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PubMed1997

Kinetic and safety studies on intrathecally infused recombinant-methionyl human brain-derived neurotrophic factor in dogs.

To define the kinetics and safety of spinally infused recombinant-methionyl human brain-derived neurotrophic factor (r-metHuBDNF), beagle dogs were prepared with lumbar intrathecal catheters passed through the cisternal membrane to the L1-L4 lumbar level. For kinetic studies, r-metHuBDNF was delivered by bolus or infusion through one catheter and lumbar CSF was sampled periodically through a second. As a lumbar bolus, r-metHuBDNF displayed a biphasic clearance with t(1/2)a = 0.7 hr and t(1/2)b = 7. 9 hr. Lumbar to cisternal concentrations after bolus delivery were approximately 60:1. For safety studies, dogs received continuous intrathecal infusion (2.4 ml/day) for 28 days of saline (n = 6), r-metHuBDNF at 200 (n = 6), 800 (n = 6), or 2000 (n = 7) microg/day. Control dogs showed no changes. Intrathecally infused r-metHuBDNF produced a dose-dependent increase in muscle tone and decreased coordination. Low-dose r-metHuBDNF was associated with moderate increases in muscle tone after 22-28 days of infusion. No clinically important changes were noted in rectal temperature, arterial pressure, respiration and heart rate, body weight, food consumption, stool or urine output, or change in blood chemistries measured throughout the study. Cisternal CSF protein and glucose sampled at 28 days were not different between dose groups and all cultures were negative. Histopathological examination of the spinal cord typically revealed some degree of chronic inflammation around the catheter, including fibrotic adhesions and focal accumulations of lymphoid and plasma cells, but these effects were not dose dependent. In other dogs receiving r-metHuBDNF (2000 or 4000 microg/day), termination of infusion resulted in significant recovery.

Animals↗
PubMed2000

Hypoxia, metabolic inhibition, and isolated rat mesenteric tone: influence of arterial diameter.

The present study examined and compared the effects of severe hypoxia (induced by either substitution of O(2) in the gassing medium with N(2) or by addition of the O(2) scavenger sodium dithionite) and metabolic inhibition (induced by addition of sodium cyanide) on the tone of isolated rat mesenteric resistance vessels. The influence of vessel diameter and the endothelium on responses to these maneuvers was investigated. Hypoxia (due to both substitution of O(2) with N(2) and by addition of 2 mM sodium dithionite) caused near maximal relaxation of all tissues studied. Addition of 10 mM dithionite, however, produced a significantly smaller response. Two mM cyanide also relaxed mesenteric arteries. In small vessels a near maximal relaxation to cyanide was observed, however, in larger vessels the relaxation to metabolic inhibition was significantly less than that observed to hypoxia. Increasing the concentration of cyanide had no further effect on responses. All responses were found to be endothelium-independent. Thus, as the effects of hypoxia and cyanide are not always similar, care must be taken when extrapolating the effects of metabolic inhibition to those of hypoxia. The results of this study suggest that, in large mesenteric vessels at least, an "O(2) sensing step," in addition to effects of metabolism, may be involved in the hypoxic response.

Animals↗
PubMedDate not supplied

Role of nitric oxide on cholinergic component of bronchial tone in pig.

In vitro studies demonstrated that stimulation of intrinsic nerves of airway smooth muscle results in a predominantly contractile response, followed by a relaxant response which involves cholinergic, adrenergic and non-adrenergic non-cholinergic (NANC) nerve activation. Thus, in this paper it is determined whether endogenous nitric oxide (NO) modulates cholinergic neurotransmission in isolated pig airway smooth muscle. Bronchial rings were suspended in organ baths for isometric measurement of tension and the contractions were induced using electrical field stimulation (EFS) techniques. Then, the effects of L-NG-nitroarginine (L-NOARG, 10 microM), an inhibitor of NO synthase, and L-arginine (L-ARG, 1 mM), a precursor of NO synthesis, were evaluated. The cholinergic contractions induced by electrical field stimulation (EFS: 60 V, 2 ms, 60 Hz) of pig lobar bronchial preparations increased (29%) in the presence of L-NOARG (10 microM). This effect may be released by nerves in pig large airways during EFS.

