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Biomedical subjects

L Kuo

Publications and source records attributed to L Kuo.

At least 19 recordsLinked to original sources
PubMed2000

Erythrocytes possess an intrinsic barrier to nitric oxide consumption.

It has been reported that free hemoglobin (Hb) reacts with NO at an extremely high rate (K(Hb) approximately 10(7) M(-1) s(-1)) and that the red blood cell (RBC) membrane is highly permeable to NO. RBCs, however, react with NO 500-1000 times slower. This reduction of NO reaction rate by RBCs has been attributed to the extracellular diffusion limitation. To test whether additional limitations are also important, we designed a competition test, which allows the extracellular diffusion limitation to be distinguished from transmembrane or intracellular resistance. This test exploited the competition between free Hb and RBCs for NO generated in a homogenous phase by an NO donor. If the extracellular diffusion resistance is negligible, then the results would follow a kinetic model that assumes homogenous reaction without extracellular diffusion limitation. In this case, the measured effective reaction rate constant, K(RBC), would remain invariant of the hematocrit, extracellular-free Hb concentration, and NO donor concentration. Results show that the K(RBC) approaches a constant only when the hematocrit is greater than 10%, suggesting that at higher hematocrit, the extracellular diffusion resistance is negligible. Under such a condition, the NO consumption by RBCs is still 500-1000 times slower than that by free Hb. This result suggests that intrinsic RBC factors, such as transmembrane diffusion limitation or intracellular mechanisms, exist to reduce the NO consumption by RBCs.

Animals↗
PubMed2000

Retargeting of coronavirus by substitution of the spike glycoprotein ectodomain: crossing the host cell species barrier.

Coronaviruses generally have a narrow host range, infecting one or just a few species. Using targeted RNA recombination, we constructed a mutant of the coronavirus mouse hepatitis virus (MHV) in which the ectodomain of the spike glycoprotein (S) was replaced with the highly divergent ectodomain of the S protein of feline infectious peritonitis virus. The resulting chimeric virus, designated fMHV, acquired the ability to infect feline cells and simultaneously lost the ability to infect murine cells in tissue culture. This reciprocal switch of species specificity strongly supports the notion that coronavirus host cell range is determined primarily at the level of interactions between the S protein and the virus receptor. The isolation of fMHV allowed the localization of the region responsible for S protein incorporation into virions to the carboxy-terminal 64 of the 1,324 residues of this protein. This establishes a basis for further definition of elements involved in virion assembly. In addition, fMHV is potentially the ideal recipient virus for carrying out reverse genetics of MHV by targeted RNA recombination, since it presents the possibility of selecting recombinants, no matter how defective, that have regained the ability to replicate in murine cells.

Amino Acid Sequence↗
PubMed2000

oxLDL specifically impairs endothelium-dependent, NO-mediated dilation of coronary arterioles.

Our previous studies implicated that oxidized low-density lipoprotein (oxLDL), a putative atherogenic agent, impairs endothelium-dependent, nitric oxide (NO)-mediated dilation of isolated coronary arterioles to pharmacological agonists. However, it is not known whether oxLDL specifically affects NO-mediated dilation or generally impairs endothelium-dependent function, including the release of hyperpolarizing factors. In this regard, we investigated the dilation of isolated porcine coronary arterioles (50- to 100-microm luminal diameter) in response to the activation of various endothelium-dependent pathways before and after intraluminal incubation of the vessels with oxLDL (0.5 mg protein/ml for 60 min). In the absence of oxLDL, all vessels developed basal tone and dilated in response to the activation of NO synthase (by flow and adenosine), cyclooxygenase (by arachidonic acid), cytochrome P-450 monooxygenase (by bradykinin), and endothelial membrane hyperpolarization (by sucrose-induced hyperosmolarity). Incubation of the vessels with oxLDL for 60 min did not alter basal tone but did inhibit the vasodilatory responses to increased flow and adenosine in a manner similar to that of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. Vasodilations in response to flow and adenosine were not affected by intraluminal incubation of the vessels with either a vehicle solution or the native LDL (0.5 mg protein/ml, 60 min). In contrast with the NO-mediated response, hyperosmotic vasodilation mediated by endothelial hyperpolarization was not affected by oxLDL. Endothelium-dependent dilations to the cyclooxygenase activator arachidonic acid and to the cytochrome P-450 monooxygenase activator bradykinin and endothelium-independent vasodilation to sodium nitroprusside were also not altered by oxLDL. Collectively, these results indicate that oxLDL has a selective effect on endothelium-dependent dilation with specific impairment of the NO-mediated response, whereas cyclooxygenase and cytochrome P-450 monooxygenase-mediated dilations are spared from this inhibitory effect. In addition, oxLDL does not appear to affect vasodilation mediated by hyperpolarization of the endothelium.

