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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension-induced cardiac hypertrophy is a predictor of the development of cardiac failure. It is unknown which cellular markers contribute to the progression from compensated hypertrophy to failure. In heart failure, several signal transduction defects leading to adenylate cyclase desensitization have been demonstrated, such as beta-adrenoceptor downregulation, increase of inhibitory G protein expression, and uncoupling of beta-adrenergic receptors, presumably by an increase of receptor kinase activity. In hypertensive heart disease, most studies have been performed in rat models of hypertension. As in heart failure, heterologous adenylyl cyclase desensitization occurs. The mechanisms are often different between the heterogeneous models for acquired and genetic hypertension, but Gi protein alterations and beta-adrenoceptor downregulation have been observed frequently. The underlying mechanism for desensitization is most likely a sympathetic activation in established hypertension rather than genetic alterations of signal transduction proteins. The data available suggest that beta-adrenergic desensitization could represent a mechanism that contributes to the progression from hypertrophy to failure. The key question remains whether those hypertensive patients who develop heart failure are more prone to beta-adrenergic desensitization or whether early intervention to reduce sympathetic activity is more effective in preventing or delaying the transition from compensated hypertrophy to overt failure.
Hypertension 1997 Mar
PMID:The cardiac beta-adrenoceptor-mediated signaling pathway and its alterations in hypertensive heart disease. 905 86

Myocardial beta-adrenoceptors and inotropic responses to beta-adrenoceptor agonists were studied in isolated hearts obtained from diabetic and/or hypertensive rats. Streptozotocin diabetic Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), as well as normoglycaemic SHR-stroke prone rats were used. At the age of 18-20 weeks, beta-adrenoceptor density was assessed in the left ventricle and isolated hearts were perfused according to Langendorff. Concentration response curves were made for dobutamine, salbutamol and the adenylyl cyclase activator forskolin. In both SHR and SHR-SP preparations a blunted inotropic response to beta-adrenoceptor stimulation was observed, although responses to forskolin and beta-adrenoceptor density and affinity were not different from those in normotensive hearts. In hearts taken from diabetic WKY and SHR, a decrease in beta-adrenoceptor density was observed, but no parallel blunted response to beta-adrenoceptor stimulation occurred. Moreover, the absolute (and percentual) inotropic responses to dobutamine and forskolin were increased in hearts from diabetic SHR when compared to their hypertensive normoglycaemic controls. These results suggest an impaired activity of the stimulatory G-protein in hearts obtained from hypertensive rats, whereas the simultaneous occurrence of hypertension and diabetes may result in a compensatory increase in activity of the adenylyl cyclase activated pathway.
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PMID:Beta-andrenoceptors in the hearts of diabetic-hypertensive rats: radioligand binding and functional experiments. 911 26

We have recently shown an enhanced expression of inhibitory guanine nucleotide regulatory proteins Gi alpha-2 and Gi alpha-3 and their respective mRNA in hearts from DOCA-salt hypertensive rats. However, it is not known whether these changes are due to the expressed hypertrophy or hypertension. The present studies were therefore undertaken to investigate this possibility. Hypertension in Sprague-Dawley rats was induced by the oral administration of the arginine analog N(omega)-nitro-L-arginine methyl ester (L-NAME) in their drinking tap water for a period of 4 weeks. The control rats were given plain tap water only. L-NAME-treated rats showed an enhanced blood pressure (190 +/- 9.23 mm Hg; n = 20) compared to control rats (121 +/- 6.3 mm Hg; n = 20). However, heart to body weight ratio was not different in the two groups. Guanosine 5'-o-(3-thiotriphosphate) (GTPgammaS) stimulated adenylyl cyclase activity in heart membranes from both groups, but the extent of stimulation was significantly decreased in L-NAME-treated rats. Similarly, stimulations exerted by isoproterenol, glucagon, NaF, and forskolin on adenylyl cyclase were also diminished in L-NAME-treated rats. On the other hand, the inhibitory effect of low concentrations of GTPgammaS on forskolin-stimulated enzyme activity was significantly enhanced. The extent of oxotremorine-mediated inhibition of adenylyl cyclase was unaltered in both control and L-NAME-induced hypertensive rats. The levels of Gi alpha-2 and Gi alpha-3, but not of stimulatory guanine nucleotide regulatory protein Gs alpha, as determined by immunoblotting, were significantly augmented in L-NAME-treated rats. Northern blot studies revealed a significant increase in Gi alpha-2 and Gi alpha-3 mRNA with no changes in Gs alpha mRNA. These results suggest that the altered expression of Gi alpha proteins and adenylyl cyclase activity in L-NAME-treated rats may be attributed to hypertension and not to hypertrophy.
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PMID:Nitric oxide synthase inhibition by N(omega)-nitro-L-arginine methyl ester modulates G-protein expression and adenylyl cyclase activity in rat heart. 912 16

