Asymmetric Interaction of Neuropeptidase Activities between Cortico-Limbic Structures, Plasma and Cardiovascular Function after Unilateral Dopamine Depletions of the Nigrostriatal System.

In emotional processing, dopamine (DA) plays an essential role, and its deterioration involves important consequences. Under physiological conditions, dopamine exhibits brain asymmetry and coexists with various neuropeptides that can coordinate the processing of brain functions. Brain asymmetry can extend into a broader concept of asymmetric neurovisceral integration, including behavior. The study of the activity of neuropeptide regulatory enzymes (neuropeptidases, NPs) is illustrative. We have observed that the left and right brain areas interact intra- and inter-hemispherically, as well as with peripheral tissues or with physiological parameters such as blood pressure or with behaviors such as turning preference. To obtain data that reflect this integrative behavior, we simultaneously analyzed the impact of left or right brain DA depletion on the activity of various NPs in corticolimbic regions of the left and right hemispheres, such as the medial prefrontal cortex, amygdala and hippocampus, as well as on the plasma activity of the same aminopeptidase activities (APs) and on systolic blood pressure (SBP). Intra- and inter-hemispheric interactions as well as the interactions of NPs from the left or right hemispheres were analyzed with the same plasma APs and the SBP obtained from sham and from left or right lesioned rats. The results demonstrate a complex profile depending on the hemisphere considered. They definitively confirm an asymmetric neurovisceral integration and reveal a higher level of inter-hemispheric corticolimbic interactions including with SBP after left dopamine depletion.

Interaction between Angiotensinase Activities in Pituitary and Adrenal Glands of Wistar-Kyoto and Spontaneously Hypertensive Rats under Hypotensive or Hypertensive Treatments.

In the present study, we analyzed the activity of several aminopeptidases (angiotensinases) involved in the metabolism of various angiotensin peptides, in pituitary and adrenal glands of untreated Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) or treated with the antihypertensive drugs captopril and propranolol or with the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). Intra- and inter-gland correlations between angiotensinase activities were also calculated. Membrane-bound alanyl-, cystinyl-, and glutamyl-aminopeptidase activities were determined fluorometrically using aminoacyl-ß-naphthylamide as substrates. Depending on the type of angiotensinase analyzed, the results reflect a complex picture showing substantial differences between glands, strains, and treatments. Alanyl-aminopeptidase responsible for the metabolism of Ang III to Ang IV appears to be the most active angiotensinase in both pituitary and adrenals of WKY and particularly in SHR. Independently of treatment, most positive correlations are observed in the pituitary gland of WKY whereas such positive correlations are predominant in adrenals of SHR. Negative inter-gland correlations were observed in control SHR and L-NAME treated WKY. Positive inter-gland correlations were observed in captopril-treated SHR and propranolol-treated WKY. These results may reflect additional mechanisms for increasing or decreasing systolic blood pressure in WKY or SHR.

The Type of Fat in the Diet Influences the Behavior and the Relationship Between Cystinyl and Alanyl Aminopeptidase Activities in Frontal Cortex, Liver, and Plasma.

Insulin-regulated aminopeptidase (IRAP, cystinyl aminopeptidase, CysAP) and aminopeptidase M (alanyl aminopeptidase, AlaAP) are closely related enzymes involved in cognitive, metabolic, and cardiovascular functions. These functions may be modulated by the type of fat used in the diet. In order to analyze a possible coordinated response of both enzymes we determined simultaneously their activities in frontal cortex, liver, and plasma of adult male rats fed diets enriched with fats differing in their percentages of saturated, mono or polyunsaturated fatty acids such as sesame, sunflower, fish, olive, Iberian lard, and coconut. The systolic blood pressure, food intake, body and liver weight as well as glucose and total cholesterol levels in plasma were measured. The type of fat in the diet influences the enzymatic activities depending on the enzyme and its location. These results suggest cognitive improvement properties for diets with predominance of polyunsaturated fatty acids. Physiological parameters such as systolic blood pressure, food intake, and biochemical factors such as cholesterol and glucose in plasma were also modified depending on the type of diet, supporting beneficial properties for diets rich in mono and polyunsaturated fatty acids. Inter-tissue correlations between the analyzed parameters were also modified depending on the type of diet. If the type of fat used in the diet modifies the behavior and relationship between CysAP and AlaAP in and between frontal cortex, liver and plasma, the functions in which they are involved could also be modified.

