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PubMed1986

Calcium-activated potassium channels in canine airway smooth muscle.

Airway smooth muscle cells from canine trachealis muscle were dispersed by treatment with collagenase and elastase. Cells were identified as smooth muscle by their binding of anti-smooth muscle gamma-isoactin monoclonal antibodies and by their contraction in response to acetylcholine. The patch-clamp technique was used to study single channel currents in cell-attached and isolated patches of membrane. The most common single channel currents had a conductance of 266 +/- 12 pS (mean +/- S.D., n = 7) in symmetrical 135 mM-K solutions. The reversal potential of the channel was unaltered by large chemical gradients for Cl, Na and Ca and was determined exclusively by the chemical K gradient. Thus, the channel is highly selective for K. In both cell-attached and isolated patches of membrane, depolarization increased the frequency of channel opening and the duration of the open state. In isolated patches of membrane, increasing [Ca] on the cytoplasmic side of the membrane from 10(-8) to 10(-6) M increased both the frequency of channel opening and the duration of the open state. Tetraethylammonium, tetramethylammonium, or Cs (10 mM) on the cytoplasmic side of the membrane caused a voltage-dependent decrease in conductance of the open channel while having no obvious effect on channel kinetics. These blocks were completely reversible. Ba (10 mM) on the cytoplasmic side of the membrane slightly decreased inward currents and completely blocked outward currents through the channel. External Ba (10 mM) caused a voltage-dependent decrease in inward current. External tetraethylammonium (10 mM) completely blocked single channel currents.

Action Potentials↗
PubMed1982

Interaction of histamine with adrenergic smooth muscle neurotransmission. I. Effects of histamine on smooth muscle contractions induced by exogenous or by endogenous noradrenaline.

The effects of histamine on contractions in response to exogenous noradrenaline or to electrical stimulation were studied on two smooth muscle preparations with adrenergic neurotransmission--rat anococcygeal muscle and vas deferens. Histamine (1 X 10(-6)M-1 X 10(-4)M) did not affect significantly the contractions of vas deferens induced by noradrenaline (1 X 10(-8)M-1 X 10(-4)M), but decreased in a concentration-dependent manner the contractile effects of noradrenaline on anococcygeal muscle. The EC50 of noradrenaline on the latter preparation was increased 2.6-16.2 times by histamine but the antagonism was of a noncompetitive type. Histamine exerted a biphasic effect on the smooth muscle contractions in response to square wave electrical stimulation with supramaximal voltage (vas deferens--0.1 Hz, 1 sh or 10 Hz, 20 sh; anococcygeal muscle--5 Hz, 8 sh or 10 Hz 20 sh). The lower histamine concentrations (1 X 10(-12)M-1 X 10(-7)M) slightly potentiated the contractions and the higher concentrations (1 X 10(-6)M-1 X 10(-4)M) markedly inhibited the contractions in response to electrical stimulation. The results obtained are consistent with the hypothesis that the modulatory role of histamine for the adrenergic neurotransmission is mediated via presynaptic inhibitory H2--and postsynaptic excitatory H1--histaminergic receptors.

Animals↗
PubMed1980

[Studies on isolated smooth muscle cells. VI. Dispersion procedures for acetylcholine-sensitive smooth muscle cells of guinea pig (author's transl)].

Dispersion procedure of smooth muscle cells from collagenase-treated minces of guinea pig taenia coli and their response to acetylcholine were examined in order to apply the single smooth muscle cells to investigation of contraction mechanisms of smooth muscle. Pipetting the mince suspension was convenient procedure for the dispersion of single cells. For good yield of acetylcholine-sensitive cells, very mild pipetting was required although yield of single cells was lower. Under the condition, 10(3)-10(4) cells were obtained from 3-4 cm of taenia coli strip and about a half of the cells were responsive to acetylcholine. The cells became 40% of the original length by administration of 10 mM acetylcholine. Once the cells were dispersed and suspended in the physiological salt solution the cells lost the sensitivity to acetylcholine within 90 minutes while very mild pipetting of the mince suspension provided acetylcholine-sensitive cells over 3 hours. These single cells were applicable to investigation of contraction mechanisms of smooth muscle in addition to whole tissue as used so far. It was also suggested in the experiment that acetylcholine-sensitive site of cells might be damaged by exposure to physiological salt solution while it was well preserved in the tissue even though the tissue was digested by collagenase.