Impaired vascular beta-adrenergic responsiveness may play an important role in the development and/or maintenance of hypertension. This defect has been associated with an alteration in receptor/guanine nucleotide regulatory protein (G-protein) interactions. However, the locus of this defect remains unclear. G-Protein-coupled receptor kinases (GRKs) phosphorylate serine/threonine residues on G-protein-linked receptors in an agonist-dependent manner. GRK activation mediates reduced receptor responsiveness and impaired receptor/G-protein coupling. To determine whether the impairment in beta-adrenergic response in human hypertension might be associated with altered GRK activity, we studied lymphocytes from younger hypertensive subjects as compared with older and younger normotensive subjects. We assessed GRK activity by rhodopsin phosphorylation and GRK expression by immunoblot. GRK activity was significantly increased in lymphocytes from younger hypertensive subjects and paralleled an increase in GRK-2 (beta ARK-1) protein expression. In contrast, no alterations in cAMP-dependent kinase (A-kinase) activity or GRK-5/6 expression were noted. GRK activity was not increased in lymphocytes from older normotensive subjects who demonstrated a similar impairment in beta-adrenergic-mediated adenylyl cyclase activation. These studies indicate that GRK activity is selectively increased in lymphocytes from hypertensive subjects. The increase in GRK activity may underlie the reduction in beta-adrenergic responsiveness characteristic of the hypertensive state.
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PMID:G-protein-coupled receptor kinase activity is increased in hypertension. 915 75

In the present studies we have investigated if the increased expression of Gi alpha proteins reported earlier in heart and aorta from SHR (spontaneously hypertensive rats) is the cause or effect of hypertension. The SHRs at various ages of the development of blood pressure (3-5 days, 2 weeks, 4 weeks and 8 weeks) and their age-matched WKY were used for these studies. The expression of Gi alpha-2 and Gi alpha-3 (inhibitory guanine nucleotide regulatory protein and Gs alpha (stimulatory guanine nucleotide regulatory protein) at protein and mRNA level was determined by immunoblotting and Northern blotting technique using specific antibodies and cDNA probes. The SHR at early ages up to 2 weeks did not show any increase in blood pressure, however it started to go up from 4 weeks. The levels of Gi alpha 2 and Gi alpha 3 at protein and mRNA in heart from SHR were not different in 3-5 days old SHR as compared to WKY (Wistar-Kyoto rats), however, the expression of Gi alpha-2 and Gi alpha-3 protein and mRNA was significantly increased in 2 weeks and older SHR. The mRNA level of the catalytic subunit type V enzyme was significantly decreased in SHR 2 weeks and later ages as compared to their age-matched WKY. On the other hand, the expression of Gs alpha was not different in SHR as compared to WKY at all the ages studied. In addition, the oxotremorine and C-ANF4-23 (a ring deleted analog of atrial natriuretic factor) mediated inhibitions of adenylyl cyclase in hearts and aorta were also significantly enhanced in 2 weeks and older SHRs as compared to WKY rats, whereas, at younger age of SHR (3-5 days old), no change in the percent inhibition of adenylyl cyclase by C-ANF4-23 was observed and oxotremorine was unable to inhibit adenylyl cyclase activity. Furthermore, the basal enzyme activity and the stimulatory responses of isoproterenol, NECA (N-ethylcarboxamideadenosine), glucagon and forskolin on adenylyl cyclase were significantly decreased at all ages of SHR as compared to WKY. These results suggest that the increased expression of genes for Gi alpha-2 and Gi alpha-3, decreased expression of type V enzyme mRNA and decreased cAMP levels precedes the development of blood pressure and may participate in the pathogenesis of hypertension.
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PMID:Enhanced expression of Gi-protein precedes the development of blood pressure in spontaneously hypertensive rats. 915 62