Functional and neurometabolic asymmetry in SHR and WKY rats following vasoactive treatments.

A lateralized distribution of neuropeptidase activities in the frontal cortex of normotensive and hypertensive rats has been described depending on the use of some vasoactive drugs and linked to certain mood disorders. Asymmetrical neuroperipheral connections involving neuropeptidases from the left or right hemisphere and aminopeptidases from the heart or plasma have been suggested to play a role in this asymmetry. We hypothesize that such asymmetries could be extended to the connection between the brain and physiologic parameters and metabolic factors from plasma and urine. To assess this hypothesis, we analyzed the possible correlation between neuropeptidases from the left and right frontal cortex with peripheral parameters in normotensive (Wistar Kyoto [WKY]) rats and hypertensive rats (spontaneously hypertensive rats [SHR]) untreated or treated with vasoactive drugs such as captopril, propranolol and L-nitro-arginine methyl ester. Neuropeptidase activities from the frontal cortex were analyzed fluorometrically using arylamide derivatives as substrates. Physiological parameters and metabolic factors from plasma and urine were determined using routine laboratory techniques. Vasoactive drug treatments differentially modified the asymmetrical neuroperipheral pattern by changing the predominance of the correlations between peripheral parameters and central neuropeptidase activities of the left and right frontal cortex. The response pattern also differed between SHR and WKY rats. These results support an asymmetric integrative function of the organism and suggest the possibility of a different neurometabolic response coupled to particular mood disorders, depending on the selected vasoactive drug.

Enkephalinase activity is modified and correlates with fatty acids in frontal cortex depending on fish, olive or coconut oil used in the diet.

OBJECTIVE: Enkephalins are neuropeptides involved in functions such as pain modulation and/ or cognitive processes. It has been reported that dietary fat modifies enkephalins in the brain. Since enkephalins are hydrolyzed by enkephalinases, the study of the influence of dietary fats, differing in their degree of saturation, on brain fatty acids content and enkephalinase activity is important to understand its regulatory role on neuropeptides under different type of diets. METHODS: We analyzed enkephalinase activity, assayed with alanine-ß-naphthylamide as sub-strate, in frontal cortex of adult male rats fed diets supplemented with fish oil, olive oil or coconut oil, which markedly differed in the saturation of their fatty acids. RESULTS: Rats fed a diet enriched with coconut oil had lower soluble enkephalinase activity than the group fed olive oil (p<0.01) and fish oil (p<0.05) whereas rats fed a diet enriched with fish oil had lower membrane-bound enkephalinase activity than the group fed with olive (p<0.001) or coconut oil (p<0.05). Significant negative correlations were observed between certain fatty acids and enkephalinase activities in the groups fed with olive and coconut oils. No correlations were observed in the group fed with fish oil. CONCLUSIONS: Dietary fat modifies enkephalinase activity in the frontal cortex depending on the degree of saturation of the used oil. It is postulated that the functions, in which enkephalins are involved, such as pain modulation or cognitive functions, may also be affected according to the type of oil used in the diet.

Enkephalinase regulation.

After millennia of knowledge of opium, it was only recently that endogenous substances called opioids with similar properties to opium and derivatives were discovered. The first to be discovered were enkephalins. In addition to the regulation of their synthesis and expression of receptors, an important mechanism for the regulation of their functions carried out by multiple proteolytic enzymes acting at all levels of their structure is described. The action of such enzymes, known as enkephalinases, is also regulated by endogenous and exogenous factors which ultimately affect the control of the enkephalins's action. For therapeutic purposes, it is not only necessary to develop specific inhibitors but also to acquire a deep knowledge of the influence that such factors exert on their activities. This knowledge could help us to establish adapted therapeutic strategies in the treatment of pain or other processes in which enkephalinases are involved. In this chapter, some of these regulatory factors are discussed, such as regional and subcellular distribution, developmental changes, diurnal variations, hormonal influences, stress, dietary factors or interactions with other neurotransmitters.