Acetylcholine↗
PubMed1994

Proliferative activity and alpha-smooth muscle actin expression in cultured rat aortic smooth muscle cells are differently modulated by transforming growth factor-beta 1 and heparin.

Locally liberated cytokines and extracellular matrix components influence the proliferation and differentiation of arterial smooth muscle cells (SMC), thus playing a role in the development of the atheromatous plaque. It has been proposed that the response of SMC to these factors is influenced by their own phenotype. We have tested the effects of transforming growth factor-beta 1 (TGF-beta 1) and heparin on proliferation and expression of alpha-smooth muscle (SM) actin, a well-established SMC differentiation marker, by cultured rat SMC obtained from the normal aorta of young or old rats and from the intimal thickening developed 15 days after endothelial denudation in young rats; these SMC are known to express different phenotypic features. Heparin and TGF-beta 1 reduced serum-induced proliferation in SMC from young and old rats. Heparin increased the expression of alpha-SM actin protein and mRNA in SMC from young and old rats, while TGF-beta 1 exerted the opposite action. Moreover, TGF-beta 1 induced the appearance of an elongated shape in SMC from both young and old rats. In SMC cultured from intimal thickening, heparin induced a reduction of cell proliferation without modifying their characteristic epithelioid shape; TGF-beta 1 increased the proliferative activity and induced an elongated cell shape as well as a "hills and valleys" growth pattern similar to that observed in control medial SMC; both heparin and TGF-beta 1 induced an increase of alpha-SM actin expression. Our results show that TGF-beta 1 and heparin exert different effects on the same SMC, suggesting that these substances act at least in part independently. They are also compatible with the view that the action of cytokines and of extracellular matrix components depends on the phenotype of target SMC.

Actins↗
PubMed1993

8-Methoxypsoralen and longwave ultraviolet irradiation are a novel antiproliferative combination for vascular smooth muscle.

BACKGROUND: Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Although the effects of arterial exposure to high-energy radiation sources such as laser have been investigated in detail, the effects on vascular cells of low-intensity radiant energy in combination with photoactive agents have not been extensively characterized. Psoralens are photoactive agents that are known to be well tolerated when used in conjunction with local exposure to ultraviolet light in the A band (UVA) for the treatment of various dermatologic proliferative disorders. METHODS AND RESULTS: We have investigated the effects of psoralen/UVA (PUVA) exposure on the proliferation of bovine aortic smooth muscle cells. Proliferation and viability were assessed over a 14-day period by trypan blue exclusion counts. Cell cycle effects were evaluated by thymidine incorporation and flow cytometry with DNA quantitation after addition of serum or platelet-derived growth factor B-chain (PDGF-BB) to subconfluent cells synchronized by serum withdrawal. No effect was observed after exposure to 8-methoxypsoralen (8-MOP) at concentrations up to 10 microM or UVA irradiation at energies up to 2.5 J/cm2. Longwave ultraviolet light and 8-MOP were found to behave synergistically as potent inhibitors of DNA synthesis in bovine aortic smooth muscle cells with the EC50 in combination ranging from 7 microM at 0.35 J/cm2 to 0.2 microM at 2.1 J/cm2. Similar antiproliferative effects were obtained by an inverse variation of dose and energy delivered. After serum stimulation, inhibition of DNA synthesis was found with either an immediate or delayed (16-hour) application of PUVA. This effect was independent of subsequent 8-MOP washout. Flow cytometry of cells treated with PUVA at several times after serum stimulation demonstrated for each time point a block in further cell cycle progression for cells in all phases of the cell cycle. Evaluation of [125I]-labeled PDGF and epidermal growth factor (EGF) binding revealed no effect of PUVA on the apparent number or affinity of PDGF binding sites present but did reveal a dose-dependent inhibition by PUVA of EGF binding. This inhibition of EGF binding occurred increasingly at higher PUVA doses than the cell cycle inhibition and accordingly did not appear to represent a critical mechanism for the antiproliferative effect. Cell counting after a single exposure to PUVA (1 microM, 1.5 J/cm2) revealed complete stasis of cell proliferation over a 28-day period without recurrent exposure. No increase in trypan-positive cells was noted over this period. CONCLUSIONS: PUVA treatment represents a novel method for locally inhibiting proliferation of vascular smooth muscle cells without producing cytolysis.

