Renin-angiotensin system in normal pregnancy and in preeclampsia: A comprehensive review.

The activation of the Renin Angiotensin System (RAS) is required during pregnancy and it seems that RAS dysfunction has some important effects on pathological pregnancy conditions, including preeclampsia (PE). The objective of this review is to summarize and to discuss the role of the RAS in normal pregnancy and in PE. We found evidence that the RAS is important for the evolution of pregnancy under physiological conditions and plays an important role in the pathogenesis of PE. In normal gestation, almost all circulating components of RAS are increased and there is a general state of non-reactivity to the vasoconstrictor actions of Angiotensin (Ang) II. In PE, changes in the circulating levels of RAS components occur, especially with an intense decrease in the levels of Ang I, Ang II and Ang-(1-7). Our findings endorse the idea that PE is a disease whose cornerstone relies on altered placental physiology. There are high tissue levels of Ang II type 1 receptor (AT1R) in the musculature of the blood vessels and in the placenta, generating a state of increased sensitivity to the vasoconstrictor action of Ang II. AT1R autoantibodies (AT1R-AA) might be one of the key points for the vicious cycle of PE, as these molecules are synthesized in situations of hypoxia and enhance placental vasoconstriction, causing even more hypoxia. Further studies are needed to investigate the role of circulating RAS, uteroplacental RAS and local RAS molecules from other tissues related to the pathogenesis of PE.

Effects of terlipressin and naloxone compared with epinephrine in a rat model of asphyxia-induced cardiac arrest.

OBJECTIVE: To evaluate the hemodynamic and metabolic effects of terlipressin and naloxone in cardiac arrest. METHODS: Cardiac arrest in rats was induced by asphyxia and maintained for 3.5 minutes. Animals were then resuscitated and randomized into one of six groups: placebo (n = 7), epinephrine (0.02 mg/kg; n = 7), naloxone (1 mg/kg; n = 7) or terlipressin, of which three different doses were tested: 50 µg/kg (TP50; n = 7), 100 µg/kg (TP100; n = 7) and 150 µg/kg (TP150; n = 7). Hemodynamic variables were measured at baseline and at 10 (T10), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes after cardiac arrest. Arterial blood samples were collected at T10, T30 and T60. RESULTS: The mean arterial pressure values in the TP50 group were higher than those in the epinephrine group at T10 (165 vs. 112 mmHg), T20 (160 vs. 82 mmHg), T30 (143 vs. 66 mmHg), T45 (119 vs. 67 mmHg) and T60 (96 vs. 66.8 mmHg). The blood lactate level was lower in the naloxone group than in the epinephrine group at T10 (5.15 vs. 10.5 mmol/L), T30 (2.57 vs. 5.24 mmol/L) and T60 (2.1 vs. 4.1 mmol/L). CONCLUSIONS: In this rat model of asphyxia-induced cardiac arrest, terlipressin and naloxone were effective vasopressors in cardiopulmonary resuscitation and presented better metabolic profiles than epinephrine. Terlipressin provided better hemodynamic stability than epinephrine.

Effects of terlipressin and naloxone compared with epinephrine in a rat model of asphyxia-induced cardiac arrest

OBJECTIVE: To evaluate the hemodynamic and metabolic effects of terlipressin and naloxone in cardiac arrest. METHODS: Cardiac arrest in rats was induced by asphyxia and maintained for 3.5 minutes. Animals were then resuscitated and randomized into one of six groups: placebo (n = 7), epinephrine (0.02 mg/kg; n = 7), naloxone (1 mg/kg; n = 7) or terlipressin, of which three different doses were tested: 50 µg/kg (TP50; n = 7), 100 µg/kg (TP100; n = 7) and 150 µg/kg (TP150; n = 7). Hemodynamic variables were measured at baseline and at 10 (T10), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes after cardiac arrest. Arterial blood samples were collected at T10, T30 and T60. RESULTS: The mean arterial pressure values in the TP50 group were higher than those in the epinephrine group at T10 (165 vs. 112 mmHg), T20 (160 vs. 82 mmHg), T30 (143 vs. 66 mmHg), T45 (119 vs. 67 mmHg) and T60 (96 vs. 66.8 mmHg). The blood lactate level was lower in the naloxone group than in the epinephrine group at T10 (5.15 vs. 10.5 mmol/L), T30 (2.57 vs. 5.24 mmol/L) and T60 (2.1 vs. 4.1 mmol/L). CONCLUSIONS: In this rat model of asphyxia-induced cardiac arrest, terlipressin and naloxone were effective vasopressors in cardiopulmonary resuscitation and presented better metabolic profiles than epinephrine. Terlipressin provided better hemodynamic stability than epinephrine. .

