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PubMed1997

Natriuretic peptide family as a novel antimigration factor of vascular smooth muscle cells.

Vascular smooth muscle cell (SMC) migration is proposed to be an important process in the initiation and/or progression of atherosclerosis. The present study examined the effects of the natriuretic peptide family (atrial, brain, and C-type natriuretic peptides; ANP, BNP, and CNP) on the migration of cultured rat SMCs, using Boyden's chamber methods. Fetal calf serum (FCS) and platelet-derived growth factor (PDGF)-BB potently stimulated SMC migration. Rat ANP(1-28), rat BNP-45, and rat CNP-22 clearly inhibited SMC migration stimulated with FCS or PDGF-BB in a concentration-dependent manner. CNP-22 had the most potent inhibitory effect compared with other natriuretic peptides. When PDGF-BB-induced migration was separated into chemotactic and chemokinetic activities, the chemotactic component was strongly inhibited by these natriuretic peptides. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cyclic GMP. The addition of a cyclic GMP analogue, 8-bromo cyclic GMP, and an activator of the cytosolic guanylate cyclase, sodium nitroprusside, significantly inhibited FCS- and PDGF-BB-stimulated migration in a concentration-dependent manner. These results suggest that natriuretic peptides, especially CNP-22, inhibit FCS- or PDGF-BB-stimulated SMC migration at least in part through a cyclic GMP-dependent process. Thus, the natriuretic peptide family may play a role as an antimigration factor of SMCs under certain circumstances.

Animals↗

PubMed1988

Na+-Ca2+ exchange in cultured vascular smooth muscle cells.

Vascular smooth muscle cells (VSMC) contract as intracellular free calcium ([Ca2+]i) rises. While Na+-Ca2+ exchange has been proposed to contribute to transmembrane Ca2+ flux, its role in cultured VSMC is unknown. Accordingly, we have investigated the role of Na+-Ca2+ exchange in unidirectional and net transmembrane Ca2+ fluxes in cultured rat aortic VSMC under basal conditions and following agonist-mediated stimulation. Transmembrane Ca2+ uptake was significantly increased in response to a low external Na+ concentration ([Na+]o) compared with 140 mM [Na+]o. Na+-dependent Ca2+ uptake in response to low [Na+]o was further increased by intracellular Na+ loading by preincubation of the VSMC with 1 mM ouabain. Under steady-state conditions, Ca2+ content varied inversely with [Na+]o, increasing from 1.0 nmol Ca2+/mg protein at 140 mM [Na+]o to 4.0 nmol Ca2+/mg protein at 20 mM [Na+]o. Increasing [K+]o to 55 mM also enhanced Na+-dependent Ca2+ influx. Augmentation of Ca2+ uptake with K+ depolarization was not significantly inhibited by the calcium channel antagonist verapamil. Transmembrane Ca2+ efflux was increased in response to 130 mM [Na+]o compared with zero [Na+]o (iso-osmotic substitution with choline+), and was further stimulated by the vasoconstrictor angiotensin II, which is known to elevate [Ca2+]i. These changes in [Ca2+]i were studied directly using fura-2 fluorescence measurements. Elevated [Ca2+]i levels returned to baseline more rapidly in the presence of normal (130 mM) [Na+]o compared with zero [Na+]o (iso-osmotic substitution with choline+). These findings suggest that a bidirectional Na+-Ca2+ exchange mechanism is present in cultured rat aortic VSMC.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed2005

Endothelin-1, superoxide and adeninediphosphate ribose cyclase in shark vascular smooth muscle.

