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M K Raizada

Publications and source records attributed to M K Raizada.

At least 37 records · Page 2Linked to original sources
PubMed2000

Targeting of the renin-angiotensin system by antisense gene therapy: a possible strategy for the long-term control of hypertension.

Traditional pharmacological agents have been successfully used for the treatment of hypertension for a number of decades. However, this therapeutic regimen has reached a conceptual plateau and a cure for the disease is far from appearing on the horizon. With this in mind, and recent advances in state of the art gene delivery system coupled with the anticipated completion of the human genome project, it is timely to think about the possibility of treating and/or curing hypertension using genetic means. In this review, we discuss the role of renin-angiotensin system (RAS) in hypertension; the current gene delivery/gene transfer systems and the RAS as a target for gene therapy to treat hypertension; the successful use of retroviral vectors to deliver antisense to the AT1 receptor (AT1-AS) to prevent the development of hypertension and cardiovascular pathophysiology; the potential use of the viral vectors for the reversal of hypertension; and the future of antisense gene therapy and potential advantages and limitations of this regimen in the treatment and/or control of hypertension.

Animals↗
PubMed2000

The angiotensin II type 2 receptor: an enigma with multiple variations.

Since it was discovered ten years ago, the angiotensin II (ANG II) type 2 (AT(2)) receptor has been an enigma. This receptor binds ANG II with a high affinity but is not responsible for mediating any of the classical physiological actions of this peptide, all of which involve the ANG II type 1 (AT(1)) receptor. Furthermore, the AT(2) receptor exhibits dramatic differences in biochemical and functional properties and in patterns of expression compared with the AT(1) receptor. During the past decade, much information has been gathered about the AT(2) receptor, and the steadily increasing number of publications indicates a growing interest in this new and independent area of research. A number of studies suggest a role of AT(2) receptors in brain, renal, and cardiovascular functions and in the processes of apoptosis and tissue regeneration. Despite these advances, nothing stands out as the major singular function of these receptors. The study of AT(2) receptors has reached a crossroads, and innovative approaches must be considered so that unifying mechanisms as to the function of these unique receptors can be put forward. In this review we will discuss the advances that have been made in understanding the biology of the AT(2) receptor. Furthermore, we will consider how these discoveries, along with newer experimental approaches, may eventually lead to the elusive physiological and pathophysiological functions of these receptors.

Animals↗
PubMed2000

Angiotensin I-converting enzyme antisense gene therapy causes permanent antihypertensive effects in the SHR.

The renin-angiotensin system plays a critical role in the control of blood pressure (BP), and its hyperactivity is associated with the development and maintenance of hypertension. Although traditional pharmacological therapies targeted toward the inhibition of the renin-angiotensin system are effective in the control of this disease, they pose significant limitations. We used an antisense gene delivery strategy to circumvent these limitations and established that a single intracardiac administration of angiotensin type 1 receptor antisense (AT(1)R-AS) causes permanent prevention of hypertension in the spontaneously hypertensive rat (SHR), an animal model of primary human hypertension. Our objectives in this study were 2-fold: to determine (1) whether the targeting of angiotensin I-converting enzyme (ACE) mRNA by a similar antisense strategy would prevent the SHR from developing hypertension and (2) whether the antihypertensive phenotype is transmitted to the offspring from the antisense-treated parents. Administration of a retroviral vector containing ACE antisense (LNSV-ACE-AS) caused a modest yet significant attenuation of high BP ( approximately 15+/-2 mm Hg) exclusively in the SHR. This was associated with a complete prevention of cardiac and renovascular pathophysiological alterations that are characteristic of hypertension. Like their parents, the F(1) generation offspring of the LNSV-ACE-AS-treated SHR expressed lower BP, decreased cardiac hypertrophy, and normalization of renal arterial excitation-coupling compared with offspring derived from the LNSV-ACE-tS (truncated sense)-treated SHR. In addition, the endothelial dysfunction commonly observed in the SHR renal arterioles was significantly prevented in both parents and offspring of the LNSV-ACE-AS-treated SHR. Polymerase chain reaction followed by Southern analysis revealed that the ACE-AS was integrated into the SHR genome and transmitted to the offspring. These observations suggest that transmission of ACE-AS by retroviral vector may be responsible for the transference of normotensive phenotypes in the SHR offspring.

