The activity of receptor guanylyl cyclases in tissues of rats with neonatal streptozotocin diabetus mellitus and the influence of intranasal administration of insulin and serotonin

Functional activity of hormanal signaling systems and their sensitivity to regulatory actions of hormones in diabetes mellitus (DM) and its complications are altered. The activity of receptor forms of guanylyl cyclases (rGC) sensitive to natriuretic peptides, ANP and CNP, in tissues of female rats with 240-days neonatal streptozotocin DM and the influence of intranasal administration of insulin and serotonin (6 weeks, daily dose is 0.48 IU of insulin or 20 microg of serotonin to rat) on this activity were studied. In diabetic animals, the increase of the basal activity of rGC in the myocardium and its decrease in the uterus and ovaries were found, whereas the brain showed no differences from control animals. The treatment of diabetic rats with insulin led to a decrease in the basal activity of rGC in the myocardium and to its restoration to normal level in the ovaries. Serotonin treatment induced a less pronounced compared with insulin decrease in the basal activity of the enzyme in the myocardium and also a slight increase the activity in the brain. In the myocardium of diabetic rats, the weakening of GC stimulating effect of ANP and, on the contrary, the strengthening of CNP effect were observed. In the ovaries, GC stimulating effect of CNP and, to a lesser degree, the corresponding effect of ANP were decreased. In the uterus and the brain, the sensitivity of rGC to hormones was practically not changed. The administration of insulin to diabetic rats induced an increase in GC effect of ANP in the myocardium to its values in control animals and a decrease in CNP effect as well as in partially restored GC effect of CNP in the ovaries. Serotonin treatment led to some increase in the effects of natriuretic peptides in the brain of both control and diabetic animals. Summing up, in neonatal model of type 2 DM in the myocardium and the tissues of reproductive system of rats the functioning of natriuretic peptide-sensitive rGC is altered in the myocardium and the tissues of reproductive system of model rats with neonatal type 2 DM. Treatment of animals with insulin substantially restores rGC activity while intranasal administration of serotonin has little effect.     

Regulatory properties of adenylyl and guanylyl cyclase in human spermatozoa

Completion of maturation of spermatozoa (capacitation) occurs in the female genital tract. As a result, spermatozoa acquire the high motility and the capability for acrosomal reaction, which determines their fertility. There are evidences that adenylyl cyclase and guanylyl cyclase signaling systems detected in human and mammalian spermatozoa are involved in these processes. The goal of the present study was characterization of these systems in human ejaculate spermatozoa (ES) and in human fertile spermatozoa (FS) isolated by a density gradient centrifugation. In FS homogenate the basal activity of the adenylyl cyclase (AC) was significantly higher as compared with ES (47 ± 5 vs. 28 ± 3 pmol cAMP/min per mg of protein). At the same time, the AC stimulatory effects of non-hormonal activators of soluble and membrane-bound forms of AC (NaHCO₃, Mn²⁺, forskolin, and non-hydrolyzable GTP analogue—GppNHp) in FS were lower as compared with ES. Isoproterenol, serotonin, PACAP-38, and, to the lesser extent, noradrenalin and adenosine stimulated the AC activity in ES. Among hormones inhibiting AC, only adenosine decreased the enzyme activity. At the same time, in FS the inhibitory AC effects of adenosine, noradrenalin, and serotonin were markedly expressed, and the stimulatory effects of these hormones were decreased or absent. The basal activity of guanylyl cyclase (GC) in ES and FS homogenates was 27 ± 3 and 21 ± 2 pmol cGMP for 1 min per 1 mg protein, respectively, and was significantly increased in the presence of 10 mM Mn²⁺. The stimulatory GC effects of natriuretic peptides—ANP and CNP, activators of receptor forms of GC, was significantly higher in ES than in FS, and the effect of ANP was more pronounced as compared with CNP. The data indicate the multiplicity of cAMP- and cGMP-dependent signaling cascades regulating fertility of human spermatozoa. We found that the sensitivity of AC and GC to hormones in the common pool of ES and in the fraction of highly motile FS isolated by centrifugation was essentially different, which is to be considered when using FS for accessory reproductive technology.     