In vascular smooth muscle (VSM) of Squalus acanthias, endothelin-1 (ET-1) signals via the ET(B) receptor. In both shark and mammalian VSM, ET-1 induces a rise in cytosolic Ca(2+) concentration ([Ca(2+)](i)) via activation of the inositol trisphosphate (IP(3)) receptor (IP(3)R) and subsequent release of Ca(2+) from the sarcoplasmic reticulum (SR). IP(3)R-mediated release of SR Ca(2+) causes calcium-induced calcium release (CICR) via the ryanodine receptor (RyR), which can be sensitized by cyclic adeninediphosphate ribose (cADPR). cADPR is synthesized from NAD(+) by a membrane-bound bifunctional enzyme, ADPR cyclase. We have previously shown that the antagonists of the RyR, Ruthenium Red, high concentrations of ryanodine and 8-Br cADPR, diminish the [Ca(2+)](i) response to ET-1 in shark VSM. To investigate how ET-1 might influence the activity of the ADPR cyclase, we employed inhibitors of the cyclase. To explore the possibility that ET-1-induced production of superoxide (O(2)*-) might activate the cyclase, we used an inhibitor of NAD(P)H oxidase (NOX), DPI and a scavenger of O(2)*-, TEMPOL. Anterior mesenteric artery VSM was loaded with fura-2AM to measure [Ca(2+)](i). In Ca(2+)-free shark Ringers, ET-1 increased [Ca(2+)](i) by 104+/-8 nmol l(-1). The VSM ADPR cyclase inhibitors, nicotinamide and Zn(2+), diminished the response by 62% and 72%, respectively. Both DPI and TEMPOL reduced the response by 63%. The combination of the IP(3)R antagonists, 2-APB or TMB-8, with DPI or TEMPOL further reduced the response by 83%. We show for the first time that in shark VSM, inhibition of the ADPR cyclase reduces the [Ca(2+)](i) response to ET-1 and that superoxide may be involved in the activation of the cyclase.

ADP-ribosyl Cyclase↗

PubMedDate not supplied

Metabolic effects of direct current stimulation on cultured vascular smooth muscle cells.

Vascular smooth muscle cells from rabbit arteries were grown in tissue culture and stimulated by DC impulses (1 mA, 1 V, 10 Hz, 1 ms/imp). Scanning microscopic examination disclosed that in stimulated cultures the cell surface was enlarged by numerous microvilli. This was interpreted as being indicative of an increase in cell activity. Cellular metabolism was characterized by analyzing the incubation medium for glucose, glutamate/glutamine, and lactate. When compared to unstimulated controls, stimulation caused an increase in the uptake of glucose and glutamine as well as an increased lactate production. The enhancing effect on metabolism was prevented when the "calcium antagonist" verapamil was present (5 X 10(-6) M). Although the exact mechanism by which DC stimulation influences the cells remains obscure, this finding indicates an important mediating role of Ca2+ ions.

Animals↗

PubMed1986

Regulation of cytoplasmic Ca2+ in vascular smooth muscle.

The vascular smooth muscle of conduit arteries can be excited by either depolarization or agonists. The former stimulus opens potential sensitive Ca2+ channels in the plasmalemma and releases bound Ca2+ from its outer surface. Ne interacts with alpha-receptors to open receptor operated Ca2+ channels which are distinct from the PSCs and also liberates surface bound Ca2+. In addition, it releases "trigger" Ca2+ from the inner plasmalemmal surface which in turn induces Ca2+ release from the sarcoplasmic reticulum. The elevated cytoplasmic free Ca2+ then combines with calmodulin to stimulate myosin light-chain kinase.

Animals↗

PubMed1995

Prostaglandin E2 contracts vascular smooth muscle and inhibits potassium currents in vascular smooth muscle cells of rat tail artery.

There is evidence to suggest that PGE2 plays an important role in the regulation of vascular smooth muscle tone. To determine the cellular basis of this action, we studied the effect of PGE2 on force in helical muscle strips from rat tail artery. PGE2 evoked a sustained contractile response. The contractile response was concentration-dependent, with an EC50 value of 9.6 microM. Patch-clamp studies were conducted to investigate the effects of PGE2 on K channels in isolated vascular smooth muscle cells from rat tail artery. Current-clamp studies showed that PGE2 (1 microM) depolarized the membrane by 15.9 +/- 1.3 mV. Under voltage-clamp conditions, a voltage-dependent, delayed outward rectifier K current was generated by stepwise depolarization from a holding potential of -80 mV. The current, which was activated at -45 to -40 mV and showed almost no inactivation, was inhibited by 45% using 10 mM TEA. PGE2 inhibited the outward K current in a concentration-dependent manner, with EC50 values of 3.5 microM and 4.9 microM in primary and subcultured cells, respectively. The PGE2 receptor antagonist sodium meclofenamate abolished the PGE2-induced K current inhibition. Furthermore, the intracellular application of guanosine 5'-O(-)[2-thiodiphosphate] (GDP beta S), a G protein inhibitor, and pretreatment of the cells with cholera toxin prevented the PGE2-induced inhibition, whereas application of pertussis toxin did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Sodium/calcium exchange and the control of contractility in cardiac muscle and vascular smooth muscle.

