Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 130 kDa atrial natriuretic factor receptor (ANF-R1) purified from bovine adrenal zona glomerulosa is phosphorylated in vitro by serine/threonine protein kinases such as cAMP-, cGMP-dependent and protein kinase C. This phosphorylation is independent of the presence of ANF (99-126) and there is no detectable intrinsic kinase activity associated with the ANF-R1 receptor or with its activated form. In bovine adrenal zona glomerulosa cells, TPA (phorbol ester) induces a marked inhibition of the ANF-stimulated cGMP accumulation as well as of the membrane ANF-sensitive guanylate cyclase catalytic activity without any change in the binding capacity or affinity for 125I-ANF. However, we have demonstrated a significant 32P incorporation in the ANF-R1 receptor of the TPA-treated cells. The effect of TPA on the zona glomerulosa ANF-R1 receptors was abolished by calphostin C, a specific protein kinase C inhibitor. Altered ANF actions due to blunted response of guanylate cyclase to ANF could be a consequence of the ANF receptor phosphorylation by excessive activity of protein kinase C and might be involved in the pathogenesis of hypertension.
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PMID:Phosphorylation of atrial natriuretic factor R1 receptor by serine/threonine protein kinases: evidences for receptor regulation. 128 Mar 21

The original observation by de Bold et al. (1981) of a rapid, massive, and short-lasting diuretic and natriuretic effect following injection of rat atrial extracts into intact rats, led to the identification, isolation and purification of the atrial natriuretic factor (ANF). ANF is stored in atrial myocytes and released into the blood stream by atrial distension. Available data suggest that the mechanism of ANF-induced natriuresis involves either renal hemodynamic effects, such as the increase in glomerular filtration rate and reduction of medullary tonicity, or direct effect on sodium transport in the medullary collecting ducts. ANF induces relaxation of vascular smooth muscle, decreases blood pressure and cardiac output. All these effects displayed by ANF are associated to the an inhibition of aldosterone, renin and vasopressin release. Most of these actions are mediated by specific high affinity receptors, which are coupled to a particulate guanylate cyclase. Although ANF levels are increased in some disorders, such as severe heart failure, hypertension, chronic renal failure, the role of the peptide is uncertain. To better define the potential physiopathological role and the possible therapeutic implications of this new hormonal system in conditions of disturbed body fluid and sodium homeostasis, further experimental and clinical data must be awaited.
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PMID:[The physiopathological aspects of the atrial natriuretic factor]. 131 27

Endothelium-derived relaxing factor (EDRF) activates soluble guanylate cyclase, resulting in an increase in vascular smooth muscle guanosine 3',5'-cyclic monophosphate (cGMP) levels, which correlates with its relaxing effect. Using a microdialysis technique, we investigated changes in right and left renal interstitial fluid cGMP levels in response to right intrarenal administration of an EDRF inhibitor, NG-monomethyl-L-arginine (L-NMMA). Studies were conducted in anesthetized dogs (n = 5) in metabolic balance at a sodium intake of 40 meq/day. Urine was collected directly from the right and left ureters individually. Changes in the right and left urinary cGMP excretion and renal function in response to cumulative doses of L-NMMA were studied. In the right kidney, 20-100 micrograms/kg/min L-NMMA caused 1) a dose-dependent decrease in renal interstitial fluid and urinary cGMP levels (p less than 0.0001 and p less than 0.001, respectively), 2) antinatriuresis (p less than 0.01), 3) antidiuresis (p less than 0.01), 4) a decrease in renal blood flow (p less than 0.01) and glomerular filtration rate (p less than 0.01), and 5) a decrease in fractional sodium excretion (p less than 0.01). No changes in left renal interstitial fluid and urinary cGMP levels or excretory and hemodynamic function were observed during right intrarenal administration of L-NMMA at 20 and 60 micrograms/kg/min.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Jun
PMID:Nitric oxide alters renal function and guanosine 3',5'-cyclic monophosphate. 131 56