Cardiovascular responses to microinjection of noradrenaline into the medial amygdaloid nucleus of conscious rats result from α2-receptor activation and vasopressin release.

The medial amygdaloid nucleus (MeA) is involved in the modulation of physiological and behavioral processes, as well as regulation of the autonomic nervous system. Moreover, MeA electrical stimulation evokes cardiovascular responses. Thus, as noradrenergic receptors are present in this structure, the present study tested the effects of local noradrenaline (NA) microinjection into the MeA on cardiovascular responses in conscious rats. Moreover, we describe the types of adrenoceptor involved and the peripheral mechanisms involved in the cardiovascular responses. Increasing doses of NA (3, 9, 27 or 45 nmol/100 nL) microinjected into the MeA of conscious rats caused dose-related pressor and bradycardic responses. The NA cardiovascular effects were abolished by local pretreatment of the MeA with 10 nmol/100 nL of the specific α2-receptor antagonist RX821002, but were not affected by local pretreatment with 10 nmol/100 nL of the specific α1-receptor antagonist WB4101. The magnitude of pressor response evoked by NA microinjected into the MeA was potentiated by intravenous pretreatment with the ganglion blocker pentolinium (5 mg/kg), and blocked by intravenous pretreatment with the selective V1-vasopressin antagonist dTyr(CH2)5 (Me)AVP (50 µg/kg). In conclusion, our results show that microinjection of NA into the MeA of conscious rats activates local α2-adrenoceptors, evoking pressor and bradycardic responses, which are mediated by vasopressin release.

L-type calcium channel ß subunit modulates angiotensin II responses in cardiomyocytes.

Angiotensin II regulation of L-type calcium currents in cardiac muscle is controversial and the underlying signaling events are not completely understood. Moreover, the possible role of auxiliary subunit composition of the channels in Angiotensin II modulation of L-type calcium channels has not yet been explored. In this work we study the role of Ca(v)ß subunits and the intracellular signaling responsible for L-type calcium current modulation by Angiotensin II. In cardiomyocytes, Angiotensin II exposure induces rapid inhibition of L-type current with a magnitude that is correlated with the rate of current inactivation. Semi-quantitative PCR of cardiomyocytes at different days of culture reveals changes in the Ca(v)ß subunits expression pattern that are correlated with the rate of current inactivation and with Angiotensin II effect. Over-expression of individual b subunits in heterologous systems reveals that the magnitude of Angiotensin II inhibition is dependent on the Ca(v)ß subunit isoform, with Ca(v)ß(1b) containing channels being more strongly regulated. Ca(v)ß(2a) containing channels were insensitive to modulation and this effect was partially due to the N-terminal palmitoylation sites of this subunit. Moreover, PLC or diacylglycerol lipase inhibition prevents the Angiotensin II effect on L-type calcium channels, while PKC inhibition with chelerythrine does not, suggesting a role of arachidonic acid in this process. Finally, we show that in intact cardiomyocytes the magnitude of calcium transients on spontaneous beating cells is modulated by Angiotensin II in a Ca(v)ß subunit-dependent manner. These data demonstrate that Ca(v)ß subunits alter the magnitude of inhibition of L-type current by Angiotensin II.

[Molecular bases of diabetic nephropathy]. / Bases moleculares da glomerulopatia diabética.

The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra- and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-beta1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-beta1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of diabetic nephropathy. New therapeutic strategies directed to the described intracellular events may give future additional benefits.

