Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelium-dependent responses are depressed in coronary and peripheral blood vessels after the onset of pacing-induced heart failure in dogs and heart failure of various etiologies in humans. The present study was designed to examine whether these responses were due to decreases in the expression of endothelial cell NO synthase (ecNOS) and cyclooxygenase-1 (COX-1). After 1 month of left ventricular pacing, 8 mongrel dogs were monitored for heart failure as defined by clinical signs and left ventricular end diastolic pressures > 25 mm Hg. Total RNA and protein were isolated from endothelial cells scraped from the thoracic aorta and analyzed by Northern and Western blotting, respectively. Blots probed with 32P-labeled cDNAs for ecNOS and COX-1 were quantified densitometrically, and results were normalized against GAPDH or von Willebrand factor (vWF). In arbitrary units, the ratios of ecNOS to GAPDH were 2.66 +/- 0.77 (mean +/- SEM, n = 17) and 1.12 +/- 0.37 (n = 6 and the ratios of COX-1 to GAPDH were 1.52 +/- 0.52 and 0.56 +/- 0.15 before and after heart failure, respectively. These represent 56% to 64% (P < .05) reductions in ecNOS and COX-1 gene expression. There was no change in the ratios of either COX-1 or ecNOS to vWF. There was also a marked reduction in ecNOS protein after heart failure, estimated at 70%. A marked reduction in nitrite production, a measure of enzyme activity, from thoracic aortas in response to stimulation by either acetylcholine or bradykinin also occurred. To determine whether ecNOS and COX-1 could be independently regulated, an orally active NO-releasing agent, CAS 936, was given to 7 normal dogs for 7 days, and aortic ecNOS and COX-1 mRNAs were analyzed. The ratio of ecNOS to GAPDH was depressed by 52% (P < .05) in aortas from these dogs, whereas the ratio of COX-1 to GAPDH was unchanged. Similar results were found when data were normalized to vWF. These results suggest that at least two endothelial vasodilator gene products are reduced in heart failure, as opposed to a selective defect in NO synthase gene expression.
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PMID:Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. 860 6

The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.
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PMID:The effect of inhaled FK224, a tachykinin NK-1 and NK-2 receptor antagonist, on neurokinin A-induced bronchoconstriction in asthmatics. 866 34

The effects of a clinically used purified micronized flavonoid fraction (S5682) containing 90% diosmin and 10% hesperidin on increased microvascular permeability induced by histamine, bradykinin and leukotriene B4 (LTB4) were investigated by intravital microscopy in the cheek pouch preparation of diabetic hamsters. We also investigated the effects of S 5682 on macro- molecular permeability increase and leukocyte adhesion during ischemia-reperfusion using the same preparation. Diabetes was induced by an intraperitoneal injection of streptozotocin (50 mg/kg). S 5682, suspended in 10% lactose solution, or vehicle (10% lactose) was administered orally for 25 days at 20 mg/kg/day (10 mg/kg twice a day), starting 5 days after the streptozotocin injection. Fluorescein isothiocyanate-labelled dextran (molecular weight 150,000) was given intravenously, 30 min after completion of the cheek pouch preparation. The leukocytes were stained by continuous intravenous infusion of acridine orange (0.5 mg/ kg/min). Histamine (2 microMs), bradykinin (1 microM), and LTB4 (0.01 microM), applied topically for 5 min, increased the number of fluorescent vascular leakage sites in postcapillary venules. A temporary ischemia (duration: 30 min) with total circulatory arrest of the cheek pouch was obtained by clamping the neck of the everted pouch. The maximum number of leaky sites (per cm2 in the prepared area) which occurs either at 5 min after the beginning of each topical application or 10 min after the onset of reperfusion was quantified in UV light microscopy. The results from 60 animals divided into ten groups of 6 animals each are presented as means +/- SEM. In comparison with vehicle, S 5682 significantly inhibited the macromolecular permeability increasing the effect of histamine (343.8 +/- 18.5 vs. 91.0 +/- 8.2 leaks/ cm2; p > 0.001), bradykinin (347.0 +/- 14.6 vs. 110.3 +/- 8.5 leaks/cm2; p < 0.001) and LTB4 (323.0 +/- 15.5 vs. 161.3 +/- 13.8 leaks/cm2; p < 0.001). At reperfusion, after 30 min ischemia, S 5682 significantly decreased the observed macromolecular permeability (168.5 +/- 19.7 vs. 52.7 +/- 6.3 leaks/cm2; p < 0.01). Flavonoid-treated animals also tended to have a lower number of leukocytes adhering to the venular endothelium (104.8 +/- 11.0 vs. 75.8 +/- 9.7/6 mm2; p > 0.05). These results demonstrate that oral administration of S 5682 for 25 days at 20mg/kg body weight/day has a protective effect on leakage of macromolecules after application of permeability-increasing substances and during ischemia-reperfusion in the cheek pouch microvasculature of diabetic hamsters. In conclusion, the present data illustrating the inhibitory effect of a clinically relevant doses of S 5682 on the inflammatory processes induced in this in vivo model of microcirculation may serve as a rational basis to explain its clinical efficacy.
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PMID:Effects of oral administration of purified micronized flavonoid fraction on increased microvascular permeability induced by various agents and on ischemia/reperfusion in diabetic hamsters. 872 38