At least two types of receptors for natriuretic peptides have been reported: biologically active receptors coupled with guanylate cyclase (atrial natriuretic peptide [ANP]-B receptors) and clearance receptors (ANP-C receptors). To elucidate the role of protein kinase C (PKC) in the regulation of ANP-B receptors, vascular smooth muscle cells in culture were treated with phorbol ester. Incubation with receptor agonists and phorbol ester led to the desensitization of receptor-mediated cyclic guanosine monophosphate (ANP-B receptor response) in rat vascular smooth muscle cells. Although a PKC inhibitor and downregulation of PKC by long-term incubation of cells with phorbol esters blocked the phorbol ester-induced desensitization of the ANP-B receptor response, they did not block the ANP-induced desensitization of the ANP-B receptor response. In addition, when desensitization by phorbol esters was observed, ANP was still capable of desensitization. These observations suggest that the mechanism for regulating ANP-B receptor sensitivity may be both PKC-dependent and PKC-independent and mediated by phorbol esters and ANP, respectively.
Hypertension 1992 Apr
PMID:Phorbol ester and atrial natriuretic peptide receptor response on vascular smooth muscle. 134 39

Seven-month-old, lean male SHHF/Mcc-cp rats, a model of spontaneous hypertension, progressive renal dysfunction, and congestive heart failure (CHF), were treated with either clonidine (CL) or enalapril (EN) or received no treatment (CON) for 20 weeks. CL significantly decreased systolic blood pressure (SBP), kidney weights, and severity of renal lesions as compared with untreated CON. EN produced a decrease in SBP comparable to that in CL. Kidney weights and severity of renal histologic changes in the EN group were intermediate between those of the CL and CON groups. Despite similar plasma atrial natriuretic peptide (ANP) concentrations, CL treatment resulted in a significant increase in the density of guanylate cyclase-linked glomerular ANP receptors, whereas EN treatment resulted in a significant decrease in the total number of ANP receptors and in the number of nonguanylate cyclase-linked receptors and an increase in overall binding affinity. These findings demonstrate that antihypertensive agents will slow progression of renal injury in SHHF/Mcc-cp rats and that CL is more effective than EN in alleviating progressive kidney damage in this model. Furthermore, different classes of antihypertensive drugs may alter the density or ratio of biologically active and clearance ANP receptor sites in the glomerulus.
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PMID:Effects of enalapril and clonidine on glomerular structure, function, and atrial natriuretic peptide receptors in SHHF/Mcc-cp rats. 137 31

Nitric oxide (NO) and atrial natriuretic factor (ANF) cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP) via activation of the soluble and particulate guanylate cyclases, respectively. The chronic effects of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine antagonist and NO synthase inhibitor, on the blood pressure and plasma and aortic cGMP levels of rats were tested. Wistar rats (n = 10 per group) were given doses of L-NAME (0, 1, 5, 10, 20, 50, and 100 mg/kg.d) by gavage twice a day for 4 wk. Chronic L-NAME induced a time- and dose-dependent increase in blood pressure. The total heart weight/body weight ratio did not change in any group, despite the hypertension. The plasma levels of cGMP did not change significantly in any group, and were correlated with the plasma ANF levels (r = 0.51, P less than 0.0001). Aortic cGMP decreased in negative correlation with increasing L-NAME from 0 to 10 mg/kg.d, culminating in a 10-fold drop arterial wall cGMP. The aortic cGMP content of rats in the four highest dose groups (from 10 to 100 mg/d) tended to increase slightly and was positively correlated with endogenous ANF (r = 0.48, P less than 0.002, n = 40). Intravenous L-arginine decreased arterial blood pressure and reversed the decline in aortic cGMP. Exogenous ANF and sodium nitroprusside both significantly increased aortic cGMP. Neither the arterial wall concentrations of cGMP-dependent kinase nor cAMP was changed by L-NAME. Thus, chronic blockade of NO synthase with L-NAME induces a dose-dependent increase in blood pressure and decrease in aortic cGMP. The in vivo basal aortic cGMP seems to be mainly dependent on NO synthase: soluble guanylate cyclase activity and to a minor extent on particulate guanylate cyclase activity.
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PMID:Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase. 137 15