Asymmetrical response of aminopeptidase A in the medial prefrontal cortex and striatum of 6-OHDA-unilaterally-lesioned Wistar Kyoto and spontaneously hypertensive rats.

Aminopeptidase A is responsible for the hydrolysis of angiotensin II and cholecystokinin. By measuring its activity we obtain a reflection of the functional status of its endogenous substrates. Dopamine coexists with these neuropeptides in striatum and prefrontal cortex. If the content of any of them is altered, the others and the functions they are involved in would also be affected. Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) are rat models with different motor behavior and mood. We hypothesized that aminopeptidase A activity could be modified in WKY or SHR affecting the brain dopamine. The results may provide new insights for the understanding of dopamine-related disorders such as schizophrenia, depression or Parkinson's disease. To analyze the influence of unilateral depletions of dopamine on the intra- and inter-hemispheric behavior of aminopeptidase A in striatum and prefrontal cortex of WKY and SHR, aminopeptidase A activity was measured fluorometrically, using an arylamide derivative as substrate, in the left and right sides of striatum and prefrontal cortex of WKY and SHR treated with saline (control groups) or following left or right intrastriatal injections of 6-hydroxydopamine (lesioned groups). Differential asymmetrical intra- and inter-hemispheric behaviors of aminopeptidase A were observed, depending on the lesioned hemisphere, the region and the strain analyzed. Results also demonstrated differential intra and inter-hemispheric correlations between striatum and prefrontal cortex and between both regions and motor behavior depending on the side of lesion. The changes mostly involved the left hemisphere. The functions in which the aminopeptidase A activity is involved could be modified depending on whether the dopamine depletion occurs on the left or right hemisphere.

Neuropeptidase activity in the frontal cortex of Wistar-Kyoto and spontaneously hypertensive rats treated with vasoactive drugs: a bilateral study.

BACKGROUND AND OBJECTIVE: Hypertension can lead to mood disorders that may worsen or ameliorate depending on the type of antihypertensive prescribed. Depression is associated with modifications in basal brain asymmetry particularly that of the frontal cortex, which is involved in blood pressure control. Furthermore, different vasoactive drugs may change the brain's asymmetry in a manner that contributes to cognition status. We studied the bilateral activity of several neuropeptidases in frontal cortex as a reflect of the functional status of certain neuropeptides involved in mood. METHODS: Using arylamide derivatives as substrates, we fluorometrically analysed the activity of these enzymes in the left and right frontal cortex of control untreated Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs) and compared their activities with WKY or SHR treated with the antihypertensive drugs captopril (CAP) and propranolol (PRO) or with the hypertensive N (G)-nitro-L-arginine methyl ester. SBP was also measured in all WKY and SHR groups. RESULTS: Untreated WKY, WKY treated with CAP or PRO and SHR treated with CAP exhibited normotensive values of SBP. However, WKY treated with N (G)-nitro-L-arginine methyl ester as well as untreated SHR and SHR treated with PRO and N(G)-nitro-L-arginine methyl ester demonstrated hypertensive values of SBP. Changes in the bilateral distribution of neuropeptidases were depending on the strain, the enzyme analysed and the drug used. Normotensive WKY groups (WKY, CAP, PRO) revealed intrahemispheric correlations mainly in the left hemisphere. In contrast, WKY treated with N(G)-nitro-L-arginine methyl ester and SHR groups demonstrated intrahemispheric correlations mainly in the right hemisphere. Interhemispheric correlations were mostly observed in WKY as well as in SHR groups with antihypertensive treatments (CAP, PRO). CONCLUSION: Our results suggest specific brain bilateral patterns of neuropeptidase activities in WKY that change in SHR. This observation may be related to the cognitive disorders that have been described in these animals and that change under antihypertensive or hypertensive drug's treatments.