Adenosine↗
PubMed2000

[Identification of Enterocytozoon bieneusi in a patient with sclerosing cholangitis and AIDS].

Enterocytozoon bieneusi is the most common microsporidian parasite found in patients with AIDS. We report the clinical features of a patient with chronic diarrhea, pancreatitis, and AIDS-related sclerosing cholangitis. Ultrasonography and endoscopic retrograde cholangiopancreatography disclosed intrahepatic and extrahepatic bile duct changes identical to those seen in sclerosing cholangitis. Enterocytozoon bieneusi was found in duodenum and peripapillary duodenum by means of light microscopy, and confirmed by PCR amplification of paraffin-embedded tissues with species-specific primers. Microsporidian infection should be suspected in patients with advanced immunodeficiency and AIDS-related sclerosing cholangitis in our country.

AIDS-Related Opportunistic Infections↗
PubMed1999

cAMP-independent dilation of coronary arterioles to adenosine : role of nitric oxide, G proteins, and K(ATP) channels.

Adenosine is known to play an important role in the regulation of coronary blood flow during metabolic stress. However, there is sparse information on the mechanism of adenosine-induced dilation at the microcirculatory levels. In the present study, we examined the role of endothelial nitric oxide (NO), G proteins, cyclic nucleotides, and potassium channels in coronary arteriolar dilation to adenosine. Pig subepicardial coronary arterioles (50 to 100 microm in diameter) were isolated, cannulated, and pressurized to 60 cm H(2)O without flow for in vitro study. The arterioles developed basal tone and dilated dose dependently to adenosine. Disruption of endothelium, blocking of endothelial ATP-sensitive potassium (K(ATP)) channels by glibenclamide, and inhibition of NO synthase by N(G)-nitro-L-arginine methyl ester and of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one produced identical attenuation of vasodilation to adenosine. Combined administration of these inhibitors did not further attenuate the vasodilatory response. Production of NO from coronary arterioles was significantly increased by adenosine. Pertussis toxin, but not cholera toxin, significantly inhibited vasodilation to adenosine, and this inhibitory effect was only evident in vessels with an intact endothelium. Tetraethylammonium, glibenclamide, and a high concentration of extraluminal KCl abolished vasodilation of denuded vessels to adenosine; however, inhibition of calcium-activated potassium channels by iberiotoxin had no effect on this dilation. Rp-8-Br-cAMPS, a cAMP antagonist, inhibited vasodilation to cAMP analog 8-Br-cAMP but failed to block adenosine-induced dilation. Furthermore, vasodilations to 8-Br-cAMP and sodium nitroprusside were not inhibited by glibenclamide, indicating that cAMP- and cGMP-induced dilations are not mediated by the activation of K(ATP) channels. These results suggest that adenosine activates both endothelial and smooth muscle pathways to exert its vasodilatory function. On one hand, adenosine opens endothelial K(ATP) channels through activation of pertussis toxin-sensitive G proteins. This signaling leads to the production and release of NO, which subsequently activates smooth muscle soluble guanylyl cyclase for vasodilation. On the other hand, adenosine activates smooth muscle K(ATP) channels and leads to vasodilation through hyperpolarization. It appears that the latter vasodilatory process is independent of G proteins and of cAMP/cGMP pathways.

Adenosine↗
PubMed1999

Intravascular flow decreases erythrocyte consumption of nitric oxide.

Nitric oxide (NO) produced by the endothelium diffuses both into the lumen and to the smooth muscle cells according to the concentration gradient in each direction. The extremely high reaction rate between NO and hemoglobin (Hb), k(Hb)= 3-5 x 10(7) M(-1).s(-1), suggests that most of the NO produced would be consumed by Hb in the red blood cells (RBCs), which then would block the biological effect of NO. Therefore, specific mechanisms must exist under physiological conditions to reduce the NO consumption by RBCs, in which the Hb concentration is very high (24 mM heme). By using isolated microvessels as a bioassay, here we show that physiological concentrations of RBCs in the presence of intravascular flow does not inhibit NO-mediated vessel dilation, suggesting that RBCs under this condition are not an NO scavenger. On the other hand, RBCs (50% hematocrit) without intravascular flow reduce NO-mediated dilation to serotonin by 30%. In contrast, free Hb (10 microM) completely inhibits NO-mediated dilation with or without intravascular flow. The effect of flow on NO consumption by RBCs may be attributed to the formation of an RBC-free zone near the vessel wall, which is caused by hydrodynamic forces on particles. Intravascular flow does not affect the reaction rate between NO and free Hb in the lumen, because the latter forms a homogeneous solution and is not subject to the hydrodynamic separation. However, intravascular flow only partially contributes to the reduced consumption of NO by RBCs, because without the flow, the NO consumption by RBCs is already about 3 orders of magnitude slower than free Hb.

