Central Angiotensin-converting Enzyme Research Articles

Relationship between Polymorphism of Angiotensin Converting Enzyme Gene with Symptoms of Depression in Schizophrenic Patients

In schizophrenic patients, symptoms of depression are often found which can lead to adverse effects on the treatment process, such as increasing the length of treatment, increasing the possibility of relapse, non-adherence in taking medication, and can also lead to suicide in schizophrenic patients. In schizophrenic patients, the activity of the central angiotensin converting enzyme (ACE) gene is altered and angiotensin II interacts with central dopamine, thereby contributing to the pathophysiology of schizophrenia. In addition, it is likely that the ACE gene variant is also involved in the development of depressive symptoms in schizophrenic patients. This research is a categorical analytic study with a cross sectional method, the sampling method is non-probability sampling with consecutive sampling type, with a total sample of 42 people. There was no significant difference between depression symptoms and ACE gene polymorphisms with P value = 0.746. There was no significant difference between depression symptoms and ACE gene polymorphisms.

Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice: Role of cholinergic neurotransmission, cerebral blood flow and brain energy metabolism

Evidences indicate that inhibition of central Renin angiotensin system (RAS) ameliorates memory impairment in animals and humans. Earlier we have reported involvement of central angiotensin converting enzyme (ACE) in streptozotocin induced neurodegeneration and memory impairment. The present study investigated the role of central ACE in cholinergic neurotransmission, brain energy metabolism and cerebral blood flow (CBF) in model of memory impairment induced by injection of scopolamine in mice. Perindopril (0.05 and 0.1mg/kg, PO) was given orally for one week before administration of scopolamine (3mg/kg, IP). Then, memory function was evaluated by Morris water maze and passive avoidance tests. CBF was measured by laser Doppler flowmetry. Biochemical and molecular parameters were estimated after the completion of behavioral studies. Scopolamine caused impairment in memory which was associated with reduced CBF, acetylcholine (ACh) level and elevated acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level. Perindopril ameliorated scopolamine induced amnesia in both the behavioral paradigms. Further, perindopril prevented elevation of AChE and MDA level in mice brain. There was a significant increase in CBF and ACh level in perindopril treated mice. However, scopolamine had no significant effect on ATP level and mRNA expression of angiotensin receptors and ACE in cortex and hippocampus. But, perindopril significantly decreased ACE activity in brain without affecting its mRNA expression. The study clearly showed the interaction between ACE and cholinergic neurotransmission and beneficial effect of perindopril can be attributed to improvement in central cholinergic neurotransmission and CBF.

Chronic Inhibition of Central Angiotensin-Converting Enzyme Ameliorates Colchicine Induced Memory Impairment in Mice

Preclinical and clinical studies indicated involvement of the central renin-angiotensin system (RAS) in memory functions. However, the role of central angiotensin-converting enzyme (ACE) in memory function is still unclear. The present study investigated the involvement of central ACE in colchicine-induced memory impairment in the context of cholinergic function and oxidative stress. Memory impairment was induced by intracerebral colchicine administration in mice. The ACE inhibitor, perindopril (0.05 and 0.1 mg/kg/day), was administered orally for 14 days. Memory function was evaluated by the Morris water maze (MWM) test from the 14th day on after colchicine injection. Donepezil was used as a standard. Parameters of oxidative stress and cholinergic function, ACE activity in serum and the brain were estimated after the completion of behavioral studies. Colchicine caused memory impairment as revealed by no significant change in latency to reach a hidden platform in the MWM test. Furthermore, there was a significant increase in MDA, ROS, and nitrite levels with a reduction in GSH level and acetylcholinesterase (AChE) activity in the brain of colchicine-treated mice. Colchicine significantly increased brain ACE activity without affecting serum ACE. Donepezil prevented colchicine-induced memory impairment in mice. The antidementic effect of perindopril may be attributed to reduced oxidative stress and improvement in cholinergic function. Moreover, the elevated brain ACE activity was also inhibited by perindopril. The study showed that central ACE plays an important role in colchicine-induced memory deficit, corroborating a number of studies that show that treatment with ACE inhibitors could be neuroprotective.

