Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defibrotide (DEF), a compound previously found to stimulate vascular prostacyclin (PGI2) formation, has been investigated in an experimental model of septic shock. Anesthetized pigs were subjected to i.v. infusion of lipid A (1.5 mg/kg per hr for 4 hr). DEF (50 mg/kg per hr) or vehicle were infused i.v. throughout the experiments, starting 1 hr prior to lipid A. Two out of 7 pigs receiving vehicle survived lipid A infusion for 4 hr, whereas 6 out of 7 DEF treated animals survived this period (P less than 0.05). DEF delayed the shock-induced depression of platelet count and preserved platelet secretory function (collagen-induced ATP-secretion). DEF increased plasma PGI2 by 45% (P less than 0.05) during lipid A infusion and tended to reduce thromboxane levels. DEF did not change eicosanoid formation in sham-shock pigs (n = 4 per group). In vivo treatment with DEF significantly increased the stimulatory effect of bradykinin (1 microM) and arachidonic acid (100 microM) on PGI2 formation ex vivo of mesenteric and iliac artery segments. The improvement of survival in lipid A-induced shock by DEF may be related to an enhancement of vascular PGI2 generation, potentially due to a reduction of shock-induced platelet activation and microcirculatory dysfunction.
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PMID:Favourable effect of defibrotide in lipid A-induced shock in pigs. 142 20

1. The effects of bradykinin (BK) in the microcirculation of the isolated perfused heart of the rat were examined. The kinin receptors mediating the effects of BK were characterized and the role of endothelium-derived relaxation factor (EDRF) and prostacyclin investigated. 2. The dose-related vasodilator responses elicited by bolus doses of BK (0.001-10.0 nmol) were competitively blocked by the selective kinin B2 receptor antagonist [D-Arg0,Hyp3, Thi5.8,D-Phe7]-bradykinin (pA2 = 6.8). Des-Arg9-bradykinin, a selective kinin B1 receptor agonist had no vasodilator activity at doses of up to 10 nmol. 3. L-NG-nitro arginine (100 microM; L-NOArg), an inhibitor of endothelium-dependent vasodilatation, reduced the duration but not the magnitude of the BK vasodilator response. This action of L-NOArg was not reversed by L-arginine (100 microM). 4. Superoxide dismutase (10 units ml-1), haemoglobin (10 microM) and methylene blue (MB; 1 microM), all known to modify EDRF-mediated responses, failed to alter the vasodilator action of BK. 5. Gossypol (1-15 microM), a presumed inhibitor of EDRF biosynthesis, caused a marked drop in perfusion pressure followed by vasoconstriction. These changes in coronary tone were accompanied by an irreversible depression of cardiac contractility and heart rate. Over the same concentration range gossypol abolished the vasodilator action of BK (1.0 nmol), however it also blocked the endothelium-independent vasodilator response to sodium nitroprusside (30 nmol) and the vasoconstrictor effect of endothelin-1 (10 pmol) which suggests non-specific toxic actions of gossypol. 6. Bolus injections of BK (0.001-1.Onmol) failed to elevate basal levels of prostacyclin (PGI2) as shown by assaying for its stable metabolite 6-keto-PGF<,,. In addition, BK-induced vasodilatation was not blocked by flurbiprofen (2 microM) or BW755C (7.5 microM) which are inhibitors of the arachidonic acid pathway. When added with L-NOArg (100 microM), flurbiprofe(10 microM) did not potentiate the inhibitory action of L-NOArg on the BK response. 7. These results show that the vasodilator action of BK in the rat heart is dependent on the activation of the kinin B2 receptors but independent of PGI2 release. Although a conclusive role for EDRF could not be established, this study has questioned the suitability of several agents commonly used as inhibitors of EDRF-mediated responses.
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PMID:Effects of bradykinin in the rat isolated perfused heart: role of kinin receptors and endothelium-derived relaxing factor. 165 68