Thyroid Disorders Change the Pattern of Response of Angiotensinase Activities in the Hypothalamus-Pituitary-Adrenal Axis of Male Rats.

Thyroid disorders affect the hypothalamic-pituitary-adrenal axis with important consequences on the cardiovascular function in which the renin-angiotensin system plays a major role. Hypo and hyperthyroidism influence the classic main components of the renin-angiotensin system. However, the behavior of other elements of the renin-angiotensin system such as Ang III, Ang 2-10, Ang IV, or AT4, regulated by angiotensinase enzymes such as alanyl- (AlaAP), cystinyl- (CysAP), glutamyl- (GluAP), or aspartyl-aminopeptidase (AspAP), has not yet been described. In order to obtain a comprehensive view on the response of the renin-angiotensin system in the hypothalamic-pituitary-adrenal axis of animals with thyroid disorders, these enzyme activities were simultaneously analyzed fluorometrically, using arylamide derivatives as substrates in hypothalamus, anterior and posterior pituitary, adrenals and plasma of euthyroid, hypothyroid, and hyperthyroid rats, and their intra- and inter-tissue correlations were evaluated. The response is depending on the type of enzyme studied, its location and the thyroid status. Anterior pituitary, adrenals and plasma were mainly affected by the thyroid disorders. In the anterior pituitary, GluAP and AspAP increased in hypothyroid rats. In adrenals, AlaAP and CysAP decreased in hypothyroid whereas GluAP and AspAP decreased in hyperthyroid rats. In plasma, while AlaAP increased in hypo- and hyperthyroid rats, CysAP and GluAP decreased only in hyperthyroid. In comparison with euthyroid, intra-tissue correlations decreased in hypothyroid but inter-tissue correlations decreased mainly in hyperthyroid rats. Thyroid disorders also produced a disruption in the pattern of inter-tissue correlations observed in euthyroid. These results suggest that thyroid hormone levels hit components of the renin-angiotensin system and may influence the paracrine and endocrine cross talk between cells.

Divergent profile between hypothalamic and plasmatic aminopeptidase activities in WKY and SHR. Influence of beta-adrenergic blockade.

AIMS: Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) differ in their renin-angiotensin system function and sympathetic tone. The metabolism of angiotensins and vasopressin depends on the action of certain aminopeptidases whose activity may be influenced by the autonomic nervous system. Their regulation may differ between WKY and SHR in hypothalamus and plasma according to the sympathetic tone. We analyzed aminopeptidases responsible for the hydrolysis of certain angiotensins, vasopressin, cholecystokinin or enkephalins in hypothalamus and plasma of WKY and SHR in untreated controls rats and under beta-adrenoceptor blockade. Systolic blood pressure, food intake, water intake and diuresis were measured as parameters modulated by the autonomic nervous system and the above mentioned peptides. MAIN METHODS: Glutamyl-, aspartyl-, cystinyl- and alanyl-aminopeptidase activities were analyzed fluorimetrically in plasma and hypothalamus of control and propranolol-treated (100mg/kg/day administered in drinking water for 1month) WKY and SHR, using arylamide derivatives as substrates. KEY FINDINGS: An opposite response of aminopeptidases to propranolol treatment between plasma and hypothalamus was observed in either WKY and SHR. Furthermore, the behavior of aminopeptidases was inversed between WKY and SHR either in hypothalamus and plasma: while the activity increased in hypothalamus and decreased in plasma of WKY, it decreased in hypothalamus and increased in plasma of SHR. SIGNIFICANCE: These results revealed an inverse response of aminopeptidases between hypothalamus and plasma and also an opposite behavior of these enzymes between WKY and SHR in hypothalamus and plasma. These observations support the involvement of the sympathetic system in the modulation of aminopeptidase activities.