Effect of intranasal insulin and serotonin on functional activity of the adenylyl cyclase system in myocardium, ovary, and uterus of rats with prolonged neonatal model of diabetes mellitus

The disturbances in hormonal signaling systems, adenylyl cyclase system (ACS) in particular, occur at the early stages of diabetes mellitus (DM) being one of the key causes of its complications. Since the correlation between the severity of DM and severity of disturbances in ACS is established, studying ACS activity can be used for monitoring DM and its complications and evaluating the effectiveness of their treatment. Recently, intranasal insulin (I-I) and the drugs increasing brain serotonin level, thus effectively restoring CNS functions, have begun to be used for the treatment of type 2 DM. However, the mechanisms of their action on peripheral tissues and organs at DM are not understood. The aim of this work was to study an influence of I-I and intranasal serotonin (I-S) on the functional activity of ACS in myocardium, ovary and uterus of rats with a neonatal model of type 2 DM. In the tissues of diabetic rats the changes in the regulation of adenylate cyclase (AC) by guanine nucleotides and hormones acting on enzyme in stimulatory and inhibitory manner were found, and these changes were characterized by receptor and tissue specificity. In diabetic rats I-I restored AC-stimulating effects of isoproterenol in the myocardium, that of guanine nucleotides and gonadotropin in the ovaries and relaxin in the uterus, as well as AC-inhibiting effects of somatostatin in all tissues and norepinephrine in the myocardium. Treatment with I-S led to a partial recovery of AC-inhibiting effect of norepinephrine in the diabetic myocardium, but did not affect the regulation of AC by other hormones. These data indicate that I-I normalizes the functional activity of ACS in the myocardium and in the tissues of reproductive system of female rats with neonatal DM, whereas the effect of I-S on ACS in the studied tissues is less pronounced. These results should be considered for the design and optimization of the strategy of I-I and I-S application for the treatment of DM and its complications.     

Natriuretic peptides--their receptors and role in cardiovascular system

Natriuretic peptides belong to a family of small proteins that play a major role in modulation of natriuresis, diuresis and vasodilatation. They counteract the activity of renin-angiotensin-aldosterone system. They are also involved in the regulation of homeostasis, fat metabolism and long bone growth. Natriuretic peptides family in mammals consists of three main members: atrial natriuretic peptide (ANP) - secreted by the atrial myocardium; brain natriuretic peptide (BNP)--secreted mainly by the ventricular myocardium, and C-type natriuretic peptide (CNP)--produced and released by endothelial cells. Secretion of these peptides is stimulated by atrial and ventricular distension, increased blood pressure, hypoxia or renal dysfunction. Natriuretic peptides play their roles via interactions with NPR-A and NPR-B receptors which are transmembrane guanylyl cyclases. Their local concentrations, regulated by internalization and degradation, are mediated by the NPR-C receptor and by neutral endopeptidase. The paper presents the current knowledge of structure and biological function of natriuretic peptides.     

C-type natriuretic peptide and guanylyl cyclase B receptor

Guanylyl cyclases (GC) are widely distributed enzymes that signal via the production of the second messenger cGMP. The particulate guanylyl cyclases share a similar topology: an extracellular ligand binding domain and intracellular regulatory kinase-homology and cyclase catalytic domains. The natriuretic peptide receptors GC-A and -B mediate the effects of a family of peptides, atrial, B- and C-type natriuretic peptide (ANP, BNP and CNP, respectively), with natriuretic, diuretic and vasorelaxant properties. ANP and BNP, through the activation of GC-A, act as endocrine hormones to regulate blood pressure and volume, and inhibit cardiac hypertrophy. CNP, on the other hand, acts in an autocrine/paracrine fashion to induce vasorelaxation and vascular remodeling, and to regulate bone growth through its cognate receptor GC-B. GC-B, like GC-A, is phosphorylated in the basal state, and undergoes both homologous and heterologous desensitization, reflected by dephosphorylation of specific sites in the kinase-homology domain. This review will examine the structure and function of GC-B, and summarize the physiological processes in which this receptor is thought to participate.     

Natriuretic peptides inhibit adenylyl cyclase activity in dispersed eel gill cells

