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

This study was aimed to make a new stable model of chronic hypertension by administration of a nitric oxide synthase inhibitor. L-Nw-nitroarginine methylester (NAME), and using this model, to investigate the roles of nitric oxide for the cardiovascular regulation. Male Wistar rats were implanted of osmotic pumps filled with saline (control group: n = 8), 0.2M NAME (low NAME group: n = 13) or 1M NAME (high NAME group: n = 12) intraperitoneally. After 4-week observation of blood pressure (BP) and heart rate (HR), blood concentrations of cathecholamine, active renin, L-arginine and L-Nw-nitroarginine were measured and histological changes in aorta and heart were examined. Age-matched SHRSP (n = 9) served as positive controls. BP elevated in the low NAME and high NAME group (113.9 +/- 3.1 to 144.0 +/- 4.4 mmHg, and 114.1 +/- 7.3 to 181.4 +/- 9.0 mmHg, respectively; mean +/- S.E.), while BP remained constant in the control group and SHRSP group (116.8 +/- 5.5 to 120.6 +/- 1.9 mmHg, 200.3 +/- 5.1 to 213.8 +/- 7.4 mmHg, respectively). HR in the low NAME and high NAME group rapidly decreased (not equal to 410 to not equal to 340 bpm) and then slowly returned to the control level. HR in the control group and SHRSP group remained constant (not equal to 420 and not equal to 450 bpm, respectively). Noradrenaline increased significantly in the high NAME group (0.21 +/- 0.03 ng/ml), and there were no significant changes in the control, low NAME and SHR group (0.13 +/- 0.02, 0.14 +/- 0.02, 0.15 +/- 0.03 ng/ml, respectively). Adrenaline, dopamine and active renin concentrations did not differ among 4 groups. Aortic wall/lumen area ratio in the high NAME group was similar to that in SHRSP group, in spite of its lower BP and shorter duration of hypertension compared with SHRSP. Left ventricular wall of the high NAME group was significantly thicker than that of SHRSP group. These findings suggest that, in addition to endothelium-derived NO, NO produced in the brain and peripheral neurons may function to regulate cardiovascular system by inhibiting noradrenaline release from sympathetic nerves or by inhibiting cardiac and vascular cell proliferation.
 ...
PMID:[Study on roles of L-arginine to nitric oxide pathway for the cardiovascular control: assessment with a new model of hypertension produced by the chronic administration of nitric oxide synthase inhibitor]. 752 39

A decrease in endothelium-derived relaxing factor or nitric oxide has been proposed as a potential mechanism of increased vascular resistance in hypertension. An increase in the generation of superoxide anions, which degrade nitric oxide and induce platelet aggregation, may also compromise regional blood flow in hypertension. Recent studies show that human neutrophils generate nitric oxide, which has a similar biologic profile to the endothelium-derived relaxing factor. This study measured nitric oxide synthase activity and superoxide generation in human neutrophils and platelet aggregation in patients with essential hypertension. Nitric oxide synthase activity, measured as conversion of 3H-L-arginine to 3H-L-citrulline, in peripheral blood neutrophils was decreased in hypertensive subjects (percent conversion of 3H-L-arginine: 4.2 +/- 0.5 vs 9.0 +/- 3.0 in control subjects; p < 0.01). Neutrophil superoxide anion generation, measured as conversion of ferricytochrome C to ferrocytochrome C, in response to phorbol-12-myristate 13-acetate (100 ng/ml) was higher in hypertensive subjects (17.5 +/- 8.1 vs 13.2 +/- 3.0 nmoles/10(6) cells/10 minutes in control subjects; p < 0.05). Patients were treated with a selective beta blocker, celiprolol, for 8 weeks. Supine blood pressure decreased from 177/103 mm Hg (mean +/- SD 18/7) to 160/92 mm Hg (mean +/- 10/5; p < 0.02), while heart rate was unchanged (73 +/- 11 vs 69 +/- 10 beats/min). Epinphrine and adenosine diphosphate-induced platelet aggregation was also increased in hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Alterations in nitric oxide synthase activity, superoxide anion generation, and platelet aggregation in systemic hypertension, and effects of celiprolol. 752 76

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

The present study evaluates the response to the L-type voltage gated calcium channel agonist Bay K 8644 in two forms of experimental hypertension (mineralocorticoid- and hypertension induced by the nitric oxide synthase inhibitor N omega-nitro-L-arginine (N-Nitro arginine)) and under conditions of acute stretch. These studies test the hypothesis that increased L-type calcium channel activity in vasculature is a hallmark or general characteristic of hypertension. Male Sprague-Dawley rats were made hypertensive by subcutaneous implantation of deoxycorticosterone acetate (200 mg/kg DOCA) and given normal or high salt water (1% NaCl + 0.2% KCl); other rats were made hypertensive by ingestion of N-Nitro arginine (2% in water). Systolic blood pressures (SBP) were taken by the standard tail cuff method. Following development of hypertension, rats were anesthetized, and aortae or mesenteric arteries were isolated for measurement of isometric contractile force. Cumulative concentration response curves to Bay K 8644 (10(-10) to 10(-6) M), KCl (6 to 100 mM), or phenylephrine (10(-10)-3 x 10(-7) M) were evaluated. Isolated mesenteric arteries from rats given both DOCA and salt were most sensitive to Bay K 8644 (SBP = 191 +/- 6 mmHg, -log EC50 = 7.78 +/- 0.13), followed by rats receiving high salt alone (SBP = 118 +/- 6 mmHg, -log EC50 = 7.30 +/- 0.17), DOCA alone (SBP = 152 +/- 2 mmHg, -log EC50 = 7.25 +/- 0.15), and finally normal sham rats (SBP = 111 +/- 5 mm Hg, -log EC50 > or = 6.80 +/- 0.10). These data indicate that both DOCA and salt intake can independently influence responsiveness to Bay K 8644.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Enhanced vascular responsiveness to Bay K 8644 in mineralocorticoid- and N-nitro arginine-induced hypertension. 753 26

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

We investigated mechanisms by which hypoxia produces relaxation of the aorta and tested the hypothesis that these mechanisms are altered during chronic hypertension. Tension of thoracic aortae from normotensive Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP) was measured in an organ bath under control conditions and at two levels of hypoxia. In WKY rats, mild and severe hypoxia produced relaxation of the aortae (precontracted with phenylephrine) by 33 +/- 4% and 82 +/- 3%, respectively (mean +/- SEM). Removal of endothelium or administration of NG-nitro-L-arginine (10(-4) mol/L), an inhibitor of nitric oxide synthase, abolished relaxation of the aortae in response to mild hypoxia but did not affect relaxation during severe hypoxia. Glibenclamide (10(-6) mol/L), an inhibitor of potassium channels, attenuated relaxation of the aortae during mild and severe hypoxia by 49 +/- 16% and 74 +/- 4%, respectively. In SHRSP, mild hypoxia produced little relaxation of the aortae (3 +/- 4%, P < .05 compared with WKY). Indomethacin did not increase relaxation to mild hypoxia in SHRSP, which suggests that a cyclooxygenase-derived contracting factor does not contribute to impaired relaxation. Severe hypoxia relaxed the aortae by 86 +/- 4% in SHRSP, and glibenclamide inhibited this response by 60 +/- 9%. These findings suggest that relaxation of the aorta in response to mild hypoxia in WKY rats is mediated primarily by endothelium-derived relaxing factor, and the response to mild hypoxia is markedly impaired in SHRSP.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Apr
PMID:Relaxation of the aorta during hypoxia is impaired in chronically hypertensive rats. 753 13


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