading depression.

The aim of the present study was to examine whether the initial transient arterial dilatation during cortical spreading depression (CSD) was mediated by the release of calcitonin gene-related peptide (CGRP) and/or nitric oxide (NO). This question is of interest as the initial phase of CSD appears to be a model of events occurring during functional hyperemia and during the first period of classic migraine. Using an open cranial window technique, pial arterial diameter in the parietal cortex of cats was recorded with an image splitting method. Employing micropuncture technique, perivascularly applied CGRP8-37 did not alter the resting diameter of pial arteries but antagonized concentration dependently (5 x 10(-9)-10(-6) M) the dilatation (35%) due to 5 x 10(-8) M CGRP. NG-Nitro-L-Arginine (NOLAG, 10(-4) M) also had no effect on resting diameter of pial arteries, indicating that their resting tone is neither mediated by a continuous release of CGRP nor of NO. CSD was triggered by a remote intracortical injection of KCl (150 mM) and recorded by a microelectrode placed adjacent to the artery under investigation. CSD elicited a transient negative DC shift which was accompanied by a peak dilatation of 44 +/- 5.2% (S.E.M.). This dilatation was reduced by approximately 50% during topical application of 10(-7) M CGRP8-37 and 10(-4) M NOLAG each. A 75% inhibition of the CSD-induced dilatation was found during simultaneous application of both compounds. These data indicate that the initial dilatation during CSD is mediated, at least in part, by a release of CGRP and NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