Acetylcholine↗
PubMed2000

Angiotensin I-converting enzyme antisense prevents altered renal vascular reactivity, but not high blood pressure, in spontaneously hypertensive rats.

The renin-angiotensin system plays a critical role in the control of blood pressure, and its hyperactivity is associated with the development of human primary hypertension. Because low-dose angiotensin I-converting enzyme (ACE) inhibitors cause small reductions in blood pressure that are associated with the complete reversal of altered vascular pathophysiology, our objective in this study was to determine whether ACE antisense (ACE-AS) gene delivery prevents alterations in renal vascular physiology in the parents and F(1) offspring of AS-treated spontaneously hypertensive rats (SHR). A single bolus intracardiac injection of ACE-AS (2x10(8) colony-forming units) in SHR neonates caused a modest (18+/-3 mm Hg, n=7 to 9) lowering of blood pressure, which was maintained in the F(1) generation offspring (n=7 to 9). Alterations in renal vascular reactivity, electrophysiology, and [Ca(2+)](i) homeostasis are underlying mechanisms associated with the development and establishment of hypertension. Renal resistance arterioles from truncated ACE sense-treated SHR showed a significantly enhanced contractile response to KCl and phenylephrine (n=24 rings from 6 animals, P<0.01) and significantly attenuated acetylcholine-induced relaxations (n=24 rings from 6 animals, P<0.01) compared with arterioles from ACE-AS-treated SHR. In addition, compared with cells dissociated from arterioles of ACE-AS-treated SHR, cells from truncated ACE sense-treated animal vessels had a resting membrane potential that was 22+/-4 mV more depolarized (n=38, P<0.01), an enhanced L-type Ca(2+) current density (2.2+/-0.3 versus 1.2+/-0.2 pA/pF, n=23, P<0.01), a decreased Kv current density (16.2+/-1.3 versus 5.4+/-2.2 pA/pF, n=34, P<0.01), and increased Ang II-dependent changes in [Ca(2+)](i) (n=142, P<0.01). Similar effects of ACE-AS treatment were observed in the F(1) offspring. These results demonstrate that ACE-AS permanently prevents alterations in renal vascular pathophysiology in spite of the modest effect that ACE-AS had on high blood pressure in SHR.

Animals↗
PubMed1999

Permanent cardiovascular protection from hypertension by the AT(1) receptor antisense gene therapy in hypertensive rat offspring.

Our previous studies have demonstrated that the introduction of angiotensin II type I receptor antisense (AT(1)R-AS) cDNA by a retrovirally mediated delivery system prevents the development of hypertension in the spontaneously hypertensive rat (SHR), an animal model for primary hypertension in humans. These results have led us to propose the hypothesis that an interruption of the renin-angiotensin system (RAS) activity at a genetic level would prevent hypertension on a permanent basis. F(1) and F(2) generations of offspring from a retroviral vector, LNSV- and LNSV-AT(1)R-AS-treated SHR, were generated, and various physiological parameters indicative of hypertension were studied and compared with those of their parents to investigate this hypothesis. Both F(1) and F(2) generations of LNSV-AT(1)R-AS-treated SHR expressed a persistently lower blood pressure, decreased cardiac hypertrophy and fibrosis, decreased medial thickness, and normalization of renal artery excitation-contraction coupling, Ca(2+) current, and [Ca(2+)](i) when compared with offspring derived from the LNSV-treated SHR. In fact, the magnitude of the prevention of these pathophysiological alterations was similar to that observed in the LNSV-AT(1)R-AS-treated SHR parent. The prevention of cardiovascular pathophysiology and expression of normotensive phenotypes are, at least in part, a result of integration and subsequent transmission of AT(1)R-AS from the SHR parents to offspring. These data demonstrate that a single intracardiac injection of LNSV-AT(1)R-AS causes a permanent cardiovascular protection against hypertension as a result of a genomic integration and germ line transmission of the AT(1)R-AS in the SHR offspring.

Animals↗
PubMed1999

Sustained inhibition of angiotensin I-converting enzyme (ACE) expression and long-term antihypertensive action by virally mediated delivery of ACE antisense cDNA.