Bases moleculares da glomerulopatia diabética / Molecular bases of diabetic nephropathy

O principal determinante da nefropatia diabética é a hiperglicemia, mas hipertensão e fatores genéticos também estão envolvidos. O glomérulo é o foco de lesão, onde proliferação celular mesangial e produção excessiva de matriz extracelular decorrem do aumento da glicose intracelular, por excesso de glicose extracelular e hiperexpressão de GLUT1. Seguem-se aumento do fluxo pela via dos polióis, estresse oxidativo intracelular, produção intracelular aumentada de produtos avançados da glicação não enzimática (AGEs), ativação da via da PKC, aumento da atividade da via das hexosaminas e ativação de TGF-beta1. Altas concentrações de glicose também aumentam angiotensina II (AII) nas células mesangiais por aumento intracelular da atividade da renina (ações intrácrinas, mediando efeitos proliferativos e inflamatórios diretamente). Portanto, glicose e AII exercem efeitos proliferativos celulares e de matriz extracelular nas células mesangiais, utilizando vias de transdução de sinais semelhantes, que levam a aumento de TGF-beta1. Nesse estudo são revisadas as vias que sinalizam os efeitos da glicose e AII nas células mesangiais em causar os eventos-chaves relacionados à gênese da glomerulopatia diabética. As alterações das vias de sinalização implicadas na glomerulopatia, aqui revisadas, suportam dados de estudos observacionais/ensaios clínicos, onde controle metabólico e anti-hipertensivo, especificamente com inibidores do sistema renina-angiotensina, têm-se mostrado importantes - e aditivos - na prevenção do início e progressão da nefropatia. Novas estratégias terapêuticas dirigidas aos eventos intracelulares descritos deverão futuramente promover benefício adicional.

The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra- and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-beta1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-beta1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of diabetic nephropathy. New therapeutic strategies directed to the described intracellular events may give future additional benefits.

Noradrenergic inhibitory modulation in the caudal commissural NTS of the pressor response to chemoreflex activation in awake rats.

In the present study we evaluated the possible modulatory role of noradrenaline on the neurotransmission of the peripheral chemoreflex afferents in the caudal commissural NTS of awake rats. To reach this goal we performed a dose-response curve to microinjection of increasing dose of noradrenaline into the caudal commissural NTS of awake rats and then the threshold dose, which produces minor changes in the baseline mean arterial pressure, was selected to be used in the chemoreflex experiment. The peripheral chemoreflex was activated with KCN before and after bilateral microinjections of noradrenaline (5 nMol/50 nL, threshold dose) into the NTS. The data show that microinjection of noradrenaline into the caudal NTS produced a significant reduction in the pressor response to the chemoreflex 30 s after the injection when compared to the control response (30+/-6 vs. 49+/-3 mm Hg) but no significant changes in the bradycardic response. The data indicate that noradrenaline in the caudal commissural NTS of awake rats may play an important inhibitory neuromodulatory role on the processing of the pressor/sympathoexcitatory component of the chemoreflex.

Angiotensin II modulates tyr-phosphorylation of IRS-4, an insulin receptor substrate, in rat liver membranes.

Angiotensin II (Ang II), a major regulator of blood pressure, is also involved in the control of cellular proliferation and hypertrophy and might exhibit additional actions in vivo by modulating the signaling of other hormones. As hypertension and Insulin (Ins) resistance often coexist and are risk factors for cardiovascular diseases, Ang II and Insulin signaling cross-talk may have an important role in hypertension development. The effect of Ins on protein tyrosine phosphorylation was assayed in rat liver membrane preparations, a rich source of Ins receptors. Following stimulation, Ins (10(-7) M) induced tyr-phosphorylation of different proteins. Insulin consistently induced tyr-phosphorylation of a 160 kDa protein (pp160) with maximum effect between 1 and 3 min. The pp160 protein was identified by anti-IRS-4 but not by anti-IRS-1 antibody. Pre-stimulation with Ang II (10(-7) M) diminishes tyr-phosphorylation level of pp160/IRS-4 in a dose-dependent manner. Okadaic acid, the PP1A and PP2A Ser/Thr phosphatase inhibitor, increases pp160 phosphorylation induced by Ins and prevents the inhibitory effect of Ang II pre-stimulation. Genistein, a tyrosine kinase inhibitor, diminishes tyr-phosphorylation level of IRS-4. PI3K inhibitors Wortmanin and LY294002, both increase tyr-phosphorylation of IRS-4, either in the presence of Ins alone or combined with Ang II. These results suggest that Ins and Ang II modulate IRS-4 tyr-phosphorylation in a PI3K-dependent manner. In summary, we showed that Ins induces tyr-phosphorylation of IRS-4, an effect modulated by Ang II. Assays performed in the presence of different inhibitors points toward a PI3K involvement in this signaling pathway.

Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation.

1. The aim of this study was to assess the effects of treatment with isoproterenol (ISO, 0.3 mg kg-1 day-1, s.c.) for 7 days on the vascular reactivity of rat-isolated aortic rings. Additionally, potential mechanisms underlying the changes that involved the endothelial modulation of contractility were investigated. 2. Treatment with ISO induced cardiac hypertrophy without changes in haemodynamic parameters. Aortic rings from ISO-treated rats showed an increase in the contraction response to phenylephrine (PHE) and serotonin, but did not change relaxations produced by acetylcholine or isoproterenol. Removal of the endothelium increased the responses to PHE in both groups. However, this procedure was less effective in ISO-treated as compared with control rats. Endothelial cell removal abolished the increase in the response to PHE in ISO-treated rats. The presence of Nomega-nitro-L-arginine methyl ester shifted the concentration-response curve to PHE to the left in both groups of rats. However, this effect was more pronounced in the ISO group. In addition, aminoguanidine (50 microM) potentiated the actions of PHE only in the ISO group. ISO treatment increased nitric oxide synthase (NOS) activity and neuronal NOS and endothelial NOS protein expression in the aorta. 3. Neither losartan (10 microM) nor indomethacin (10 microM) abolished the effects of ISO on the actions of PHE. Superoxide dismutase (SOD, 150 U ml-1) and L-arginine (5 mM), but neither catalase (300 U ml-1) nor apocynin (100 microM), blocked the effect of ISO treatment. In addition, we observed an increase in superoxide anion levels as measured by ethidium bromide fluorescence and of copper and zinc superoxide dismutase protein expression in ISO-treated rats. 4. In conclusion, our data suggest that ISO treatment alters the endothelial cell-mediated modulation of the contraction to PHE in rat aorta. The increased maximal response of PHE seems to be due to an increase in superoxide anion generation, which inactivates some of the basal NO produced and counteracts NO-mediated negative modulation even in the presence of high NO production and antioxidant defence.

Increased vascular angiotensin II binding capacity and ET-1 release in young cardiomyopathic hamsters.

Heart failure (HF) is a multifactorial and progressive disease that has been associated with multiple systemic and vascular alterations. Previous reports from our laboratory showed that in 2-month-old Bio-To2 Syrian cardiomyopathic hamsters (SCH) that have not yet developed the clinical manifestations of HF, the vascular contractility induced by 0.1 microM angiotensin II was approximately 35% greater than in control animals. This finding was observed concomitantly with an increased aortic ACE activity. To further evaluate the mechanisms underlying angiotensin II-enhanced vascular contraction, concentration-response curves for angiotensin II (0.01 nM-10 microM) were constructed before and after the addition of prazosin (alpha-1 blocker), NS-398 (selective COX-2 blocker) and BQ-123 (ET-1A-receptor antagonist) in aortic rings from 2-month-old SCH. The binding capacity and affinity of the AT-1 receptors were also evaluated in aortic homogenates using 125I-angiotensin II. Age-matched golden hamsters were used as controls (CT). Our results indicate that incubation with either 10 microM prazosin or 10 microM NS-398 did not modify EC50 or Emax values for angiotensin II indicating that norepinephrine and prostaglandins are not involved in the enhanced contractile action of angiotensin II. However, 10 microM BQ-123 reduced by 40% the contraction induced by 1.0 microM angiotensin II (from 1.05+/-0.04 to 0.6475+/-0.06 g/mg tissue, n = 5, P < 0.05), suggesting that in cardiomyopathic hamsters, the action of angiotensin II is mediated in part by ET-1. At lower angiotensin II concentration (0.1 microM), the ET-1-dependent contraction decreases to 29%. In addition, although dissociation constants for labeled angiotensin II were found to be similar in the aorta of SCH and control animals (K(D): CT = 7.8 nM and SCH = 5.1 nM), 125I-angiotensin II binding capacity was about 2-fold greater in SCH than in controls (Bmax: SCH = 1113 and CT = 605 fmol/mg protein). Altogether these results suggest that in 2-month-old SCH the enhanced response of angiotensin II in the vasculature is mediated both by an increased binding capacity for the hormone and facilitation of the ET-1 action.

