bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrastructural Changes in the Cerebral Artery Wall Induced by Long-Term Sympathetic Denervation
Authors: Dimitriadou V. , Aubineau P. , Taxi J. , Seylaz J.
Published: September 2008

This study was performed to determine to what extent the morphology of the rabbit middle cerebral artery is affected by the absence of the sympathetic nervous system. Six weeks after unilateral ablation of the superior cervical ganglion, which induced ipsilateral degeneration and disappearance of the perivascular noradrenergic nerve fibers, comparison between the ipsi- and the contralateral middle cerebral arteries revealed that the denervated arterial wall underwent significant thickening. This thickening was principally due to hypertrophy of the smooth muscle cells (SMC), together with an increase in the amount of medial and adventitial collagen. The hypertrophied SMC showed important morphological and ultrastructural modifications – irregular shape, increase in the number of organdies (particularly of Golgi apparatus, free ribosomes, rough endoplasmic reticulum and microtubules), large indented nuclei rich in euchromatin – indicating profound changes in their metabolic and contractile activity which could result in an alteration of their mechanical properties. As these alterations were strictly ipsilateral to the sympathectomy it is likely that they are the direct consequence of the suppression of a regulatory ‘trophic’ factor linked to the presence of sympathetic nerve fibers. This concept is reinforced by the fact that the first SMC affected are those situated at the media/adventitial border, in the vicinity of adventitial nerve bundles. Thus, the sympathetic nervous system appears to play a key role in the long-term regulation of the cerebral vascular tree structure.
Electrophysiological Properties of the Mesenteric Artery of the Rabbit with Perinephritis Hypertension
Authors: Wadsworth R.M. , Neild T.O.
Published: September 2008

Membrane potential and tension were simultaneously recorded in ileal arteries isolated from rabbits with perinephritis hypertension and from sham operated controls. Stimulation of perivascular nerves with single pulses produced excitatory junction potentials, action potentials and contraction. Setting resting tension to levels equivalent to intra-luminal pressures of 23, 70 and 114 mm Hg had no effect on the resting membrane potential, excitatory junction potential amplitude, action potential threshold or membrane time constant. The resting membrane potential in arteries from hypertensive rabbits was 3.7 mV less negative than in the shams. There were no significant changes in the action potential threshold or membrane time constant. It is suggested that the changes observed in the membrane potential may contribute to the increased responsiveness found in arteries from this model of hypertension.
Effect of Dietary Salt and Cholesterol Loading on Vascular Adrenergic Receptors
Authors: Tsutsumi Seiji , Tsuji Kazuhiko , Ogawa Kouichi , Ito Takayuki , Satake Tatsuo
Published: September 2008

To evaluate the effects of salt and cholesterol intake on vascular responses to catecholamines, α1- and β-adrenergic receptor densities were determined in control, cholesterol-loaded, salt-loaded with desoxycorticosterone acetate (DOCA) and furosemide-loaded male rabbits, using [3H]-prazosin and (–)-[125I]-cyanopindolol as ligands, respectively. In the aortic membrane, the density of α1-adrenergic receptors (Bmax = 120 ± 14 fmol/mg protein, Kd = 0.48 ± 0.05 nM) was higher than that of β -adrenergic receptors (Bmax = 10.5 ± 1.7 fmol/mg protein, Kd 47.1 ± 8.6 pM). Salt loading and depletion did not alter the density or affinity of either the α1- or β -adrenergic receptors. By contrast, cholesterol loading significantly decreased αi-adrenergic receptor affinity to a Kd value of 0.81 ± 0.11 nMfrom the control level of 0.48 ± 0.05 and increased the β -adrenergic receptor density to a Bmax of 18.7 ± 1.9 fmol/mg protein from the control level of 10.5 ± 1.7. These results showed that the density of α1-adrenergic receptors was higher than that of β-adrenergic receptors in the rabbit aortic membrane preparation, and suggested that the sensitivity of aortic membrane to catecholamines was changed by cholesterol loading.
Differences in Norepinephrine Dynamics in Large and Small Pulmonary Arteries of Dog
Authors: Rorie Duane K. , Tyce Gertrude M.
Published: September 2008

These studies address the apparent dissociation between the amounts of norepinephrine (NE) released from small and large pulmonary arteries of dogs by a standard electrical stimulus and the contractile tensions that developed in these tissues. Segments of vessels were studied in organ baths or in a superfusion apparatus during electrical stimulation. Endogenous NE was quantitated using liquid chromatography with electrochemical detection. ‘Release’ of NE was studied under conditions in which uptakes of NE from the synaptic cleft were impaired, and overflow of NE was studied when these uptakes were operative. ‘Release’ of NE was predictably greater than overflow in all arteries. In the large pulmonary artery, greater contractile tensions were measured when greater amounts of NE were present in superfusate. In the small pulmonary artery, contractile tensions did not directly correlate with the amounts of NE measured in the superfusate. These studies indicate that NE dynamics are different at neuroeffector junctions in large and small pulmonary arteries. Several explanations to account for these differences are discussed.
Distinctive Characteristics of the Splenic Vein in the Dog
Authors: Yoshioka Koichi , Hayakawa Akemi , Furuta Tatsuji , Ishikawa Naohisa , Shigei Tatsuro
Published: September 2008