In this study, the effect of bradykinin on coronary flow in the isolated rat heart was significantly potentiated when cysteine or the sulfhydryl-containing converting enzyme inhibitors captopril and zofenoprilat were administered simultaneously. In contrast, the effect of concomitant administration of enalaprilat only slightly increased the effect of bradykinin on coronary flow. In nitrate-tolerant hearts of rats pretreated with isosorbide dinitrate (15 mg daily), the increase in coronary flow by nitroglycerin and bradykinin was significantly less when compared to control hearts. The effect of captopril was not affected by pretreatment. The involvement of endothelium-derived relaxing factor (EDRF) in the effect of captopril was apparent from experiments with L-arginine, the precursor of EDRF, and L-NMMA, the "false" precursor of EDRF. L-Arginine increased the effect of captopril, whereas L-NMMA showed a competitive antagonism for the effect of captopril on coronary flow in the isolated rat heart. Clinically, the effect of captopril was studied in 10 patients with stable, exercise-induced angina pectoris that had been treated for 3 weeks with slow-release isosorbide dinitrate (20 mg four times daily). At day 7, a baseline exercise test was obtained. Subsequently, patients with chest pain and at least 1-mm ST-segment depression on the ECG during exercise were included. They received on day 14 and 21 either captopril (25 mg) or placebo 1 h before exercise testing in a randomized, double-blind, crossover design. Captopril significantly improved the combined score of maximal ST-segment depression, maximal workload, and time to angina when compared to placebo. No differences in the pressure-rate index at rest and during exercise were seen. These results indicate that the sulfhydryl group of certain angiotensin converting enzyme inhibitors can potentiate their effect on the endogenous nitrovasodilator EDRF. In the clinical situation, this may lead to an improved exercise performance in patients with stable angina pectoris during chronic nitrate treatment, independent of its systemic vascular effects.
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PMID:Converting enzyme inhibitors and the role of the sulfhydryl group in the potentiation of exo- and endogenous nitrovasodilators. 172 Aug 43

To verify whether plasma beta-endorphin and bradykinin affects the pathophysiology of myocardial ischemia and the perception of cardiac pain, 35 patients with coronary artery disease were subjected to treadmill testing and 48-hour Holter ECG monitoring to measure their pain thresholds. Patients were divided into two groups during exercise testing: group 1 (N = 19) who had ST segment depression, and group 2 (N = 16), who had chest pain. Both groups were then compared with 12 age-matched control subjects. Pain thresholds were measured after Holter ECG monitoring, and blood samples were drawn before and immediately after exercise. No statistical differences were noted between groups 1 and 2 with regard to the severity of myocardial ischemia as assessed by ST segment depression or exercise tolerance time. The frequency of the episodes of silent myocardial ischemia in group 1 was found to be significantly (p less than 0.05) higher than that in group 2. The duration of the episodes of silent myocardial ischemia in group 1 was 41.9 minutes (range 3 to 343 minutes), which was significantly (p less than 0.05) longer than that in group 2 (11.5 minutes; range 0 to 74). The pain threshold in group 1 was a statistically (p less than 0.05) higher value than that in group 2. Although the resting plasma beta-endorphin level in group 1 was not statistically significantly different from values in either group 2 or the control group, during exercise the plasma beta-endorphin levels in both group 1 and the control group were significantly (p less than 0.05) elevated in comparison with their resting levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differences in plasma beta-endorphin and bradykinin levels between patients with painless or with painful myocardial ischemia. 173 63

1. Bradykinin (cumulative concentrations of 0.007-0.09 micrograms ml-1) produced a dose-related, but statistically insignificant depression of the isometric contraction of the isolated, spontaneously beating atria of the guinea-pig. The same concentrations of bradykinin did not change the atrial rate, but a tendency to a slight decrease was observed. 2. Enalapril (4.06 or 13.54 mumol l-1), produced a dose-related potentiation of the effect of the highest concentration of bradykinin on the isometric contraction. 3. Captopril (equimolar concentrations) also potentiated the effect of the highest concentration of bradykinin on the isometric contraction. This effect of captopril was not dose-related. 4. Both enalapril and captopril did not change the effect of bradykinin on the heart rate. 5. Bradykinin induced dose-related hypotensive responses in anaesthetized cats (0.03-1.0 microgram/kg b.w., i.v.) with a tendency towards bradycardia. 6. Enalapril (0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. However, the potentiating effect of enalapril was not dose-dependent. 7. Captopril (0.1, 0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. Also, the potentiating effect of captopril was not dose-dependent. 8. The failure of ACE inhibitors to potentiate the cardiodepressant and hypotensive effects of bradykinin in a dose-dependent manner is explained with some other mechanism(s) independent of ACE inhibition.
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PMID:The potentiation of cardiodepressant and hypotensive effects of bradykinin by enalapril and captopril both in vitro and in vivo. 181 Aug 15