Angiotensin II-induced venoconstriction involves both AT1 and AT2 receptors and is counterbalanced by nitric oxide.

The venoconstrictor effect of Angiotensin II (Ang II) was investigated in the rat mesenteric venules and portal vein. Mesenteric venules were perfused at a constant rate and reactivity to Ang II (0.1 nmol) was evaluated as changes in the perfusion pressure. Rings of portal vein were mounted in organ baths and curves to Ang II (0.1-100 nmol/L) were generated. In venules, Ang II-contraction (10.6+/-1.1 mmHg) was abolished by losartan (0.9+/-0.3 mmHg*), reduced by PD 123,319 (5.8+/-0.9 mmHg*), increased by L-NAME (16.5+/-1.8 mmHg*) and not altered by indomethacin. In portal veins, curves to Ang II (-logEC50: 8.9+/-0.1 mol/L) were shifted to the right by losartan (-log EC50: 7.5+/-0.1 mol/L*) and by PD 123,319 (-logEC50: 8.0+/-0.1 mol/L*). L-NAME increased the maximal response to Ang II (Emax: 0.91+/-0.1g versus 1.62+/-0.3g*) and indomethacin had no effect. In conclusion, Ang II induces venoconstriction by activating AT1 and AT2 receptors. Data obtained with L-NAME provide evidence that the basal nitric oxide release from the endothelium of the venous system can modulate the Ang II-induced venoconstriction.

The endothelin/sarafotoxin-induced increase of the proliferation of undifferentiated and DMSO-differentiated GEM-81 goldfish erythrophoroma cells is mediated by ETB receptors.

Endothelins (ETs) and sarafotoxins (SRTXs) have been reported to exert ET(B)-mediated effects on vertebrate pigment cells. GEM-81 cell line, a red pigment cell-derived cutaneous tumor of the teleost Carassius auratus, expresses ET(B) receptors and can be differentiated with 1.5% DMSO treatment, thus constituting an useful model to investigate ET and SRTX effects on cultured fish pigment cells. Our aim was to characterize the pharmacology and biological effects mediated by ET receptors in DMSO-differentiated and undifferentiated cells. ET subtype receptors and their respective Ki values in both cell types were determined by competitive binding assays using (125)I ET-1 and BQ-485 (an ET(A) antagonist) or BQ-788 (an ET(B) antagonist). BQ-788, but not BQ-485, significantly reduced (125)I-ET-1 binding in both cell types, with similar low (Ki > nM) affinities. To determine the proliferation effects of ETs/SRTXs, cells were treated for 72 h with the hormones, and counted in a hemocytometer. The proliferation assays were repeated for SRTX S6c in the presence or absence of BQ-788. The results demonstrated that, with the exception of ET-1 (biphasic effect) and ET-3 (no significant effect) in undifferentiated GEM-81 cells, all the tested hormones induced increases in the proliferation of both types of cells. The hormones were equipotent in DMSO-differentiated cells, which exhibited increased sensitivity to ETs, but not to SRTXs, as compared with undifferentiated cells. The BQ-788 antagonistic effect was also exerted on the proliferation responses to SRTX S6c. These results corroborate the long and important evolutionary history of the ET/SRTX receptor system in vertebrate pigment cells.

[Vasopressin use in shock]. / Uso de la vasopresina en el estado de choque.

Arginine-vasopressin (VP), also known as the antidiuretic hormone, is essential for water homeostasis. Its synthesis and liberation depends on regulation of osmotic, hypovolemic, hormonal, and nonosmotic stimuli. It has been demonstrated that it is key for maintenance of cardiovascular homeostasis through vasomotor regulation, the determinant of systemic vascular resistance and mean arterial pressure, a process acting through V1 receptors. Shock state with refractory vasodilation seen in sepsis, systemic inflammatory response, hypovolemia, cardiac arrest, polytrauma, etc., is characterized by an initial phase of liberation and increased levels of VP followed by a second phase characterized by inappropriately low levels of this hormone that are associated with refractoriness to management with volume, inotropics, and vasopressors. It has been demonstrated in clinical and experimental studies that exogenous VP treatment under this condition increases systemic vascular resistance, perfusion pressure, and oxygen supply to peripheral tissues, which makes it possible to decrease and to suspend vasopressors and also to increase survival.

