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

Vascular endothelial cells produce various biologically active factors regulating blood pressure, coagulation, and possibly cell growth of the vascular wall. Of the factors, nitric oxide (NO) has been the object of attention because of its quite simple molecular structure and variety of biological functions. In the present review, we focused on the physiologic and pathologic aspects of NO in hypertension. In experimental animals, both acute and chronic inhibition of NO synthase (NOS) with arginine derivatives produce a significant rise in blood pressure, indicating that tonic production of NO regulates basal vascular tonus. The chronic hypertension caused by NOS inhibitor is associated with cardiac hypertrophy and renal insufficiency. Sodium retention, though transient, and the plasma and tissue renin/angiotensin system in addition to the reduced production of NO have been implicated in the development of hypertension. Hypertension and the associated target organ failure can be reversed by co-administration of L-arginine or blockades of the renin/angiotensin system. Studies in which L-arginine as the substrate of NO or NOS inhibitor was administered demonstrated an important role of NO in the regulation of tonic vascular tonus also in normal subjects. In hypertensive subjects, however, endothelium-dependent vasorelaxation and production of NO are impaired, possibly due to a deficiency of L-arginine and/or a disorder of its utilization. Recent advances in the methods of detecting NO enabled us to demonstrate its diminished production from endothelial cells of hypertensive rats in vitro, although no definite biochemical evidence has been obtained in hypertensive subjects. The endothelial dysfunction, however, is not a primary cause of hypertension but a secondary result since it is commonly observed in various types of hypertension and can be reversed by correcting the blood pressure. Other common diseases including atherosclerosis and diabetes mellitus are also associated with similar abnormalities of the endothelium. NO has anti-atherogenic actions: inhibition of platelet functions and proliferation of vascular smooth muscle cells. Therefore, potentiation of endogenous NO and/or supplement of exogenous NO donors could be novel therapeutic approaches for the treatment of hypertension and atherosclerosis, while potential adverse effects of NO including cytotoxicity, immunosuppressibility, and hypotensive shock should be taken into account.
 ...
PMID:[Clinical significance of nitric oxide in hypertension]. 752 65

Nitric oxide (NO) is an important molecular messenger accounting for endothelium-derived relaxing factor. Recently, NO synthase (NOS) from cultured endothelial cells has been purified and molecularly cloned. To evaluate the effect of phosphorylation by protein kinase C (PKC) and cyclic AMP-dependent protein kinase (PKA) on endothelial constitutive NOS catalytic activity, we incubated purified endothelial NOS with PKC or PKA. Endothelial NOS was stoichiometrically phosphorylated by PKC and PKA. In intact bovine aortic endothelial cells (BAECs), NOS was phosphorylated by stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA). NOS activity measured by the conversion of [3H]arginine to [3H]citrulline in homogenates of BAECs treated with TPA or phorbol 12,13-dibutyrate was reduced by 30%, whereas dibutylyl cyclic AMP did not affect NOS activity. Moreover, we measured NO release from cultured BAECs by a chemiluminescence method to examine the effect of PKC and PKA on endothelial NOS activity. In cultured BAECs, ATP gamma S and A23187 induced NO release in time- and dose-dependent manners. Phorbol esters such as TPA and phorbol 12,13-dibutyrate dose dependently inhibited NO release stimulated by A23187 as well as ATP gamma S. Reduction of NO release by TPA was almost completely prevented by pretreatment with staurosporine, an inhibitor of PKC. NO release by A23187 was increased in PKC-downregulated BAECs. In contrast, dibutylyl cyclic AMP or 8-bromo cyclic GMP had no effect on NO release from BAECs induced by A23187 or ATP gamma S. These results indicate that phosphorylation of NOS by PKC is associated with a reduction of its catalytic activity in vascular endothelial cells.
Hypertension 1995 Feb
PMID:Inhibition of endothelial nitric oxide synthase activity by protein kinase C. 753 Nov 74