Animals↗
PubMed2001

Identification of a CArG box-dependent enhancer within the cysteine-rich protein 1 gene that directs expression in arterial but not venous or visceral smooth muscle cells.

Smooth muscle cells (SMCs) are heterogeneous with respect to their contractile, synthetic, and proliferative properties, though the regulatory factors responsible for their phenotypic diversity remain largely unknown. To further our understanding of smooth muscle gene regulation, we characterized the cis-regulatory elements of the murine cysteine-rich protein 1 gene (CRP1/Csrp1). CRP1 is expressed in all muscle cell types during embryogenesis and predominates in vascular and visceral SMCs in the adult. We identified a 5-kb enhancer within the CRP1 gene that is sufficient to drive expression in arterial but not venous or visceral SMCs in transgenic mice. This enhancer also exhibits region-specific activity in the outflow tract of the heart and the somites. Within the 5-kb CRP1 enhancer, we found a single CArG box that binds serum response factor (SRF), and by mutational analysis, demonstrate that the activity of the enhancer is dependent on this CArG element. Our findings provide further evidence for the existence of distinct regulatory programs within SMCs and suggest a role for SRF in the activation of the CRP1 gene.

Animals↗
PubMed2002

Differentiation of smooth muscle cells in chicken gizzard. Self-catalytic mechanism for the production of smooth muscle cells.

During development of the chicken gizzard, a thick layer of undifferentiated cells (mesenchymal cells) is constructed, and the cells differentiate into smooth muscle cells or connective tissues. We found that the differentiation of smooth muscle cells occurred first near the outer surface of the gizzard and the differentiated area spread to the inside of the gizzard. Therefore, we assumed that the differentiation of most of the smooth muscle cells in the gizzard is induced by differentiated smooth muscle itself. When undifferentiated cells from gizzard of 7-day-old embryo (Hamburger and Hamilton's stages 26-27) were cultured on a coverglass coated with extract of gizzard that contained differentiated smooth muscle cells, the cells attached to the coverglass and differentiated into smooth muscle cells. On the other hand, extract of gizzard from 7-day-old embryo did not induce the differentiation of smooth muscle cells, though it induced the attachment of cells. We found that activity for the differentiation of smooth muscle cells appeared when differentiated smooth muscle cells appeared in developing gizzard. Gizzard contained higher activity for the differentiation of smooth muscle cells than the other tissues. Transforming growth factor-beta (TGF-beta), which induces the differentiation of vascular smooth muscle cells, did not induce the differentiation of smooth muscle cells in gizzard, though extract of aorta induced the differentiation of smooth muscle cells in gizzard. The results obtained here support evidence that the differentiation of most of the smooth muscle cells in gizzard is induced by a self-catalytic mechanism in which differentiated smooth muscle itself induces the differentiation of smooth muscle cells.

Animals↗
PubMed1990

Changes in expression and organization of smooth-muscle-specific alpha-actin during fibronectin-mediated modulation of arterial smooth muscle cell phenotype.

The spreading of freshly isolated arterial smooth muscle cells on a substrate of fibronectin is mediated by an integrin receptor on the cell surface. It is associated with organization of actin filaments in stress fibers and marked changes in cell morphology and function, collectively referred to as a transition from a contractile to a synthetic phenotype. To study further how extracellular matrix components affect smooth muscle phenotype, we have analyzed the expression and organization of smooth-muscle-specific alpha-actin in freshly isolated rat aortic smooth muscle cells cultured on a substrate of fibronectin under serum-free conditions. Northern-blot analysis showed that the expression of mRNA for smooth muscle alpha-actin, but not for nonmuscle actin, was strongly repressed during primary culture. On the other hand, the cellular content of alpha-actin was only moderately changed during the same period. Indirect immunofluorescence staining revealed that nonmuscle actin was rapidly organized in stress fibers, which did not stain with a monoclonal antibody against smooth muscle alpha-actin. Filament bundles containing alpha-actin were most prominent in the central parts of the cytoplasm and gradually disappeared as the spreading of the cells progressed. In contrast to the situation with nonmuscle actin, there was no apparent overlap in the staining for alpha-actin and the fibronectin receptor (alpha 5 beta 1), indicating that this receptor interacted with nonmuscle actin during the initial spreading process. Taken together, the results show that the expression and organization of smooth muscle alpha-actin are changed during interaction of the cells with fibronectin early in primary culture. They support the notion that integrin-mediated interactions between extracellular matrix components and arterial smooth muscle cells take part in the control of smooth muscle phenotype.