The effects of protein kinase C activation by 12-O-tetra-decanoyl-phorbol-13-acetate (TPA) on the functions of guinea-pig smooth muscle taenia coli have been studied, using double-sucrose-gap method. A 15-20-min treatment of the muscle with 2 X 10(-8) M TPA caused a progressing inhibition of spontaneous electrical activity and mechanical tension, suppression of post-hyperpolarizing electrical and contractile "off-responses", a decrease in the number of action potentials during superthreshold membrane depolarization, depression of electrical and mechanical responses induced by acetylcholine, histamine, bradykinin mediators. The treatment of pre-depolarized (140 mM kappa+) muscle with 2.10(-8) TPA has led to a considerable reduction in contractile responses induced by the above mediators. The results obtained indicate that protein kinase C is capable of regulating both voltage-sensitive and receptor-operated ionic channels in smooth muscle cells.
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PMID:[Role of protein kinase C in regulating smooth muscle electrical and contractile activity: the effect of phorbol ester]. 244 75

The neurokinins, physalaemin, substance P, neurokinin A and bradykinin, were tested on the responses of single spinal neurons to the purines, adenosine 5'-triphosphate (ATP) and adenosine 5'-monophosphate and to GABA. Experiments were done on anaesthetized cats, recording extracellularly from functionally identified sensory neurons in the lumbar dorsal horn. All compounds were administered by iontophoresis. Neurokinins caused a slow, prolonged excitation which outlasted the period of application. Physalaemin was tested on responses to ATP in 24 units. In each case application of ATP caused either depression, excitation or a biphasic response when the application was not pre-conditioned by ejection of physalaemin. For 11 units, with ATP applications subthreshold to alter the on-going firing rate, such applications caused depression when they were preceded by administration of physalaemin. Three units were tested with ATP applications which caused the excitatory response; when the applications of ATP were preceded by ejection of physalaemin, there was then a depressant component in the response. In these 14 cases, the magnitude of the depression or of the depressant component of the response, was measured using currents which failed to produce depression in the absence of physalaemin ejection; the mean magnitude of this depression was 34.7 +/- 1.6% (+/- S.E.M.). With the 10 remaining units, responses to ATP were unaffected by application of physalaemin. The early components of the biphasic and excitatory responses were unaffected by physalaemin and hence it appeared to have a differential effect, enhancing only the depressant effects of ATP. The enhancement of depression was reversible, lasting up to 30 min following a single ejection. Neither control current nor glutamate mimicked the effect of physalaemin in the responses to application of ATP. The depressant response to adenosine 5'-monophosphate was also enhanced by physalaemin: ejections of adenosine 5'-monophosphate subthreshold to affect the on-going firing rate caused depression after physalaemin application in 3 of 8 units (average depression: 35.0 +/- 3.3%). On the other hand, depression induced by GABA was unaffected by physalaemin in every case (n = 8); in 4 of these cases GABA was tested on units for which purine-induced depression was enhanced by physalaemin. Thus, physalaemin preferentially affected depressant responses to ATP and to adenosine 5'-monophosphate.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Purine-induced depression of dorsal horn neurons in the cat spinal cord: enhancement by tachykinins. 244 38

Canine and human coronary arteries were studied in organ baths to compare the responses to acetylcholine and serotonin in the two species. The human coronary rings were isolated from seven patients without cardiac disease (mean age 15 years, range 7-20). In one set of experiments canine and human preparations were incubated with phentolamine, propranolol and ketanserin (all at 1 mumol.litre-1 concentration) and precontracted with prostaglandin F2 alpha (PGF2 alpha 1-2 mumol.litre-1). Acetylcholine (0.1-10 mumol.litre-1) and serotonin (0.1-100 mumol.litre-1) relaxed canine preparations dose dependently, the maximum responses (expressed as % of depression of PGF2 alpha response) being 84 (SEM 6)% (n = 9) and 51(5)% (n = 6) respectively. In the same experimental conditions, acetylcholine and serotonin failed to relax the human coronary rings (n = 11) while substance P and bradykinin induced relaxations of 72(4)% (n = 11) and 66(7)% (n = 11) of PGF2 alpha response respectively. In another set of experiments, dose-contraction curves were constructed for acetylcholine or serotonin (in presence of phentolamine and propranolol). On human rings with endothelium, methylene blue (10 mumol.litre-1), a non-specific inhibitor of endothelium derived relaxing factor (EDRF), potentiated these dose-contraction curves: markedly for serotonin, the EC50 decreasing from 1.2(0.2) to 0.22(0.08) mumol.litre-1 (n = 11, p less than 0.01) with a significant increase in the maximal response); and slightly for acetylcholine, EC50 decreasing from 0.84(0.11) to 0.40(0.13) mumol.litre-1 (n = 10, p less than 0.05) without significant change in the maximal response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of responses to acetylcholine and serotonin on isolated canine and human coronary arteries. 248 33