Angiotensin I-converting enzyme (ACE) inhibitors have been proven to be highly effective and are for the most part the drugs of choice in the treatment and control of hypertension, congestive heart failure, and left ventricular dysfunction. Despite this, questions regarding side effects and compliance with this traditional pharmacological strategy remain. In view of these observations, coupled with recent advances in gene-transfer technology, our objective in this study was to determine whether the expression of ACE could be controlled on a permanent basis at a genetic level. We argued that the introduction of ACE antisense to inhibit the enzyme would be a prerequisite in considering the antisense gene therapy for the control of hypertension and other related pathological states. Retroviral vectors (LNSV) containing ACE sense (LNSV-ACE-S) and ACE antisense (LNSV-ACE-AS) sequences were constructed and were used in rat pulmonary artery endothelial cells (RPAECs) to determine the feasibility of this approach. Infection of rat RPAECs with LNSV-ACE-S and LNSV-ACE-AS resulted in a robust expression of transcripts corresponding to ACE-S and ACE-AS, respectively, for the duration of these experiments, ie, 8 consecutive passages. The expression of ACE-AS but not of ACE-S was associated with a permanent decrease of approximately 70% to 75% in ACE expression and a 50% increase in the B(max) for the AT(1)s. Although angiotensin II caused a concentration-dependent stimulation of intracellular Ca(2+) levels in both ACE-S- and ACE-AS-expressing cells, the stimulation was significantly higher in ACE-AS-expressing RPAECs. In vivo experiments demonstrated a prolonged expression of ACE-AS transcripts in cardiovascularly relevant tissues of rats. This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. These observations demonstrate that delivery of ACE-AS by retroviral vector results in a permanent inhibition of ACE and a long-term reduction in high blood pressure in the spontaneously hypertensive rat.

Angiotensin II↗
PubMed1999

Role of phosphatidylinositol 3-kinase in angiotensin II regulation of norepinephrine neuromodulation in brain neurons of the spontaneously hypertensive rat.

Chronic stimulation of norepinephrine (NE) neuromodulation by angiotensin II (Ang II) involves activation of the Ras-Raf-MAP kinase signal transduction pathway in Wistar Kyoto (WKY) rat brain neurons. This pathway is only partially responsible for this heightened action of Ang II in the spontaneously hypertensive rat (SHR) brain neurons. In this study, we demonstrate that the MAP kinase-independent signaling pathway in the SHR neuron involves activation of PI3-kinase and protein kinase B (PKB/Akt). Ang II stimulated PI3-kinase activity in both WKY and SHR brain neurons and was accompanied by its translocation from the cytoplasmic to the nuclear compartment. Although the magnitude of stimulation by Ang II was comparable, the stimulation was more persistent in the SHR neuron compared with the WKY rat neuron. Inhibition of PI3-kinase had no significant effect in the WKY rat neuron. However, it caused a 40-50% attenuation of the Ang II-induced increase in norepinephrine transporter (NET) and tyrosine hydroxylase (TH) mRNAs and [3H]-NE uptake in the SHR neuron. In contrast, inhibition of MAP kinase completely attenuated Ang II stimulation of NET and TH mRNA levels in the WKY rat neuron, whereas it caused only a 45% decrease in the SHR neuron. However, an additive attenuation was observed when both kinases of the SHR neurons were inhibited. Ang II also stimulated PKB/Akt activity in both WKY and SHR neurons. This stimulation was 30% higher and lasted longer in the SHR neuron compared with the WKY rat neuron. In conclusion, these observations demonstrate an exclusive involvement of PI3-kinase-PKB-dependent signaling pathway in a heightened NE neuromodulatory action of Ang II in the SHR neuron. Thus, this study offers an excellent potential for the development of new therapies for the treatment of centrally mediated hypertension.

Angiotensin II↗
PubMed1999

Angiotensin II type 1 receptor-modulated signaling pathways in neurons.

Mammalian brain contains high densities of angiotensin II (Ang II) type 1 (AT1) receptors, localized mainly to specific nuclei within the hypothalamus and brainstem regions. Neuronal AT1 receptors within these areas mediate the stimulatory actions of central Ang II on blood pressure, water and sodium intake, and vasopressin secretion, effects that involve the modulation of brain noradrenergic pathways. This review focuses on the intracellular events that mediate the functional effects of Ang II in neurons, via AT1 receptors. The signaling pathways involved in short-term changes in neuronal activity, membrane ionic currents, norepinephrine (NE) release, and longer-term neuromodulatory actions of Ang II are discussed. It will be apparent from this discussion that the signaling pathways involved in these events are often distinct.