Animals↗
PubMed1999

A concise promoter region of the heart fatty acid-binding protein gene dictates tissue-appropriate expression.

The heart fatty acid-binding protein (HFABP) is a member of a family of binding proteins with distinct tissue distributions and diverse roles in fatty acid metabolism, trafficking, and signaling. Other members of this family have been shown to possess concise promoter regions that direct appropriate tissue-specific expression. The basis for the specific expression of the HFABP has not been previously evaluated, and the mechanisms governing expression of metabolic genes in the heart are not completely understood. We used transient and permanent transfections in ventricular myocytes, skeletal myocytes, and nonmyocytic cells to map regulatory elements in the HFABP promoter, and audited results in transgenic mice. Appropriate tissue-specific expression in cell culture and in transgenic mice was dictated by 1.2 kb of the 5'-flanking sequence of FABP3, the HFABP gene. Comparison of orthologous murine and human genomic sequences demonstrated multiple regions of near-identity within this promoter region, including a CArG-like element close to the TATA box. Binding and transactivation studies demonstrated that this element can function as an atypical myocyte enhancer-binding factor 2 site. Interactions with adjacent sites are likely to be necessary for fully appropriate, tissue-specific, developmental and metabolic regulation.

Animals↗
PubMed1999

Coronary arteriolar dilation to acidosis: role of ATP-sensitive potassium channels and pertussis toxin-sensitive G proteins.

BACKGROUND: We previously demonstrated that coronary arteriolar dilation in response to acidosis is mediated by the opening of ATP-sensitive potassium (KATP) channels. However, the signal transduction involved in the KATP-channel activation during acidosis has not been elucidated. A recent study in cardiac myocytes implied that pertussis toxin (PTX)-sensitive G proteins may be involved in the signal transduction for KATP-channel activation. However, it remains unclear whether this transduction process also occurs in the vascular tissue and, in particular, whether it exerts functional dilation in response to acidosis. METHODS AND RESULTS: To examine the signaling pathway for acidosis-induced dilation, porcine coronary arterioles were isolated, cannulated, and pressurized for in vitro study. The GTPase activity in reconstituted G proteins was examined at different levels of pH. Extravascular acidosis (pH 7.3 to 7.0) produced a graded dilation of coronary arterioles. This dilation was not affected by removal of endothelium but was significantly attenuated after inhibition of KATP channels and G proteins by glibenclamide and PTX, respectively. Glibenclamide and PTX attenuated the acidosis-induced arteriolar dilation to the same extent, and combined administration of both inhibitors did not further inhibit the vasodilation. These results indicated that both inhibitors act on the same vasodilatory pathway. Furthermore, vasodilation of coronary arterioles to the KATP-channel opener pinacidil and to the endothelium-independent vasodilator sodium nitroprusside was not affected by PTX. Because PTX inhibited acidosis-induced vasodilation without inhibiting KATP-channel function, it is suggested that PTX inhibits the vasodilatory pathway upstream from KATP channels. GTPase activity in reconstituted G proteins was significantly enhanced by a reduction in pH, indicating that G proteins were directly activated by acidosis. CONCLUSIONS: On the basis of these findings, we conclude that acidosis-induced coronary arteriolar dilation is mediated by the opening of smooth muscle KATP channels through the activation of PTX-sensitive G proteins.

Acidosis↗
PubMed1999

Changes in coronary endothelial cell Ca2+ concentration during shear stress- and agonist-induced vasodilation.