Bradykinin and beta-endorphin increases during acute pancreatitis are thought to contribute to the development of hypotension and myocardial depression in acute pancreatitis. beta-Endorphin release is mediated by trypsin-like enzymes and bradykinin from the pituitary gland. This study was undertaken to investigate the effect of a long-acting bradykinin receptor antagonist on bradykinin and beta-endorphin release and on hemodynamic changes during acute pancreatitis. Pancreatitis was induced by the injection of autologous bile mixed with trypsin into the main pancreatic duct after ligation of the accessory duct. Serum bradykinin and plasma beta-endorphin levels and cardiovascular function were measured. Twelve dogs (control group) were given 10 ml/kg/h of lactate Ringer's solution intravenously beginning 1 h before the induction of pancreatitis and continuing throughout the experiments. Six dogs received an intravenous infusion of 0.6 mg/kg/h of a new bradykinin receptor antagonist, HOE 140, D-Arg-[Hyp3, Thi5, D-Tic, Oic8]-bradykinin, in lactate Ringer's solution soon after the induction of pancreatitis. Six of twelve dogs in the control group, and none of the six dogs in the bradykinin receptor antagonist group, died during the experiments. Serum bradykinin levels in both groups increased until 1 h after the induction of pancreatitis, but thereafter the levels in the bradykinin receptor antagonist group decreased gradually until 5 h after induction, and levels were significantly lower than those in the control group (p < 0.05). Plasma beta-endorphin levels in the control group increased significantly, to 291.8 pg/ml (+/- 6.6 SEM) 5 h after the induction of pancreatitis, from the mean levels of 47.8 pg/ml before the induction of pancreatitis, while the mean beta-endorphin level in the bradykinin receptor antagonist group did not increase after the induction of pancreatitis. Infusion of the bradykinin receptor antagonist improved survival rates, hypotension, myocardial depression, and plasma lactate, suggesting that the bradykinin receptor antagonist inhibited the release of bradykinin and beta-endorphin, which contributed to the clinical improvement.
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PMID:Effects of bradykinin receptor antagonist on the release of beta-endorphin and bradykinin and on hemodynamic changes in a canine model of experimental acute pancreatitis. 892 25

