Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Nitric oxide (NO) is an important intercellular signaling molecule synthesized in diverse human tissues by proteins encoded by a family of NO synthase (NOS) genes. The similarity of sequence and cofactor binding sites has suggested that the NOS genes may also be related to cytochrome P450 reductase, as well as to plant and bacterial oxidoreductases. Endothelial NOS activity is a major determinant of vascular tone and blood pressure, and in several important (and sometimes hereditary) disease states, such as hypertension, diabetes, and atherosclerosis, the endothelial NO signaling system appears to be abnormal. To explore the relationship of the endothelial NOS gene to other similar genes, and to delineate the genetic factors involved in regulating endothelial NOS activity, we isolated the human gene encoding the endothelial NOS. Genomic clones containing the 5' end of this gene were identified in a human genomic library by applying a polymerase chain reaction (PCR)-based approach. Identification of the human gene for endothelial NOS (NOS3) was confirmed by nucleotide sequence analysis of the first coding exon, which was found to be identical to its cognate cDNA. The NOS3 gene spans at least 20 kb and appears to contain multiple introns. The transcription start site and promoter region of the NOS3 gene were identified by primer extension and ribonuclease protection assays. Sequencing of the putative promoter revealed consensus sequences for the shear stress-response element, as well as cytokine-responsive cis regulatory sequences, both possibly important to the roles played by NOS3 in the normal and the diseased cardiovascular system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene. 751 68

Nitric oxide (NO) has effects on renal blood flow, glomerular filtration rate, renin secretion, and renal sodium excretion. Four isoforms of nitric oxide synthase (NOS) have been cloned to date. However, the molecular identity of NOS present in the renal vasculature is unknown. Endothelial NOS (NOS-III) is regulated both acutely by cell calcium and chronically by shear stress. To determine if renal blood vessels and the glomerulus express NOS-III mRNA, we used degenerate polymerase chain reaction (PCR) to clone a portion of rat NOS-III. We then assayed NOS-III mRNA in microdissected renal structures by reverse transcriptase-PCR. NOS-III mRNA was expressed at high levels in glomeruli, arcuate vessels, and interlobular artery/afferent arterioles. NOS-III mRNA was detected inconsistently in proximal tubules, thick ascending limbs, and cortical and inner medullary collecting ducts. Previous studies have shown that chronic oral treatment with the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) decreases NO synthesis and causes hypertension. To determine if the systemic blockade occurs only by competitive inhibition, we determined the effect of L-NAME on glomerular NOS-III mRNA. L-NAME administration (5 days) decreased NOS-III mRNA in the glomerulus to 25 +/- 12% of control levels. We conclude that endothelial NOS-III mRNA is preferentially expressed in the glomerulus and renal vasculature, where it can modulate renal blood flow and glomerular filtration rate. Furthermore, glomerular NOS-III may be modulated at the level of mRNA abundance in vivo by systemic L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization and regulation of endothelial NO synthase mRNA expression in rat kidney. 752 Jun 68

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

Protein kinase C (PKC) plays a key role in a variety of signal transduction processes. The promoter region of the endothelial constitutive nitric oxide synthase (ecNOS) gene contains a transcriptional factor AP-1 binding element. In the present study, we sought to determine the effect of PKC inhibition on the expression of ecNOS in cultured bovine aortic endothelial cells (BAEC). The PKC inhibitor staurosporine (10 to 100 nmol/L) increased the expression of ecNOS mRNA, assessed by Northern analysis, in a dose-dependent manner. A newly developed, more specific PKC inhibitor, chelerythrine (1 to 3 mumol/L), also increased the level of ecNOS mRNA. Incubation of BAEC with phorbol 12-myristate 13-acetate (100 nmol/L) for 24 hours, which downregulates PKC, increased ecNOS mRNA expression. The protein content of ecNOS, assessed by Western analysis, was also increased in staurosporine-treated or chelerythrine-treated BAEC. The release of nitrogen oxides from staurosporine-treated or chelerythrine-treated cells both under basal conditions and in response to calcium ionophore A23187 was significantly increased (P < .05). In conclusion, the present study suggests that regulation of ecNOS is mediated by PKC. The increased release of nitric oxide induced by PKC inhibition may play a protective role against atherogenic process.
Hypertension 1995 Mar
PMID:Regulation of endothelial constitutive nitric oxide synthase by protein kinase C. 753 40