Vascular characteristics of the splenic vein are entirely different from the portal vein in the dog. We compared the responsiveness of the splenic capsule, which contains abundant smooth muscle with the portal and splenic veins. With respect to potentiation of acetylcholine-induced contraction by neostigmine, the relaxation response to isoproterenol and the contractile response to 5-hydroxytryptamine, the splenic capsule differed from the splenic vein, but was rather similar to the portal vein. A site of morphological and pharmacological discontinuity between the portal vein and the splenic vein occurred at the junction of the splenic vein and the left gastric vein to form the gastrosplenic vein. This junction may coincide with the site of connection of the embryonic splenic vein, a newly formed efferent vein of the spleen, with the portal vein, which was reported by Miki [cf. Bevan et al.: 4th Int. Symp. on Vascular Neuroeffector Mechanisms; Raven Press, New York 1983]. On the splenic side, histological examination revealed that smooth muscle of the splenic capsule and trabeculae are interconnected, but did not extend to the splenic vein. At openings of the trabecular veins into the ‘intrasplenic’ portion of the splenic vein the trabecular smooth muscle continued to the extended capsule. The site of change in pharmacological responses was also found to be located between the trabeculae and the intrasplenic portion of the splenic vein. Thus the splenic vein can be regarded as a distinct segment of vessel inserted between the portal vein and the spleen. This may reflect differences in embryogenesis of their smooth muscle.
Spontaneous Rupture of the Internal Elastic Lamina in the Rat: The Manifestation of a Genetically Determined Factor Which May Be Linked to Vascular Fragility
Authors: Capdeville Michelle , Coutard Michele , Osborne-Pellegrin Mary J.
Published: September 2008

The spontaneous rupture of the internal elastic lamina (IEL) in various arteries occurs to different extents in different rat strains. We have quantified this phenomenon in the caudal and renal arteries and abdominal aorta in two normotensive inbred strains: the Brown Norway (BN) and Long Evans (LE) strains. At 5 weeks of age, BN rats of both sexes exhibited small numbers of interruptions in the IEL of the caudal artery, whereas LE rats did not. Postpubertal male and female BN rats presented large numbers of IEL interruptions in the caudal artery and significant numbers in the renal artery and abdominal aorta, whereas LE rats showed few in the caudal artery and none in the other arteries. Treatment with β -aminopropionitrile (BAPN, an inhibitor of lysyl oxidase, the enzyme involved in the formation of cross-links in elastin and collagen) increased the formation of IEL ruptures in both strains in the caudal and renal artery and in the abdominal aorta in BN rats, but not in the abdominal aorta of LE rats. Apart from IEL ruptures, which were more prevalent in BN rats, no differences were observed in the ultrastructure of the aortic elastic fibers between the two strains, either in controls or in BAPN-treated rats. When male rats of both strains were made hypertensive by unilateral nephrectomy and administration of deoxycorticosterone and salt, mortality was more precocious in the BN strain although blood pressure was significantly higher in the BN strain at only one time point. The incidence of cerebrovascular hemorrhage was 48% in BN rats and 0% in LE rats. Hypertension increased the formation of ruptures in the IEL in some arteries – to a greater extent in the BN than in the LE rats. These results raise the possibility that the propensity to spontaneous rupture of the IEL, which is in part genetically determined, may reflect a latent form of vascular fragility which becomes significant in hypertension, resulting in poor survival and susceptibility to cerebrovascular accidents.
Differential Contractile Responses of Pressurized Porcine Coronary Resistance-Sized and Conductance Coronary Arteries to Acetylcholine, Histamine and Prostaglandin F2α
Authors: Nakayama Kengo , Osol George , Halpern William
Published: September 2008

The reactivities of porcine resistance-sized arteries (270 µm o.d.) and conductance coronary arteries (4.2 mm o.d.) were compared in the presence of a functional and morphologically intact endothelium using a pressurized in vitro preparation. In resistance vessels, acetylcholine (ACh) produced maximal diameter reductions of 42 % and the EC50 was 0.19 µM. Constrictions to histamine and prostaglandin F2α (PGF2«), however, were either absent or minimal. In contrast, maximum diameter constrictions of conductance vessels were 19, 33 and 22% in response to ACh, histamine and PGF2α, respectively. Corresponding EC50 values were 0.58, 2.8 and 2.9µM. The significant differences in reactivity between resistance and conductance arteries underscore the potential importance of regional specialization in the coronary blood flow regulation.
Peptide-Containing Nerves in the Rat Femoral Artery and Vein
Authors: Edvinsson L. , Gulbenkian S. , Wharton J. , Jansen I. , Polak J.M.
Published: September 2008