Uso de la vasopresina en el estado de choque / Vasopressin Use in Shock

La arginina-vasopresina (VP) también conocida como hormona antidiurética es esencial para mantener el equilibrio hídrico. Su síntesis y liberación depende de la interacción de estímulos osmóticos, hipovolémicos, hormonales y no osmóticos. Se ha demostrado que en estados de choque es fundamental para mantener la homeostasis cardiovascular a través de la regulación del tono vasomotor, el cual determina las resistencias vasculares sistémicas y la presión arterial media, a través de los receptores VI. El estado de choque con vasodilatación refractaria que se presenta en sepsis, respuesta inflamatoria sistémica, hipovolemia, paro cardiaco, politraumatismo, etc... se caracteriza por una fase inicial en la que hay liberación y aumento en los niveles séricos de VP, ésta es seguida por una segunda fase en la que se presentan niveles inapropiadamente bajos de la hormona y éstos se asocian con refractariedad al manejo con volumen, inotrópicos y vasopresores. Se ha demostrado, en estudios experimentales y clínicos, que en esta condición el tratamiento con vasopresina exógena incrementa la resistencia vascular sistémica, la presión de perfusión y el aporte de oxígeno a los tejidos periféricos lo cual hace posible la disminución y suspensión de los vasopresores e incrementa la supervivencia.

Arginine-vasopresin (VP), also known as the antidiuretic hormone, is essential for water homeostasis. Its synthesis and liberation depends on regulation of osmotic, hypovolemic, hormonal, and nonosmotic stimuli. It has been demonstrated that it is key for maintenance of cardiovascular homeostasis through vasomotor regulation, the determinant of systemic vascular resistance and mean arterial pressure, a process acting through VI receptors. Shock state with refractary vasodilation seen in sepsis, systemic inflamatory response, hypovolemia, cardiac arrest, polytrauma, etc., is characterized by an initial phase of liberation and increased levels of VP followed by a second phase caracterized by inappropirately low levels of this hormone that are associated with refractariness to management with volume, inotropics, and vasopressors. It has been demonstrated in clinical and experimental studies that exogenous VP treatment under this condition increases systemic vascular resistance, perfusion pressure, and oxygen supply to peripheral tissues, which makes it possible to decrease and to suspend vasopressors and also to increase survival.

The cross-talk between angiotensin and insulin differentially affects phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-mediated signaling in rat heart: implications for insulin resistance.

Insulin and angiotensin II (AngII) may act through overlapping intracellular pathways to promote cardiac myocyte growth. In this report insulin and AngII signaling, through the phosphatidylinositol 3-kinase (PI 3-kinase) and MAPK pathways, were compared in cardiac tissues of control and obese Zucker rats. AngII induced Janus kinase 2 tyrosine phosphorylation and coimmunoprecipitation with insulin receptor substrate 1 (IRS-1) and IRS-2 as well as an increase in tyrosine phosphorylation of IRS and its association with growth factor receptor-binding protein 2. Simultaneous treatment with both hormones led to marked increases in the associations of IRS-1 and -2 with growth factor receptor-binding protein 2 and in the dual phosphorylation of ERK1/2 compared with the administration of AngII or insulin alone. In contrast, an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity was induced by both hormones. Insulin stimulated the phosphorylation of MAPK equally in lean and obese rats. Conversely, insulin-induced phosphorylation of Akt in heart was decreased in obese rats. Pretreatment with losartan did not change insulin-induced activation of ERK1/2 and attenuated the reduction of Akt phosphorylation in the heart of obese rats. Thus, the imbalance between PI 3-kinase-Akt and MAPK signaling pathways in the heart may play a role in the development of cardiovascular abnormalities observed in insulin-resistant states, such as in obese Zucker rats.