Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The spontaneously hypertensive rat (SHR) has many characteristics indicative of an overactive brain-angiotensin system. Since converting enzyme inhibitors are powerful hypotensive agents, the SHR was used to study the mechanisms of blood pressure reduction with MK421, MK422, Hoe498, and ramiprilat. A comparison of intraventricular (i.v.t.) to intravenous (i.v.) routes of administration showed that with MK421 the i.v.t. route was far more potent than the i.v. area. MK421 i.v.t. produced a profound and prolonged lowering of blood pressure in SHR. The blood pressure was reduced for a longer period than angiotensin II (ANG II) formation was inhibited. Ramiprilat decreased blood pressure in SHR for a prolonged period but was not significantly effective in the Wistar-Kyoto rats (WKY). The inhibition of ANG I pressor action correlated to the depressor effect. Brain ANG II was measured in different parts of the brain and plasma. With Hoe498 i.v. 50 micrograms/kg, there was an increase in hypothalamic angiotensin and plasma angiotensin. With MK422 i.v.t., there was a decrease in brain ANG II. Ramiprilat i.v.t. increased plasma ANG II and the variability of brain ANG II in different brain regions. In the SHR, ramiprilat decreased brainstem ANG II but did not change hypothalamic ANG II. High-pressure liquid chromatography characterization showed that the ANG II measured was authentic. In the SHR brain, ANG II was significantly higher in certain regions than in WKY. The results showed an increase of brain ANG II in normotensive animals with angiotensin converting enzyme inhibitor but a reduction of brainstem ANG II in the SHR. This may indicate the mechanism of lowering blood pressure in SHR is by disinhibition of the baroreflex.
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PMID:Converting enzyme inhibitors and brain angiotensin. 243 97

1. The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. 2. The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. 3. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(-)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. 4. The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. 5. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. 6. It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the 5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse.
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PMID:The influence of 5-HT2 and 5-HT4 receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test. 940 75

Antisocial personality traits are an important topic for research. The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes. Catecholamine genes are being studied to facilitate this understanding, and some tentative findings are being reached about several of these genes. It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious. One conclusion that could be drawn from the current research findings is that DA2 like receptors (DRD2, DRD3, DRD4) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors. DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition. When these receptors are less active by genetically decreased density, lower affinity, or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state. Peripheral metabolism is increased and behavioral activation is noted. Renin is disinhibited in this setting thus allowing sympathetic nervous system activation. The fight or flight behaviors thus produced, in the extreme, would be the setting of antisocial behavior. Research validates this hypothesis. Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others. ACE inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders.
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PMID:ACE inhibitors could be therapeutic for antisocial personality disorder. 2389 Oct 37