Peptide-containing nerves have been examined in the rat femoral artery and vein using immunocytochemical and vasomotor techniques. The general neuronal marker PGP 9.5 revealed a moderate supply of nerve fibres and fascicles forming a loose network in the adventitia and the adventitial-medial border of the artery and vein. The majority of the nerve fibres in both the artery and vein displayed immunoreactivity for neuropeptide Y (NPY) and tyrosine hydroxylase (TH). The distribution pattern and number of these two types correlated well. The artery had a slightly richer PGP 9.5- immunoreactive nerve supply compared to the vein, but the nerve plexus in the vein displayed a more uniform arrangement. In contrast, relatively few nerve fibres displayed calcitonin gene-related peptide, substance P, or vasoactive intestinal peptide immunoreactivity in either the artery or vein. The calcitonin gene-related peptide immunoreactive fibres had a similar distribution to that of the substance P containing fibres. Using a sensitive in vitro method the vasomotor responses to perivascular peptides were characterized. In the femoral artery NPY potentiated α1-adrenoceptor mediated contractions, and had very little effect by itself. In contrast, 10–7M NPY contracted femoral veins by up to 68% relative to 60 mM potassium induced conctraction, and there was no potentiation of α-adrenoceptor mediated contractions. Acetylcholine, peptide histidine isoleucine, vasoactive intestinal peptide, substance P and calcitonin gene-related peptide, all relaxed the contracted femoral artery and vein. Regarding the putative parasympathetic neurotransmitters, acetylcholine caused stronger relaxation of veins as compared to arteries whereas for vasoactive intestinal peptide and peptide histidine isoleucine the relaxations were stronger in the arterial preparation. These three agonists were more potent in the femoral vein. Substance P was more potent on the femoral vein, having the same maximum response in both preparations. On the other hand, the response induced by CGRP was some three times greater in the venous than in the arterial preparation. These data reveal that although there appear to be only minor differences in the peptidergic innervation of the rat femoral artery and vein pronounced differences occur in the peptide effector responses. The data support the concept that perivascular peptides play different roles in regulating various parts of the circulation.
Paradoxical Effects of Isothiocyanate Analog of Tolazoline on Rat Aorta and Human Platelets
Authors: Venkataraman B.V. , Hamada A. , Shams G. , Miller D.D. , Feller D.R. , Patil P.N.
Published: September 2008

The isothiocyanate analog (IBI) of tolazoline produced contraction of the rat aortic strip, with an ED50 value of 1.63 × 10–5 M. The maximum contraction of the analog was nearly equal to that of tolazoline or phenylephrine. At 27 °C the tissue reactivity of phenylephrine and IBI was similar. When compared at equiactive concentrations, the total duration of contraction of IBI was three times longer than that of tolazoline. Thus, the longer duration of action of IBI may be attributed to the S=C=N group substitution of the molecule. IBI at 10-6 M shifted the dose-response curve of phenylephrine to the right with reduction in maxima. Phentolamine and other α1or α2 adrenoceptor blockers failed to block the responses of IBI in aorta, whereas verapamil or nifedipine blocked the response significantly. It appears that IBI is acting through calcium-channel-sensitive or calcium-receptor-related mechanism(s). In aspirin-treated platelets from human plasma, a distinct phase of aggregation induced by epinephrine can be blocked by IBI with KB of 2 × 10–5 M. This indicates a small but selective α2 related action of IBI. The aggregation induced by ADP or second component of aggregation induced by epinephrine were also blocked by IBI at concentrations comparable to that of the 012-adrenoceptor-mediated response. This indicates a lack of specificity of IBI in differentiating various phases of aggregation. Therefore, as compared to tolazoline, IBI presents an interesting paradox in its interaction with various receptors or mechanisms in the vascular tissue and platelets.
Effects of Oxygen and Flow on the Diameter of the Femoral Artery of the Rabbit
Authors: Hoogerwerf N. , van de Linden P.J.W. , Sipkema P.
Published: September 2008

Contradictory results concerning the effects of oxygen and flow on blood vessel dimensions have been published. The aim of this study was to investigate the diameter changes in isolated, cannulated femoral arteries (n = 5) of the rabbit in a preconstricted state (two norepinephrine levels) during high and low pO2 (both inside and outside) at different flow levels. In this way the interaction between oxygen and flow is also investigated. Results were normalized to relative diameters, where the diameter at zero flow, during high pO2 and low norepinephrine concentration was considered as a control diameter (100%). We found three effects in this study: (1) going from high to low oxygen, there was a global vasoconstriction (repeated measures, analysis of variance, p = 0.016 with low norepinephrine and p = 0.015 with high norepinephrine); (2) when flow was increased from 1 to 100 ml/h, we found a significant (p < 0.001) flow-dependent constriction under all four conditions, and (3) there is an interaction between flow and oxygen, for example at low norepinephrine the constriction due to low oxygen is 16 % at zero flow and 1 % at a flow of 1 ml/h, at high norepinephrine these numbers are 22 and 10%, respectively.
A Monoclonal Antibody which Identifies an Antigen in Endothelial Cell and Epithelial Basement Membrane
Authors: Matsuo Shinobu , Penneys Neal S. , Fine Jo-David , Gay Steffen , Nadji Mehrdad
Published: September 2008

We isolated a monoclonal antibody which decorates the endothelial cells of normal and lymphatic vessels in formalin-fixed, paraffin-embedded tissue. In addition, the antibody recognizes a previously undescribed substance found in the basement membrane zone and subbasement membrane zone of a variety of epithelia. By ELISA assay, the antigen recognized by this monoclonal antibody is not laminin, type IV collagen or fibronectin. This antibody may be used as a diagnostic tool because it identifies an epitope in neoplasms differentiating towards endothelial cell such as angiosarcoma and Kaposi’s sarcoma.
Peptidergic Vasodilator Nerves in the Peripheral Circulation and in the Vascular Beds of the Heart and Brain
Authors: Owman Christer
Published: September 2008