A sodium/calcium exchange mechanism that mediates both Ca2+ exit and Ca2+ entry is present in the sarcolemma of most types of muscle including mammalian cardiac muscle and vascular smooth muscle (VSM). The rate and direction of Ca2+ transport mediated by the exchanger are normally regulated primarily by: (a) the intracellular free Ca2+ concentration (since both Ca2+ entry and exit are activated by intracellular Ca2+), (b) the intracellular Na+, and (c) the absolute difference between the membrane potential and the exchanger reversal potential. In both cardiac muscle and VSM, the exchanger biases the level of [Ca2+]i and thereby controls the amount of Ca2+ stored in the sarcoplasmic reticulum and, thus, the amount available for release when the cells are activated. In both tissues, the exchanger also plays an important role in the extrusion of Ca2+ following contractile activation.

Animals↗

PubMed1980

Permanently proliferating rat vascular smooth muscle cell with maintained expression of smooth muscle characteristics, including actin of the vascular smooth muscle type.

Cells of an established clonal line (RVF-SMC) derived from rat vena cava are described by light and electron microscope methods and biochemical analysis of the major proteins. The cells are flat, and they moderately elongate and form monolayers. They are characterized by prominent cables of microfilaments bundles decoratable with antibodies to actin and alpha-actinin. These bundles contain numerous densely stained bodies and are often flanked by typical rows of surface caveolae and vesicles. The cells are rich in intermediate-sized filaments of the vimentin type but do not show detectable amounts of desmin and cytokeratin filaments. Isoelectric focusing and protein chemical studies have revealed actin heterogeneity. In addition to the two cytoplasmic actins, beta and gamma, common to proliferating cells, two smooth muscle-type actins (an acidic alpha-like and a gamma-like) are found. The major (alpha-type) vascular smooth muscle actin accounts for 28% of the total cellular actin. No skeletal muscle or cardiac muscle actin has been detected. The synthesis of large amounts of actin and vimentin and the presence of at least three actins, including alpha-like actin, have also been demonstrated by in vitro translation of isolated poly(A)+ mRNAs. This is, to our knowledge, the first case of expression of smooth muscle-type actin in a permanently growing cell. We conclude that permanent cell growth and proliferation is compatible with the maintained expression of several characteristic cell features of the differentiated vascular smooth muscle cell including the formation of smooth muscle-type actin.

Actins↗

PubMed2001

A novel transgenic marker for migrating limb muscle precursors and for vascular smooth muscle cells.

A unique pattern of LacZ expression was found in a transgenic mouse line, likely due to regulatory elements at the site of integration. Two new genes flanking the transgene were identified. At early stages of development, the transgene is transiently expressed in ventro-lateral demomyotomal cells migrating from the somites into the limb buds. At late developmental stages and in the adult, lacZ staining marks vascular smooth muscle cells throughout the vascular bed, with the exception of the major elastic arteries, and in pericytes. No expression was detected in skeletal and smooth muscles. Different patterns of expression in vascular smooth muscles was observed at distinct levels of the vascular tree, in arteries as well as in veins. Vessel injury, resulting in stimulation of smooth muscle cells proliferation and migration, is associated with transgene down-regulation. After the formation of neointima thickening, it is reactivated. This transgenic insertion may therefore be used as a useful marker to identify novel physiological cues or genetic elements involved in the regulation of the vascular smooth muscle phenotype(s). It may also provide an experimental tool for studying vasculature and the involvement of pericytes in regulating microvascular homeostasis.

Animals↗

PubMed2003

Cholesterol is necessary both for the toxic effect of Abeta peptides on vascular smooth muscle cells and for Abeta binding to vascular smooth muscle cell membranes.