Diurnal opposite variation between angiotensinase activities in photo-neuro-endocrine tissues of rats.

Central and peripheral renin-angiotensin systems (RASs) act in a coordinated manner for the physiologic functions regulated by neuroendocrine events. However, whereas the diurnal rhythm of peripheral circulatory and tissue RASs is well known, the circadian behaviour of their components in central photo-neuro-endocrine structures, key elements for the control of circadian rhythms, has been barely studied. In the present study, we analysed the aspartyl- (AspAP) and glutamyl-aminopeptidase (GluAP) (aminopeptidase A) activities, the angiotensinases responsible for the metabolism of Ang I to Ang 2-10 and Ang II to Ang III, respectively, in the retina, anterior hypothalamus and pituitary at different light and dark time-points of a 12:12 h light:dark cycle (7-19 h light), using arylamide derivatives as substrates. The results demonstrated that while retina and pituitary exhibited their highest levels of AspAP activity in the light period and the lowest in the dark one, the contrary occurred in the hypothalamus - the lowest levels were observed in light conditions and the highest in darkness. The outcome for GluAP showed the highest levels in the light period and the lowest in the dark one in the three tissues analysed. In conclusion, changes in angiotensinase activities throughout the daytime may cause changes of their respective substrates and derived peptides and, consequently, in their functions. This observation may have implications for the treatment of hypertension.

Bilateral distribution of enkephalinase activity in the medial prefrontal cortex differs between WKY and SHR rats unilaterally lesioned with 6-hydroxydopamine.

Changes in the basal brain bilateral morphologic, neurochemical and/or functional patterns may be partly responsible for some brain disorders such as those involving mood. WKY and SHR strains as well as 6-hydroxydopamine (6-OHDA)-lesioned animals are validated models for the study of mood disorders. Because dopamine and enkephalins are involved in anxiety-related behaviors, the aim of our study was to analyze enkephalinase activity, assayed as aminopeptidase M activity, in the left and right medial prefrontal cortex (mPFC) of WKY and SHR treated with saline (sham group) or following left or right intrastriatal injections of the neurotoxic 6-OHDA. Sham left and sham right WKY exhibited a significant left predominance. Left 6-OHDA-lesioned rats inverted the left predominance of sham to right predominance. In right 6-OHDA-lesioned rats, the left predominance in sham right rats disappeared. Sham left as well as sham right SHR did not show any bilateral differences. In contrast, while the left lesion demonstrated a highly significant left predominance, the right lesion showed a slight but significant right predominance. A significant negative correlation between enkephalinase activity of the right mPFC and blood pressure and heart rate was observed only in left-lesioned SHR. Our results demonstrate that unilateral nigrostriatal injections of 6-OHDA influence the bilateral distribution of enkephalinase activity depending on both the side of the lesion and the strain analyzed. These results support the hypothesis that DA pathways may interact asymmetrically with enkephalins in the mPFC and that enkephalinase activity may play a role in the regulatory mechanisms underlying this interaction.

Neuropeptidase activities in plasma after acute restraint stress. Interaction with cortico-limbic areas.

OBJECTIVE: To evaluate the influence of acute restraint stress (ARS) on plasma enkephalinase and oxytocinase activities. ARS modifies basal activities in cortico-limbic regions of rats and induces changes in the correlations observed between these regions. The interactions between plasma and cortico-limbic activities will be also evaluated. METHODS: Enkephalinase (AlaAP and LeuAP) and oxytocinase (P-LeuAP) activities were fluorometrically determined in plasma of control and stressed rats using aminoacyl-ß-naphthylamides (aaNNap), AlaNNap and LeuNNap as substrates. RESULTS: No differences in enzymatic activities were observed between control and stressed animals in plasma. In contrast, highly significant positive and negative correlations between plasma and cortico-limbic regions were demonstrated in controls. Stress conditions significantly alter the pattern of these correlations. CONCLUSION: The present results clearly support a connection between plasma and brain involving certain neuropeptidase activities that change under stress conditions.