This overview focusses on the ubiquitous presence of immunohistochemically visible peptidergic nerves with vasodilatory function. The nerve fibres are primarily related to the parasympathetic system (vasoactive intestinal polypeptide or VIP), the sympathetic system including the adrenal medulla (enkephalins) and to the sensory system (substance P as well as calcitonin gene-related peptide, CGRP). Substance P and probably also CGRP seem to be the mediators of antidromic vasodilatation. Enkephalins appear to be released both from nerve endings and from the adrenomeduUary cells. The vasodilatory nerve fibres in the heart distribute both to the coronary vessels and to functionally important parts of the myocardium, where interesting relations exist between the peptidergic flow regulation and contractile force. In the brain the sensory and parasympathetic pathways for VIP and substance P/CGRP have recently been mapped in detail, and a new peptidergic intracranial ganglion has been discovered. The selective electrical stimulation of the sensory and post-ganglionic parasympathetic fibres, respectively, in the brain circulation has been found to evoke a pronounced flow increase which does not appear to involve cholinergic mediation. There is also experimental evidence that the mentioned systems of fibres may interact with each other and with the sympathetic nervous system by way of neuronal cross-talk.
Mechanisms Involved in Serotonin-Induced Vasodilatation
Authors: Mylecharane E.J.
Published: September 2008

In vitro investigations have identified three major mechanisms which could contribute to the vasodilator action of serotonin (5-hydroxytryptamine, 5-HT): direct vascular smooth muscle relaxation; prejunctional inhibition of noradrenaline release from vascular sympathetic nerve terminals; and release of endothelium-derived relaxing factor (EDRF). In vivo studies have shown that in pig and cat common carotid circulations, rabbit hind-quarter and mesenteric circulations, and rat systemic vasculature, direct vascular smooth muscle relaxation may be the predominant mechanism involved, but the contribution of EDRF release remains to be established. In other circulations in vivo (dog femoral and common carotid), prejunctional inhibition of vascular sympathetic tone is the predominant mechanism responsible for serotonin-induced vasodilatation. All of these actions are mediated by 5-HT1-like receptors, but different subtypes seem to be involved in each of these mechanisms. The prejunctional inhibitory receptor has been the most studied; depending on the tissue, these subtypes may resemble 5-HT1A, 5-HT1B, 5-HT1c or 5-HT1D binding sites, or the contractile receptor in dog saphenous vein.
Lymphatic Innervation
Authors: McHale Noel G.
Published: September 2008

Bovine mesenteric lymphatic vessels have nerves in their walls which in response to field stimulation cause an increase in freqency of spontaneous lymphatic contractions and this could be blocked by α-antagonists. When vessels were loaded with [3H]-noradrenaline, 3H-effiux was increased in response to field stimulation and this was potentiated by α2-antagonists and depressed by α2-agonists. Electrical activity in these vessels consisted of a single action potential which preceded each contraction. Mean resting potential was –61 mV ± 5.7 (SD). Stimulation of postsynaptic α-receptors caused a depolarization accompanied by a decrease in membrane conductance while β-receptor stimulation had the opposite effect. Lymphatic noradrenergic nerves appear to have a role in the living animal since stimulation of the sympathetic chain in anaesthetized sheep increased popliteal efferent lymph flow and this could be blocked by α-adrenergic blockers.
Physiological Modulation of α-Adrenoceptor and 5HT Receptor Expression in Blood Vessels
Authors: McGrath J.C. , Dunn W.R. , Templeton A.G.B.
Published: September 2008

In vitro experiments on vascular smooth muscle often fail to reveal phenomena clearly demonstrable in vivo. Several recent observations in our laboratory have revealed the facility to uncover responses mediated by receptors whose functional expression had remained hidden with the standard experimental conditions first employed: conversely manipulation of conditions can selectively hide a particular receptor’s response. Examples include the uncovering of responses to: 5HT1 receptors by raised O2 tension (via cyclooxygenase products) in human umbilical vessels; α2-adrenoceptors in rabbit saphenous artery by angiotensin II and α2-adrenoceptors in perfused rat tail by elevating tone with vasopressin. The powerful synergism of agonists which cannot on their own cause contraction, can lead to inaccurate interpretations of agonist-antagonist interactions. Finally, the influence of tissue metabolism on receptor expression clearly illustrates the complex processes which must be involved in vivo.
Receptor Regulation of Atrial Natriuretic Factor
Authors: Chabrier P.E. , Roubert P. , Lonchampt M.O. , Plas P. , Braquet P.
Published: September 2008

Two atrial natriuretic factor (ANF) receptor subtypes are present in vascular nooth muscle cells: the B receptors (or biologically active) coupled to a guanylate cyclase ad the C receptors (clearance) representing 95% of the total number of ANF binding sites but noncoupled to a guanylate cyclase. Using binding experiments with 125I-ANF and measurement of cGMP production stimulated by ANF, we were able to demonstrate that ANF receptors are sensitive to homologous (induced by ANF) and heterologous regulation (induced by angiotensin II, All) in rat cultured vascular smooth muscle cells. The effect of the two hormones showed marked differences, in their time course, their reversibility and their consequence on guanylate cyclase activity. Although both ANF and All reduced the total umber of ANF binding sites after 18 h, ANF induced a desensitization of the guanylate cyclase whereas All elicited a potentialization of this system. From these results, we have included that in vascular cells B receptors are sensitive to homologous regulation and C receptors are sensitive to heterologous regulation by All. This also highlights a specific interaction between ANF and All at the receptor level.
Leukocyte-Dependent and Leukocyte-Independent Mechanisms of Impairment of Endothelium-Mediated Vasodilation
Authors: Lefer Allan M. , Aoki Nobuo
Published: September 2008