Animals↗
PubMed1999

The effects of excitatory amino acids on isolated gut segments of the rat.

Glutamate and aspartate are excitatory neurotransmitters in both central and peripheral nervous systems, acting on ionotropic and metabotropic receptors. In our study we have examined the effects of glutamate, aspartate, N-methyl-d-aspartate (NMDA), kainic acid and (+/-)-1-aminocyclopentane-cis-1,3-dicarboxylic acid (ACPD) on tone and spontaneous activity of isolated rat gastric fundus, jejunum, ileum, ascending colon and rectum. Both glutamate and aspartate produced concentration-dependent tonic contractions of rat fundus and rectum; the other gut segments used in the study were not responsive. While only NMDA and kainic acid produced concentration-dependent tonic contractions of isolated rat gastric fundus, all three type-selective agonists of glutamate receptors (NMDA, kainic acid and ACPD) produced tonic contractions of isolated rat rectum. The results of our study suggest that glutamate and aspartate in rat gastric fundus activate excitatory intrinsic neurons through only ionotropic receptors (NMDA and non-NMDA receptors), while the same action in rat rectum is mediated through both ionotropic and metabotropic receptors.

Animals↗
PubMed2002

Role of tachykininergic and cholinergic pathways in modulating canine gastric tone and compliance in vivo.

Acetylcholine and tachykinins act as co-transmitters along excitatory pathways at different gut levels. Since cholinergic pathways are involved in maintaining gastric tone during fasting, our aim was to study the possible role of tachykininergic pathways in modulating canine gastric tone and compliance in vivo by using selective tachykinin receptor antagonists. In four fasting, conscious dogs, we characterized the pressure-volume relationship in the proximal stomach by using a barostat. We increased the pressure of the intragastric bag by 2 mmHg increments every 3 min, starting from a baseline value of 2 up to 12 mmHg. Drug effects were investigated by studying pressure-volume relationships before and 15 min after intravenous (i.v.) administration of SR140333, SR48968, or SR142801 (respectively, NK (1)-, NK (2)-, and NK (3)-receptor antagonist, each at the dose of 1 mg kg (-1)) or atropine (100 microg kg (-1)). Pressure-volume curves were fitted by nonlinear regression analysis. Before drug administration, the curve that best fitted the pressure-volume relationship was exponential. SR140333, SR48968 and SR142801 did not affect baseline gastric tone or the gastric pressure-volume curve at any distension level. At a distending pressure of 6 mmHg, the Delta volumes obtained after administration of SR140333, SR48968 or SR142801 vs control were 65 +/- 28, 27 +/- 26, 14 +/- 20 ml, respectively. The same was true even when all three antagonists were administered together to achieve simultaneous blockade of all three tachykinin receptor subtypes. Atropine increased baseline gastric volume (Delta volume = 237 +/- 15 ml; P< 0.01) and significantly (P< 0.0001) shifted the pressure-volume curve to the left. After atropine, a linear equation best fitted the pressure-volume curve. We conclude that tachykininergic pathways are not involved in modulating canine gastric tone and compliance during fasting, whereas cholinergic pathways play a major role not only in maintaining gastric tone, but also in modulating the compliance of the proximal stomach to a distending stimulus.

Animals↗
PubMed2002

Hypochlorous acid is a potent inhibitor of acetylcholinesterase.

The role of hydrogen peroxide and peroxynitrite in the induction of airway hyperreactivity has been well described. Another reactive species which is formed during airway inflammation is hypochlorous acid (HOCl). In the present investigation the effect of HOCl on cholinergic innervation of the airway was investigated. It was observed that HOCl was capable of increasing the basal tension of electrically stimulated tracheal smooth muscle. It was found that HOCl inhibits purified acetylcholinesterase with an IC50 value of 0.66 microM. Decreased acetylcholinesterase activity could allow accumulation of acetylcholine and increased airway muscle tension. The effects of HOCl on the isolated organ and the enzyme preparation could be precluded with thiol group-containing compounds such as reduced glutathione and N-acetylcysteine. The present findings indicate that HOCl can act as inhibitor of acetylcholinesterase. The implications of this finding for the induction of airway hyperreactivity are discussed.