Angiotensin II↗
PubMed1999

Regulation of brain glucose transporters by glucose and oxygen deprivation.

Brain cells are dependent on glucose and oxygen for energy. We investigated the effects of hypoxia, glucose deprivation, and hypoxia plus glucose deprivation on mRNA and protein levels of glucose transporter (GLUT1) and GLUT3 and 2-deoxyglucose (2-DG) uptake in primary cultures of rat neurons and astroglia. Hypoxia for 24 hours did not significantly affect cell viability but increased neuronal GLUT1 and GLUT3 mRNA up to 40-fold and fivefold, respectively, above control levels. Similar changes in GLUT1 mRNA were measured in glia. The effects of hypoxia on GLUT1 and GLUT3 mRNA were reversible. The increase in GLUT1 mRNA could be detected within 20 minutes of hypoxia and was blocked by actinomycin D. Nuclear runoff transcription assays showed that hypoxia did not alter the transcription rate of GLUT1. However, hypoxia enhanced the stability of GLUT1 mRNA in neurons (half-life [t(l/2)] > 12 hours) compared with normoxic conditions (t(1/2) approximately 10.4 hours), suggesting the existence of a posttranscriptional mechanism for the regulation of GLUT1 transcript levels. Twenty-four hours of normoxia and 1.0 mmol/L glucose increased neuronal GLUT1 mRNA less than threefold above basal, but 24 hours of glucose and oxygen deprivation increased GLUT1 over 111-fold above basal. Induction of neuronal GLUT1 mRNA was temporally associated with increased levels of GLUT1 protein and with stimulation of intracellular 2-DG accumulation. We conclude that hypoxia reversibly increases the transcript levels of GLUT1 and GLUT3 in rat brain cells and stimulates GLUT1 transcript levels by posttranscriptional mechanisms. Although glucose deprivation alone produces minimal effects on GLUT mRNA levels, hypoxia plus glucose deprivation synergize to markedly increase GLUT gene expression.

Animals↗
PubMed1999

Reversal of hypertension by angiotensin II type 1 receptor antisense gene therapy in the adult SHR.

Pharmacological blockade of the renin-angiotensin system in both hypertensive patients and animal models such as the spontaneously hypertensive rat (SHR) effectively reduces blood pressure (BP). Recent studies have established that virally mediated delivery (vector LNSV) of antisense to the angiotensin II type 1 receptor (LNSV-AT1R-AS) will attenuate or abolish the development of hypertension in the SHR. However, the effectiveness of this gene therapy approach to reduce high BP once it is established in the adult has not been ascertained. In this study, we investigated the hypothesis that viral delivery of AT1R-AS into the adult SHR will reduce BP and reverse the vascular reactivity associated with the hypertension. Intracardiac injection of virus particles containing LNSV-AT1R-AS into adult SHR resulted in a 30- to 60-mmHg reduction in BP that was maintained for up to 36 days compared with SHR treated with virus alone (LNSV without antisense). Measurement of renal resistance arteriolar reactivity demonstrated a leftward shift in the KCl and phenylephrine concentration-response relationships and an impaired endothelium-dependent relaxation to ACh in LNSV-treated SHR compared with control Wistar-Kyoto rats. These vascular alterations were reversed in the LNSV-AT1R-AS-treated SHR. Collectively, these data demonstrate that virally mediated gene delivery of AT1R-AS can effectively reduce BP and reverse renovascular pathophysiology associated with the hypertensive state when administered to the adult SHR.

Animals↗
PubMed1999

Increased expression of calreticulin is linked to ANG IV-mediated activation of lung endothelial NOS.

