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At least 595 records · Page 33Linked to original sources
PubMed1993

Platelet-activating factor induces selective pulmonary arterial hyperreactivity in isolated perfused rabbit lungs.

The role of vasoreactivity in PAF-induced pulmonary hypertension (PHT) was assessed in isolated, perfused rabbit lungs. We evaluated the steady-state pulmonary vascular response to five vasoconstrictors: PGF2 alpha, norepinephrine, angiotensin II, PAF, and KCl. Pulmonary arterial pressure and pulmonary vascular resistance (PVR) were significantly greater in lungs of rabbits treated with PAF for 28 days than in control rabbits in response to PGF2 alpha and norepinephrine. When resistance was partitioned by the vascular occlusion method, at baseline the vascular resistance was equally distributed between arterial and venous segments in both experimental groups. Arterial resistance accounted for approximately 76% of PVR during norepinephrine injection and 60% of PVR during PGF2 alpha injection in PAF-treated lungs. Whereas arterial resistance accounted for approximately 63% of PVR during norepinephrine injection and 52% of PVR during PGF2 alpha injection in control lungs, there was no significant difference in the response to angiotensin II, acute PAF, and KCl in lungs from chronic PAF-treated rabbits compared with responses in control rabbit lungs, though the pressor response to acute PAF tended to be blunted in PAF-treated lungs. Chronic PAF treatment results in enhanced pulmonary arterial reactivity to selected autacoids in isolated perfused lungs.

Angiotensin II↗
PubMed1991

Protein kinase C regulates the synthesis of platelet-activating factor by human monocytes.

Human peripheral blood monocytes synthesize the potent lipid autacoid platelet-activating factor (PAF) following appropriate stimulation. We examined the role of protein kinase C (PKC) in regulating the synthesis of PAF by stimulated monocytes. 4 beta-phorbol 12-myristate 13-acetate (PMA) and 1,2-dioctanoyl-sn-glycerol, which directly activate PKC, stimulated the synthesis of PAF. Sphingosine, a long-chain amine that inhibits PKC, blocked both the binding of phorbol esters to monocytes and the synthesis of PAF in response to PMA (half-maximal inhibition at 5 to 10 microM and complete inhibition at 10 to 30 microM sphingosine). Thus, the activation of PKC was necessary and sufficient for PAF synthesis in response to phorbol ester. Sphingosine also blocked PAF synthesis in response to the calcium ionophore A23187 and opsonized zymosan particles by specific inhibition of PKC. Two other PKC inhibitors, stearylamine and staurosporine, also blocked PAF synthesis following A23187 or opsonized zymosan stimulation. These experiments demonstrated that PKC activation was required for PAF synthesis in response to the calcium signal generated by A23187 or a receptor-mediated agonist, opsonized zymosan. The synthesis of PAF and leukotriene B4 were temporally coupled following cell stimulation. Further, production of these two lipid mediators, and the release of arachidonic acid, were inhibited in parallel by sphingosine. Thus, PKC regulate the synthesis of both PAF and leukotriene B4 at a common step, probably phospholipase A2.

Binding Sites↗
PubMed1985

Histamine modulates contraction and cyclic nucleotides in cultured rat mesangial cells. Differential effects mediated by histamine H1 and H2 receptors.