Acetylcholinesterase↗
PubMed1988

The influence of oxygen tension on membrane potential and tone of canine carotid artery smooth muscle.

In vascular smooth muscle of canine carotid artery segments the decrease in oxygen tension from approximately 550 mmHg to approximately 30 mmHg leads to a dose-dependent hyperpolarization and relaxation of the vessel strip. At PO2 values below approximately 15-20 mmHg depolarization and subsequent contraction were found. All changes of the parameters investigated were reversible. Indomethacin (10(-5) M) had no significant effect on the hypoxia-dependent potential and tension changes. The hyperpolarized part of the activation curve was obtained by plotting tension versus membrane potential values.

Animals↗
PubMed1984

Isotonic contraction of temp-step activated muscle fibers with varied tonicity: effects of cell volume and the degree of activation.

These studies on intact fibers describe the effects of calcium, ionic strength and volume on the contraction properties. The results provide firm evidence that cell volume affects the speed but not the force. On the other hand, sarcoplasmic ionic strength affects the force development, with no effect on unloaded speed of shortening. These results suggest that there are essential differences in the rate limiting steps for isometric and isotonic properties of the cross-bridge mechanism. The studies at various degrees of activation indicate that Ca acts as a simple "on-off" switch for cross-bridge activation, in intact fibers.

Animals↗
PubMed1984

The toxic effects of clofibrate and its metabolite on mammalian skeletal muscle: an electrophysiological study.

Membrane electrical parameters of rat extensor digitorum longus muscles were analysed in vitro, with intracellular microelectrodes, after chronic treatment with clofibrate or after in vitro application of chlorophenoxyisobutyric acid, the in vivo metabolite of clofibrate. Clofibrate caused only a 38% decrease in the membrane chloride conductance while its metabolite induced a large decrease of chloride conductance and drastic changes in the excitability characteristics of the muscles sampled. The capability of clofibrate to induce two types of myotonia is discussed.

Action Potentials↗
PubMed1991

Effects of native and oxidized low-density lipoproteins on endothelium-dependent and endothelium-independent vasomotion.

Native and oxidized low-density lipoproteins (LDL) were investigated for their direct influence on EDRF-formation, EDRF-activity, and vascular smooth muscle tone. Native (n) LDL, isolated from fresh human plasma, was oxidized by Cu(2+)-incubation. EDRF released from cultured endothelial cells was inactivated by both n-LDL and ox-LDL (1 mg/ml) as detected in a bioassay system. n-LDL reduced the EDRF-mediated vasodilations of the detector segments by 38.5 +/- 5.3%, and ox-LDL by 55.5 +/- 4.6%. The effects of lipoproteins on EDRF-formation were studied on cultured endothelial cells, preincubated with either n-LDL or ox-LDL (1 mg/ml, 1 h) and stimulated for EDRF-release with bradykinin after washout of the lipoproteins. EDRF was assessed by measuring its stimulatory effect on the activity of a purified soluble guanylate cyclase. Preincubation with both n-LDL and ox-LDL did not reduce the bradykinin-induced EDRF-formation. Accordingly, acetylcholine-induced, EDRF-mediated dilations of intact rabbit femoral artery segments were not impaired by luminal exposure to n-LDL or ox-LDL (1 h, 1mg/ml). Effects of n-LDL and ox-LDL on vascular smooth muscle tone were investigated in isolated perfused rabbit femoral arteries. Perfusion of endothelium-intact and -denuded segments with ox-LDL (80-500 micrograms protein/ml) caused no or only weak vasoconstrictions in the absence of contractile agonists. However, in the presence of ox-LDL, vasoconstrictions to threshold concentrations of norepinephrine (NE), serotonin (5-HT), phenylephrine (PE) or potassium were significantly enhanced. Native LDL (80-1000 micrograms/ml) had no effect on vascular tone, neither in presence nor in absence of contractile agonists. Preincubation with verapamil, diltiazem, and nitrendipine inhibited vasoconstrictions evoked by ox-LDL. The contractile responses to ox-LDL were significantly greater in endothelium-denuded segments than in endothelium-intact segments. In conclusion, neither n-LDL nor ox-LDL acutely impair the formation of EDRF, but do inactivate EDRF after its release from endothelial cells. n-LDL has no direct influence on vascular smooth muscle tone, but ox-LDL greatly enhances vasoconstrictions to various contractile agonists by direct interaction with vascular smooth muscle. Thus, in regions of lipoprotein-accumulation in the arterial wall, both n-LDL and ox-LDL may favor inappropriate vasoconstrictions.