The purposes of the present study were to examine the natural course of the impairment of endothelium-dependent relaxations during a regeneration and tissue repair process after balloon endothelium removal and to elucidate the cellular mechanism(s) underlying it. Twenty-three male Yorkshire pigs underwent balloon endothelium removal along the proximal portion of either the left anterior descending or circumflex coronary artery and were then maintained on a regular chow for 4, 8, 16, or 24 weeks. Endothelium-dependent responses were examined in vitro in rings taken from the control and previously denuded arteries studied in parallel. Morphometric analysis revealed that intimal thickening developed only at the previously denuded area. In the previously denuded arteries with regenerated endothelium, the endothelium-dependent relaxations to UK 14304 (a selective alpha 2-adrenergic agonist), serotonin, and aggregating platelets were impaired 4 weeks after endothelium removal and remained so throughout the study. The endothelium-dependent relaxations to thrombin and adenosine diphosphate became depressed 8 weeks after endothelium removal and those to bradykinin became depressed 16 weeks after endothelium removal, while those to the calcium ionophore A23187 were maintained throughout the study. Endothelium-dependent relaxations to all vasoactive agents were unaltered in the control arteries. In the control arteries, pertussis toxin, an inhibitor of certain G proteins, markedly inhibited the endothelium-dependent relaxations to UK 14304 and serotonin and partially inhibited those to thrombin and aggregating platelets. The responses inhibited by the toxin in control arteries were significantly reduced in the reduced in the previously denuded arteries with regenerated endothelium. The inhibitory effect of pertussis toxin was markedly reduced in those arteries with regenerated endothelium. In quiescent rings, the presence of normal endothelium inhibited the contractions caused by serotonin and aggregating platelets; this endothelium-dependent depression was markedly impaired in the previously denuded arteries throughout the study. Direct relaxation of the coronary smooth muscle to nitric oxide or sodium nitroprusside or direct contraction to KCl or serotonin were comparable between the control and previously denuded arteries. These experiments indicate that endothelium-dependent relaxations progressively worsen after regeneration of the endothelium and that the dysfunction of a pertussis toxin-sensitive G protein partly account for the endothelial dysfunction in the chronic regenerated state.
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PMID:Natural course of the impairment of endothelium-dependent relaxations after balloon endothelium removal in porcine coronary arteries. Possible dysfunction of a pertussis toxin-sensitive G protein. 250 8

During coronary catheterization under general anesthesia, the endothelium of a portion of the proximal left circumflex coronary artery of dogs was removed (injured). Segments from the denuded and normal (distal circumflex and left anterior descending coronary) regions were removed immediately in some animals (acute studies) or 5 wk after the injury in other animals (chronic studies). No significant differences in passive mechanics or active stress normalized to medial thickness were found between segments from normal and denuded regions in acute studies or normal and injured segments in chronic studies. Intimal thickening was found in the chronically injured segments, which averaged 32% of the total media-adventitia thickness. No significant differences were found in potassium dose-response relations in acute or chronic studies. Maximum responses to serotonin were increased in acutely denuded but not in chronically injured segments. Sensitivity to serotonin was increased in chronically injured but not acutely denuded segments. Endothelium-dependent relaxation responses produced by acetylcholine, bradykinin, and the Ca2+ ionophore A23187 were all depressed in chronically injured segments compared with normal, as were relaxation responses to sodium nitroprusside. In acutely denuded segments, the former agents produced only small contractions at high doses, whereas nitroprusside relaxations were augmented compared with sites with intact endothelium. Relaxation responses to isoproterenol and forskolin were not significantly affected by acute denudation or by chronic injury. The results of this study suggest a "chronic" depression of relaxation responses mediated by the guanosine 3',5'-cyclic monophosphate pathway and increased serotonin vasoconstriction sensitivity in arteries 5 wk after an endothelial denudation injury.
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PMID:Effects of endothelium regeneration on canine coronary artery function. 258 21


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