Histamine influences the glomerular microcirculation and modulates immune-inflammatory responses. In the rat kidney, histamine is synthesized by glomeruli and stimulates cyclic nucleotide production specifically in glomeruli. We investigated the in vitro effect of histamine on cyclic nucleotide accumulation in rat cultured glomerular mesangial and epithelial cells. Histamine stimulated cyclic AMP (cAMP) accumulation in cultured mesangial cells (64.0 +/- 22.1 to 511.4 +/- 86.6 pmol/mg protein, n = 9) but had no effect on cAMP accumulation in epithelial cells. This effect was dose-dependent and time-dependent. Stimulation of cAMP accumulation occurred in the range of 5 X 10(-6) M-10(-4) M histamine with a half maximal stimulatory effect of 2 X 10(-5) M. Initial stimulation was noted by 30 s, and maximum stimulation was observed at 5 min. The H2 antagonist cimetidine (10(-4) M) abolished the stimulatory effect of histamine (10(-4) M), while equimolar concentrations of the H1 antagonist diphenhydramine had no significant effect on cAMP accumulation. Moreover, the specific H2 agonist dimaprit, but not the H1 agonist 2-pyridylethylamine, stimulated cAMP accumulation. Histamine had no effect on cAMP accumulation in epithelial cells or on cyclic guanosine monophosphate accumulation in epithelial or mesangial cells. Since the in vivo infusion of histamine reduces ultrafiltration coefficient and since mesangial cell contraction is thought to be responsible for the reduction in the ultrafiltration coefficient, we examined the effect of histamine on the contractile property of mesangial cells. Histamine (5 X 10(-6)-10(-4) M) contracted mesangial cells, and the H1 antagonist diphenhydramine (10(-4) M) but not the H2 antagonist cimetidine (10(-4) M) prevented histamine (10(-4) M) induced contraction. In addition, the H1 agonist 2-pyridylethylamine, but not the H2 agonist dimaprit, contracted mesangial cells. Histamine and its specific agonists and antagonists induced contraction of isolated glomeruli as assessed by glomerular planar surface area in a manner parallel to their effect on mesangial cells. Cinnarizine (10(-5) M), a Ca++ channel blocker, or Ca++, Mg++-free medium prevented histamine (10(-4) M) induced mesangial cell and glomerular contraction. Thus, histamine enhances cAMP accumulation specifically in mesangial cells via an H2 receptor. In contrast, histamine contracts mesangial cells and glomeruli via an H1 receptor, an effect that is dependent on extracellular Ca++ entry. These findings show that histamine potentially influences intraglomerular hemodynamics via effects on mesangial cell contraction. Moreover, our findings considered with the in vivo observation that histamine reduces kf via and H1 receptor provide further support of the hypothesis that mesangial cell contraction regulates the glomerular capillary surface area available for filtration. Our studies also show that this contractile effect of histamine is dependent on extracellular calcium. The presence of a cAMP system sensitive to histamine may have major implications in the pathogenesis of inflammatory glomerulopathies. Mesangial cells possess characteristics similar to circulating and tissue immune effector cells, including lysosomal enzyme release, oxygen radical production, and release of a number of immunomodulatory factors. Histamine and cAMP have been shown to modulate such characteristics of inflammatory cells. It is therefore conceivable that histamine, via its interaction with H2 receptors and subsequent generation cAMP, may have profound effects on such properties of mesangial cells, suggesting that this autacoid may modulate not only glomerular hemodynamics but also immune, inflammatory responses within the glomerulus.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Inhibition of platelet function by an aspirin-insensitive endothelial cell ADPase. Thromboregulation by endothelial cells.

We previously reported that platelets become unresponsive to agonists when stimulated in combined suspension with aspirin-treated human umbilical vein endothelial cells. Inhibition occurred concomitant with metabolism of platelet-derived endoperoxides to prostacyclin by endothelial cells. We now demonstrate that if aspirin-treated platelets which fully respond to appropriate doses of agonists are exposed to aspirin-treated endothelial cells, they remain unresponsive despite absence of prostacyclin. Platelet inhibition is due in large part to ecto-ADPase activity on the endothelial cells. This was established by incubating aspirin-treated endothelial cells with 14C-ADP. Radio-thin layer chromatography and aggregometry demonstrated that 14C-ADP and induction of platelet activation decreased rapidly and concurrently. AMP accumulated transiently, was further metabolized to adenosine, and deaminated to inosine. The apparent Km of the endothelial cell ADPase was 33-42 microM and the Vmax 17-43 nmol/min per 10(6) cells, values in the range of antithrombotic potential. Thus, at least three complementary systems in human endothelial cells control platelet responsiveness: a cell-associated, aspirin-insensitive ADPase which functions in parallel with fluid phase autacoids such as the aspirin-inhibitable eicosanoids, and the aspirin-insensitive endothelium-derived relaxing factor.

Adenosine Diphosphate↗
PubMed1993

Cell-cell signaling between adult rat ventricular myocytes and cardiac microvascular endothelial cells in heterotypic primary culture.