Increases in intraluminal shear stress are thought to cause vasodilation of coronary arterioles by activation of Ca2+-dependent endothelial nitric oxide synthase followed by release of nitric oxide. We tested the hypothesis that endothelium-dependent vasodilation of isolated coronary arterioles to shear stress and agonists is necessarily preceded by an increase in endothelial cell Ca2+ concentration ([Ca2+]i). After selective loading of endothelium in isolated rabbit coronary arterioles with fura 2, simultaneous changes in diameter and [Ca2+]i were recorded. Vasodilations recorded in response to ACh, substance P, or shear stress were accompanied by significant increases in endothelial cell [Ca2+]i. Vasodilations to shear stress were accompanied by smaller changes in endothelial cell [Ca2+]i than equivalent dilations evoked by substance P or ACh. To test the role for Ca2+ as an activator of endothelial nitric oxide synthase, the endothelium was treated with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid. 1,2-Bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid eliminated significant changes in endothelial cell [Ca2+]i and inhibited dilations to ACh and substance P but did not significantly affect shear stress-induced vasodilation. The data indicate that endothelium-dependent vasodilation of coronary arterioles in response to agonists and shear stress is mediated in part through a rise in endothelial cell [Ca2+]i but that a substantial component of the shear stress-induced response occurs through a Ca2+-insensitive pathway.

Acetylcholine↗
PubMed1999

Adenosine A(2A) receptors mediate coronary microvascular dilation to adenosine: role of nitric oxide and ATP-sensitive potassium channels.

Adenosine is a potent vasodilator that plays an important role in the regulation of coronary microvascular diameter. Although multiple adenosine receptor subtypes have been recently cloned, the specific adenosine receptor subtypes and the underlying mechanisms responsible for the vasodilation to adenosine in the coronary microcirculation remain unknown. Therefore, in the present study we determined the receptor subtypes for coronary arteriolar dilation to adenosine and investigated the role of nitric oxide (NO) and ATP-sensitive potassium (K(ATP)) channels in this vasodilatory response. Pig coronary arterioles (50-100 microm in situ) were isolated, cannulated, and pressurized without flow for in vitro study. Arterioles developed basal tone and dilated in a concentration-dependent manner to adenosine and to adenosine receptor agonists (2S)-N(6)-[2-endo-norbornyl]adenosine (A(1)), 2-[p-(2-carboxyethyl)]phenylethyl-amino-5'-N-ethylcarboxamidoadenosin e (CGS21680; A(2A)), N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (A(3)), and N-ethylcarboxamidoadenosine (nonselective adenosine receptor activation). The selective A(2A) receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-y l amino]ethyl)phenol attenuated vasodilation to adenosine and to all adenosine receptor agonists tested, suggesting that the vasodilatory responses were primarily mediated by A(2A) receptors. Adenosine- and CGS21680-induced dilations were attenuated in a similar manner by endothelial removal and by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. In denuded vessels, both adenosine- and CGS21680-induced dilations were nearly abolished by the K(ATP) channel inhibitor glibenclamide. The selective A(2A) agonist CGS21680 mechanistically mimics the vasodilation in response to adenosine. Collectively, our results suggest that the dilation of coronary arterioles to adenosine is mediated predominantly by A(2A) receptors. Activation of this receptor subtype elicits vasodilation by endothelial release of NO and by the smooth muscle opening of K(ATP) channels.

Adenosine↗
PubMed1998

LDLs impair vasomotor function of the coronary microcirculation: role of superoxide anions.

Oxidized LDLs (Ox-LDLs) inhibit endothelium-dependent dilation of isolated conduit arteries in a manner comparable to the impairment demonstrated in atherosclerotic vessels. However, it is not known whether the microvessels, which do not develop atherosclerotic lesions, are susceptible to Ox-LDL. Since endothelial release of NO plays an important role in vasodilation and since its dysfunction associated with atherosclerosis has been shown to extend into the coronary microcirculation, we hypothesized that Ox-LDLs impair endothelium-dependent vasodilation of coronary arterioles by reducing the synthesis and/or release of NO. To test this hypothesis, porcine subepicardial vessels (50 to 100 microm) were isolated, cannulated, and pressurized to 60 cm H2O without flow for in vitro study. Isolated vessels developed basal tone and dilated in a dose-dependent manner to the endothelium-dependent vasodilators serotonin, ATP, and ionomycin. These vasodilatory responses were inhibited by the NO synthase inhibitor NG-monomethyl-L-arginine and were subsequently reversed by extraluminal administration of the NO precursor L-arginine (3 mmol/L), suggesting the involvement of NO in these vasomotor responses. Intraluminal incubation of the vessels with native LDL (N-LDL) or Ox-LDL (1 mg protein/mL) significantly attenuated dilations to serotonin, ATP, and ionomycin. Ox-LDL produced more severe inhibition than did N-LDL, and the inhibitory effect was comparable to that of NG-monomethyl-L-arginine. The inhibitory effects of N-LDL and Ox-LDL were reversed by exogenous L-arginine (3 mmol/L) and were prevented by sodium dihydroxybenzene disulfonate (Tiron), a cell-permeable superoxide scavenger. In contrast, administration of the cell-impermeable superoxide scavenger superoxide dismutase prevented the inhibitory effect of N-LDL but not of Ox-LDL. In addition, the inhibitory effects of LDL were not restored by D-arginine or by removal of intraluminal LDL. Neither N-LDL nor Ox-LDL altered endothelium-independent vasodilation to sodium nitroprusside. These results indicate that coronary arterioles are susceptible to LDLs that specifically impair endothelium-dependent vasodilation by reducing NO synthesis. It is suggested that the initiation of superoxide anion production and the subsequent L-arginine deficiency may be responsible for the detrimental effect of LDL.