Accumulation of beta amyloid (Abeta) in the brain is central to the pathogenesis of Alzheimer's disease. Abeta can bind to membrane lipids and this binding may have detrimental effects on cell function. In this study, surface plasmon resonance technology was used to study Abeta binding to membranes. Abeta peptides bound to synthetic lipid mixtures and to an intact plasma membrane preparation isolated from vascular smooth muscle cells. Abeta peptides were also toxic to vascular smooth muscle cells. There was a good correlation between the toxic effect of Abeta peptides and their membrane binding. 'Ageing' the Abeta peptides by incubation for 5 days increased the proportion of oligomeric species, and also increased toxicity and the amount of binding to lipids. The toxicities of various Abeta analogs correlated with their lipid binding. Significantly, binding was influenced by the concentration of cholesterol in the lipid mixture. Reduction of cholesterol in vascular smooth muscle cells not only reduced the binding of Abeta to purified plasma membrane preparations but also reduced Abeta toxicity. The results support the view that Abeta toxicity is a direct consequence of binding to lipids in the membrane. Reduction of membrane cholesterol using cholesterol-lowering drugs may be of therapeutic benefit because it reduces Abeta-membrane binding.

Amyloid beta-Peptides↗

PubMed1984

Heterogeneity of myosin antigenic expression in vascular smooth muscle in vivo.

Rabbit antisera elicited against purified human nonmuscle (platelet) and smooth muscle (uterine myometrium) myosins identified distinct species of myosin when frozen sections of a variety of mammalian tissues were examined by immunofluorescence microscopy. Antiplatelet myosin antiserum specifically stained several nonmuscle cell types including epithelial, some connective tissue, and all vascular endothelial (arterial, venous, capillary) cells. Antismooth muscle myosin antiserum stained only smooth muscle and no other cell types. Neither antiserum reacted with rat cardiac (ventricular) or skeletal muscle cells. Antismooth muscle myosin antiserum staining was detectable in medial vascular smooth muscle in all vessels examined from rat, bovine, human, and guinea pig sources (including elastic and muscular arteries, arterioles, venules, and veins). Although antiplatelet myosin antiserum did not stain nonvascular smooth muscle or vascular smooth muscle in muscular arteries, arterioles, venules, or veins, it did uniformly and specifically stain medial vascular smooth muscle in elastic arteries. This staining of elastic arteries was abolished by absorption of antiplatelet myosin antiserum with purified platelet myosin but not uterine myosin. Similarly, the reactivity of antismooth muscle myosin antiserum was abolished by incubation with uterine but not platelet myosin. The differences in staining patterns observed with antiplatelet myosin antiserum and antismooth muscle myosin antiserum in elastic arteries versus other blood vessels suggests a heterogeneity of antigenic expression in vascular smooth muscle myosin. The most likely explanations for this heterogeneity are the presence of different gene products (myosin isozymes) or a posttranslational alteration (possibly conformational) of a single myosin species. Heterogeneity in this important component of the contractile apparatus of vascular smooth muscle may have significant implications for the physiology and pathophysiology of the vessel wall.

Animals↗

PubMed1982

Fluorescence demonstration of a cathepsin H-like protease in cardiac, skeletal and vascular smooth muscles.

A cathepsin H-like enzyme was localized by histochemical techniques in cardiac muscle, extensor digitorum longus and soleus skeletal muscles, and vascular smooth muscle. Using the specific exopeptidase activity of this enzyme against the substrate arg-4-methoxy-beta-naphthylamide, valid histochemical assay conditions were developed. More fluorescent granules were observed in cardiac muscle than in the soleus and about equal amounts in vascular smooth muscle and the extensor digitorum longus. The reaction rate was enhanced by chloride ions and inhibited by 1 mM p-chloromercuribenzoate. The maximal activity was observed between pH 5.5 and 6.0 Chemical fixation with periodate-lysine-paraformaldehyde preserved a small amount of enzymatic activity.

Animals↗

PubMed1999

Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells--a cell system which resembles the system in bone cells.