Actins↗
PubMed2006

Identification of a 94-bp GC-rich element in the smooth muscle myosin heavy-chain promoter controlling vascular smooth muscle cell-specific gene expression.

The previously described rabbit 2.3-kilobase smooth muscle myosin heavy-chain (SMHCwt) promoter targets gene expression in transgenic animals to vascular smooth muscle cells (SMCs), including coronary arteries. Therefore, SMHCwt is thought to provide a promising tool for human gene therapy. In the present study, we examined tissue specificity and expression levels of wild-type and mutated SMHC promoters within the system of high-capacity adenoviral (hcAd) vectors. SMHCwt and a series of SMHC promoter deletion mutants, a triple promoter as well as a cytomegalovirus-SMHC hybrid promoter driving the enhanced green fluorescence protein (EGFP) reporter gene were transiently transfected into aortic SMCs. Fluorescence intensity was measured by flow cytometric analysis. Consecutively, hcAd vectors were constructed with the SMHCwt and the mutant promoter with the highest fluorescence activity. Levels of EGFP expression were determined after transduction of SMCs derived from human coronary arteries. For analysis of tissue specificity, embryonic stem (ES) cell-derived SMCs (ESdSMHCs) and cardiomyocytes (ESdCMs) were used. In comparison with SMHCwt, only the SMHCdel94 mutant lacking a 94-bp GC-rich element revealed a 1.5-fold increased fluorescence activity. Transduction of primary SMCs of human coronary arteries with hcAd vectors confirmed an increased EGFP expression driven by the SMHCdel94 promoter. In ES-cell-derived embryoid bodies, SMHCwt was exclusively active in transduced ESdSMCs. In contrast, expression of SMHCdel94 was also found in ESdCMs and other nontarget cells of the embryoid body. The tissue-specific rabbit SMHCwt promoter seems to be suitable for adenoviral gene transfer in SMCs of human coronary arteries and deletion of a 94-bp negative cis-acting GC-rich element results in loss of specificity.

Animals↗
PubMed1992

Phosphorylation of smooth muscle caldesmon by mitogen-activated protein (MAP) kinase and expression of MAP kinase in differentiated smooth muscle cells.

Smooth muscle caldesmon was phosphorylated in vitro by sea star p44mpk up to 2.0 mol of phosphate/mol of protein at both Ser and Thr residues. The phosphorylation sites were contained mainly in the COOH-terminal 10-kDa cyanogen bromide fragment which houses the binding sites for calmodulin, tropomyosin, and F-actin. Tryptic peptide maps of 32P-labeled caldesmon by p44mpk and p34cdc2 showed that while both enzymes recognized similar sites of phosphorylation, they have different preferred sites. Phosphorylation of caldesmon attenuated slightly its interaction with actin and had no effect on its binding to calmodulin and tropomyosin. Smooth muscle cell extracts from chicken gizzard and rat aorta contained 42- and 44-kDa proteins, respectively, which were cross-reactive with an antibody to sea star p44mpk. Immunoprecipitates from gizzard and aorta cell extracts, generated with the p44mpk antibody, possessed kinase activities toward myelin basic protein as well as caldesmon. These results suggest that MAP kinase may have functions in the differentiated smooth muscle cells distinct from those involved in the cell cycle.

Amino Acid Sequence↗
PubMed1989

Effects of bradykinin on prostaglandin synthesis and cytosolic calcium in rabbit subcultured renal cortical smooth muscle cells.

Smooth muscle cells were cultured from an arteriole-rich fraction of the rabbit renal cortex and characterized by their ultrastructural and immunohistochemical features, their high content in creatine kinase (60-times that of the initial preparation) and their ability to synthesize renin. Cells, studied between passages 2 and 5, produced mainly PGE2 and, to a lesser extent, PGF2 alpha. Bradykinin (BK) (0.1 nM-1 microM) induced a concentration-dependent increase in PGE2 (28-40-times basal value at 1 microM after a 5 min incubation period) and stimulated also the free cytosolic calcium concentration [( Ca2+]i) with a 2-fold maximal rise to its basal value. Both effects, inhibited by the anti-B2 receptor [Thi5.8D-Phe7] BK, were not reproduced by DesArg9 BK. A decrease in the extracellular calcium concentration and incubation in the presence of a calcium-channel blocker (lanthanum chloride) inhibited the BK-dependent rise of [Ca2+]i but not that of PGE2. Preincubation with phorbol myristate acetate increased basal and BK-induced PGE2 synthesis but prevented the effect of BK on [Ca2+]i. These results demonstrate the ability of BK to increase [Ca2+]i and PGE2 production in cultured vascular cells from the rabbit renal cortex and suggest that kinins might act on the cortical microcirculation via their direct effects on arteriolar smooth muscle cells.