This study demonstrates that ANG IV-induced activation of lung endothelial cell nitric oxide synthase (ecNOS) is mediated through mobilization of Ca(2+) concentration and by increased expression and release of the Ca(2+) binding protein calreticulin in pulmonary artery endothelial cells (PAEC). In Ca(2+)-free medium and in the presence of the ANG II AT(1) and AT(2) receptor antagonists losartan and PD-123319 (1 microM each), respectively, ANG IV (5, 50, and 500 nM) significantly increased intracellular Ca(2+) release in PAEC (P < 0.05 for all concentrations). In contrast, ANG IV-mediated activation of ecNOS was abolished by the intracellular Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM. ANG IV stimulation resulted in significantly increased expression of calreticulin in cells as well as release of calreticulin into the medium of cells as early as 2 h after ANG IV stimulation (P < 0.05). Catalytic activity of purified ecNOS in the absence of calmodulin was increased in a concentration-dependent fashion by calreticulin. Immunocoprecipitation studies revealed that ecNOS and calreticulin were coprecipitated in ANG IV-stimulated PAEC. These results demonstrate that ANG IV-mediated activation of ecNOS is regulated by intracellular Ca(2+) mobilization and by increased expression of calreticulin, which appears to involve interaction of ecNOS and calreticulin proteins in PAEC.

Angiotensin II↗
PubMed1999

Angiotensin II type 1 receptor antisense gene therapy prevents altered renal vascular calcium homeostasis in hypertension.

Intracellular Ca2+ ([Ca2+]i) homeostasis regulates vascular smooth muscle tone, and alteration in [Ca2+]i handling is associated with the development and establishment of hypertension. We have previously established in the spontaneously hypertensive rat (SHR) that virally mediated delivery of angiotensin II type 1 receptor antisense (AT1R-AS) prevents the development of high blood pressure and some pathophysiology associated with hypertension for 120 days. In light of this, our objectives in this study were to determine whether AT1R-AS gene therapy (1) could have a longer duration in the prevention of hypertension and (2) would attenuate the alterations in renal vascular Ca2+ homeostasis and therefore vasoconstriction, characteristics of hypertension. Intracardiac delivery of AT1R-AS in neonates prevented the development of hypertension in SHR for at least 210 days. At this time, untreated SHR renal resistance arterioles showed a significantly enhanced contractile response to KCl and angiotensin II (Ang II) when compared with normotensive Wistar-Kyoto rats. In addition, L-type Ca2+ current density and Ang II-dependent increases in [Ca2+]i were significantly increased in cells dissociated from renal resistance arterioles of the untreated SHR. AT1R-AS treatment prevented all of the above vascular alterations associated with the hypertensive state in SHR. Finally, Western blot analysis of L-type Ca2+ channel (alpha1C) protein levels in renal resistance arterioles of untreated SHR showed no significant difference when compared with control. These results are novel and demonstrate that viral-mediated delivery of AT1R-AS not only attenuates the development of hypertension on a long-term basis but prevents changes in renal vascular Ca2+ homeostasis associated with the disease.

Angiotensin II↗
PubMed1999

The potential use of gene therapy in the control of hypertension.

Essential hypertension is a progressive disease characterized by chronically elevated blood pressure of unknown etiology. Because antihypertensive treatments cannot be aimed at a specific cause, traditional pharmacological therapy targets elements such as the renin-angiotensin system (RAS), that are known to be directly involved in the control of blood pressure. Current pharmacological treatment effectively lowers blood pressure but may not prevent end organ damage or propensity for other disease or death and has other significant disadvantages such as unpleasant side effects. The development of gene therapy directed at RAS is a significant advance toward managing high blood pressure associated with hypertension and reversing its associated pathophysiology. It was our intent to provide "proof of principle" for gene therapy by the interruption of RAS at the genetic level in order to achieve long-term control of hypertension and reverse the pathophysiology associated with this disease. In general, delivery of antisense to the angiotensin II type 1 receptor (AT1R) successfully prevented blood pressure elevation, alterations in calcium homeostasis, ion channel activity and cardiovascular ultrastructure changes for up to 18 months in spontaneously hypertensive rats (SHRs) when compared to control rats. These results demonstrate that antisense gene delivery is useful in the long-term treatment of hypertension in animal models.

Journal Article↗
PubMed1998

Regulation of angiotensin II-induced neuromodulation by MARCKS in brain neurons.