It is unclear whether signaling between endothelial cells and muscle cells within ventricular myocardium, known to be important during cardiac development, remains physiologically relevant in the adult heart. Also, the mechanisms regulating the synthesis and activation of locally acting autacoids such as endothelins, cytokines known to have potent effects on contractile function and gene expression in cardiac myocytes, are unknown, as their cells of origin within ventricular muscle. Microvascular endothelial cells isolated from ventricular tissue of adult rats do not express endothelins constitutively. However, the appearance of preproendothelin mRNA can be increased in cardiac microvascular endothelial cells by heterotypic primary culture with adult rat ventricular myocytes. Cell-cell contact, or at least close apposition, appears to be necessary to increase preproendothelin mRNA, as medium conditioned by ventricular myocytes alone was ineffective when applied to monocultures of microvascular endothelial cells. The level of TGF beta precursor mRNA is also markedly increased in microvascular endothelial cells in coculture and precedes the appearance of endothelin precursor transcripts. In coculture, TGF beta acts as an autocrine cytokine, increasing endothelin precursor mRNA and inhibiting the rate of microvascular endothelial cell proliferation. This regulation of endothelial cell phenotype in heterotypic primary cultures suggests that dynamic, reciprocal cell-cell signaling may also be occurring between microvascular endothelium and ventricular myocytes in vivo.

Amino Acid Sequence↗
PubMed1995

All-trans-retinoic acid stimulates synthesis of cyclic ADP-ribose in renal LLC-PK1 cells.

Cyclic adenosine diphospho-ribose (cADPR) triggers Ca2+ release from intracellular stores and is therefore proposed to function as a second messenger in cellular signaling; however, an extracellular stimulus, i.e., first messenger (hormone or autacoid) that modulates cADPR metabolism has not been identified. We discovered that all-trans-retinoic acid (atRA) is a potent stimulus to increase cADPR synthesis by cultured LLC-PK1 cells. The stimulation of cADPR synthesis by atRA is dose dependent between 0.1 nM and 1 microM (maximum increase approximately delta + 600%), while atRA does not alter the rate of cADPR hydrolysis by LLC-PK1 cells. The activity of other intrinsic apical membrane enzymes was not significantly altered. The stimulation of cADPR synthesis by atRA occurs after a lag period of 6-8 h, and the stimulation is inhibited by actinomycin D and by cycloheximide. Our results therefore demonstrate that atRA in physiological concentrations is a potent extracellular stimulus, first messenger, that enhances cADPR synthesis, and the effect of atRA requires de novo protein synthesis. We suggest that some of the diverse biologic actions of atRA such as morphogenetic and cell differentiation may be mediated via cADPR.

ADP-ribosyl Cyclase↗
PubMed1996

Spinal cord adenosine receptor stimulation in rats inhibits peripheral neutrophil accumulation. The role of N-methyl-D-aspartate receptors.

The effect of spinal adenosine receptor ligation on peripheral leukocyte accumulation was studied in two rat models of inflammation. Neutrophil infiltration into dermal inflammatory sites was signficantly reduced by adenosine A1 receptor agonists injected through intrathecal catheters. These effects were reversed by N-methyl-D-aspartate (NMDA), and were mimicked by (+/-)-2-amino-5-phosphonopentanoic acid (AP-5), a glutamate NMDA receptor antagonist. Peripheral adenosine levels, as measured in air pouch exudates, decreased markedly in inflamed pouches but remained near normal after intrathecal treatment with AP-5. Moreover, the antiinflammatory effects of intrathecal A1 receptor agonists and AP-5 were reversed by an adenosine A2 receptor antagonist administered intraperitoneally. Hence, central NMDA receptor activity can regulate neutrophil accumulation in peripheral inflammatory sites by reducing local levels of adenosine, an antiinflammatory autacoid which inhibits neutrophil function through A2 receptor activation. This represents a previously unknown pathway by which the central nervous system influences inflammatory responses.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1997

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

Cartilage specimens from osteoarthritis (OA)-affected patients spontaneously released PGE2 at 48 h in ex vivo culture at levels at least 50-fold higher than in normal cartilage and 18-fold higher than in normal cartilage + cytokines + endotoxin. The superinduction of PGE2 production coincides with the upregulation of cyclooxygenase-2 (COX-2) in OA-affected cartilage. Production of both nitric oxide (NO) and PGE2 by OA cartilage explants is regulated at the level of transcription and translation. Dexamethasone inhibited only the spontaneously released PGE2 production, and not NO, in OA-affected cartilage. The NO synthase inhibitor HN(G)-monomethyl-L-arginine monoacetate inhibited OA cartilage NO production by > 90%, but augmented significantly (twofold) the spontaneous production of PGE2 in the same explants. Similarly, addition of exogenous NO donors to OA cartilage significantly inhibited PGE2 production. Cytokine + endotoxin stimulation of OA explants increased PGE2 production above the spontaneous release. Addition of L-NMMA further augmented cytokine-induced PGE2 production by at least fourfold. Inhibition of PGE2 by COX-2 inhibitors (dexamethasone or indomethacin) or addition of exogenous PGE2 did not significantly affect the spontaneous NO production. These data indicate that human OA-affected cartilage in ex vivo conditions shows (a) superinduction of PGE2 due to upregulation of COX-2, and (b) spontaneous release of NO that acts as an autacoid to attenuate the production of the COX-2 products such as PGE2. These studies, together with others, also suggest that PGE2 may be differentially regulated in normal and OA-affected chondrocytes.