L-Arginine-derived nitric oxide (NO) maintains the systemic and renal vasculature in a state of active vasodilation. Inhibition of NO synthesis increases renal vascular tone, reducing RBF and GFR. Similar effects reproduced in other vascular beds result in systemic hypertension. In addition, NO modulates natriuresis by a direct effect on renal tubular function. Abnormalities of the L-arginine:NO pathway occur in experimental hypertension and renal disease and could contribute to alterations in vascular tone; similar abnormalities are seen in essential hypertension in humans. In dialysis-dependent renal failure, the accumulation of endogenous compounds that inhibit NO synthase could exacerbate renal hypertension by inhibiting vascular and renal tubular NO synthesis and might provoke atherogenesis.
 ...
PMID:Nitric oxide in essential and renal hypertension. 753 11

This in vivo electrophysiological study concerns the role of nitric oxide (NO) in mechanical and thermal spinal nociceptive reflexes in alpha-chloralose anaesthetized rats. The effects of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 5-40 mg/kg i.v.) on reflexes were compared both in normal rats and in those with peripheral inflammation induced neurogenically (mustard oil) and non-neurogenically (carrageenan). Methoxamine (0.1 mg/kg i.v.) was used to mimic the marked hypertension caused by L-NAME. Thermal nociceptive reflexes were equally reduced by methoxamine and L-NAME in both normal and inflamed rats, implying that NO has no role in mediating thermal reflexes. However, L- (but not D-) NAME dose dependently and significantly inhibited mechanical reflexes in both carrageenan inflamed (to 37 +/- 12% control) and mustard oil inflamed rats (to 75 +/- 8% control). Moreover, these reductions were greater than those by methoxamine. In contrast, L-NAME did not reduce mechanical reflexes in rats with no inflammation or in spinalized rats with inflammation. The inhibition of mechanical reflexes with L-NAME in carrageenan inflamed rats was reversed and prevented by pre- or post-treatment with L- (but not D-) arginine (50-200 mg/kg i.v.). These data imply a supraspinal role for NO in mediating mechanical (but not thermal) nociceptive reflexes only in those rats with peripheral inflammation.
 ...
PMID:The role of nitric oxide in spinal nociceptive reflexes in rats with neurogenic and non-neurogenic peripheral inflammation. 753 33

Neuronal nitric oxide synthase (nNOS) has been suggested to be involved in cardiovascular homeostasis. We studied the regulation of nNOS expression, determining nNOS mRNA expression levels in various tissues in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We also investigated the effects of antihypertensive treatment with the angiotensin II antagonist hydralazine or reserpine on nNOS mRNA expression. The expression levels of nNOS mRNA and nNOS protein were determined by Northern and Western blot analysis, respectively. NADPH-diaphorase histochemistry was used to identify cells in the adrenal medulla that expressed nNOS. No significant differences in expression levels in SHR and WKY were observed in the cerebellum and brain stem. nNOS mRNA expression levels in the decapsular portion of the adrenal gland were developmentally modulated and in a 24-week-old WKY were 2.5 times higher than in an age-matched SHR. This reduced expression of nNOS mRNA in the decapsular portion of the adrenal gland of SHR seemed to be a result of hypertension in the SHR, because administration of either an angiotensin II antagonist (TCV-116) or hydralazine upregulated nNOS mRNA expression in both SHR and WKY. Marked augmentation of nNOS mRNA expression in the decapsular portion of the adrenal gland by reserpine treatment suggested an intimate relation between nNOS in the decapsular portion of the adrenal gland and the sympathoadrenal system. Reserpine treatment also increased the expression of nNOS protein; however, reserpine treatment did not affect the distribution pattern of nNOS-positive cells (NADPH-diaphorase-positive cells) in the adrenal medulla.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Mar
PMID:Regulation of neuronal nitric oxide synthase in rat adrenal medulla. 753 41