Central Angiotensin I Increases Swallowing Activity and Oxytocin Release in the Near-Term Ovine Fetus

The brain renin-angiotensin system (RAS) plays an important role in hydromineral and neuroendocrine balance. Although previous studies showed that exogenous angiotensin (Ang) II increased dipsogenic and vasopressin responses in near-term fetuses, little is known about the functional development of fetal endogenous brain RAS in the regulation of body fluid homeostasis. To determine the functional development of the central angiotensin-converting enzyme (ACE) in utero, we investigated the electrocortical (ECoG) activity, swallowing activity, oxytocin (OT) release, and c-fos expression in response to intracerebroventricular Ang I administration in the near-term fetal lamb. Ang I did not change fetal low-voltage (LV) and high-voltage (HV) ECoG temporal distributions, but increased fetal swallowing activity during LV ECoG (1.0 ± 0.1 to 3.5 ± 0.4 swallows/min). Additionally, Ang I evoked an increase in c-fos-immunoreactivity in putative dipsogenic centers, including the supraoptic and paraventricular nuclei of the hypothalamus, accompanied by an increase in fetal plasma OT levels. The expression of c-fos was demonstrated in OT neurons in the hypothalamus. The Ang I-mediated increase in fetal swallowing and plasma OT was inhibited by captopril. These results demonstrate the functional development of the fetal brain ACE system in the last trimester of gestation, which plays an important role in the RAS-mediated dipsogenic response and OT release in the regulation of body fluid homeostasis.

Central angiotensin I increases fetal AVP neuron activity and pressor responses

Angiotensin (Ang) II plays a critical role in cardiovascular homeostasis and neuroendocrine regulation. Little is known about whether central angiotensin-converting enzyme (ACE) is functional in the fetal brain. We investigated cardiovascular and neuroendocrinological responses to intracerebroventricular (icv) application of Ang I in the chronically prepared near-term ovine fetus in utero and examined the action sites marked by c-fos expression in the fetal hypothalamus. ACE mRNA was detected in the specific central areas. Intracerebroventricular Ang I significantly increased fetal blood pressure and c-fos expression in the supraoptic nuclei (SON) and the paraventricular nuclei (PVN) in the hypothalamus, accompanied by an increase of fetal plasma arginine vasopressin (AVP). Double labeling demonstrated that AVP neurons in the fetal SON and PVN were expressing c-fos. Captopril, an inhibitor of ACE, significantly suppressed fetal pressor responses and plasma AVP. Double labeling experiments showed colocalization of AT(1) receptor (AT(1)R) and c-fos expression in both SON and PVN following icv Ang I. The results indicate that central endogenous ACE has been functional at least at the last third of gestation and the endogenous brain renin-angiotensin system-mediated pressor responses and AVP release via AT(1)Rs by acting at the sites consistent with the cardiovascular network in the hypothalamus.

Central angiotensin‐converting enzyme 2 overexpression decreases blood pressure and enhances baroreflex function in mice with chronic heart failure

Central angiotensin‐converting enzyme 2 (ACE2) contributes to the regulation of cardiovascular function through modulating other components of the renin‐angiotensin system (RAS) in the brain. Since chronic heart failure (HF) is associated with sympathoexcitation, impaired baroreflex function and activation of the central RAS, we hypothesized that overexpression of ACE2 decreases blood pressure (BP) and improves baroreflex sensitivity in HF. Transgenic mice overexpressing human ACE2 selectively in the brain (Syn‐hACE2) and their wild type littermates (WT) were used, both of which developed HF (ejection fraction <45%, echocardiography) four weeks after coronary artery ligation. 24‐hour BP was monitored by radiotelemetry. Compared with WT HF group, Syn‐hACE2 HF mice exhibited lower mean BP, and ameliorated the spontaneous baroreflex sensitivity (SBRS, sequence method). These data indicate a beneficial role of central ACE2 overexpression during HF, and we speculate that ACE2 overexpression attenuates the augmented sympathetic outflow through decreasing angiotensin (Ang) II and/or increasing Ang 1–7 in the brain. WT Sham (n=5) Syn‐ACE2 Sham (n=5) WT HF (n=4) Syn‐ACE2 HF (n=4) Mean BP (mmHg) 113±3.2 113.7±5.0 109.2±4.7 88.9±4.7# Heart Rate (bpm) 599.5±18.9 578.1.5±21.2 647.2±20.8 644.8±10.8 SBRS (ms/mmHg) 2.21±0.24 2.91±0.51 0.82±0.15* 1.80±0.19# p<0.05 vs. WT sham; p<0.05 vs. WT HF.