Matrix GLA protein (MGP) is an inhibitor of calcification in the arterial wall and its activity is dependent upon vitamin K-dependent gamma-carboxylation. This modification is carried out by a warfarin sensitive enzyme system that converts specific Glu residues to gamma-carboxyglutamic acid (GLA) residues. Recent studies have demonstrated that the gamma-carboxylation system in the arterial wall, in contrast to that in the liver, is unable to use vitamin K as an antidote to warfarin. By use of immunohistochemistry we demonstrate that MGP is expressed in the arterial wall and immunocytochemistry localized the MGP precursors to the endoplasmic reticulum in vascular smooth muscle cells. Resting smooth vascular muscle cells in the aortic wall and proliferating cells from explants of the aorta have all the enzymes needed for gamma-carboxylation of MGP. However, when compared to the liver system, expression of the enzymes of the gamma-carboxylation system in vascular smooth muscle cells is different. Of particular interest is the finding that the specific activity of the warfarin sensitive enzyme vitamin K epoxide reductase is 3-fold higher in vascular smooth muscle cells than in liver. DT-diaphorase, which catalyses the antidotal pathway for vitamin K reduction in liver, is 100-fold less active in resting vascular smooth muscle cells than in liver. Data obtained from an in vitro gamma-carboxylation system suggest that the antidotal pathway catalyzed by DT-diaphorase in the vessel wall is unable to provide the carboxylase with enough reduced vitamin K to trigger gamma-carboxylation of MGP. This finding provides an explanation to the inability of vitamin K to work as an antidote to warfarin intoxication of the arterial wall. Therefore the vitamin K dependent gamma-carboxylation system in the arterial wall share a common feature with the system in bone cells by being unable to utilize vitamin K as an antidote.

Animals↗

PubMed1999

Vasopressin increases vascular endothelial growth factor secretion from human vascular smooth muscle cells.

Vascular endothelial growth factor (VEGF) is a potent and specific mitogen of vascular endothelial cells which promotes neovascularization in vitro. To determine whether vasopressin induces VEGF secretion in human vascular smooth muscle cells, we performed enzyme-linked immunosorbent assays. Vasopressin potently induced a time-dependent and concentration-dependent (maximal, 10(-7) M) increase in VEGF secretion by human vascular smooth muscle cells that was maximal after 24 h. Furthermore, vasopressin also concentration-dependently caused mitogenic effect, as reflected by total protein content of cells per culture well. These vasopressin-induced VEGF secretion increase and mitogenic effect of these cells were potently inhibited by vasopressin V1A receptor antagonists, confirming this is a vasopressin V1A receptor-mediated event. These results indicate that vasopressin increases VEGF secretion in human vascular smooth muscle cells, the magnitude of VEGF secretion being temporally related to the mitogenic effect of vascular smooth muscle cells and the potency of the growth-promoting stimulus. Vasopressin-induced VEGF secretion by proliferating vascular smooth muscle cells could act as a paracrine hormone to powerfully influence the permeability and growth of the overlying vascular endothelium, vasopressin play a more fundamental role in the regulation of vascular function than has previously been recognized.

Antidiuretic Hormone Receptor Antagonists↗

PubMed1999

Effects of novel pyridothiazepines and pyridothiazines on contractility of isolated guinea-pig heart muscle and vascular smooth muscle preparations.

The effects of newly synthesized pyridothiazepines MM 4 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4 -tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate), MM 6 (1-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminopropionyl]-1,2, 3,4-tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate) and the novel pyridothiazines MM 10 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminoacetyl+ ++]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminopropio nyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) on the contractility of isolated papillary muscles and aortic preparations of guinea pigs were studied using isometric contraction force measurements. The EC50 values for the negative inotropic effect were 27 micromol/l (MM 4), 19 micromol/l (MM 6), 32 micromol/l (MM 10) and 24 micromol/l (MM 11). In K+-precontracted aortic rings ([K+]o 60 mmol/l), the compounds induced relaxation with EC50 values of 27 micromol/l (MM 4), 24 micromol/l (MM 6), 84 micromol/l (MM 10) and 68 micromol/l (MM 11). Pyridothiazepines as well as pyridothiazines (100 micromol/l) were able to depress norepinephrine bitartrate (NE 10 micromol/l)-induced contraction of aortic rings in a calcium-free solution. It was concluded that the investigated compounds exert calcium antagonistic properties in both cardiac and smooth muscle. This antagonistic effect might be due to the inhibition of transmembrane calcium influx and/or intracellular calcium release.

Animals↗

PubMed2000

C-type natriuretic peptide inhibits upregulation of alpha1-adrenoceptor and inositol 1,4,5-trisphosphate receptor in rat vascular smooth muscle after vascular endothelial injury.