Disturbance of the balance between excitatory and inhibitory activity of the airway sensory nerves has been implicated in asthma pathogenesis, particularly during exacerbations of the disease. The objective of this study was to examine the effect of experimental rhinovirus 16 (RV16) infection on airway responsiveness to bradykinin, a potent sensory nerve stimulus, in asthma. Thirteen atopic, mildly asthmatic subjects participated in a parallel, placebo-controlled study. A total dose of 2.6 to 5.6 x 10(4) TCID50 RV16 (n = 7) or its diluent (n = 6) was inoculated on 2 consecutive days (Days 0 and 1). Histamine and bradykinin challenges were performed before (Days-7 and-6) and after (Days 3 and 4) inoculation. The response was measured by FEV1 and partial flow-volume curves, and it was expressed as PC20FEV1 and PC40V40p, respectively (changes expressed in doubling dose: DD). Before inoculation, PC20FEV1 and PC40V40p to histamine were not significantly different between the groups (p > or = 0.22), whereas PC20FEV1 and PC40V40p to bradykinin tended to be higher in the RV16 group (p = 0.11 and p = 0.06, respectively). PC20FEV1 and PC40V40p to histamine decreased significantly in the RV16 group (mean change +/- SEM: -0.65 +/- 0.20 DD, p = 0.02 and -0.98 +/- 0.28 DD, p = 0.01, respectively), but not in the placebo group (p > or = 0.26). PC40V40p to bradykinin increased significantly in the placebo group (+2.46 +/- 0.92 DD, p = 0.04), with a similar trend for PC20FEV1 (+1.50 +/- 0.62 DD, p = 0.06), whereas there were no significant changes in the RV16 group (p > or = 0.77). These changes in PC40V40p to histamine and bradykinin were significantly different between the groups (p = 0.02). We conclude that repeated bradykinin challenge over a 10-d interval induces tachyphylaxis in asthmatic subjects in vivo and that experimental RV16 infection abolishes such tachyphylaxis to bradykinin while it enhances airway responsiveness to histamine. These results do not favor a predominant role of airway sensory nerves in rhinovirus-induced exacerbations of asthma.
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PMID:Effects of experimental rhinovirus 16 infection on airway hyperresponsiveness to bradykinin in asthmatic subjects in vivo. 911 13

The effects of a clinically used purified micronized flavonoid fraction (S 5682) containing 90% diosmin and 10% hesperidin on increased microvascular permeability induced by histamine, bradykinin, and leukotriene B4 (LTB4) were investigated by intravital microscopy in the hamster cheek pouch preparation. The authors also investigated the effects of S 5682 on macromolecular permeability increase and leukocyte adhesion during ischemia-reperfusion by using the same preparation. S 5682, suspended in 10% lactose solution, or vehicle (10% lactose) was administered orally to male hamsters for ten days at 20 mg/kg/day (10 mg/kg twice a day). Fluorescein isothiocyanate (FITC)-labeled dextran (mol wt 150,000) was given intravenously, thirty minutes after completion of the cheek pouch preparation. The leukocytes were stained by continuous IV infusion of acridine orange (0.5 mg/kg/minute). Histamine (2 microM), bradykinin (1 microM), and LTB4 (0.01 microM), applied topically for five minutes, increased the number of fluorescent vascular leakage sites in postcapillary venules. A temporary ischemia with total circulatory arrest of the cheek pouch was obtained by clamping the neck of the everted pouch. The maximum number of leaky sites (per cm2 in the prepared area) that occurred either at five minutes after the beginning of each topical application or ten minutes after the onset of reperfusion was quantified in ultraviolet light microscopy. The results from 60 animals divided into 10 groups of 6 animals each are presented as means +/- SEM. In comparison with vehicle, S 5682 significantly inhibited the macromolecular permeability increasing effect of histamine (343.5 +/- 22.3 versus 207.5 +/- 32.0 leaks/cm2; P < 0.01), bradykinin (345.2 +/- 19.0 versus 206.2 +/- 21.6 leaks/cm2; P < 0.01), and LTB4 (353.3 +/- 27.5 versus 242.7 +/- 33.6 leaks/cm2; P < 0.05). At reperfusion, after thirty minutes of ischemia, S 5682 significantly decreased the observed macromolecular permeability (103.6 +/- 15.4 versus 42.6 +/- 9.3 leaks/cm2; P < 0.01). Flavonoid-treated animals also displayed a statistically significant lower number of adhering leukocytes to the venular endothelium (83.5 +/- 9.5 versus 48.4 +/- 12.3 per 6 mm2; P < 0.05). These results demonstrate that oral administration of S 5682 for ten days at 20 mg/kg body weight/day had a protective effect against leakage of macromolecules after application of permeability-increasing substances and during ischemia-reperfusion in the cheek pouch microvasculature. Since firm leukocyte attachment to the endothelial wall and subsequent emigration of leukocytes into the interstitium is a mechanism for tissue damage during inflammation, attenuation of this phenomenon during conditions of ischemia-reperfusion can in part explain previous observations that this purified micronized flavonoid fraction decreases edema formation. The present data illustrating the inhibitory effect of a clinically relevant dose of S 5682 on the inflammatory processes induced in this in vivo model of microcirculation may serve as a rational basis to explain its clinical efficacy.
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PMID:Effects of oral administration of purified micronized flavonoid fraction on increased microvascular permeability induced by various agents and on ischemia/reperfusion in the hamster cheek pouch. 915 83