Leukocytes release cytokines and oxygen derived free radicals upon activation. Both superoxide (O2) and tumor necrosis factor (TNF) inhibit endothelium-dependent vasodilation in the intact circulation as well as in isolated blood vessels. Superoxide inactivates endothelium-derived relaxing fator (EDRF) rapidly, whereas TNF required 2 h to block EDRF release due to synthesis of adhesive proteins on the surface of neutrophils and/or the expression of their ligands on endothelial cells. Thus, vasodilation to acetylcholine is markedly attenuated by either O2or TNF, whereas the vasodilation to NaNO2 at pH 2.0 or to nitroglycerin is not affected. Superoxide dismutase restores acetylcholine responses to myocardial ischemia followed by reperfusion, whereas cycloheximide restores acetylcholine responses to TNF. This occurs both in the isolated perfused rat heart (perfused without plasma or blood cells) and in isolated perfused cat carotid arteries. EDRF may be important in preserving integrity of vital tissues during ischemic states.
Voltage-Dependent and Agonist-Activated Ionic Currents in Vascular Endothelial Cells: A Review
Authors: Takeda K. , Klepper M.
Published: September 2008

Vascular endothelial cells produce a variety of substances known to modulate the tone of surrounding smooth muscle, but the initial steps involved in receptor-response coupling are poorly characterized in these cells. Because the stimulated release of endothelium-derived relaxing factor depends on the presence of external calcium, ion channel-mediated calcium influx might represent an essential first link. Furthermore, agonist-induced endothelial cell hyperpolarization has been widely described, although the ion channels involved and the functional significance of this response remain uncertain. A review of the available literature to date concerning voltage-dependent and agonist-activated ionic currents obtained using patch clamp techiques in vascular endothelial cells is presented here. A discussion of the possible functional roles of the underlying ion channels is included.
Modulation of the Action of Calcium Antagonists in Arteries
Authors: Godfraind T. , Morel N. , Wibo M.
Published: September 2008

This paper is a review of the experimental evidence showing that specific binding sites for dihydropyridine Ca antagonists are involved in inhibition of stimulus-dependent Ca entry into arterial cells and thereby in inhibition of the contractile response. The apparent affinity of the dihydropyridine binding site is related to the proportion of a high- and a low-affinity state which is regulated by membrane potential but could also be dependent upon other factors such as G proteins. Among Ca antagonists, a subgroup of agents exhibiting voltage dependence may be identified. Their apparent pharmacological potency is highly dependent on resting membrane potential and on the duration of the depolarizing stimulus.
The First Robert Furchgott Lecture: From Endothelium-Dependent Relaxation to the L-Arginine:NO Pathway
Authors: Moncada S.
Published: September 2008

Nitric oxide (NO) is released from vascular endothelial cells and fresh vascular tissue in amounts sufficient to account for the biological actions of endothelium-derived relaxing factor. It is synthesized from the terminal guanidino nitrogen atom(s) of L-arginine, a process that is inhibited by NG-monomethyl-L-arginine (L-NMMA). Studies using L-NMMA have shown that NO is constantly generated by the vessel wall to maintain vasodilator tone. The L-arginine:NO pathway has now been identified in a number of other cells and tissues, in many of which it acts as the transduction mechanism for stimulation of the soluble guanylate cyclase.
Nonpeptide Angiotensin II Receptor Antagonists: A Novel Class of Antihypertensive Agents
Authors: Timmermans Pieter B.M.W.M. , Carini David J. , Chiu Andrew T. , Duncia John V. , Price, Jr. William A. , Wells Gregory J. , Wong Pancras C. , Wexler Ruth R. , Johnson Alexander L.
Published: September 2008

The most direct approach to block the function of the renin-angiotensin system would be to antagonize angiotensin II (All) at the level of its receptor. However, the All receptor antagonists currently available, such as saralasin, are peptides which still retain agonistic activity and lack oral bioavailability. We have identified the N-benzylimidazoles, S-8307 and S-8308, as weak, but selective nonpeptide All receptor antagonists. These initial leads were subsequently converted into more potent compounds, such as EXP6155, EXP6803 and EXP7711, while maintaining the selectivity. The compounds displace 3H-AII from its specific binding sites in adrenal cortical membranes and smooth muscle cells. They competitively inhibit the vasoconstrictor response to All in various in vivo and in vitro preparations, but do not influence those to KC1, norepinephrine, and vasopressin. Converting enzyme and renin are not affected by these agents. In renal hypertensive rats and sodium-depleted dogs our compounds cause a sustained decrease in arterial pressure following intravenous and oral (EXP7711) administration, and are devoid of agonistic properties. Taken together, these nonpeptide structures are true competitive All receptor antagonists and represent a new class of effective antihypertensive agents.
Endothelium-Dependent Effects of Beta-Adrenergic Blockers
Authors: Vanhoutte Paul M.
Published: September 2008

Nonselective β-adrenergic blockers have been reported to affect endothelium-dependent responses in isolated blood vessels in the following ways: (a) cause endothelium-augmented direct relaxations; (b) facilitate the endothelium-dependent relaxations evoked by α2-adrenergic activation, or by acetylcholine; (c) augment the intraluminal release of vasodilator prostanoids, and (d) inhibit endothelium-dependent contractions to anoxia. Important species differences exist in terms of the endothelium-dependent effects of the compounds. If they were to occur in the intact organism, the endothelium-dependent effects of the β-adrenergic blockers could help to explain their vasodilator properties.
The Potassium Channel Openers: A New Class of Vasorelaxants
Authors: Weston A.H. , Longmore J. , Newgreen D.T. , Edwards G. , Bray K.M. , Duty S.
Published: September 2008