Angiotensin-converting Enzyme Inhibitors, Inhibition of Brain and Peripheral Angiotensin-converting Enzymes, and Left Ventricular Dysfunction in Rats After Myocardial Infarction

The brain renin-angiotensin system contributes significantly to progressive left ventricular (LV) dysfunction in rats after myocardial infarction (MI). The present study evaluated the effects of central versus peripheral plus central angiotensin-converting enzyme (ACE) blockade on sympathetic activity, and LV anatomy and function after MI. Wistar rats were treated for 4 weeks after MI with the lipophilic ACE inhibitor trandolapril at 5 mg/kg/day or the hydrophilic blocker lisinopril at 50 mg/kg/day by once daily subcutaneous injection, or with a central infusion of lisinopril at 0.1 mg/kg/day. At 24 hours after the last dose, subcutaneous trandolapril caused 70% to 80% ACE inhibition in both brain and kidneys; lisinopril caused 10% to 20% less. Central infusion of lisinopril caused 70% inhibition of brain ACE and minimal (6%) inhibition in the kidneys. All three treatments similarly improved sympathetic reactivity and arterial baroreflex function. All three treatments lowered cardiac Ang I and II, and similarly attenuated the increases in LV end diastolic pressure, circumference, and fibrosis. Both subcutaneous treatments further decreased LV peak systolic pressure and dP/dt max, whereas icv lisinopril caused no change. Despite marked differences in the extent of peripheral blockade, all three treatments similarly affected sympathetic activity and decreased cardiac Ang II, preload and remodeling after MI. One may speculate that central and peripheral ACE-mediated mechanisms are sequential and therefore only minor additional effects of peripheral ACE blockade are noted.

Roles of Peripheral and Central Angiotensin-Converting Enzyme (ACE) in Hypovolemic Thirst Induced by Compound 48/80 in Rats

Subcutaneous (s.c.) injection of Hoe 498, an angiotensin converting enzyme (ACE) inhibitor, at the doses of 0.1, 0.5, 1.0 and 4.0 mg/kg produced a dose-related inhibition of compound 48/80-induced hypovolemic thirst in rats. A significant time-response relationship was observed between the pretreatment time of Hoe 498 at a dose of 4.0 mg/kg and the inhibition of compound 48/80-induced water intake. Nearly 90% of plasma ACE activity was inhibited by Hoe 498 at all doses used, and this inhibition at the dose of 4.0 mg/kg of Hoe 498 continued for more than 4 hr. Intracerebroventricular (i.c.v.) or s.c. injection of Hoe 498 in doses ranging from 0.5 to 20 μg comparably inhibited plasma ACE activity in a dose-dependent manner. The compound 48/80-induced water intake was significantly reduced by i.c.v. injection of Hoe 498 (20 μg) 30 min after compound 48/80 administration, but not reduced when the drug was given 15 min prior to injection of dipsogen. The inhibition of water intake by Hoe 498 seems to be dependent on the dose and time between administration of Hoe 498 and compound 48/80. The present data suggest that brain ACE is more involved in compound 48/80-induced water intake than peripheral systemic ACE.

Comparative Effects of Enalapril, Enalaprilic Acid and Captopril in Blocking Angiotensin I-Induced Pressor and Dipsogenic Responses in Spontaneously Hypertensive Rats

The role of central angiotensin converting enzyme (ACE), in the maintenance of high blood pressure, was examined in unanesthetized spontaneously hypertensive rats (SHR). Pressor and dipsogenic responses induced by intracerebroventricular (ICV) injections of angiotensin I (AI) were elicited before and 30 min after either captopril (120-800 nanomoles ICV), enalapril (66-460 nanomoles ICV) and enalaprilic acid (70-280 nanomoles ICV). Enalapril was 1.6 (0.7-3.9) and 1.7 (0.9-2.9) times more potent than captopril in inhibiting AI-induced pressor and dipsogenic responses, respectively. Enalaprilic acid was 2.7 (1.1-7.1) and 2.9 (1.9-4.8) times more potent than captopril in inhibiting AI- (ICV administration) induced pressor and dipsogenic responses, respectively. None of the ACE inhibitors, in contrast, reduced the central actions of AII. Basal mean arterial pressure was not reduced by these ACE inhibitors after ICV administration. Administered orally at doses which produced similar hypotensive responses, neither captopril (30 mg/kg) nor enalapril (3 mg/kg) blocked the responses induced by AI given ICV (10 ng). These findings indicate that ACE inhibitors given acutely do not penetrate into the central nervous system sufficiently to block the dipsogenic and pressor responses induced by AI given ICV, and suggest that inhibition of central ACE may not be important to the acute antihypertensive activity of the ACE inhibitors tested.