As interactions between the renin-angiotensin and sympathetic nervous systems have been suggested in the pathogenesis of hypertension, we wanted to investigate the effect of chronic renin-angiotensin blockade with losartan and enalaprilat on the sympathetic reactivity to hypotension and on the cardiac beta-adrenergic-coupled adenylyl cyclase pathway in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Both treatments, exerting equipotent shifts of angiotensin-pressure responses, lowered blood pressure and attenuated cardiac hypertrophy similarly in SHR. The nitroprusside-induced hypotension was similar in both strains, but the associated increases in plasma catecholamines and heart rate were higher in SHR. In SHR treated with losartan and enalaprilat, the nitroprusside-induced hypotension was greater and associated with markedly attenuated increases in norepinephrine and heart rate. The binding affinity of cardiac beta-adrenoceptors was significantly lower, and beta2-adrenoceptor subtype was dominant in untreated SHR in contrast to WKY, in which beta1-adrenoceptor subtype was dominant. Enalaprilat treatment increased total beta-adrenoceptor density, whereas both treatments restored the binding affinity and beta1- and beta2-adrenoceptor proportions to normal in SHR. Isoproterenol-, guanylylimidodiphosphate [Gpp(NH)p]-, and forskolin-stimulated adenylyl cyclase reactivity was increased in SHR. Enalaprilat restored adenylyl cyclase reactivity to normal in SHR and reduced the sensitivity (EC50) of Gpp(NH)p-induced cAMP formation in both strains. The present study supports the possibility that functional alterations of the renin-angiotensin and sympathetic systems are involved in hypertension in SHR. The antihypertensive action of losartan and enalaprilat in SHR may be partly mediated through the normalization of sympathetic hyperreactivity and the restoration of beta-adrenergic signaling pathway sensitivity.
Hypertension 1997 Aug
PMID:Effects of renin-angiotensin blockade on sympathetic reactivity and beta-adrenergic pathway in the spontaneously hypertensive rat. 926 Sep 93

Atrial natriuretic peptide (ANP) regulates a variety of physiological parameters, including the blood pressure and intravascular volume, by interacting with its receptors present on the plasma membrane. ANP receptors are of three subtypes: ANP-A, -B and -C receptors. ANP-A and ANP-B receptors are guanylyl cyclase receptors, whereas ANP-C receptors are coupled to adenylyl cyclase inhibition or phospholipase C activation through inhibitory guanine nucleotide-regulating protein. Unlike other G protein-coupled receptors, ANP-C receptors have a single transmembrane domain and a short cytoplasmic domain of 37 amino acids, the cytoplasmic domain has a structural specificity like those of other single-transmembrane-domain receptors and 37 amino-acid cytoplasmic domain peptide is able to exert is inhibitory effect on adenylyl cyclase. The activation of ANP-C receptor by C-ANP(4-23) (a ring-deleted peptide of ANP) and C-type natriuretic peptide inhibits the mitogen-activated protein kinase activity stimulated by endothelin-3, platelet-derived growth factor and phorbol-12 myristate 13-acetate. C-ANP also inhibits mitogen-induced stimulation of DNA synthesis, indicating that the ANP-C receptor plays a role in cell proliferation through an inhibition of mitogen-activated protein kinase and suggesting that the ANP-C receptor might also be coupled to other signal transduction mechanism(s) or that there might be an interaction of the ANP-C receptor with some other signalling pathways. ANP receptor binding is decreased in most organs in hypertensive subjects and hypertensive animals. This decrease is consistent with there being fewer guanylyl cyclase-coupled receptors in the kidney and vasculature and selective inhibition of the ANP-C receptor in the thymus and spleen. Platelet ANP-C receptors are decreased in number in hypertensive patients and spontaneously hypertensive rats. ANP-A, -B and -C receptors are decreased in number in deoxycorticosterone acetate-salt-treated kidneys and vasculature; however, the responsiveness of adenylyl cyclase to ANP is augmented in the vasculature and heart and is attenuated completely in platelets. These alterations in ANP receptor subtypes may be related to the pathophysiology of hypertension. Several hormones such as angiotensin II, ANP and catecholamines, the levels of which are increased in hypertension, downregulate or upregulate ANP-C receptors and ANP-C receptor-mediated inhibition of adenylyl cyclase. It can be suggested that the antihypertensive action of several types of drugs such as angiotensin converting enzyme inhibitors, angiotensin type 1 receptor antagonists and beta2-adrenergic antagonists may partly be attributed to their ability to modulate the expression and function of the ANP-C receptor.
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PMID:Atrial natriuretic peptide-C receptor and membrane signalling in hypertension. 928 Feb 3

Vasoactive peptides such as angiotensin II (AII), atrial natriuretic peptide (ANP) and vasopressin play an important role in the regulation of blood pressure. We have recently shown an augmentation of Gi alpha levels in heart and aorta from genetic and experimentally-induced hypertensive rats, which may be attributed to the increased levels of vasoactive peptides. We have therefore investigated the effect of AII and ANP on the expression of G-proteins (Gi alpha and Gs alpha) in cultured vascular smooth muscle cells (VSMC) and their relationship with adenylyl cyclase activity. Exposure of VSMC with AII resulted in the augmentation of the levels of Gi alpha-2 and Gi alpha-3 proteins and Gi alpha-2 and Gi alpha-3 mRNA and not of Gs alpha as determined by immunoblotting and Northern blotting techniques respectively. However, the stimulatory effects of N-ethylcarboxamide adenosine (NECA) and isoproterenol on adenylyl cyclase was diminished by AII treatment, whereas the inhibitory effects of AII and C-ANP4-23 were completely attenuated. On the other hand, pretreatment of the cells with C-ANP4-23 resulted in the reduction of the levels of Gi alpha-2 and Gi alpha-3 and not of Gs alpha. The inhibitory responses of adenylyl cyclase to C-ANP4-23 and AII were also attenuated and the stimulatory effects of GTP gamma S and other agonists were significantly augmented. These data indicate that AII and ANP modulate the expression of Gia protein in a different manner. It may be suggested that the enhanced levels of Gi alpha protein observed in hypertension may be attributed to the augmented levels of AII and not to ANP.
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PMID:Differential regulation of G-protein expression by vasoactive peptides. 940 40