The effect of natriuretic peptides on forskolin-evoked adenylyl cyclase activity was investigated in dispersed gill cells from the Australian short-finned eel (Anguilla australis). Molecular cloning techniques were employed to identify the putative G-protein-activating motif within the intracellular domain of the eel natriuretic peptide C receptor. Eel ANP, eel CNP and the NPR-C-specific C-ANF inhibited the forskolin-stimulated production of cyclic AMP. This effect was abolished by pretreatment of cells with pertussis toxin. Eel VNP was without effect on adenylyl cyclase activity. PCR and molecular cloning indicated that the intracellular domain of A. australis NPR-C has the same amino acid sequence as Anguilla japonica. Alignment of these sequences with Rattus norvegicus NPR-C indicated conservation of the putative G-protein-activating motif BB...BBXXB (B=basic, X=nonbasic residues). These data suggest that branchially-expressed NPR-C may play a physiological role additional to that of ligand clearance.Abbreviations ANP atrial natriuretic peptide - CNP C-type natriuretic peptide - cAMP cyclic adenosine monophosphate - cGMP cyclic guanosine monophosphate - eANP-NH₂ amidated form of eel ANP - GC guanylyl cyclase - G_i inhibitory G-protein - IBMX isobutylmethylxanthine - NP natriuretic peptide - NPR natriuretic peptide receptor - PCR polymerase chain reaction - PTX pertussis toxin - VNP ventricular natriuretic peptideCommunicated by I.D. Hume     

Inhibitory effect of Ca(2+) on ATP-mediated stimulation of NPR-A-coupled guanylyl cyclase in renal glomeruli from spontaneously hypertensive and normotensive rats.

Atrial natriuretic peptide (ANP) regulates blood pressure mainly through the occupation of the guanylyl cyclase-coupled receptor NPR-A, which requires ATP interaction for maximal activation. This study investigates the effect of extracellular Ca(2+) on ATP-mediated regulation of NPR-A-coupled guanylyl cyclase activity in glomerular membranes from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). ATP induced a significant increase in basal and ANP(1-28)-stimulated guanylyl cyclase activity that was greater in SHR than in WKY. Extracellular Ca(2+) inhibited ATP-stimulated guanylyl cyclase activity in a concentration-dependent manner, but did not modify basal and ANP(1-28)-stimulated guanylyl cyclase activity. In the presence of ATP, NPR-A showed higher affinity for ANP(1-28) and lower Bmax. Ca(2+) did not modify NPR-A-ANP(1-28) binding properties. The different effects of extracellular Ca(2+) on ANP(1-28)- or ATP-mediated guanylyl cyclase activation suggest that these events are differentially regulated. Addition of extracellular Ca(2+) induced similar effects in hypertensive and normotensive rats, suggesting that it is not responsible for the elevated cGMP production observed in SHR.     

Cardiac and intestinal natriuretic peptides: insights from genetically modified mice

Since the original discovery of atrial natriuretic peptide (ANP) more than two decades ago, the application of gene targeting technology in mice has provided new insights into the diverse physiological functions of natriuretic peptides and their membrane guanylyl cyclase (GC) receptors. Disruption of the genes for ANP or its receptor, GC-A, demonstrated that this system is not only essential for the maintenance of normal blood pressure and volume, but in addition exerts local antihypertrophic effects in the heart. Disruption of the genes encoding B-type (BNP) or C-type natriuretic peptides (CNP) or the CNP-receptor, GC-B, demonstrated that these "natriuretic" peptides are in fact unlikely to physiologically regulate renal sodium excretion but instead exert important autocrine/paracrine cGMP-mediated effects on cellular proliferation and differentiation in various tissues. Notably, the intestinal peptide uroguanylin, which activates a third guanylyl cyclase receptor (GC-C), exerts diuretic/natriuretic activity and links the intestine and kidney in an endocrine way to modulate renal function in response to oral salt load. Reviewed here is the physiology of cardiac and intestinal natriuretic peptides and their guanylyl cyclase receptors, with special focus on the information gained to date from genetically modified mice.     

Regulation of C-type natriuretic peptide expression

C-type natriuretic peptide (CNP) is a member of the small family of natriuretic peptides that also includes atrial natriuretic peptide (ANP) and brain, or B-type natriuretic peptide (BNP). Unlike them, it performs its major functions in an autocrine or paracrine manner. Those functions, mediated through binding to the membrane guanylyl cyclase natriuretic peptide receptor B (NPR-B), or by signaling through the non-enzyme natriuretic peptide receptor C (NPR-C), include the regulation of endochondral ossification, reproduction, nervous system development, and the maintenance of cardiovascular health. To date, the regulation of CNP gene expression has not received the attention that has been paid to regulation of the ANP and BNP genes. CNP expression in vitro is regulated by TGF-β and receptor tyrosine kinase growth factors in a cell/tissue-specific and sometimes species-specific manner. Expression of CNP in vivo is altered in diseased organs and tissues, including atherosclerotic vessels, and the myocardium of failing hearts. Analysis of the human CNP gene has led to the identification of a number of regulatory sites in the proximal promoter, including a GC-rich region approximately 50 base pairs downstream of the Tata box, and shown to be a binding site for several putative regulatory proteins, including transforming growth factor clone 22 domain 1 (TSC22D1) and a serine threonine kinase (STK16). The purpose of this review is to summarize the current literature on the regulation of CNP expression, emphasizing in particular the putative regulatory elements in the CNP gene and the potential DNA-binding proteins that associate with them.     