OBJECTIVE: In a model of balloon injury of rat aortic endothelium, the effects of C-type natriuretic peptide (CNP) on alpha1-adrenoreceptor and inositol 1,4,5-triphosphate (IP3) receptor were studied. METHODS: Aortic injuries were produced by vascular endothelium-denudation. Alpha1-adrenoreceptor in smooth muscle sarcolemma and IP3 receptor in smooth muscle sarcoplasmic reticulum in the rat aorta were assayed by radioactive analysis method. RESULTS: It was found that neointima was formed and the contents of DNA, collagen and elastin of each intima-media were sigificantly increased in 7 days and 21 days after balloon injury of rat aorta. Alpha1-adrenoreceptor in smooth muscle sarcolemma and IF3 receptor in sarcoplasmic reticulum were also upregulated. Results also showed that the administration of CNP i.p. significantly decreased the contents of DNA, collagen and elastin of each intima-media, and inhibited the up-regulation of alpha1-adrenoreceptor and IP3 receptor. CONCLUSION: The inhibition of the up-regulation of alpha1-adrenoreceptor and IP3 receptor by CNP might be one of the mechanisms of its suppressive action on intimal proliferation.

Animals↗

PubMed1997

TNF-alpha and IL-4 synergistically increase vascular cell adhesion molecule-1 expression in cultured vascular smooth muscle cells.

Vascular cell adhesion molecule-1 (VCAM-1) is expressed on the endothelium and vascular smooth muscle in atherosclerosis, where it is thought to recruit alpha4 integrin-positive leukocytes, which play a role in disease progression. In this study, we show an increase of VCAM-1 expression on vascular smooth muscle cells (VSMC) results in increased adhesion of alpha4 integrin-positive lymphocytes. Additionally, we examine the regulation of VCAM-1 expression by cytokines in cultured VSMC. Previously in endothelial cells, we have demonstrated that TNF-alpha increases transcription of the VCAM-1 gene, whereas IL-4 acts to increase VCAM-1 mRNA stability. The combination of a cytokine that increases transcription with a cytokine that stabilizes mRNA results in a synergistic increase in VCAM-1 expression. In this study, we show that the combination of TNF-alpha with IL-4 also resulted in a synergistic increase in VCAM-1 expression on VSMC; however, the mechanism of cytokine activation differed. In contrast to endothelial cells, IL-4 stimulated VCAM-1 gene transcription in the VSMC, but there was little effect of TNF-alpha alone. Additionally, the synergy between TNF-alpha and IL-4 appears to result, at least in part, from a cooperative transcriptional mechanism.

Cells, Cultured↗

PubMed1998

Relaxant effects of L-citrulline in rabbit vascular smooth muscle.

1. Vascular endothelium plays a pivotal role in the control of vascular tone through the release of vasoactive factors such as EDRF (NO). 2. The aim of this study was to investigate whether the addition of exogenous L-citrulline, the byproduct of the NO-synthesis, could relax vascular smooth muscle. 3. L-citrulline relaxed both endothelium-denuded and endothelium-intact rabbit aortic rings precontracted with noradrenaline 10(-6) M (maximum relaxations induced by L-citrulline 10(-8) M were 74.1+/-5.2% vs 51.3+/-2.8% in endothelium-denuded and endothelium-intact arteries, respectively). 4. This relaxant effect was enhanced by zaprinast (a phosphodiesterase type 5 inhibitor) and inhibited by HS-142-1 (a particulate guanylate cyclase inhibitor) and by apamin (a K(Ca)-channel blocker). 5. L-citrulline (10(-13)-10(-8) M) increased cGMP levels in aortic rings (maximum value with L-citrulline 10(-8) M was 0.165+/-0.010 pmol cGMP mg(-1) of tissue vs 0.038+/-0.009 pmol mg(-1) of tissue in basal). 6. L-citrulline as well as NO were released from endothelial cells in culture stimulated with ACh. The values were 6.50+/-0.50 microM vs 2.30+/-0.20 microM (stimulated with ACh and basal respectively) for L-citrulline and 4.22+/-0.10 microM vs 0.87+/-0.26 microM (stimulated with ACh and basal respectively) for NO. 7. These results suggest that L-citrulline could be released together with NO from endothelium and may have actions complementary to those of NO in the control of vascular smooth muscle relaxation.

Animals↗