Tissue distribution of CysAP activity and its relationship to blood pressure and water balance.

AIMS: To better understand the functional role of soluble (Sol) and membrane-bound (MB) cystinyl-aminopeptidase (CysAP) activities, we studied differentially their organ distribution in adult male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR)with or without treatment with captopril.We searched for a possible tissue-specific association of CysAP with water balance and blood pressure. MAIN METHODS: We used twenty WKY rats distributed in ten controls and ten captopril-treated, and sixteen SHR divided in eight controls and eight captopril-treated. Captopril (100 mg/kg/day) was administered in drinking water for 4 weeks. Systolic blood pressure, water intake and diuresis were measured individually. CysAP was assayed fluorometrically using L-cystine-di-ß-naphthylamide as substrate. KEY FINDINGS: Sol or MB activities were generally higher in SHR compared to WKY notably in hypothalamus and kidney than in the other tissues. Captopril mainly decreased CysAP in SHR whereas it increased in WKY. The distribution of Sol CysAP was more homogeneous among tissues ofWKY than SHR. In contrast, the distribution of MB CysAP was more heterogeneous than Sol CysAP in both WKY and SHR. This suggests that MB CysAP activity acts in a more tissue-specific manner than Sol CysAP. The majority of the significant correlations between tissue activities and the measured physiological parameters were observed mostly in renal medulla and hypothalamus. SIGNIFICANCE: Sol and MB CysAP activities, acting separately or in concert and mainly in renal medulla, regulate the function of their susceptible endogenous substrates, and may participate meaningfully in the control of blood pressure and fluid balance.

Interaction of neuropeptidase activities in cortico-limbic regions after acute restraint stress.

Brain enkephalin, vasopressin and oxytocin are anxiolytic agents involved in the stress response. Acute restraint stress influences certain neuropeptidase activities, such as some enkephalin-degrading peptidases and vasopressinase/oxytocinase, in the medial prefrontal cortex (mPFC), amygdala (AM) or hippocampus (HC), which are involved in this response. Because these regions form a unified circuit and cooperate in their response to stress, it is important to analyze the profile of the regional distribution of these activities as well as their inter-regional model of interaction in this circuit. Regarding the regional study, although most activities showed a marked predominance of the AM over the HC and mPFC, both in control and stressed animals, enkephalin-degrading activity, assayed as membrane-bound alanyl aminopeptidase activity, showed a change after stress, increasing in the HC and decreasing in the AM. The correlational study in controls indicated essentially a positive interaction between the mPFC and AM. In marked contrast, there was a highly significant change in the functional status of this circuit after stress, showing mainly a positive correlation between the mPFC and HC and between the AM and HC. The existence of correlations does not demonstrate a direct relationship between regions. However, reasons for such strong associations after restraint stress should be examined. The present study may indicate a connection between neuropeptidase activities and their corresponding neuropeptidergic substrates due to significant changes in the functional status of the cortico-limbic circuit after restraint stress.

Brain, heart and kidney correlate for the control of blood pressure and water balance: role of angiotensinases.

The renin-angiotensin system (RAS) plays a major role in the control of blood pressure (BP) and water balance by coordinating brain, heart and kidney functions, connected with each other by hormonal and neural mechanisms through the autonomic nervous system (ANS). RAS function may be monitored by the study of the enzymes (angiotensinases) involved in the metabolism of its active peptides. In order to study the relationship between the brain-heart-kidney axis and the control of BP and water balance, we analyzed the correlation of angiotensinase activities, assayed as arylamidase activities, between hypothalamus, left ventricle, renal cortex and renal medulla, collected from Wistar-Kyoto and spontaneously hypertensive rats, treated or not treated with L-NAME [N(G)-nitro-L-arginine methyl ester]. This compound not only inhibits the formation of nitric oxide but also disrupts the normal function of the ANS activating the sympathetic nervous system (SNS) to increase BP. In addition, to assess the influence of the SNS, we studied the effect of its blockade by treatment of both strains with propranolol. The present results support the notion that RAS function of the brain-heart-kidney axis, as reflected by the activities of angiotensinases, is reciprocally connected by afferent and efferent mechanisms between these locations, presumably through the ANS. These results reveal new aspects of neuroendocrine regulation possibly involving the ANS.