Cardiac natriuretic peptides and pancreatic islet blood flow in anesthetized rats.

The aim of the study was to evaluate effects of cardiac natriuretic peptides on splanchnic circulation, especially to the pancreatic islets. Pentobarbital-anesthetized rats were infused intravenously (0.01 ml/min for 20 min) with saline, atrial natriuretic peptide (ANP; 0.25 or 0.5 microg/kg BW/min), brain natriuretic peptide (BNP; 0.5 microg/kg BW/min) or C-type natriuretic peptide (CNP; 0.5 or 2.0 microg/kg BW/min). Splanchnic blood perfusion was then measured with a microsphere technique. Mean arterial blood pressure was decreased by ANP and BNP, but not by CNP. The animals given the highest dose of ANP became markedly hypoglycemic, whilst no such effects were seen in any of the other groups of animals. Total pancreatic blood flow was decreased by the highest dose of CNP, whereas no change was seen after administration of the other peptides. Islet blood flow was increased by the highest dose of ANP. Neither BNP nor CNP affected islet blood flow. None of the natriuretic peptides influenced duodenal, colonic or arterial hepatic blood flow. It is concluded that cardiac natriuretic peptides exert only minor effects on splanchnic blood perfusion in anesthetized rats. However, islet blood perfusion may be influenced by ANP.     

Extracellular domain-IgG fusion proteins for three human natriuretic peptide receptors. Hormone pharmacology and application to solid phase screening of synthetic peptide antisera.

The natriuretic peptide receptors (NPRs) are a family of three cell surface glycoproteins, each with a single transmembrane domain. Two of these receptors, designated NPR-A and NPR-B, are membrane guanylyl cyclases that synthesize cGMP in response to hormone stimulation. The third receptor, NPR-C, has been reported to function in the metabolic clearance of ligand and in guanylyl cyclase-independent signal transduction. We engineered three chimeric proteins consisting of the natriuretic peptide receptor extracellular domains fused to the Fc portion of human IgG-gamma 1. These molecules provide material for detailed studies of the human receptor's extracellular domain structure and interaction with the three human natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and type-C natriuretic peptide (CNP). The homodimeric fusion proteins, designated A-IgG, B-IgG, and C-IgG, were secreted from Chinese hamster ovary cells and purified by protein-A affinity chromatography. We present here the primary characterization of these fusion proteins as represented by the intrinsic hormone affinities measured by saturation binding and competition assays. The dissociation constant of 125I-ANP for A-IgG was 1.6 pM and for C-IgG, 1.2 pM. The dissociation constant of 125I-Y0-CNP (CNP with addition of tyrosine at the amino terminus) for B-IgG was 23 pM. The rank order of potency in competitive binding for A-IgG was ANP greater than BNP much greater than CNP, whereas for B-IgG the ranking was CNP much greater than ANP greater than BNP. For C-IgG, we observed ANP greater than CNP greater than or equal to BNP. These data demonstrate that the receptor-IgG fusion proteins discriminate among the natriuretic peptides in the same manner as the native receptors and provide a basis for future structural studies with these molecules. The purified fusion proteins have a variety of potential applications, one of which we illustrate by a solid phase screening assay in which rabbit sera from a series of synthetic-peptide immunizations were titered for receptor reactivity and selectivity.     

Atrial natriuretic peptide provokes a dramatic increase in cyclic GMP formation and markedly inhibits muscarinic-stimulated Ca2+ mobilisation in SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells

We investigated the effects of cGMP-elevating agents, including atrial natriuretic peptide (ANP), C-type natriuretic peptide (CNP) and sodium nitroprusside (SNP), on cGMP accumulation and on carbachol (CCh)-stimulated intracellular calcium ([Ca2+]i) mobilisation in SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells and in primary cultured cat iris sphincter smooth muscle (CISM) cells. The stimulatory effects of the natriuretic peptides on cGMP production correlated well with their inhibitory effects on CCh-induced [Ca+1]i mobilisation, and these effects were significantly more pronounced in the SV-CISM-2 cells than in the CISM cells. Thus, ANP (1 microM) increased cGMP production in the SV-CISM-2 cells and CISM cells by 487- and 1.7-fold, respectively, and inhibited CCh-induced [Ca2+]i mobilisation by 95 and 3%, respectively. In the SV-CISM-2 cells, ANP and CNP dose dependently inhibited CCh-induced [Ca2+]i mobilisation with IC50 values of 156 and 412 nM, respectively, and dose dependently stimulated cGMP formation with EC50 values of 24 and 88 nM, respectively, suggesting that the inhibitory actions of the peptides are mediated through cGMP. Both ANP and CNP stimulated cGMP accumulation in a time-dependent manner. The potency of the cGMP-elevating agents were in the following order: ANP>CNP>SNP; these agents had no effect on cAMP accumulation. The inhibitory effects of the natriuretic peptides were mimicked by 8-Br-cGMP, a selective activator of cGMP-dependent protein kinase. LY83583, a soluble guanylyl cyclase inhibitor, significantly inhibited SNP-induced cGMP formation but had no effect on those of ANP and CNP. The basal activities of the guanylyl cyclase and the dissociation constant (Kd) and total receptor density (Bmax) values of the natriuretic peptide receptor for [125I]ANP binding were not significantly different between the two cell types. The cGMP system, as with the cAMP system, has a major inhibitory influence on the muscarinic responses in the iris sphincter smooth muscle cells, and SV-CISM-2 cells can serve as an excellent model for investigating the cross talk between cGMP and the Ca2+ signalling system.     

Functional activity of adenylyl and guanylyl cyclases in human spermatozoa with different motility

The most important functional characteristic of ejaculated spermatozoa is their ability to engage in directed sustained movement, which to a large extent determines their fertility. It is assumed that enzymes with cyclase activity—adenylyl cyclase (AC) and guanylyl cyclase (GC)—soluble and membrane-bound forms of which are found in human and mammalian sperm, play the key role in regulation of motility. However, the functional activity of the cyclases in ejaculated spermatozoa with different motilities and their contribution to the regulation of this process are virtually unexplored. The goal of this work was to determine the functional characteristics of AC and GC in ejaculates of human spermatozoa with different contents of motile forms and the study of regulation of these enzymes by hormones and nonhormonal agents. We found differences in the activity and regulatory properties of AC and GC in ejaculates differing in motile forms of spermatozoa. The basal AC activity and its sensitivity to bicarbonate anions and manganese cations, activators of cytosolic AC (cAC), were increased in ejaculates with a high proportion of motile spermatozoa. At the same time, the AC effects of forskolin, GppNHp, and adrenergic receptor agonists acting via membrane-bound AC (mAC) in this case were significantly reduced. Cytosolic GC in the ejaculates with a high proportion of motile spermatozoa was more sensitive to manganese cations, but the basal activity of GC was altered slightly. An increase in the content of motile spermatozoa in ejaculate led to a decrease in the sensitivity of CNP to receptor GC, while the sensitivity to ANP was maintained, which indicates a change in the pattern of enzyme regulation with natriuretic peptides in favor of ANP, an important regulator of sperm chemotaxis. Thus, we have concluded that the change in proportion of motile spermatozoa in ejaculate induces changes of functional activity and regulatory properties of soluble and membrane-bound forms of AC and GC, which can be used to control the motility, chemotaxis, acrosomal reaction, and other processes determining fertility of male germ cells.     

Altered role of C-type natriuretic peptide-activated pGC-cGMP-PDE3-cAMP signaling in hyperthyroid beating rabbit atria

The role of C-type natriuretic peptide (CNP) in the pathophysiology of atrial function in hyperthyroidism has not been defined. This study was to define the role of CNP-activated particulate (p) guanylyl cyclase (GC)-cGMP-phosphodiesterase (PDE)3 signaling in the regulation of cAMP levels and contractile and secretory functions in the atria from hyperthyroid rabbits. Experiments were performed in perfused beating rabbit atria. CNP was used to activate pGC. In euthyroid atria from sham-treated rabbits, CNP (100 nM) increased cGMP and cAMP efflux by 176.7+/-17.7 and 55.3+/-10.0%, respectively. CNP decreased stroke volume and pulse pressure and ANP release by 51+/-7 and 41+/-2 and 60.4+/-3.2%, respectively. Pretreatment with milrinone blocked the CNP-induced increase of cAMP but without significant changes in decrease of atrial dynamics and ANP release. In hyperthyroid atria, CNP-induced increase of cGMP levels was accentuated, while CNP-induced increase of cAMP was attenuated. The gain of cAMP, i.e., change in cAMP efflux concentration in terms of cGMP was attenuated in the hyperthyroid compared to euthyroid atria. CNP rather increased atrial dynamics in hyperthyroid atria instead of decrease. CNP-induced decrease in atrial ANP release was attenuated. Pretreatment with milrinone blocked the CNP-induced increase of cAMP levels concomitantly with a decrease of atrial dynamics. The present study demonstrates that altered role of CNP-activated pGC-cGMP-PDE3-cAMP signaling is involved in the pathophysiology of hyperthyroid heart.     