The main purpose of this investigation was to evaluate whether the cyclic AMP-adenosine pathway, ie, the conversion of cAMP to AMP and, hence, to adenosine, is involved in the regulation of nitric oxide (NO) synthesis by vascular smooth muscle cells (SMCs). Treatment of confluent monolayers of SMCs with adenosine, 2-chloroadenosine (stable analog of adenosine), and agents that elevate endogenous (SMC-derived) adenosine (EHNA and iodotubericidin) increased nitrite/nitrate (stable metabolites of NO) levels in the medium and enhanced the conversion of 3H-L-arginine to 3H-L-citrulline by cytosolic extracts obtained from the pretreated SMCs. The stimulatory effects of adenosine were not mimicked by low (1 to 100 nmol/L) concentrations of CGS21680, an A2A receptor agonist, or CPA, a selective A1 receptor agonist. The stimulatory effects of 2-chloroadenosine and EHNA plus iodotubericidin were significantly inhibited by KF17837, a selective A2 receptor antagonist, and by DPSPX, an A1/A2 receptor antagonist, but not by DPCPX, a selective A1 receptor antagonist. DDA (adenylyl cyclase inhibitor) and Rp-cyclic AMP (protein kinase A inhibitor) did not block the effects of adenosine on NO synthesis. Incubation of SMCs with exogenous cyclic AMP, at concentrations previously shown to elevate levels ofadenosine in the medium, also increased nitrite/nitrate levels and 3H-L-citrulline formation, and the effects of cyclic AMP on NO synthesis were blocked by DPSPX and KF17837, but not by DPCPX. These findings provide evidence that exogenous and SMC-derived adenosine induce NO synthesis via A2B receptors linked to a pathway not involving adenylyl cyclase/protein kinase A. Moreover, extracellular cyclic AMP induces NO synthesis via conversion to adenosine and activation of A2B adenosine receptors. The cyclic AMP-adenosine pathway may be importantly involved in the vascular production of NO.
Hypertension 1998 Jan
PMID:Cyclic AMP-adenosine pathway induces nitric oxide synthesis in aortic smooth muscle cells. 945 19

Inhibition of the renin-angiotensin system has been shown to improve symptoms and prognosis in heart failure. We compared the effects of inhibition of angiotensin-converting enzyme or blockade of angiotensin II type 1 (AT1) receptors in a model with renin-induced hypertension that is known to exhibit similar changes in sympathetic activation and beta-adrenergic desensitization, as observed in heart failure. Treatment with captopril (100 mg/kg of feed) or the AT1-antagonist Bay 10-6734 (100 mg/kg of feed) was performed in transgenic rats harboring the mouse renin 2d gene [TG(mREN2)27]. Neuropeptide Y and angiotensin II levels, adenylyl cyclase activity, beta-adrenergic receptors, G(salpha), and G(ialpha) were investigated. TG(mREN2)27 showed a depletion of myocardial neuropeptide Y stores and an increase in myocardial angiotensin II concentrations. Isoprenaline- and guanylylimidodiphosphate-stimulated adenylyl cyclase activities and beta-adrenergic receptor density were reduced, whereas the catalyst and G(salpha)-function were unchanged. G(ialpha) protein and mRNA concentrations were increased. All alterations were normalized by both treatments. Systolic left ventricular pressures, plasma atrial natriuretic peptide, and myocardial steady state atrial natriuretic peptide mRNA concentrations and heart weights were similarly reduced by both treatments. Sympathetic neuroeffector defects are similarly reversed by angiotensin-converting enzyme inhibition or AT1 antagonism. The data support the concept that pharmacological interventions in the myocardial renin-angiotensin system significantly reverse local sympathetic neuroeffector defects. This could be important for the beneficial effects of these agents.
Hypertension 1998 Mar
PMID:Effects of angiotensin II type 1 receptor blockade and angiotensin-converting enzyme inhibition on cardiac beta-adrenergic signal transduction. 949 57


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