Animals↗
PubMed1996

Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. II. Effect of various PDE inhibitors on smooth muscle tone and cyclic nucleotide levels in vitro.

Phosphodiesterases (PDEs) regulate intracellular cyclic nucleotide metabolism and, thus, contraction and relaxation of smooth musculature. The aim of the present study was to evaluate the functional effects of isoenzyme-selective inhibitors and their effects on cyclic nucleotide levels in the human detrusor smooth muscle. In addition, the functional relevance of the cAMP versus the cGMP pathways in the regulation of the detrusor smooth muscle tone was assessed. Relaxant responses to various PDE inhibitors, forskolin and sodium nitroprusside (SNP) were investigated in vitro using a standard organ bath setup. Cyclic nucleotide levels were measured after incubation with the same substances using cAMP and cGMP radioimmunoassays (RIAs). Significant relaxant responses were only induced by non-selective PDE inhibition, the PDE I inhibitor vinpocetine and the adenylate cyclase activator forskolin. Relaxant responses to these substances were paralleled by increases in cyclic nucleotide levels. Our data suggest that the cAMP pathway and calcium/calmodulin-stimulated PDE (PDE I) may be of functional importance in the regulation of the human detrusor smooth muscle tone in vitro.

Cyclic AMP↗
PubMed1986

The action potential of guinea pig bladder smooth muscle.

The smooth muscle of the guinea pig bladder demonstrates in vitro spontaneous electrical activity in the form of action potentials which are associated with contraction. The action potential frequency is highly voltage-sensitive. The relative contributions of Na, Ca and K to the action potential elicited by depolarizing current have been studied using intracellular microelectrodes. In solutions in which NaCl is replaced by sucrose, the membrane hyperpolarizes and the rate of rise and after-hyperpolarization of the elicited action potential is increased. The amplitude is unaffected. In Ca-deficient solutions, the membrane depolarizes, the rate of rise and amplitude of the action potential is reduced, and the after-hyperpolarization is decreased. Nifedipine reduces amplitude and rate of rise but does not affect after-hyperpolarization. In the presence of the K-channel antagonist TEA, the duration of the action potential is prolonged, but the amplitude and rate of rise are unaffected. After-hyperpolarization is not reduced. It is concluded that the action potential of guinea pig bladder muscle, like many other smooth muscles studied, is Ca-based. Repolarization depends on changes in K conductance. The after-hyperpolarization is voltage-sensitive.

Action Potentials↗
PubMed2000

Mitogen-induced up-regulation of non-smooth muscle isoform of alpha-tropomyosin in rat aortic smooth muscle cells.

Correlation between the expression of the alpha-tropomyosin isoforms and cell growth was investigated in rat aortic smooth muscle cells. The levels of exon 1a, exons 1a+2a (smooth muscle type) and exons 1a+2b (non-smooth muscle type) were determined by reverse transcription-polymerase chain reaction (RT-PCR). When the cells were cultured, the level of exons 1a+2b transiently increased while reaching a maximum at 3-5 days. When the serum-deprived confluent cells were stimulated with 3-20% serum for 1.5 h, the level of exons 1a+2b increased by about twofold. The 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (H-7) but not 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimi de (GF 109203X) inhibited this up-regulation. Phorbol-12, 13-dibutyrate (PDB) mimicked the effect of serum. The DNA synthesis as determined by the incorporation of 5-bromo-2'-deoxy-uridine (BrdU) was not enhanced by the 1.5 h stimulation with serum or phorbol ester. The up-regulation of non-smooth muscle isoform of alpha-tropomyosin occurred during G(0)/G(1) transition before entering S phase. Protein phosphorylation is suggested to be involved in the up-regulation. However, the responsible kinase(s) remain to be elucidated.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

The cytoskeleton of the vertebrate smooth muscle cell.