Animals↗
PubMed1998

Lipopolysaccharide activates endothelial nitric oxide synthase through protein tyrosine kinase.

Vascular endothelial cell injury or activation by lipopolysaccharide (LPS) plays an important role in the pathogenesis of endotoxin shock. However, the effect of LPS on NO production from vascular endothelial cells (ECs) is incompletely understood. In this study, bovine coronary venular ECs were treated with LPS and the release of NO and expression of the endothelial NO synthase (ecNOS) were examined. We found that the ecNOS activity is transiently enhanced by LPS within the time scale of about 10 h due to the interplay between two LPS-induced mechanisms. Within the first 10 h of LPS treatment, the specific activity of ecNOS is increased by a post-translational modification mediated through a protein tyrosine kinase cascade. After about 10 h of treatment, however, LPS destabilizes the transcript of ecNOS and thus decreased the expression level and total activity.

Animals↗
PubMed1998

Targeted recombination between MHV-2 and MHV-A59 to study neurotropic determinants of MHV.

MHV-A59 produces acute encephalitis, acute hepatitis and chronic demyelination in infected mice. MHV-2 produces only hepatitis and mild meningitis but without encephalitis or demyelination. We have previously studied a set of recombinant viruses between these two strains. The common denominator of viruses that produced encephalitis was a membrane (M) gene derived from MHV-A59. Thus to study the potential contribution of the M gene to acute encephalitis, chimeric viruses were produced in which the M gene of MHV-A59 was substituted with the M gene of MHV-2 by targeted recombination. A control virus was produced in which the M gene of A59 was recombined back into an A59 background. Viruses were then analyzed for their biologic properties and compared with the phenotypes of MHV-A59 and MHV-2 by histopathology and plaque assays for viral titers in organs following intracerebral (IC) inoculation. All three chimeric viruses had a phenotype similar to MHV-A59. Thus, the replacement of the M gene of MHV-A59 with that of MHV-2 is insufficient to produce a phenotype that lacks encephalitis similar to MHV-2.

Animals↗
PubMed1998

Coronavirus particle assembly: primary structure requirements of the membrane protein.

Coronavirus-like particles morphologically similar to normal virions are assembled when genes encoding the viral membrane proteins M and E are coexpressed in eukaryotic cells. Using this envelope assembly assay, we have studied the primary sequence requirements for particle formation of the mouse hepatitis virus (MHV) M protein, the major protein of the coronavirion membrane. Our results show that each of the different domains of the protein is important. Mutations (deletions, insertions, point mutations) in the luminal domain, the transmembrane domains, the amphiphilic domain, or the carboxy-terminal domain had effects on the assembly of M into enveloped particles. Strikingly, the extreme carboxy-terminal residue is crucial. Deletion of this single residue abolished particle assembly almost completely; most substitutions were strongly inhibitory. Site-directed mutations in the carboxy terminus of M were also incorporated into the MHV genome by targeted recombination. The results supported a critical role for this domain of M in viral assembly, although the M carboxy terminus was more tolerant of alteration in the complete virion than in virus-like particles, likely because of the stabilization of virions by additional intermolecular interactions. Interestingly, glycosylation of M appeared not essential for assembly. Mutations in the luminal domain that abolished the normal O glycosylation of the protein or created an N-glycosylated form had no effect. Mutant M proteins unable to form virus-like particles were found to inhibit the budding of assembly-competent M in a concentration-dependent manner. However, assembly-competent M was able to rescue assembly-incompetent M when the latter was present in low amounts. These observations support the existence of interactions between M molecules that are thought to be the driving force in coronavirus envelope assembly.