Cromakalim, pinacidil, nicorandil, diazoxide and RP- 49356 belong to the class of drugs termed potassium channel openers. In rat portal vein diazoxide, like cromakalim, abolished spontaneous mechanical and electrical activity and in rat aorta caused an increase in 86Rb efflux and inhibited KCl (20 mM)-induced contractions. However, in contrast to cromakalim, diazoxide (>100 µM) also inhibited mechanical responses evoked by 80 mM KCl in rat aorta suggesting that it possesses pharmacological properties in addition to K channel opening. Since glibenclamide can attenuate the effects of cromakalim and diazoxide in vascular tissues, it is possible that a channel resembling the ATP-sensitive K channel found in pancreatic β-cells may be involved in the vasorelaxant effects of these agents. However, differences exist in the order of potency of cromakalim and diazoxide for producing smooth muscle relaxation and for decreasing insulin secretion in pancreatic β-cells. Furthermore galanin (which opens ATP-sensitive K channels in β-cells) increases mechanical activity in rat portal vein. It is anticipated that new chemical developments will produce K channel opening molecules with greater potency and tissue selectivity.
Mechanism of the Vasodilator Action of Pinacidil
Authors: Mulvany M.J. , Videbœk L.M. , Hughes A.D. , Aalkjœr C.
Published: September 2008

The mechanism of the vasodilator action of pinacidil has been studied in rat mesenteric small arteries. The results show, first, that the use of flux studies to make measurements of ion permeability requires knowledge of the membrane potential, especially as regards K+ permeability. Second, the results confirm that the vasodilator effect of pinacidil is due to an increase in K+ permeability. Lastly, the results suggest that the K+ channels involved are sensitive to glibenclamide.
Scope of Vasodilatory Effects of Calcium Antagonists
Authors: Fleckenstein-Grün G. , Fleckenstein A.
Published: September 2008

Specific Ca antagonists of the verapamil, nifedipine, and diltiazem type have become the drugs of choice in the therapy of cardiac hyperkinetic disorders and of vascular hypertonicity (spasms). The specific mechanism of vasodilatation by Ca antagonists was substantiated by electrophysiological, radionuclear and mechanical measurements on rather different types of arterial vasculature, including the systemic resistance vessels, as well as on portal veins. The results indicate that the vasodilator efficacy of these Ca antagonists is mainly based on at least three components: (1) Suppression of the generation of Ca-carried membrane spike potentials; (2) decrease of direct transmembrane supply of activator Ca through potential- or receptor-operated membrane channels, and (3) interference with Ca-triggered intracellular Ca release in an indirect way, in that Ca antagonists block the influx of small amounts of trigger Ca or produce depletion of intracellular Ca stores. In any case, contractile activation practically ceases if transmembrane Ca supply is totally cut off upon addition of Ca antagonists to a Ca-deficient medium.
Prostanoids Contribute to Endothelium-Dependent Coronary Vasodilation in Guinea Pigs
Authors: Lee Linda , Bruner Cathy A. , Webb Clinton
Published: September 2008

This study characterizes the contribution of prostanoids to endothelium-dependent responses in two vascular regions of the guinea pig. We compared the mechanisms of relaxation responses to acetylcholine and adenosine triphosphate (ATP) in the coronary vasculature and in the abdominal aorta of the guinea pig. Endothelium-dependent responses were examined in an isolated, potassium-arrested guinea pig heart utilizing a modified Lan-gendorff preparation. Coronary vessels were constricted with prostaglandin F2α and dilated with acetylcholine (10–910–6 mol) or ATP (10–10–10–7 mol) before and after exposure to indomethacin (14 µM, n = 6) or ibuprofen (150 µM, n = 5). Helically cut strips of abdominal aorta (n = 6) were suspended in isolated tissue baths for measurement of isometric force. Relaxation to acetylcholine (5.5 × 10–7M) and ATP (10–5 M) was quantified in strips contracted with norepinephrine before and after exposure to indomethacin (14 µM). In addition, the endothelium was damaged by exposing vessels to free radicals generated by electrolysis of the buffer (4 Hz, 9 V, 1 ms, 5 min). Following electrolysis of the buffer, relaxation responses to acetylcholine and ATP were significantly attenuated in both preparations. In the perfused heart, endothelium-dependent dilatation to acetylcholine, but not ATP were significantly inhibited in the presence of indomethacin or ibuprofen. In contrast, acetylcholine- and ATP-induced relaxation responses in the aorta were not altered by indomethacin. We conclude that prostaglandins contribute to acetylcholine-induced dilatation in the coronary bed but not in the abdominal aorta of the guinea pig. Furthermore, in the coronary bed, different endothelial factors mediate relaxation to acetylcholine and ATP.
Effect of Age on Rabbit Aortic Responses to Relaxant Endothelium-Dependent and Endothelium-Independent Agents
Authors: Chinellato A. , Pandolfo L. , Ragazzi E. , Zambonin M.R. , Froldi G. , De Biasi M. , Caparrotta L. , Fassina G.
Published: September 2008