Adult↗
PubMed1997

Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors.

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.

Angiotensin Receptor Antagonists↗
PubMed1995

Salivary PAF levels correlate with the severity of periodontal inflammation.

Platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, has been previously identified in inflamed gingival tissues and gingival crevicular fluid. However, the role of PAF in oral pathobiology remains unknown. The purpose of the present study was to evaluate the relationship between salivary PAF levels and the severity of periodontal inflammation. PAF activity in lipid extracts of whole (mixed) saliva collected from 69 untreated subjects immediately prior to routine oral evaluation was determined by platelet bioassay. Significant positive correlations were observed between the level of PAF in saliva and measures of periodontal inflammation, i.e., the percentage of periodontal probing depths greater than 4 mm, the number of periodontal bleeding sites, and the number of histologically identified polymorphonuclear neutrophilic leukocytes (PMN) in saliva. Moreover, when subjects were subdivided into groups on the basis of periodontal probing depths, a significant correlation was observed between salivary PAF levels and the extent of periodontal disease, i.e., PAF levels in saliva progressively increased from the healthiest group to the most severely affected group. Thus, salivary PAF levels correlate with the severity of periodontal inflammation. These results support the hypothesis that this pro-inflammatory phospholipid autacoid may participate in the pathogenesis of periodontal tissue injury and disease.

Adolescent↗
PubMed2003

Ion channel gene expression in human lung, skin, and cord blood-derived mast cells.

Immunoglobulin E (IgE)-dependent activation of human mast cells (HMC) is characterized by an influx of extracellular calcium (Ca(2+)), which is essential for subsequent release of preformed (granule-derived) mediators and newly generated autacoids and cytokines. In addition, flow of ions such as K(+) and Cl(-) is likely to play an important role in mast cell activation, proliferation, and chemotaxis through their effect on membrane potential and thus Ca(2+) influx. It is therefore important to identify these critical molecular effectors of HMC function. In this study, we have used high-density oligonucleotide probe arrays to characterize for the first time the profile of ion channel gene expression in human lung, skin, and cord blood-derived mast cells. These cells express mRNA for inwardly rectifying and Ca(2+)-activated K(+) channels, voltage-dependent Na(+) and Ca(2+) channels, purinergic P2X channels, transient receptor potential channels, and voltage-dependent and intracellular Cl(-) channels. IgE-dependent activation had little effect on ion channel expression, but distinct differences for some channels were observed between the different mast cell phenotypes, which may contribute to the mechanism of functional mast cell heterogeneity.

Adult↗
PubMed1984

The effect of flurbiprofen, a potent inhibitor of prostaglandin synthesis, on insulin and glucagon release from isolated rat pancreas.

The influence of different levels of inhibition of prostaglandin (PG) synthesis on the release of insulin and glucagon was investigated in the basal state (5.6 mM glucose) and in response to 30-min perfusion of 16.7 mM glucose using the isolated perfused rat pancreas model. Flurbiprofen (FLR), a potent and selective inhibitor of PG synthesis, was present in the perfusate during the entire experimental period at a concentration of 10(-8), 5 X 10(-8), or 10(-6) M; control experiments were performed without the drug. Levels of immunoreactive PGE2, PGF2 alpha, insulin, and glucagon were measured in the portal venous effluent. FLR inhibited PG synthesis in a dose-related manner; PGE2 was inhibited more than PGF2 alpha. Basal and glucose-induced secretion of insulin was augmented by FLR at 5 X 10(-8) M, but was inhibited at 10(-6) M. At 10(-6) M FLR, basal glucagon secretion was inhibited; glucose-induced suppression still occurred without any potentiation. We conclude that 1) endogenous PGs modulate the secretion of insulin and glucagon; 2) divergence of the effects of low and high levels of inhibition of PG biosynthesis on insulin release may be due to altered tissue proportions of various PGs and related autacoids; and 3) the predominant effect of endogenous PGs on glucagon release is tonic stimulation.

Animals↗
PubMed1993

Prostaglandin F2 alpha mediates platelet-activating factor-stimulated atrial natriuretic factor release from the isolated rat heart.