Smooth muscle cells possess a structural lattice composed of two primary parts: the 'cytoskeleton' that pervades the cytoplasm and the 'membrane skeleton' that provides anchorage for the cytoskeleton and contractile apparatus at the cell surface. The cytoskeleton contains two major components: first, a complement of actin filaments that links the cytoplasmic dense bodies at equispaced intervals in longitudinal fibrils; and second, a network of desmin intermediate filaments that co-distributes with the cytoskeletal actin. The actin filaments of the contractile apparatus are presumed to interface with the cytoskeleton at the cytoplasmic dense bodies and with the longitudinal rib-like arrays of dense plaques of the membrane skeleton that couple to the extracellular matrix. The present report focuses attention on the functional role of intermediate filaments and on the molecular domain structure of the protein calponin, which is found both in the cytoskeleton and the contractile apparatus. New information about the role of intermediate filaments in smooth muscle has come from studies of transgenic mice in which desmin expression has been ablated. These have shown that while desmin is dispensable for normal development and viability its absence has significant consequences for the mechanical properties of muscle tissue. Thus, the visceral smooth muscles develop only 40% of the normal contractile force and the maximal shortening velocity is reduced by 25-40%. Intermediate filaments therefore play an active role in force transmission and do not contribute solely to cell shape maintenance, as has hitherto been presumed. Recent studies on calponin have revealed a second actin binding domain at the C-terminus of the molecule and have also pinpointed an N-terminal domain that shares homology with a growing family of actin binding and signalling molecules. How these newly identified features of calponin relate to its function in vivo remains to be established.

Animals↗
PubMed1988

Characterization of a mammalian smooth muscle myosin heavy chain cDNA clone and its expression in various smooth muscle types.

A cDNA clone, SMHC-29, encoding the light meromyosin of smooth muscle myosin heavy chain (MHC), was isolated from a rabbit uterus cDNA library constructed in phage lambda gt11. This smooth muscle MHC cDNA demonstrates significant nucleotide and amino acid sequence homologies with known sarcomeric MHC genes from rabbit, rat skeletal, and nematode body wall myosin, and even with nonmuscle MHC gene from a slime mold (Dictyostelium discoideum), suggesting that smooth muscle, striated muscle, and nonmuscle MHC genes diverged from a common ancestor. The deduced amino acid sequences of the smooth muscle light meromyosin show very similar periodic distributions of hydrophobic and charged residues as found for the light meromyosin of striated muscle MHCs together with a high potential for alpha-helical formation, indicating an alpha-helical coiled-coil structure for the smooth muscle light meromyosin sequences. Furthermore, S1 nuclease mapping has revealed that this smooth muscle MHC gene for SMHC-29 is specifically expressed in smooth muscles of vascular and nonvascular types but not in the striated muscles or nonmuscle cells.

Amino Acid Sequence↗
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↗
PubMed1997

The relaxant effect of adrenomedullin on particular smooth muscles despite a general expression of its mRNA in smooth muscle, endothelial and epithelial cells.

1. By use of the reverse transcription polymerase chain reaction (RT-PCR), we determined the expression of adrenomedullin (AM) mRNA in the various tissues of the pig. To evaluate the significance of the expression of AM mRNA, we also determined the effects of AM on the cytosolic Ca2+ concentration ([Ca2+]i) and tension development of the porcine smooth muscle strips obtained from the coronary artery, pulmonary vein, trachea, ileum and urinary bladder. 2.AM mRNA was widely expressed in the porcine tissues examined, which included myocardium (left and right ventricle and right atrium), kidney, lung, endothelial cells (aorta and aortic valve), smooth muscles (aorta, main pulmonary artery, pulmonary vein, renal artery and vein, coronary artery, ileum, trachea and urinary bladder) and epithelial cells (trachea and urinary bladder). 3. AM induced a decrease in [Ca2+]i and tension of the coronary artery, but not the pulmonary vein. AM had no effects on either the [Ca2+]i or tension of the trachea and urinary bladder strips or on the tension development of strips of ileum. 4. These results indicated that AM has a role as an autocrine and/or paracrine regulator of the coronary arterial tone. AM probably does not have an important role in the regulation of the pulmonary venous, tracheal, ileac and urinary bladder smooth muscle tone, even though AM mRNA is expressed in these tissues; the functional significance of AM in these smooth muscles remains to be determined.

Adrenomedullin↗