Enkephalinase ‘A’ inhibition by thiorphan: Central and peripheral cardiovascular effects

On the basis of the distribution of enkephalins within the central and peripheral nervous systems as well as on response to their administration, it has been suggested that these peptides participate in the regulation of the circulation. The present series of experiments examined the effects of thiorphan, an inhibitor of enkephalinase A, on cardiovascular responses to intracerenroventricular (i.c.v.) administration of [D-Ala 2,Met 5]enkephalin (DAME) and its amide and on peripheral interactions with the sympathetic nervous system and vasoactive peptides. Thiorphan (30 μg i.c.v.) potentiated and the pressor response to i.c.v. DAME and DAMEamide in conscious spontaneously hypertensive rats. Responses to i.c.v. angiotensin I (AI) were unaffected suggesting lack of inhibition of central angiotensin converting enzyme (ACE). Peripheral administration of relatively large doses of thiorphan (30 and 100 mg/kg s.c.) attenuated the pressor response to i.v. AI by 30–40% and enhanced the depressor effect of i.v. bradykinin in anesthetized normotensive rats indicating inhibition of peripheral ACE. Pressor and tachycardic responses to activation of spinal sympathetic outflow were not altered by thiorphan in pithed normotensive rats. Thiorphan itself did not affect baseline blood pressure or heart rate in any of these experiments. In conclusion, inhibition of central enkaphalinase A by i.c.v. administration of thiorphan potentiates the pressor response to i.c.v. DAME. The compound inhibits peripheral ACE but has little direct cardiovascular activity in its own right.

Central angiotensin converting enzyme blockade and thirst

The role of endogenous brain angiotensin II (AII) in various thirst states was examined in the rat using the angiotensin converting enzyme inhibitor, captopril. Intracereborventricular (ICV) captopril (7 μg) significantly attenuated the dipsonegic response to centrally administered angiotensin I(AI) (200 ng) for up to 2 hours. The same dose of captopril significantly potentiated the dipsonegic response to ICV AII (100 ng) but failed to alter the dipsogenic response to ICV carbachol (200 pmoles). Central pretreatment with captopril (7 μg), for 30 minutes, failed to alter markedly the cumulative water intake of 24 hour water deprived rats However, a small, significant 8% decrease in water intake was noted in ICV captopril treated rats 60 minutes following the return of water. The same dose of captopril, administered intraperitoneally, significantly potentaited the cumulative water intake of 24 hour water deprived rats. Central pretreatment with captopril (7 μg), for 30 minutes, failed to alter the cumulative water intake of rats treated intraperitoneally with hypertonic saline (0.75 M given at a dose of 1% of the body weight). From these studies it would appear that central angiotensin converting enzyme plays only a minor role in thirst induced by water deprivation.

Exaggerated salt appetite of spontaneously hypertensive rats is decreased by central angiotensin-converting enzyme blockade.

Injection of angiotensin II (AII) into the cerebral ventricles at doses as low as 1 pmol h-1 results in a marked stimulation of salt and water ingestion in the rat. Evidence that AII is produced in the central nervous system independently of the circulating renin-angiotensin system (RAS) raises the possibility that endogenous brain AII is involved in the physiological regulation of thirst. The role of brain AII in salt appetite is still unclear. Here we confirm that the spontaneously hypertensive rat (SHR), believed to have elevated levels of brain AII, possesses an exaggerated salt appetite compared with its normotensive controls. We also show that this exaggerated salt appetite is reduced by chronic central treatment with the angiotensin-converting enzyme inhibitor, captopril, while that of the normotensive controls is unaffected. Our study suggests that a central neuropeptide, probably AII, is involved in the maintenance of the exaggerated salt appetite in this model of hypertension.