Angiotensin II (Ang II) exerts chronic stimulatory actions on tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DbetaH), and the norepinephrine transporter (NET), in part, by influencing the transcription of their genes. These neuromodulatory actions of Ang II involve Ras-Raf-MAP kinase signal transduction pathways (Lu, D., H. Yang, and M.K. Raizada. 1997. J. Cell Biol. 135:1609-1617). In this study, we present evidence to demonstrate participation of another signaling pathway in these neuronal actions of Ang II. It involves activation of protein kinase C (PKC)beta subtype and phosphorylation and redistribution of myristoylated alanine-rich C kinase substrate (MARCKS) in neurites. Ang II caused a dramatic redistribution of MARCKS from neuronal varicosities to neurites. This was accompanied by a time-dependent stimulation of its phosphorylation, that was mediated by the angiotensin type 1 receptor subtype (AT1). Incubation of neurons with PKCbeta subtype specific antisense oligonucleotide (AON) significantly attenuated both redistribution and phosphorylation of MARCKS. Furthermore, depletion of MARCKS by MARCKS-AON treatment of neurons resulted in a significant decrease in Ang II-stimulated accumulation of TH and DbetaH immunoreactivities and [3H]NE uptake activity in synaptosomes. In contrast, mRNA levels of TH, DbetaH, and NET were not influenced by MARKS-AON treatment. MARCKS pep148-165, which contains PKC phosphorylation sites, inhibited Ang II stimulation of MARCKS phosphorylation and reduced the amount of TH, DbetaH, and [3H]NE uptake in neuronal synaptosomes. These observations demonstrate that phosphorylation of MARCKS by PKCbeta and its redistribution from varicosities to neurites is important in Ang II-induced synaptic accumulation of TH, DbetaH, and NE. They suggest that a coordinated stimulation of transcription of TH, DbetaH, and NET, mediated by Ras-Raf-MAP kinase followed by their transport mediated by PKCbeta-MARCKS pathway are key in persistent stimulation of Ang II's neuromodulatory actions.

Amino Acid Sequence↗
PubMed1998

Prevention of renovascular and cardiac pathophysiological changes in hypertension by angiotensin II type 1 receptor antisense gene therapy.

Hypertension produces pathophysiological changes that are often responsible for the mortality associated with the disease. However, it is unclear whether normalizing blood pressure (BP) with conventional therapy is effective in reversing the pathophysiological damage. The duration and initiation of treatment, site of administration, and agent used all appear to influence the reversal of the pathophysiological alterations associated with hypertension. We have previously established that retrovirally mediated delivery of angiotensin II type 1 receptor antisense (AT1R-AS) attenuates the development of high BP in the spontaneously hypertensive (SH) rat model of human essential hypertension. Our objective was to determine whether this attenuation of high BP is associated with prevention of other pathophysiological changes induced by the hypertensive state. Intracardiac delivery of AT1R-AS in neonates prevented the development of hypertension in SH rats for at least 120 days. Contractile experiments demonstrated an impaired endothelium-dependent vascular relaxation (acetylcholine) and an enhanced contractile response to vasoactive agents (phenylephrine and KCl) in the SH rat renal vasculature. In addition, the voltage-dependent K+ current density, which is believed to contribute to smooth muscle resting membrane potential and basal tone, was decreased in renal resistance artery cells of the SH rat. AT1R-AS treatment prevented each of these renal vascular alterations. Finally, AT1R-AS delivery prevented the pathological alterations observed in the SH rat myocardium, including left ventricular hypertrophy, multifocal fibrosis, and perivascular fibrosis. These observations demonstrate that viral-mediated delivery of AT1R-AS attenuates the development of hypertension on a long term basis, and this is associated with prevention of pathophysiological changes in SH rats.

Acetylcholine↗
PubMed1998

Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling.

The objective of this review is to examine the role of neuronal angiotensin II (Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have been identified in cardiovascularly relevant areas of the brain: the AT1 and the AT2. We have utilized neurons in culture to study the signaling mechanisms of AT1 and AT2 receptors. Neuronal AT1 receptors are involved in norepinephrine (NE) neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE neuromodulation involves AT1 receptor-mediated, losartan-dependent, rapid NE release, inhibition of K+ channels and stimulation of Ca2+ channels. AT1 receptor-mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an increase in NE transporter, tyrosine hydroxylase and dopamine beta-hydroxylase mRNA transcription. Neuronal AT2 receptors signal via a Gi protein and are coupled to activation of PP2A and PLA2 and stimulation of K+ channels. Finally, putative cross-talk pathways between AT1 and AT2 receptors will be discussed.

Animals↗