Amino Acid Sequence↗
PubMed1998

Arginase modulates nitric oxide production in activated macrophages.

In macrophages and many other cell types, L-arginine is used as a substrate by both nitric oxide synthase (NOS) and arginase to produce nitric oxide (NO) and urea, respectively. Because the availability of L-arginine is a major determinant for NO synthesis in the activated macrophage, we hypothesized that NO production may be reduced by arginase via depleting the common substrate in this cell type. To test this hypothesis, we investigated the effect of an arginase inhibitor, L-norvaline, on NO production in J774A.1 mouse macrophages activated by lipopolysaccharide (LPS, 1.0 microgram/ml) for 22 h. In the absence of LPS, macrophages produced a low level of NO. In contrast, NO production from these cells was significantly increased in the presence of LPS. Increasing extracellular levels of L-arginine (0.01-0.8 mM) produced a concomitant increase in NO production of activated macrophages. L-Norvaline (10 mM), which specifically inhibits arginase activity (i.e., reducing urea production by 50%) without altering NOS activity, enhanced NO production (by 55%) from activated macrophages. The enhancement of NO production by L-norvaline was inversely related to the extracellular level of L-arginine. A more pronounced increase in NO production was observed at the lower level of extracellular L-arginine, i.e., a 55 vs. 28% increase for 0.05 and 0.1 mM extracellular L-arginine, respectively. When the L-arginine concentration exceeded 0.5 mM, the L-norvaline effect was abolished. These results indicate that arginase can compete with NOS for their common substrate and thus inhibit NO production. This regulatory mechanism may be particularly important when the extracellular supply of L-arginine is limited.

Animals↗
PubMed1998

Effective diffusion distance of nitric oxide in the microcirculation.

Despite its well-documented importance, the mechanism for nitric oxide (NO) transport in vivo is still unclear. In particular, the effect of hemoglobin-NO interaction and the range of NO action have not been characterized in the microcirculation, where blood flow is optimally regulated. Using a mathematical model and experimental data on NO production and degradation rates, we investigated factors that determine the effective diffusion distance of NO in the microcirculation. This distance is defined as the distance within which NO concentration is greater than the equilibrium dissociation constant (0.25 microM) of soluble guanylyl cyclase, the target enzyme for NO action. We found that the size of the vessel is an important factor in determining the effective diffusion distance of NO. In approximately 30- to 100-micron-ID microvessels the luminal NO concentrations and the abluminal effective diffusion distance are maximal. Furthermore, the model suggests that if the NO-erythrocyte reaction rate is as fast as the rate reported for the in vitro NO-hemoglobin reaction, the NO concentration in the vascular smooth muscle will be insufficient to stimulate smooth muscle guanylyl cyclase effectively. In addition, the existence of an erythrocyte-free layer near the vascular wall is important in determining the effective NO diffusion distance. These results suggest that 1) the range of NO action may exhibit significant spatial heterogeneity in vivo, depending on the size of the vessel and the local chemistry of NO degradation, 2) the NO binding/ reaction constant with hemoglobin in the red blood cell may be much smaller than that with free hemoglobin, and 3) the microcirculation is the optimal site for NO to exert its regulatory function. Because NO exhibits vasodilatory function and antiatherogenic activity, the high NO concentration and its long effective range in the microcirculation may serve as intrinsic factors to prevent the development of systemic hypertension and atherosclerotic pathology in microvessels.

Animals↗
PubMed1998

Estimation of nitric oxide production and reaction rates in tissue by use of a mathematical model.

Nitric oxide (NO) produced by the vascular endothelium is an important biologic messenger that regulates vessel tone and permeability and inhibits platelet adhesion and aggregation. NO exerts its control of vessel tone by interacting with guanylyl cyclase in the vascular smooth muscle to initiate a series of reactions that lead to vessel dilation. Previous efforts to investigate this interaction by mathematical modeling of NO diffusion and reaction have been hampered by the lack of information on the production and degradation rate of NO. We use a mathematical model and previously published experimental data to estimate the rate of NO production, 6.8 x 10(-14) micromol . micron-2 . s-1; the NO diffusion coefficient, 3,300 micron2 s-1; and the NO consumption rate coefficient in the vascular smooth muscle, 0.01 s-1 (1st-order rate expression) or 0.05 microM-1 . s-1 (2nd-order rate expression). The modeling approach is discussed in detail. It provides a general framework for modeling the NO produced from the endothelium and for estimating relevant physical parameters.

Endothelium, Vascular↗