摘要:

Blockade of in vitro contractile responses to angiotensins II and III by the reversible competitive angiotensin antagonist [Sar1, Tyr(Me)4]ANG II (sarmesin) was investigated in 3 rat smooth muscle tissues. The pA2 values for sarmesin were: rat uterus, 7.46 ± 0.04 versus ANG II and 7.46 ± 0.07 versus ANG III; rat aorta, 7.98 ± 0.07 versus ANG II and 7.67 ± 0.08 versus ANG III; rat portal vein, 7.75 ± 0.05 versus ANG II and 7.41 ± 0.08 versus ANG III. Statistical analysis revealed that the pA2 values in each tissue were not significantly different, suggesting that ANG II and ANG III interact with the same receptors in each tissue. This conclusion was supported by cross-tachyphylaxis studies. Further statistical analysis revealed that pA2 values were not significantly different between tissues, suggesting that there are no readily discernible differences between angiotensin receptors in the 3 smooth muscle preparations investi

ISSN:0031-7012    

DOI:10.1159/000138457

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

Imipramine is a tricyclic antidepressant that has been demonstrated to be useful in the treatment of certain voiding dysfunctions. Imipramine has a variety of pharmacological effects including direct antimuscarinic activity, inhibition of catecholamine reuptake, direct muscle relaxant, and calcium antagonism. Using the in-vitro whole bladder model we have studied the effect of imipramine on the rate and magnitude of both intravesical pressure generation and bladder emptying in response to field stimulation. The results can be summarized as follows: at concentrations as low as 1 μmol/l imipramine causes a significant inhibition of volume expulsion without significantly affecting pressure generation. Imipramine produced a dose-dependent inhibition of both pressure development and percent volume emptying; however, it was substantially more potent in inhibiting the ability of the bladder to empty than to generate pressure

ISSN:0031-7012    

DOI:10.1159/000138458

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

Cultured human monocytes, lymphocytes, Fischer rat liver (TRL-2) cells, and Buffalo rat liver (BRL) cells catalyzed the conversion of 3H(-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene [3H(-)t-7,8-dihydrodiol BP] to r-7, t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (diol epoxide I) and r-7, t-7-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetra-hydrobenzo[a]pyrene (diol epoxide II; r-7 indicates that the substituent at the 7-position is the reference, and t and c indicate that the substituents trans and cis, respectively, to the reference substituent). These appear to be the most reactive metabolites of benzo[a]pyrene (BP) and were covalently bound to both exogenous and intact cellular DNA in tissue culture media. The cells induced by benzanthracene (BA) exhibited greater levels of DNA binding than the controls and this binding was linear with increasing cell content in human monocytes, in TRL-2 cells and in Buffalo rat liver cells. The binding to DNA was greater than controls in BA-preinduced lymphocytes, but was not linear. The DNA binding in control cells showed a nonlinear increase with increasing cell concentration in all experiments. The addition of human liver epoxide hydrolase (EC 3.3.2.3) to the incubation medium reduced the amount of reactive metabolites binding to DNA by 12–15 % in control and by 23–41 % in BA-induced monocytes. Thus, with whole cell systems of either human monocytes or lymphocytes, the addition of purified human liver epoxide hydrolase reduced the binding of 3H(–)t-7,8-dihydrodiol BP metabolites to DNA. Human monocytes and lymphocytes also catalyzed the covalent binding of 3H(–)t-7,8-dihydrodiol BP to intact cellular DNA. The addition of 3H(–)t-7,8-dihydrodiol BA to tissue culture media caused the inhibition of covalent DNA binding in BA-preinduced monocyte by 58% and lymphocytes by 25%. Previous work has shown that BA is metabolized and converted to BA-diol epoxides by microsomes. These results indicate that BA-diol epoxides and BP diol epoxides are competing for the same binding sites on DNA. On the other hand, the addition of 10 nmol of 3H(–)t-7,8-dihydrodiol BP to the incubation of control and BA-preinduced cell homogenate and further incubation at 37 °C for 25 min showed that the DNA binding in BA-preinduced cell homogenates was much greater than controls. Homogenates of cells induced by BA exhibited a greater level of DNA binding than controls. The increases, were 110% in monocytes, 119% in lymphocytes, 157% in TRL-2 cells and 140% in BRL cells. The increase of binding to cellular DNA resulted from the induction of the mixed-function oxidase enzyme systems by BA treatment. The addition of human liver epoxide hydrolase to tissue culture media reduced DNA binding by 30% in control and by 45% in BA-induced monocytes. The decrease was 47% in control and 66 % in BA-induced lymphocytes. When cells were harvested, washed, disrupted and incubated at 37 °C for 25 min by addition of 3H(–)t-7,8-dihydrodiol BP, DNA binding was still reduced by 29% in control and 33% in BA-induced lymphocytes. However, when the same amounts of bovine serum albumin were added to tissue culture media, no inhibition of DNA binding was detected. These results suggest that the inhibition of DNA binding was due to the effect of ep

ISSN:0031-7012    

DOI:10.1159/000138459

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

The influence of changes in the sodium balance on angiotensin II induced pressor responses were studied in the pithed rat preparation, which is characterized by a highly activated renin-angiotensin-aldosterone system (RAAS) with high plasma renin and angiotensin II concentrations. The pressor response to angiotensin II was enhanced by excessive sodium loading only, as induced by a high sodium diet combined with a mineralocorticoid, but not by a high salt diet as such. The stimulating effect of salt loading directly influences angiotensin II vasoconstriction without indirectly involving a facilitation of symphatetic neurotransmission. Salt depletion by a low salt diet combined with furosemide treatment did not alter the vasopressor response to angiotensin II. Changes in endogenous angiotensin II production secondary to alterations in serum sodium are of minor relevance in the pithed rat because of the strongly stimulated RAAS. Our finding that in this preparation excessive sodium loading still appears to enhance pressor responses to angiotensin II supports the conclusion that increased sodium load directly sensitizes vascular angiotensin II receptors.