Platelet-activating factor (PAF) and the prostaglandins have recently been shown to stimulate atrial natriuretic factor (ANF) secretion from the heart. As PAF also potentiates the release of cyclooxygenase products from isolated hearts, the role of these substances in PAF-induced ANF secretion was investigated. Using an isolated perfused rat heart preparation, cyclooxygenase inhibition by indomethacin or meclofenamic acid (10 microM for each) significantly attenuated the rise in ANF associated with PAF administration (2.5 nmol). Prostaglandin F2 alpha (PGF) produced an immediate and dose-dependent increase in ANF secretion, which was significant at 0.01 mumol and reached 348 +/- 66% over baseline values after a 1-mumol injection. Prostaglandin E2 (PGE) generated a much smaller 98 +/- 25% increase after a 1-mumol administration. Furthermore, PGF but not PGE was released from isolated hearts immediately after PAF administration. PGF release reached a maximum of 0.06 nmol/min g Heart-1 1 min after PAF stimulation and had returned to undetectable baseline values by 6 min. Cyclooxygenase inhibition abolished the release of PGF after PAF, in addition to attenuating (by 60-70%) the increased secretion of ANF after PAF injection. These results demonstrate very clearly that PGF is the major mediator for PAF-stimulated ANF secretion. Such an interaction may provide an alternative mechanism to atrial distension for the secretion of ANF in pathologies such as myocardial infarction, where autacoids such as PAF and the PGs are released from damaged cardiac muscle and elevated plasma levels of ANF are observed.

Animals↗
PubMed2006

ATP participates in the regulation of microvessel permeability.

We demonstrated previously that stimulation of the P2Y receptor enhanced the macromolecular permeability of cultured endothelial cell monolayers via the paracellular pathway. To determine whether the P2Y receptor participates in the regulation of permeability in intact microvessels, we have examined the effects of exogenous and endogenous ATP on the permeation of the surface tissue of perfused rat tail caudal artery using a fluorescein isothiocyanate-dextran (FD-4; MW 4400; 1.0 mg mL(-1)). The permeation of FD-4 was assessed by a confocal fluorescence imaging system. We found that 2-methylthioadenosine 5'-triphosphate, a P2Y receptor agonist, enhanced the fluorescence intensity of FD-4 in the surface of the rat caudal artery tissue and that it was inhibited by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, a P2 receptor antagonist. Also, noradrenaline, a sympathetic neurotransmitter, and bradykinin, an inflammatory autacoid, enhanced the fluorescence intensity of FD-4 in the surface tissue of the rat caudal artery. The enhancement by noradrenaline was significantly inhibited by the P2 receptor antagonist. In addition, noradrenaline and bradykinin caused the release of ATP, ADP, AMP and adenosine from the endothelium of the rat caudal artery. These results indicated that the exogenous and endogenous ATP increased the macromolecular permeability of blood capillaries via the P2Y receptor. Such purinergic regulation of endothelial permeability may function in physiological and pathophysiological conditions.

Adenosine Triphosphate↗
PubMed2005

Potentiation of neutrophil cyclooxygenase-2 by adenosine: an early anti-inflammatory signal.

Neutrophils, which are often the first to migrate at inflamed sites, can generate leukotriene B(4) from the 5-lipoxygenase pathway and prostaglandin E(2) through the inducible cyclooxygenase-2 pathway. Adenosine, an endogenous autacoid with several anti-inflammatory properties, blocks the synthesis of leukotriene B(4) while it potentiates the cyclooxygenase-2 pathway in fMLP-treated neutrophils, following activation of the A(2A) receptor. Using the murine air pouch model of inflammation, we observed that inflammatory leukocytes from mice lacking the A(2A) receptor have less cyclooxygenase-2 induction than wild-type animals. In human leukocytes, A(2A) receptor activation specifically elicited potentiation of cyclooxygenase-2 in neutrophils, but not in monocytes. Signal transduction studies indicated that the cAMP, ERK1/2, PI-3K and p38K intracellular pathways are implicated both in the direct upregulation of cyclooxygenase-2 and in its potentiation. Together, these results indicate that neutrophils are particularly important mediators of adenosine's effects. Given the uncontrolled inflammatory phenotype observed in knockout mice and in view of the potent inhibitory actions of prostaglandin E(2) on inflammatory cells, an increased cyclooxygenase-2 expression resulting from A(2A) receptor activation, observed particularly in neutrophils, may take part in an early modulatory mechanism promoting anti-inflammatory activities of adenosine.