The aim of this study was to evaluate the effects of aging on endothelium-dependent and endothelium-independent relaxation of rabbit thoracic aorta from New Zealand white rabbits aged 4–6 and 7–12 months. The contractile response to noradrenaline (NA) decreased with increasing age, but NA [EC50] did not vary significantly. Acetylcholine (Ach)-induced relaxation of aortic rings precontracted with NA [EC50] did not change significantly with increasing age. The relaxation induced by ATP of aortic rings, precontracted with NA [EC50], was signficantly greater in young than in adult rabbits. This difference between young and adult animals became more evident in aortic rings deprived of endothelium: in adult animals, the ATP-induced relaxation of aortic rings with endothelium was significantly greater than in the rings without endothelium. The endothelium-independent relaxation by sodium nitrite (NaNO2) at lower concentrations was significantly greater in young than in adult rabbit aortic rings precontracted with NA [EC50]. Concluding, the age-induced changes in vascular response in male New Zealand white rabbits are related to an impaired mechanism at smooth muscle level.
Growth Responses in Isolated Elastic, Muscular and Resistance-Sized Arterial Segments of the Rat
Authors: De Mey Jo G.R. , Uitendaal Martin P. , Boonen Harrie C.M. , Schiffers Paul M.H. , Fazzi Gregorio E.
Published: September 2008

To evaluate whether intravascular phenomena contribute to local differences in growth responses of the arterial wall, we evaluated responses to organoid culture in a broad variety of arterial preparations. Arterial segments were isolated from adult, normotensive rats, sympathectomized, denuded from endothelium, and suspended in medium supplemented with serum. As judged from the nuclear incorporation of the thymidine analogue 5-bromo-2’-deoxyuridine (BrdUrd), this induced a transient stimulation of DNA synthesis in only a fraction of the arterial smooth muscle cells in all types of arteries. This intramedial DNA synthesis was more marked in renal arteries than in carotid arteries or aortae and was least pronounced in main pulmonary, femoral, and superior mesenteric artery and in mesenteric resistance-sized arteries. Organoid culture of isolated arteries did not increase the cross-sectional area of the media or the number of medial cells. It rather resulted in proliferation of smooth-muscle-like cells outside the media. In addition, smooth-muscle-like cells migrated out of the isolated arterial segments during culture. The rate of proliferation of these isolated cells did not differ between large arteries of different anatomical origin. However, isolated cells derived from mesenteric resistance arteries proliferated at a rate that was 4 times slower than that of large artery cells. The presence of endothelium significantly reduced medial DNA synthesis in carotid and renal artery segments, but not in mesenteric resistance-sized preparations. These data indicate that growth responses of the arterial wall differ quantitatively with the anatomical location and branching order of the vascular segment. In addition to the regional heterogeneity of endothelial effects on mitogenic responses of arterial smooth muscle, this seems to be due to regional differences in the susceptibility of arterial smooth muscle to exogenous growth factors. In this respect, we speculate that subsets of growth-resistant and growth-prone arterial smooth muscle cells could be heterogeneously distributed over the arterial tree.
Metabolic Syndrome, Inflammation, and Incident Heart Failure in the Elderly
Authors: Suzuki Takeki , Katz Ronit , Jenny Nancy Swords , Zakai Neil A. , LeWinter Martin M. , Barzilay Joshua I. , Cushman Mary
Published: September 2008

Background—

Inflammation markers and metabolic syndrome (MetS) are associated with risk of congestive heart failure (CHF). We evaluated whether combining inflammation markers and MetS provided additive information for incident CHF and if incorporating inflammation markers to the MetS definition added prognostic information.

Methods and Results—

We studied 4017 men and women ≥65 years old, without baseline CHF or diabetes, participating in the Cardiovascular Health Study, an observational study with 12.2 years follow-up and 966 cases of incident CHF. Baseline “C-reactive protein (CRP)-MetS” or “interleukin (IL)-6–MetS” were defined as presence of 3 out of 6 components, with elevated CRP (≥3 mg/L) or IL-6 (≥2.21 pg/mL) as a sixth component added to ATPIII criteria. Cox models adjusted for CHF risk factors and incident coronary disease were used to calculate hazard ratios for CHF. MetS and elevated inflammation markers were independently associated with CHF risk (hazard ratios, 95% CI: 1.32, 1.16 to 1.51 for MetS; 1.53, 1.34 to 1.75 for CRP; 1.37, 1.19 to 1.55 for IL-6). There was a 20% relative excess risk attributed to the combination of MetS and CRP (95% CI, −44% to 88%). CRP-MetS and IL-6–MetS definitions reclassified 18% and 13%, respectively of participants as MetS. Both CRP-MetS and IL-6–MetS increased risk of CHF by 60% compared with those without MetS.

Conclusion—

MetS and inflammation markers provided additive information on CHF risk in this elderly cohort. Inflammation-incorporated MetS definitions identified more participants with the same risk level as ATPIII MetS. Considering inflammation markers and MetS together may be useful in clinical and research settings.
The 2008 William M. Feinberg Lecture
Authors: Johnston S. Claiborne
Published: September 2008

Stroke is a tremendous burden to health worldwide both in the developed and developing world. Current levels of research funding do not adequately reflect this burden, particularly when expected increases in stroke rates are considered. Of course, an investment in stroke research is only justified if a return can be expected. The ultimate goal of stroke research is to reduce the burden of disease, and clinical trials are the clearest expression of the value of research because their results can directly impact health. In a review of stroke trials funded by the US National Institute of Neurological Disorders and Stroke, we found that the overall impact of the trials was dramatically positive and justified the entire research budget of the Institute. Nonetheless, there were obvious opportunities for improvement. Methods for selecting trials to fund could be improved and better aligned with disease burden and potential impact. Furthermore, clinical trial costs are increasing rapidly and reversing this trend must be a priority. More creative and systematic approaches to defining the research agenda and enhancing trial methods could substantially accelerate the rate of discovery and increase the impact of those discoveries on public health. To get there, we desperately need more research on research—meta-research—on topics not just relevant to stroke, but to the study of all disease.
Cultural Differences in Perception: Observations from a Remote Culture
Authors: Davidoff Jules , Fonteneau Elisabeth , Goldstein Julie
Published: September 2008