Animals↗
PubMed1991

Endothelium-dependent control of vascular tone: effects of age, hypertension and lipids.

As a source of several vasoactive factors, the endothelium takes part in the regulation of vascular tone. The most important endothelium-derived vasoactive substances are nitric oxide, prostacyclin, endothelin-1 and contracting factors requiring the activity of cyclooxygenase. The endothelium is an obvious target organ of cardiovascular risk factors. Accordingly, functional alterations do occur with aging, hypertension, and lipids. All three conditions are associated with a decreased basal and stimulated release of endothelium-derived nitric oxide. On the other hand, the release of endothelin-1 appears to increase with age, while the sensitivity to the peptide markedly decreases under the same conditions. In the spontaneously hypertensive rat, acetylcholine and stretch evoke the release of cyclooxygenase-dependent endothelium-derived contracting factor, most likely prostaglandin H2. The sensitivity and circulating levels of endothelin-1, on the other hand, are reduced in this experimental model of hypertension. In the porcine coronary circulation, oxidized low-density lipoproteins selectively reduce endothelium-dependent relaxations to aggregating platelets, serotonin, and thrombin which are mediated by nitric oxide. The alterations of endothelial function occurring with aging, hypertension, and hyperlipidemia may have important clinical implications for the pathogenesis of cardiovascular disease.

Aging↗
PubMed1993

Angiotensin, ACE-inhibitors and endothelial control of vasomotor tone.

The renin angiotensin system and endothelium-derived vasoactive substances are both important regulators of vascular tone. Recent evidence suggests that the two systems may be tightly interconnected and drugs interfering with one system may also affect the other. Beside the circulating renin angiotensin system, a vascular wall renin angiotensin system has been postulated and various components of it have been demonstrated in endothelial and vascular smooth muscle cells. Of particular importance is the angiotensin converting enzyme (ACE) which is identical to kininase II, which breaks down bradykinin into inactive components. Bradykinin is a potent activator of the L-arginine nitric oxide system (endothelium-derived relaxing factor). Hence, ACE-inhibitors not only deactivate the pressor system, but increase the local concentrations of bradykinin and thereby stimulate a potent endothelium-derived vasodilator system. Angiotensin II not only can activate vascular smooth muscle cells (where it causes contraction and proliferation), but also endothelial cells. In certain blood vessels, angiotensin II can stimulate prostacyclin production; in addition, angiotensin II activates endothelin messenger RNA in endothelial cells. This activation of the endothelin vasopressor system increases vascular tone and enhances the local vasoconstrictor responses (due to the amplifying effects of endothelin on noradrenaline- and serotonin-induced contractions). Although the acute effects of ACE-inhibitors in isolated blood vessels are restricted to inhibition of angiotensin I-induced contractions and augmentation of bradykinin-induced endothelium-dependent relaxations, chronic therapy with the drugs appears to enhance endothelium-dependent responses to several agonists, particularly in hypertensive animals. Hence, this mechanism of action of ACE-inhibitors may account for an important vascular protective effect of the drugs. Thus, in summary, the renin angiotensin system and endothelium-derived vasoactive substances are tightly interconnected. This may be important under physiological and pathophysiological conditions, and is of importance for the action of currently available cardiovascular drugs, in particular, ACE-inhibitors.

Angiotensin II↗
PubMed2002

Cyclic variation of cerebral pial arteriolar diameter synchronized with positive-pressure inhalation.