Adenosine↗
PubMed2006

Medical benefits of using natural compounds and their derivatives having multiple pharmacological actions.

The multiple pharmacological actions of a unique compound are a prerequisite for classifying drugs as highly efficacious, because the multiple pharmacological actions offer the possibility of treating various symptoms of chronic diseases as described below. 1) Sustained hyperglycemia induces macrovascular and microvascular complications in type 2 diabetes mellitus. Antihyperglycemic medication and the control of postprandial hyperglycemia are essentially important for normalizing plasma glucose level. Gymnemic acid IV isolated from Gymnema sylvestre (Asclepiadaceae) leaves has antisweet, antihyperglycemic, glucose uptake inhibitory, and gut glycosidase inhibitory effects. Most of these pharmacological effects may synergistically contribute to alleviating type 2 diabetes-related symptoms. 2) Diabetic skeletal and vascular smooth muscles are hypersensitive to chemical transmitters, cytokines and autacoids. The sensitivity of neuromuscular synapses is enhanced in diabetes, which seems to be closely associated with neuropathy as one of the diabetic complications. beta-Eudesmol found in Atractylodes lancea rhizome has a desensitizing channel blocking action to nicotinic acetylcholine receptors, anti-angiogenic action in vascular endothelium, and neuronal differentiation actions. These multiple pharmacological actions are favorable for treating angiogenic diseases possibly including the complications of diabetes, namely, retinopathy and nephropathy, and cancer. 3) Nipradilol is clinically utilized as a topical antiglaucoma drug. The ocular hypotensive effects of this compound are brought about by its alpha1 and beta-adrenergic receptor blocking actions, and nitric oxide (NO) releasing action. NO directly activates cyclooxygenases. All these pharmacologic effects are beneficial for treating glaucoma. The selectivity and specificity of drug action are required for treating acute diseases, infections or for acting as useful reagents. The pleiotropic actions of natural compounds and their derivatives serve as important clues for developing new drugs for various chronic diseases.

Adrenergic Antagonists↗
PubMed1997

[Regulation of biological functions by the Kallikrein-Kinin system].

Research on the kallikrein-kinin system started from the discovery of urinary hypotensive substance in Germany around 1940-1950. Since then, numbers of researchers have explored this field including related inhibitors, enzymes and autacoids, from all over the world. Components of the kallikrein-kinin system have been analysed extensively, especially since the epoch of the discovery of the deficient patients in these components. Recent progress of gene techniques also enhanced the progress of the study in the kallikrein-kinin field. In this review I discuss about 1) Components and the difference of plasma kallikrein system and glandular kallikrein system; 2) Impact of the discovery of the deficient plasma in Factor XII, prekallikrein, kininogens as well as in C1INH, and consequent knowledge from the studies of these deficients; 3) Biological roles of the kallikrein-kinin system; and recent topics in this field.

Animals↗
PubMed1997

Roles of nitric oxide and adenosine in the regulation of coronary conductance in the basal state and during reactive hyperemia.

Nitric oxide (NO) and adenosine are important mediators in the regulation of coronary vascular tone and are released into the interstitium from the vascular endothelium and myocardium, respectively. The roles of these autacoids in the regulation of coronary flow in the basal and reactive hyperemic states were examined in Langendorff rabbit hearts perfused with oxygenated Krebs-Henseleit solution at 37 degrees C and 110 mmHg pressure. Instantaneous perfusion pressure-flow relationships were analyzed to derive coronary conductance both in the basal state and during the early phase of reperfusion (hyperemic state). N omega-nitro-L-arginine methyl ester (L-NAME) at increasing concentrations (10(-6) to 10(-4) mol/L) (n = 7) and 8-phenyltheophylline (8-PT) at increasing concentrations (10(-9) to 10(-6) mol/L) (n = 7) were applied to assess the role of NO and adenosine, respectively. L-NAME dose-dependently reduced the coronary conductance in both the basal and early hyperemic states, while 8-PT dose-dependently reduced conductance only in the hyperemic state. Changes in conductance during the early hyperemic phase correlated well with changes in the debt repayment ratio for either L-NAME (r = 0.94) or 8-PT (r = 0.99). These data suggest that a flow-related NO release mechanism regulates the coronary conductance in both the basal and hyperemic states while the metabolic regulation of adenosine release plays a role in the presence of ischemia.

Adenosine↗