ISSN:0031-7012    

DOI:10.1159/000138460

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

The role of thromboxane as a contributor to the genesis of ventricular tachycardia and fibrillation was examined in conscious dogs which had been subjected to myocardial infarction. CGS 12970, a thromboxane synthetase inhibitor was administered in a dose of 10 mg/kg (i.v.) every 12 h. Ex vivo thrombin-activated thromboxane synthesis, as determined by assay for thromboxane B2, was reduced to 15 % of baseline 2 h after administration of CGS 12970. Drug administration was found to inhibit ex vivo platelet aggregation significantly in response to arachidonic acid, while aggregation to ADP and collagen was unaffected. CGS 12970 did not protect against the induction of ventricular tachycardia by programmed electrical stimulation of the postinfarcted heart. During provocative electrical stimulation, 9 of 11 (82 %) animals continued to respond in the post-treatment period with the development of VT. Pretreatment with CGS 12970 failed to prevent the spontaneous development of ventricular fibrillation which occurred in 7 of 10 (70%) animals when a secondary ischemic event was superimposed in the region of the noninfarct-related circumflex coronary artery. The results suggest that the thromboxane synthetase inhibitor, CGS 12970, when administered in the subacute phase of recovery from myocardial infarction, does not protect against the induction of ventricular tachycardia by programmed electrical stimulation or the spontaneous development of ventricular fibrillation in the postinfarcted canine heart. The findings suggest that thromboxane may not serve a critical role in the genesis of ventricular tachyarrhythmias and ventricular fibrillation in the postinfarcted canine heart.

ISSN:0031-7012    

DOI:10.1159/000138461

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

HA 1004 is a calcium antagonist vasodilator that inhibits contraction in vascular smooth muscle and lowers arterial blood pressure. The effects of HA 1004 on guinea pig airway smooth muscle contraction were compared to the effects of the calcium antagonists, verapamil and nifedipine and the bronchodilator, albuterol. In vitro, HA 1004, verapamil, nifedipine and albuterol inhibited Ca2+-induced contractions of the depolarized guinea pig trachea. HA 1004 and albuterol also relaxed the basal tracheal tone, whereas verapamil and nifedipine were inactive. The bronchorelaxant activity of HA 1004 was not blocked by propranolol. In vivo, intravenous administration of HA 1004, verapamil, nifedipine and albuterol effectively blocked bronchoconstriction induced by intravenous histamine and methacholine. HA 1004 also reversed a histamine-induced bronchospasm, as did albuterol, verapamil and nifedipine. Intratracheal administration of HA 1004 and albuterol inhibited histamine-induced bronchoconstriction without effecting blood pressure, whereas intratracheal administration of verapamil and nifedipine caused a significant reduction of blood pressure at their pulmonary active doses. These results show that HA 1004 has the ability to relax airway smooth muscle, inhibit contractile responses in the guinea pig airways, and there is separation of its cardiovascular and pulmonary effects when HA 1004 is administered directly to the lungs. The results are discussed in terms of the regulatory enzymes and sources of calcium that are involved in airway smooth muscle contraction.

ISSN:0031-7012    

DOI:10.1159/000138462

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

The effect of etorphine (ET) on nerve stimulation-mediated release of norepinephrine (NE) was investigated in isolated rat and guinea pig hearts. Hearts were perfused with Krebs bicarbonate solution via the aorta and the overflow of NE was measured after stimulation of the heart. ET (0.001–0.1 μmol/l) caused a dose-dependent inhibition of NE release in both preparations. Inhibition of NE release from guinea pig hearts ranged from 13% at 0.001 μmol/l to 24% at 0.1 μmol/l. The same concentrations of ET decreased NE release by 10 and 36% in the rat heart. The inhibitory effect of ET was blocked by naloxone. It is concluded that presynaptic opioid receptors located on the adrenergic neuronal terminals may be involved in the regulation of adrenergic neurotransmission in the rat and guinea pig h

ISSN:0031-7012    

DOI:10.1159/000138463

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

Harmaline, a known type A monoamine oxidase (MAO) inhibitor in adult brain of various species was found to elevate whole brain levels of dopamine and serotonin (5-HT) in rat fetuses of mothers injected 2–4 h before Caesarean delivery. Similar stimulatory effects were observed for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), however, no significant effect was obtained for norepinephrine. The dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA) were decreased with the same treatment. These results imply that harmaline or one of its metabolites may cross the placental barrier to affect the fetal brain system not merely as a type A MAO inhibitor (i.e., relatively 5-HT-specific), but possibly also as a stimulatory agent for aldehyde reductase or catechol-O-methyltransferase (COMT) or alternately as an agent inhibiting the conjugation, efflux, or turnover of biogenic amine metabolites such as MHP

ISSN:0031-7012    

DOI:10.1159/000138464

出版商:S. Karger AG    

年代:1988

数据来源: Karger