Kallistatin is a serine proteinase inhibitor which binds to tissue kallikrein and inhibits its activity. The aim of this study is to evaluate if kallistatin has a direct effect on the vasculature and on blood pressure homeostasis. We found that an intravenous bolus injection of human kallistatin caused a rapid, potent, and transient reduction of mean arterial blood pressure in anesthetized rats. Infusion of purified kallistatin (0.07-1.42 nmol/kg) into cannulated rat jugular vein produced a 20-85 mmHg reduction of blood pressure in a dose-dependent manner. Hoe 140, a bradykinin B2-receptor antagonist, had no effect on the hypotensive effect of kallistatin yet it abolished the blood pressure-lowering effect of kinin and kallikrein. Relaxation of isolated aortic rings by kallistatin was observed in the presence (ED50 of 3.4 x 10(-9) M) and in the absence of endothelium (ED50 of 10(-9) M). Rat kallikrein-binding protein, but not kinin or kallikrein, induced vascular relaxation of aortic rings. Neither Hoe 140 nor Nomega-nitro--arginine methyl ester, a nitric oxide synthase inhibitor, affected vasorelaxation induced by kallistatin. Kallistatin also caused dose-dependent vasodilation of the renal vasculature in the isolated, perfused rat kidney. Specific kallistatin-binding sites were identified in rat aorta by Scatchard plot analysis with a Kd of 0.25+/-0.07 nM and maximal binding capacity of 47.9+/-10.4 fmol/mg protein (mean+/-SEM, n = 3). These results indicate that kallistatin is a potent vasodilator which may function directly through a vascular smooth muscle mechanism independent of an endothelial bradykinin receptor. This study introduces the potential significance of kallistatin in directly regulating blood pressure to reduce hypertension.
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PMID:Kallistatin is a potent new vasodilator. 920 51

Histamine plays an important part in the cutaneous weal and flare response which underlies many allergic skin conditions. It has a direct effect on the local vasculature to promote vasodilatation and increase microvascular permeability and may also initiate the more widely spread neurogenic flare. Quantification of these responses and studies of the mediator mechanisms underlying them have been limited by the lack of appropriate techniques to investigate them. To address this we have used two relatively new techniques, scanning laser Doppler imaging (LDI) and dermal microdialysis to measure changes in skin blood flow and the release of histamine within the weal and flare, following intradermal injection of histamine or bradykinin. These measurements have been made both in the absence and presence of the H1 receptor blockers cetirizine and loratadine. Scanning LDI of the inflammatory response revealed marked differences in both the development and steady state responses to the intradermal injection of histamine (1-3 mumol/L) and bradykinin (1 mumol/L). The development of the flare and the weal response to both histamine and bradykinin was significantly reduced by cetirizine but not by loratadine. The histamine-induced flare area fell by 57 +/- 4% (mean +/- SEM, n = 10, P < 0.001) after cetirizine and the area of the weal fell by 73 +/- 11% (P < 0.009). Bradykinin-induced inflammatory responses were similarly reduced by cetirizine, the weal by 60 +/- 16% (P < 0.02) and the flare by 61 +/- 4% (P < 0.005). Measurement of histamine concentration in skin using microdialysis, in six subjects, confirmed that histamine levels rose in the dialysate collected from the weal to 310 +/- 16 nmol/L following injection of histamine. Histamine levels also rose following bradykinin injection in some subjects (mean 147 +/- 46 nmol/L, range 18-336). Little increase in histamine concentration was seen in the dialysate from the flare following injection of either histamine or bradykinin. The histamine concentration in dialysate from unprovoked skin was 4.19 +/- 0.75 nmol/L. These data reveal differences in the dermal responses to different mediators when assessed using scanning LDI. They confirm that histamine is released within the weal but not the flare response to the intradermal injection of both histamine and bradykinin and that its effects on the local vasculature to cause the oedematous weal and the axon reflex-mediated flare are significantly attenuated by the H1 antagonist cetirizine and to a lesser extent by the H1 antagonist loratadine.
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PMID:Effects of H1 antagonists on the cutaneous vascular response to histamine and bradykinin: a study using scanning laser Doppler imaging. 966 26