NO, a simple molecule synthesized from L-arginine by NO synthases, has been identified to play an important role in cell communication, cell defense and cell injury. The half life of NO is very short because NO either reacts with superoxide anion (O2-), and/or binds to heme molecules or Fe-S groups present in proteins. The biological effects of NO depend on both the concentration of NO at the site of action as well as upon the specific location where NO is generated. Small quantities of NO are generated by cNOS such as that present in the vascular endothelium, while large quantities of nitric oxide are synthesized by iNOS in response to cytokines or bacterial products. Within the kidney NO generated by endothelial cNOS participates in the regulation of the glomerular microcirculation by modifying the tone of the afferent arteriole and mesangial cells (Fig. 4). In addition, NO generated by macula densa and the afferent arteriole control glomerular hemodynamics via TGF and by modulating renin release. Therefore NO is important in the physiologic regulation of glomerular capillary blood pressure, glomerular plasma flow and the glomerular ultrafiltration coefficient. Through its actions on glomerular pressures and flows, NO may also regulate the macro- and micromolecular traffic through the mesangium. Chronic NO insufficiency causes hypertension and glomerular damage and may be causally involved in the genesis of salt dependent hypertension. Increased NO production may be involved in the early pathogenic hemodynamic changes in diabetes and in the physiologic hemodynamic responses to normal pregnancy. Maintenance of the antithrombogenic properties of the endothelium is another important action of NO which inhibits platelet aggregation and adhesion. Large quantities of NO such as that synthesized by either glomerular cells or macrophages during glomerular inflammation may lead to glomerular injury. A better understanding of the physiology and pathophysiology of NO in the kidney will lead to the development of new therapeutic avenues.
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PMID:Glomerular actions of nitric oxide. 756 80

To elucidate whether cytokines induce nitric oxide synthase in vascular smooth muscle cells, we studied the effects of human recombinant interleukin-1 beta on the synthesis and release of nitric oxide in cultured rat vascular smooth muscle cells by measurement of NO2-/NO3- levels. Furthermore, we performed Northern blot analysis using subcloned polymerase chain reaction products as probes for constitutive and inducible nitric oxide synthase. Interleukin-1 beta dose dependently (1 to 20 ng/mL) stimulated NO2-/NO3- production as a function of time. Northern blotting demonstrated the interleukin-1 beta-induced expression of messenger RNA for an inducible but not for the constitutive nitric oxide synthase after 3 hours. NG-Monomethyl L-arginine completely blocked the interleukin-1 beta-induced NO2-/NO3- production, the effect of which was reversed by L-arginine but not by D-arginine. Dexamethasone inhibited the interleukin-1 beta-induced NO2-/NO3- production in a dose-dependent manner (10(-9) to 10(-7) M) and the interleukin-1 beta-inducible nitric oxide synthase messenger RNA levels. Neither a calmodulin inhibitor (W-7) nor a protein kinase C inhibitor (staurosporine) showed any effects on the induction of nitric oxide synthase transcripts or production of NO2-/NO3- stimulated by interleukin-1 beta, whereas cycloheximide and actinomycin D completely inhibited the basal and stimulated NO2-/NO3- production. These data demonstrate for the first time that interleukin-1 beta induces gene expression of inducible nitric oxide synthase and its de novo protein synthesis in rat vascular smooth muscle cells, thereby leading to generation of nitric oxide via Ca2+/calmodulin-independent and protein kinase C-independent mechanisms.
Hypertension 1993 Jul
PMID:Induction of nitric oxide synthase gene by interleukin in vascular smooth muscle cells. 768 32