Perceptual similarity was examined in a remote culture (Himba) and compared
to that of Western observers. Similarity was assessed in a relative size
judgement task and in an odd-one-out detection task. Thus, we examined the
effects of culture on what might be considered low-level visual abilities.
For both tasks, we found that performance was affected by stimuli that were
culturally relevant to the tasks. In Experiment 1, we showed that the use of
cow stimuli instead of the standard circles increased illusory strength for
the Himba. In Experiment 2, only the Himba showed more accurate detection
based on category differences in the displays. It is argued that that
Categorical Perception in Experiment 2, based on its presumed Whorfian
origins, was the more reliable procedure for examining the effects of
culture on perception.
Evidence Against Linguistic Relativity in Chinese and English: A Case Study of Spatial and Temporal Metaphors
Authors: Tse Chi-Shing , Altarriba Jeanette
Published: September 2008

To talk about time, English speakers often use horizontal spatial metaphors whereas Chinese speakers use both vertical and horizontal spatial metaphors. Boroditsky (2001) showed that while Chinese-English bilinguals were faster to verify a temporal target like June comes earlier than August after they had seen a vertical spatial prime rather than a horizontal spatial prime, English monolinguals showed the reverse pattern, thus supporting the linguistic relativity hypothesis. This finding was not conceptually replicated in January and Kako's (2007) six experiments for English monolinguals. In the current experiment, we failed to conceptually replicate her English monolinguals' findings: both Chinese-English bilinguals and English monolinguals were faster to verify the sentences after seeing a vertical spatial prime than a horizontal spatial prime. While we replicated Boroditsky's findings, in part, for our Chinese-English bilinguals, the similarity in the pattern of findings for both Chinese-English bilinguals and English monolinguals argues against the linguistic relativity hypothesis.
The Application of Uncitral Model Law Principles in the Middle East Region
Authors: Sadah Muhammad Abu , Norton Simon
Published: September 2008

This article presents an empirical analysis of the impact of the enforcement of substantive UNCITRAL Model Law principles in the Middle East region. Despite the main differences in the schools of thought and jurisdictions in the Middle East, the major conclusion is that UNCITRAL principles are applicable. As compared with data taken from legislations and case law after adopting the UNCITRAL Model Law, in an extension of the analysis, findings show a marginally significant change and deviations from the basic principles of the Model Law in these countries. Analysis of the implications of these changes from the perspective of the role played by the Model Law, shows that there was significant theoretical and practical negative impact upon the overall objectives of the law enforcement effort.
References to Islam and Women in the Afghan Constitution
Authors: Kamali Mohammad Hashim
Published: September 2008

This paper is presented in three parts and several sections. The first part consists of a stocktaking of recent developments and dynamics that have engaged President Hamid Karzai's government ever since he came to power in December 2001. A mixed picture is presented which draws attention to many problems that have impeded reconstruction efforts in the country. Some positive developments have also occurred including, for example, the introduction of a new constitution, presidential and parliamentary elections, as well as resumption of schooling for children that by mid-2006 had numbered four million throughout the country. An overview of the previous constitutions and a brief historical perspective attempt to show how leadership flaws and internal differences in the royal household plunged Afghanistan into a succession of coups, foreign invasions, and catastrophic consequences for its people. Are there any lessons to be learnt? The second part of this essay focuses on a review and analysis of the 2004 constitution with special reference to Islam, and the last part takes a similar approach to women's rights.
Altered States of Knowledge: The Attainment of Gnōsis in the Hermetica
Authors: Hanegraaff Wouter
Published: September 2008

Research into the so-called “philosophical” Hermetica has long been dominated by the foundational scholarship of André-Jean Festugière, who strongly emphasized their Greek and philosophical elements. Since the late 1970s, this perspective has given way to a new and more complex one, due to the work of another French scholar, Jean-Pierre Mahé, who could profit from the discovery of new textual sources, and called much more attention to the Egyptian and religious dimensions of the hermetic writings. This article addresses the question of how, on these foundations, we should evaluate and understand the frequent hermetic references to profound but wholly ineffable revelatory and salvational insights received during “ecstatic” states. Festugière dismissed them as “literary fictions”, whereas Mahé took them much more seriously as possibly reflecting ritual practices that took place in hermetic communities. Based upon close reading of three central texts (CH I, CH XIII, NH VI6), and challenging existing translations and interpretations, this article argues that the authors of the hermetic corpus assumed a sequential hierarchy of “levels of knowledge”, in which the highest and most profound knowledge (gnōsis) is attained only during ecstatic or “altered” states of consciousness that transcend rationality. While the hermetic teachings have often been described as unsystematic, inconsistent, incoherent or confused, in fact they are grounded in a precise and carefully formulated doctrine of how the hermetic initiate may move from the domain of mere rational discourse to the attainment of several “trans-rational” stages of direct experiential knowledge, and thereby from the limited and temporal domain of material reality to the unlimited and eternal one of Mind.