Laboratory observations have noted that during normocapnia and intact vascular tone, changes in the intracranial pressure (ICP) and arterial blood pressure (ABP) recordings are not similar. The purpose of the present study was to determine whether: 1) the diameter of cerebral pial arterioles synchronously increases during positive pressure inhalation and decreases during the expiration phase of ventilation; and 2) the variation in arteriolar diameter is greater when vascular tone is intact than when arterioles are maximally dilated. Severe hypercapnia was induced by prolonged ventilation with gas mixture of 20% O2, 10% CO2, and 70% N2 in 8 piglets. S-VHS recordings of 3600X magnification of nine pial arterioles were obtained during conditions of normal vascular tone and severe hypercapnia and digitally analyzed by an image-averaging method. Variation of the amplitude of arteriolar diameter over the ventilation cycle was computed and found to synchronously increase during positive pressure inhalation and to decrease to a steady state baseline during passive expiration. Mean amplitude of variation in diameter (+/- S.D.) during normal tone and hypercapnia was computed as 1.63 (+/- 0.693) microns and 1.012 (+/- 0.869) microns respectively and found to be significantly greater during the condition of normal vascular tone than during hypercapnia (p < .006). These results suggest that a cyclic variation of arteriolar blood volume is one causal factor related to the low frequency variation of the baseline of ICP associated with positive pressure ventilation.

Animals↗
PubMed1993

Tension transients in skeletal muscle fibres of the frog at varied tonicity of the extracellular medium.

Length steps (complete in 0.2 ms; amplitude < 2% of the fibre length) were applied during the tetanus plateau of intact frog muscle fibres (1.7-3.2 degrees C). The effects of varied tonicity on the early changes in tension in response to the length steps were studied. The solutions were made hypotonic by reduction of the NaCl concentration from 115.5 mM to 92.4 mM and hypertonic by addition of 98 mmol sucrose per litre of the normal Ringer fluid. In all solutions tested, the length step first caused tension to change simultaneously with the step reaching an extreme value T1. After completion of the length change, tension recovered quickly to an intermediate level T2 and, after a period with slowing or reversal of the recovery, it returned slowly to the steady-state value. The maximum isometric tension was significantly reduced by increases in tonicity. In contrast, there were only small effects of varied tonicity on the peak tension-change in response to a length step (the stiffness) and on the amplitude of the fast force recovery (T2-T1) after releases. The slope of the T2-curve (a plotting of T2 versus amplitude of the length step) was reduced for releases and increased for stretches when tonicity was raised. Furthermore, the T2-curve intersected the length axis for smaller releases at high tonicity levels. The reduced isometric tension to stiffness ratio at raised tonicity could be interpreted as a reduced average force per crossbridge. Simulations using the crossbridge model of Huxley and Simmons (1971) showed that the lack of change of the recovery amplitude (T2-T1) after releases and the changes in the T2-slope are in accordance with this interpretation. The shift of the T2 length intercept is consistent with the idea that the distance traversed by the crossbridges during the power-stroke is reduced by raised tonicity.

Animals↗
PubMed1989

The pathological basis of angina pectoris.

Coronary stenoses may be either concentric without any potential for variation in the degree of obstruction to flow or eccentric, where the cross-sectional area of the lumen can alter with vasomotor tone. Variable obstruction at eccentric stenoses is due to the retention of an arc of normal vessel wall opposite the plaque. Abnormal vasomotor responses are a feature of both human and experimental atheromatous coronary arteries; such an abnormality is likely to reflect endothelial dysfunction with loss or neutralization of endothelial-derived relaxant factor (EDRF). Structural studies show that superficial intimal injury, with migration of monocytes and focal endothelial denudation leading to deposition of small numbers of platelets on the exposed intimal collagen, is found in both experimental and human atheroma. Such endothelial changes may be responsible for arterial constriction leading to transient myocardial is-chemia in both patients with stable exertional angina and in those without overt ischemic heart disease. Larger coronary thrombi are associated with deep intimal tears or fissures that extend into the lipid pool of an atheromatous plaque. The resultant thrombi, large enough to be seen angiographically, project into the arterial lumen and are associated with un-stable angina of the abrupt-onset crescendo type. Nonoccluding mural thrombi in a coronary artery are a source of distal microemboli into the myocardium.

Angina Pectoris↗