During the last decade, a multitude of experimental arguments have led to the concept that EDRF is nitric oxide (NO), a messenger not only involved in the control of vasomotor tone but also in vascular homeostasis, neuronal and immunological functions. Regardless of its origin, endogenous NO is produced through the conversion of L-arginine to L-citrulline by NO-synthase (NOS) from which several isoforms have recently been isolated, purified and cloned. NOS-type I (isolated from brain) and type III (isolated from endothelial cells) are termed "constitutive-NOS" and produce picomolar levels of NO from which only a small fraction elicits physiological responses. These isoforms are regulated by Ca(2+)-calmodulin with NADPH, FAD/FMN and tetrahydrobiopterin as co-factors and reveal a high degree of homology with the amino-acid sequence of cytochrome P450 reductase within the C-terminal domain. Functionally, neuronal-NOS type I is important in neurotransmission (modulation of NMDA receptor), the central control of vascular homeostasis and possibly learning and memory. In the peripheral nervous system, NOS appears to be linked to nonadrenergic noncholinergic (NANC) neuronal pathways. Endothelial-NOS type III is essential for the control of vascular tone in response to the release of endogenous mediators, although shear stress is the major trigger of endothelial-NOS activity under physiological conditions. NOS-type III also contributes to the prevention of abnormal platelet aggregation. NOS-types II and IV (isolated from macrophages) are Ca(2+)-calmodulin independent and are termed "inducible-NOS" since their activation is only promoted under pathophysiological situations where macrophages exert cytotoxic effects in response to cytokines. In contrast with NOS-types I and III, activation of NOS-type II in these cells induces the formation of nanomolar levels of NO which act as a defense mechanism of the immune system. Dysfunctions of the L-arginine-NO pathway have been characterized in multiple diseases (atherosclerosis, hypertension, diabetes, sepsis, cerebral ischemia, etc) and the design of more selective activators/inhibitors of NOS isoforms is a new challenge for the understanding of their pathophysiology and treatment.
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PMID:Nitric oxide: an ubiquitous messenger. 829 80

To examine whether endothelial dysfunction in hypertension is reversible or not, we studied the effects of imidapril, an angiotensin-converting enzyme inhibitor, on nitric oxide release in stroke-prone spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. After a 4-week treatment with imidapril (1 or 10 mg/d SC) or vehicle, acetylcholine-induced vasodilation and nitric oxide release in the isolated kidneys were determined. Nitric oxide release was measured by a chemiluminescense assay. Imidapril lowered blood pressure in stroke-prone SHR in a dose-dependent manner. Untreated stroke-prone SHR exhibited significantly attenuated responses to acetylcholine (10(-8) mol/L) of both renal perfusion pressure (stroke-prone SHE 42 +/- 4% versus Wistar-Kyoto rats [WKY] 58 +/- 4% [mean +/- SE], P < .01) and nitric oxide release (stroke-prone SHR +7.6 +/- 2.1 versus WKY +29.7 +/- 9.7 fmol/min per gram of kidney wt, P < .01). Imidapril at 10 mg/d significantly increased acetylcholine-induced renal vasodilation and nitric oxide release in stroke-prone SHR (renal perfusion pressure, 56 +/- 3%; nitric oxide release, +27.1 +/- 6.4 fmol/min per gram of kidney wt; both P < .01 versus stroke-prone SHR treated with vehicle). On the other hand, imidapril neither decreased blood pressure nor changed nitric oxide release induced by acetylcholine in DOCA-salt hypertensive rats. Staining for endothelial nitric oxide synthase and brain nitric oxide synthase was clearly detected in the kidneys of both stroke-prone SHR and WKY, whereas staining intensity was weaker in DOCA-salt hypertensive rats. Inducible nitric oxide synthase immunoreactivity was barely noticeable in any type of rat. Thus, imidapril restored endothelial damage by pressure-dependent mechanisms. Most of the nitric oxide detected in the perfusate seemed to be derived from constitutive nitric oxide synthase.
Hypertension 1996 Mar
PMID:Nitric oxide release from kidneys of hypertensive rats treated with imidapril. 861 23