C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain

Two types of natriuretic peptide, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), very similar to each other in structure and in pharmacological effect, are known to be present in mammalian heart and brain. In our present survey for unidentified peptides in porcine brain extracts, we found a new peptide of 22 amino acid residues, eliciting a potent relaxant activity on chick rectum. The amino acid sequence determined for the peptide shows remarkable similarity to those of ANP and BNP, especially in the 17-residue sequences flanked by two cysteine residues. The peptide shows a pharmacological spectrum similar to ANP and BNP. Thus, the peptide was designated "C-type natriuretic peptide (CNP)", the third member to join the natriuretic peptide family. In contrast to ANP and BNP, CNP terminates in the second cysteine residue, lacking a further C-terminal extension.     

Natriuretic peptides: a new lipolytic pathway in human adipocytes.

Atrial natriuretic peptide (ANP) receptors have been described on rodent adipocytes and expression of their mRNA is found in human adipose tissue. However, no biological effects associated with the stimulation of these receptors have been reported in this tissue. A putative lipolytic effect of natriuretic peptides was investigated in human adipose tissue. On isolated fat cells, ANP and brain natriuretic peptide (BNP) stimulated lipolysis as much as isoproterenol, a nonselective beta-adrenergic receptor agonist, whereas C-type natriuretic peptide (CNP) had the lowest lipolytic effect. In situ microdialysis experiments confirmed the potent lipolytic effect of ANP in abdominal s.c. adipose tissue of healthy subjects. A high level of ANP binding sites was identified in human adipocytes. The potency order defined in lipolysis (ANP > BNP > CNP) and the ANP-induced cGMP production sustained the presence of type A natriuretic peptide receptor in human fat cells. Activation or inhibition of cGMP-inhibited phosphodiesterase (PDE-3B) (using insulin and OPC 3911, respectively) did not modify ANP-induced lipolysis whereas the isoproterenol effect was decreased or increased. Moreover, inhibition of adenylyl cyclase activity (using a mixture of alpha(2)-adrenergic and adenosine A1 agonists receptors) did not change ANP- but suppressed isoproterenol-induced lipolysis. The noninvolvement of the PDE-3B was finally confirmed by measuring its activity under ANP stimulation. Thus, we demonstrate that natriuretic peptides are a new pathway controlling human adipose tissue lipolysis operating via a cGMP-dependent pathway that does not involve PDE-3B inhibition and cAMP production.     

Effect of brain serotonin on the arterial pressure and plasma renin in normal and hypertensive rats]

The effects of changes in brain serotonin content after injections of p-chlorophenylalanine (p-CPA), L-5-hydroxytryptophan (L-5HTP) and 5-6-dihydroxytryptamine (5-6DHT) on the mean arterial pressure (MAP), plasma renin activity (PRA) and peripheral levels of atrial natriuretic peptide (ANP) have been studied in normal and hypertensive (2K:1C model) male Wistar rats. The p-CPA (250 mg/kg) and L-5HTP (200 mg/kg) were injected i.p., while 5-6 DHT (15 micrograms/animal in 10 mu/animal vehicle) was injected into lateral brain ventricles. The effects were studied 24 h after the p-CPA injection, 2 h after L-5HTP and 10 or 20 days after 5-6DHT administration. The fall in brain serotonin produced by p-CPA and 5-6DHT did not modify the MAP values in the normal and hypertensive rat model, whereas the increase induced after L-5HTP injection only caused a slight decrease in arterial pressure in normotensive animals. The ARP experimented remarkable rises in the normal and hypertensive rats, these values increasing after L-5HTP and falling after p-CPA and 5-6 DHT injections. Similar changes are detected in the normal group after administration of these substances related to serotoninergic brain activity. The ANP levels rose after renal artery constriction, and they are not affected by the above mentioned substances. Only p-CPA and 5-6DHT reduced a low decrease in the ANP levels 10 days after their administration.(ABSTRACT TRUNCATED AT 250 WORDS)