Besides its glomerular hemodynamic effects, nitric oxide (NO) inhibits platelet aggregation and mesangial cell proliferation, two mechanisms possibly involved in the pathogenesis of glomerulosclerosis (GS). Chronic NO synthase inhibition in the rat leads to marked arterial hypertension and promotes glomerular and interstitial injury, but only mild GS. In this study, NO synthase blockade by nitro-L-arginine methyl ester (L-NAME) was associated with 5/6 nephrectomy, a well-known model of GS. Sixty-eight adult male Munich-Wistar rats were distributed among four groups: SHAM (no renal ablation or drug treatment), NX (5/6 nephrectomy), NX+NAME (5/6 nephrectomy and chronic treatment with L-NAME, 5 mg/dL in drinking water) and NX+NAME+L (as in group NX+NAME but also receiving the angiotensin II receptor inhibitor Losartan potassium (L), 25 mg/dL in drinking water). One week after ablation, rats of Group NX showed moderate glomerular hypertension and hypertrophy. Although glomerular enlargement was also modest in Group NX+NAME, glomerular hypertension was particularly severe in this group. Both alterations were absent in Group NX+NAME+L. Only incipient glomerular and interstitial injury occurred at this phase. Three weeks after ablation, renal structural injury was still modest in Group NX. By contrast, Group NX+NAME exhibited marked GS, glomerular ischemic injury, interstitial expansion, and creatinine retention. Renal injury was largely prevented in Group NX+NAME+L. Tuft enlargement occurred in all groups but was most prominent in Group NX. NO synthase inhibition aggravates parenchymal injury and functional impairment in the remanent kidney by mechanisms that may involve glomerular hypertension and renin-angiotensin activation but that appear to be unrelated to glomerular enlargement.
 ...
PMID:Chronic nitric oxide synthase inhibition aggravates glomerular injury in rats with subtotal nephrectomy. 753 72

Nitric oxide (NO) is intimately involved in the regulation of vascular tone, renal haemodynamics and sodium balance. The physiological actions of NO suggest important vascular and renal protective roles for NO. When produced in large amounts, however, NO may also mediate cytotoxic effects. Increasing evidence suggests that endothelial function, notably the NO pathway, may be compromised in hypertension. It is not known, however, whether changes in endothelial function are primary or secondary to the development of hypertension. In renal diseases evidence for both excessive and deficient activity of NO pathway has been found. Increased glomerular production of NO via inducible NO synthase (NOS) with potential cytotoxic consequences has been demonstrated in experimental acute glomerulonephritis. On the other hand, indirect evidence obtained by means of NOS inhibitors point out to an important renoprotective role for NO in renal diseases. NO may counteract disease progression in renal diseases by preventing glomerular microthrombi, maintaining renal perfusion and medullary oxygenation, and via its anti-inflammatory/antiproliferative effects. However, these beneficial effects of NO may be compromised (endothelial and/or tubular dysfunction) in chronic nephropathies resulting in an accelerated course of renal disease. In future, more specific inhibitors and activators of different NOS isoforms are needed to elucidate the role of NO in various renal diseases in detail, and for treatment strategies aimed at modifying the NO pathway.
 ...
PMID:Nitric oxide in hypertension and renal diseases. 754 25

We studied vasodilator innervation in canine cerebral arteries and analyzed mechanisms of neurally induced vasodilatation. Available pharmacological, biochemical and histological evidence supports the hypothesis that nitric oxide (NO) synthesized in nerve terminals acts as a neurotransmitter that activates soluble guanylate cyclase in vascular smooth muscle and increases the production of cyclic GMP, resulting in relaxation. Peripheral arteries, such as the mesenteric, temporal, saphenous, uterine, and retinal, arteries, respond to nerve stimulation with contractions that are reversed to relaxations by alpha-adrenoceptor blockade. The relaxation is also mediated by NO derived from perivascular nerves. Thus, reciprocal regulation by NO-mediated (nitroxidergic) and adrenergic nerves is speculated. Potentiation by NO synthase inhibitors of the arterial contraction associated with adrenergic nerve stimulation in vitro is ascribed to depressed vasodilator nerve function. Systemic blood pressure in anesthetized dogs is increased by intravenous injections of NO synthase inhibitors. Our evidence strongly suggests that the pressor response is associated with suppressed synthesis and release of NO derived mainly from vasodilator nerves. It is concluded that nitroxidergic vasodilator nerves play important roles in the regulation of vascular tone in vitro and in vivo and in the control of systemic blood pressure. Presented here are new concepts for the mechanism of hypertension and the role played by NO-mediated nerve function.
 ...
PMID:Nitroxidergic nerves and hypertension. 758 5

Elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. Whether this exudative response is related to associated hypertension or another effect of AngII is uncertain. We therefore monitored plasma and cardiac lymph total protein, albumin and fibronectin and calculated transvascular clearances for total protein (TVPC) and albumin (TVAC) and lymph fibronectin transport (LFT) every 30 min in open-chested, instrumented dogs. After baseline observations were obtained over 30 min, pressor (250 ng.kg.min-1) or nonpressor (11 ng.kg.min-1) doses of AngII were given intravenously for 90 min. Saline-treated, instrumented dogs served as controls. To address a potential secondary effect of AngII on vascular protein clearance, we monitored lymph prostaglandin E2 and cGMP (a marker of released nitric oxide, NO). At > or = 30 min, each dose of AngII was associated with a significant (P < or = 0.05) and comparable increase in TVPC, TVAC and LFT over baseline, indicating that increase in protein clearance was not related to elevated arterial pressure. Lymph cGMP rose significantly (P < or = 0.05) at 30 min for each dose of AngII and remained elevated thereafter. Lymph PGE2 was increased at > or = 60 min (P < or = 0.05) but only with the pressor dose. To determine the contribution of NO and PGE2 on AngII-induced transcoronary protein clearance, each dose of AngII was accompanied by co-administration of either the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or the cyclo-oxygenase inhibitor, indomethacin. L-NAME completely inhibited the release of cGMP and the increase in protein clearance was not seen. Indomethacin suppressed the release of PGE2, but did not prevent the increase in protein clearance. Thus, AngII-induced increase in transcoronary protein clearance is not related to arterial hypertension or the release of PGE2, but instead appears to be mediated by NO release.
 ...
PMID:Angiotensin-II-induced increase in transcoronary protein clearance: role of hypertension vs. nitric oxide or cyclo-oxygenase products. 758 17

The immune system of the spontaneously hypertensive rat is dysfunctional compared with that of normotensive control strains. Previous studies from our laboratory have shown that immunodepression in the spontaneously hypertensive rat was mediated by macrophages. The current study examines the mechanism for the depressed proliferative responses to concanavalin A typically observed by splenic mononuclear cells of spontaneously hypertensive rats. We tested various inhibitors of known macrophage products responsible for suppressing lymphoid function. The nitric oxide synthetase inhibitor NG-monomethyl L-arginine produced dose-dependent derepression of the proliferative responses of splenic mononuclear cells to concanavalin A. In contrast, indomethacin and catalase exhibited only weak derepression of the proliferative responses. Subsequent analysis showed that splenic mononuclear cells from spontaneously hypertensive rats generated greater nitric oxide levels than cells from Wistar-Kyoto rats, and nitric oxide levels were reduced when the inhibitor was added to splenic mononuclear cell cultures from spontaneously hypertensive rats. We further demonstrated that L-arginine is required for the development of the depressed mitogen-induced proliferative responses in these cells. Addition of L-arginine in excess of 10 microM to cultures diminished cell proliferation and increased nitric oxide. Polyclonal antibodies to murine interferon gamma reduced nitric oxide accumulation by approximately 50%, suggesting that interferon gamma is partially responsible for enhancing nitric oxide production in mitogen-stimulated splenic mononuclear cell cultures from spontaneously hypertensive rats. Thus, this study provides evidence that the immune depression observed in the spontaneously hypertensive rat is nitric oxide dependent.
Hypertension 1993 Feb
PMID:Nitric oxide mediates immune dysfunction in the spontaneously hypertensive rat. 767 89


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>