The adaptive changes that occur in the left ventricle (LV) and vessels in response to hypertension, namely, muscle hypertrophy/hyperplasia, endothelial dysfunction, and extracellular matrix increase, do not depend solely on blood pressure elevation. These changes are in fact, maladaptive since they are forerunners of cardiac failure, stroke, and renal failure. Nitric oxide, an endogenous vasodilator and inhibitor of vascular smooth muscle cell growth, is synthesized in the endothelium by constitutive nitric oxide synthase (cNOS). We investigated the relationships among LV and aortic cNOS activity (conversion of [14C] L-arginine to [14C] L-citrulline), with LV hypertrophy (LV weight/body weight), and (2) aortic hypertrophy (aortic weight/ length) in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats matched for blood pressure (219 +/- 12 versus 211 +/- 7 mm Hg, P = NS) and age. Compared with their normotensive counterparts, aortic cNOS activity was increased 106% in SHR but reduced by 73% in DS rats. The correlation between blood pressure and aortic cNOS activity was positive (r = .74, P < .01) in SHR and negative (r = -.82, P < .01) in DS rats, LV cNOS activity was increased 73% in SHR compared with normotensive Wistar-Kyoto rats (P < .01). On the other hand, LV cNOS activity was not increased in hypertensive DS rats compared with normotensive DS rats. In SHR, aortic hypertrophy did not increase significantly and LV hypertrophy increased only 15%, whereas in hypertensive DS rats the aorta and LV hypertrophied 36% and 88%, respectively (both P < .01). Moreover, in DS rats there was a negative correlation between cNOS activity and aortic hypertrophy (r = -.70, P < .01). In DS rats, antihypertensive therapy consisting of an angiotensin-converting enzyme inhibitor, perindopril, and a diuretic, indapamide, normalized blood pressure, aortic cNOS activity, and LV hypertrophy and reduced aortic hypertrophy. Our studies imply that upregulation of vascular cNOS activity has a protective cardiovascular homeostatic role in hypertension. Clinically, the variable end-organ disease observed in individuals with similar severity of hypertension may be explained, at least in part, by genetically conditioned differences in vascular cNOS activity in response to hypertension.
Hypertension 1997 Jan
PMID:The link among nitric oxide synthase activity, endothelial function, and aortic and ventricular hypertrophy in hypertension. 903 8

Young (approximately 1 month old) male normotensive Wistar-Kyoto rats (n=26) and spontaneously hypertensive rats (n=38) were randomized into three groups treated via drinking water for approximately 2 years with, respectively, placebo, low doses, or high doses of an angiotensin-converting enzyme inhibitor, ramipril (10 microg x kg[-1] x d[-1], non-blood pressure-lowering dose, or 1 mg x kg[-1] x d[-1], blood pressure-lowering dose). Relative to placebo treatment in each respective rat strain, both ramipril dosages increased endothelial constitutive nitric oxide synthase expression (Western blot) and resultant synthesis of nitric oxide (porphyrinic sensor) in freshly excised carotids and thoracic aortas, respectively. Paradoxically, this activity was associated with an increased/decreased superoxide accumulation (chemiluminescence) in freshly excised aortas from 24-/22-month-old normotensive/hypertensive rats. In normotensive rats, relative to placebo treatment, the threefold increase in superoxide accumulation with antihypertensive ramipril treatment is most likely from the >300% increase in endothelial constitutive nitric oxide synthase expression (some of which may be disarranged by local insufficiencies in L-arginine or tetrahydrobiopterin). In hypertensive rats, relative to placebo treatment, the 35% increase in nitric oxide availability by long-term antihypertensive ramipril treatment may contribute to the preservation of the endothelium and prevent its dysfunction by inhibiting superoxide production. Increased nitric oxide production with concomitant decreased superoxide accumulation (approximately one third of placebo levels) correlates positively with the previously reported +40% life span extension for rats with genetic hypertension that were treated with antihypertensive doses of ramipril.
Hypertension 1997 Nov
PMID:Angiotensin-converting enzyme inhibition alters nitric oxide and superoxide release in normotensive and hypertensive rats. 936 74


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