The migration and proliferation of endothelial cells play a pivotal role in various vascular diseases. We have previously reported that atrial natriuretic polypeptide (ANP) exerts an antigrowth effect on vascular smooth muscle cells via the guanylate cyclase-coupled mechanism. Because the endothelial cells are known to possess a large number of guanylate cyclase-coupled ANP receptors, we examined the action of ANP on the growth of endothelial cells. ANP (10(-7) and 10(-6) M) significantly attenuated serum-stimulated DNA synthesis of cultured bovine aortic endothelial cells with concomitant reduction of the increase in cell number. A ring-deleted analogue of ANP exerted less prominent antiproliferative action, and 8-bromo cyclic GMP (cGMP) mimicked the action of ANP, suggesting the involvement of cGMP cascade in the endothelial growth. Moreover, the proliferative action of exogenously administered basic fibroblast growth factor on endothelial cells was significantly attenuated by the simultaneously administered 8-bromo cGMP. Taken together, the present results demonstrate a potential novel role of ANP in the regulation of endothelial cell growth, which is implicated in angiogenesis or reendothelialization.
Hypertension 1992 Jun
PMID:Atrial natriuretic polypeptide as a novel antigrowth factor of endothelial cells. 153 17

Opening of K+ channels in cell membranes with resulting increase in K+ conductance, shifts the membrane potential in a hyperpolarizing direction towards the K+ equilibrium potential. Hyperpolarization reduces the opening probability of ion channels involved in membrane depolarization and excitation is reduced. K+ channel openers are believed to hyperpolarize smooth muscle cells by a direct action on the cell membrane. The best known members of the group are cromakalim, nicorandil and pinacidil, but several new compounds are being evaluated. In addition, it has recently been shown that also clinically well-known drugs like, e.g. diazoxide and minoxidil exhibit K+ channel opening properties. Nicorandil and new compounds containing nitro groups have a dual mechanism of action, also activating guanylate cyclase, an effect that contributes to their cardiovascular effect profile. K+ channel openers have a wide range of effects. Some of their properties and actions are summarized, and their present applications and/or potential for future application, in e.g. hypertension, angina pectoris, asthma, bladder instability, and several other disorders are discussed. It is concluded that K+ channel openning represents an interesting pharmacological principle with many potential clinical applications. However, most available drugs do not seem to have a sufficient tissue selectivity to be useful therapeutic alternatives. Before the potential of the new members of the group on clinical trials can be properly evaluated, clinical experiences are needed.
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PMID:Clinical pharmacology of potassium channel openers. 153 27

The endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) or a closely related nitrosothiol derivative. It is formed from the amino acid, L-arginine. NO is rapidly inactivated locally and is instantly destroyed by haemoglobin when released into the blood stream. EDRF-NO as well as NO generated from vasodilator nitrates act by activation of soluble guanylate cyclase, elevating cellular cyclic GMP levels, causing vasodilatation and inhibition of platelet aggregation. Endothelium-dependent vasodilatation is attenuated in hypertension, atherosclerosis and diabetes. This is due to either loss of endothelium or deficient formation of EDRF-NO. In these conditions, therapy with exogenous nitrates may substitute for a failing endogenous mechanism.
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PMID:Endogenous and exogenous nitrates. 155 42

Acetylcholine evokes the simultaneous release of endothelium-derived relaxing and contracting factors in aortas from spontaneously hypertensive rats. Only relaxing factors are released in aortas from normotensive controls. Experiments were designed to determine whether inhibitors of endothelium-dependent relaxations modify endothelium-dependent contractions. Rings of thoracic aortas of normotensive and spontaneously hypertensive rats, with and without endothelium, were suspended in organ chambers for isometric tension recording. Oxyhemoglobin (a scavenger of endothelium-derived relaxing factor) and NG-monomethyl L-arginine (an inhibitor of nitric oxide formation) augmented the contractions to acetylcholine. Methylene blue (an inhibitor of soluble guanylate cyclase) and superoxide dismutase (a scavenger of superoxide anions) did not modify these contractions. The contractions in the presence of oxyhemoglobin or NG-monomethyl L-arginine, like those in untreated rings, were endothelium-dependent; they only occurred in aortas from spontaneously hypertensive rats and were abolished by indomethacin. The contractions to acetylcholine in the presence of oxyhemoglobin were not affected by superoxide dismutase or deferoxamine. These data suggest that endothelium-derived relaxing factor inhibits endothelium-dependent contractions to acetylcholine in the spontaneously hypertensive rat aorta, probably by chemical inactivation of the endothelium-derived contracting factor rather than by stimulation of guanylate cyclase or scavenging of oxygen-derived free radicals.
Hypertension 1992 May
PMID:Nitric oxide inactivates endothelium-derived contracting factor in the rat aorta. 156 62


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