In previous studies, we demonstrated that in ANG II-treated rats, prevention of cardiac hypertrophy (CH) by enalapril was blunted by bradykinin (BK) blockade by Hoe140. The putative role of BK was assessed by chronic exogenous BK infusion and in 46 male Sprague-Dawley rats infused with ANG II. ANG II (200 ng/kg/min) alone and associated with BK at low (BKlow, 15 ng/kg/day), mid (BKmid, 100 ng/kg/day) and high doses (BKhigh, 100 ng/kg/min) were delivered by Alzet osmotic pumps for 10 days and compared to control animals (Veh). Values of systolic arterial pressure (SAP, mmHg) in conscious rats and heart weight (HW, mg/g bw) at the end of the study are reported below. Results were submitted to ANOVA and are expressed as mean +/- SEM.
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PMID:[Effect of chronic bradykinin infusion on angiotensin II hypertension in rats]. 974 60

The aim of this study was to measure vascular reactivity in the isolated middle cerebral artery (MCA) after brain injury. Segments of MCA were prepared from control, sham-operated, and cold-lesioned rats. Cold lesion was induced by application of a precooled (-78 degrees C) copper cylinder (diameter 5 mm) for 60 sec to the intact dura over the parietal cortex. Endothelin-1 (ET-1) (10(-12) to 3 x 10(-7) M) induced a dose-dependent contraction with a pD2 (-log10 EC50) of 8.36+/-0.12 (mean+/-SEM) and an Emax (maximal response) of 2.41+/-0.15 mN (millinewton) at 10(-7) M in sham-operated animals under resting conditions. This maximum contraction induced by 10(-7) M ET-1 was significantly (p < 0.05) reduced 24 and 48 h after cold lesion by 41% and 30%, respectively. After precontraction with 10(-5) M prostaglandin (PG) F2alpha, ET-3 (10(-12) to 10(-8) M) relaxed the MCA with an Emax of 0.42+/-0.07 mN at 10(-8) M and a pD2 of 9.20+/-0.19 in sham-operated animals. This relaxation was reduced 24 and 48 h after cold lesion by 19% and 62% at 10(-8) M, respectively. Concentration-effect curves for bradykinin (BK, 10(-8) to 10(-5) M) in uridine triphosphate (UTP, 10(-4) M)-precontracted MCA segments revealed relaxation with a pD2 of 7.08+/-0.10 and an Emax of 0.65+/-0.06 mN at 10(-6) M in sham-treated animals. This effect of BK was reduced by 35% and 20% at 10(-6) M 24 and 48 h after cold lesion, respectively. In addition, the contractile responses to 124 mM K+, 10(-5) M PGF2alpha and the dilation induced by 10(-3) sodium nitroprusside (SNP) were reduced in MCA segments taken 24 and 48 h after lesion compared with shams. We conclude that attenuation of ET effects can be explained, at least in part, by tachyphylaxis to ETs. The unspecific reduction of vascular reactivity may result from spreading depression.
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PMID:Reduced reactivity of the middle cerebral artery and its large branches after cold lesion. 987 63


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