The brain-heart connection: frontal cortex and left ventricle angiotensinase activities in control and captopril-treated hypertensive rats-a bilateral study.

The model of neurovisceral integration suggests that the frontal cortex (FC) and the cardiovascular function are reciprocally and asymmetrically connected. We analyzed several angiotensinase activities in the heart left ventricle (VT) of control and captopril-treated SHR, and we search for a relationship between these activities and those determined in the left and right FC. Captopril was administered in drinking water for 4 weeks. Samples from the left VT and from the left and right FC were obtained. Soluble and membrane-bound enzymatic activities were measured fluorometrically using arylamides as substrates. The weight of heart significantly decreased after treatment with captopril, mainly, due to the reduction of the left VT weight. In the VT, no differences for soluble activities were observed between control and treated SHR. In contrast, a generalized significant reduction was observed for membrane-bound activities. The most significant correlations between FC and VT were observed in the right FC of the captopril-treated group. The other correlations, right FC versus VT and left FC versus VT in controls and left FC versus VT in the captopril group, were few and low. These results confirm that the connection between FC and cardiovascular system is asymmetrically organized.

Asymmetrical effect of captopril on the angiotensinase activity in frontal cortex and plasma of the spontaneously hypertensive rats: expanding the model of neuroendocrine integration.

There is a reciprocal connection between the frontal cortex (FC) and cardiovascular function, and this connection is functionally lateralized. The possible pathophysiological impact of neuroendocrine asymmetries is largely underestimated. Our aim was to examine the activity of soluble (SOL) and membrane-bound (MB) aminopeptidases (APs) involved in the renin-angiotensin system in the peripheral plasma and in the left and right FC, in both untreated (control) and captopril-treated spontaneously hypertensive rats (SHRs). Enzymatic activities were measured fluorometrically using arylamide derivatives as substrates. Captopril reduced systolic blood pressure, but no differences in plasma AP activity were observed between the control and treated SHRs. In contrast, whereas the bilateral pattern (left vs. right differences) of SOL activities did not substantially change in the FC after captopril treatment, the asymmetries observed for MB activities in the FC markedly increased compared with the control group. Moreover, correlations between the AP activities in the plasma and those in the left or right FC were observed. In the control rats, the plasma AP activities correlated significantly with those in the right FC, whereas they correlated with those in the left FC in the captopril-treated group. In both groups (control and captopril), these correlations were negative for the SOL activity but positive for the MB activity. The present results reveal a pattern of bilateral behavior between the nervous and cardiovascular systems. The inverted bilateral behavior after captopril treatment suggests a systematized, lateralized neuroendocrine response representing a regular bilateral behavior that has yet to be analyzed.

Lateralized response of oxytocinase activity in the medial prefrontal cortex of a unilateral rat model of Parkinson's disease.

Individuals in the early stage of Parkinson's disease exhibit cognitive impairments as a result of hemisphere damage. The mesocortical dopamine system, particularly the medial prefrontal cortex (mPFC), is implicated in cognitive functions and is characterized by an asymmetric organization. Oxytocinase activity (OX) is also asymmetrically distributed in the mPFC of normal rats and is involved in cognitive functions. OX was measured in the left and right mPFC of rats with left or right hemi-parkinsonism, induced by intrastriatal injections of 6-hydroxydopamine, and compared with sham controls. These results demonstrated that the striking basal left predominance of OX observed in both the left and the right sham controls was radically disrupted in lesioned animals. The bilateral distribution in lesioned animals was altered differently depending on the injured hemisphere. These results may reflect changes in the enzyme substrates and consequently in the functions in which they are involved. These results may account, in part, for the cognitive abnormalities observed in hemi-parkinsonism.