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)

Group B Streptococcus (GBS) is the most common cause of neonatal sepsis and meningitis. Despite antibiotics, GBS in the newborn initiates a cascade of molecular and biological events leading to altered cerebral perfusion, blood-brain barrier disruption, cerebral edema, intracranial hypertension, neurological damage, and even death. Having previously shown that GBS infection impairs cerebral blood flow autoregulation and increases prostaglandin (PG) levels, we examined the regulation of some crucial inflammatory mediators (PGs, nitric oxide (NO), tumor necrosis factor-a) in the brain and cerebral microvessels (MVs) from newborn piglets. Cyclooxygenase (COX), the key enzyme in PG biosynthesis, exists in two isoforms, COX-1 and COX-2. Both may be directly induced by NO in a model of renal inflammation. Besides its neurotransmitter role, NO is a potent vasorelaxant whose production is catalyzed by at least three distinct nitric oxide synthases (NOS) (bNOS, ecNOS, iNOS). Western blot analyses showed that the newborn (4 day old) brain expressed lower levels of COX-1 (8-fold), COX-2 (20-fold), bNOS (12-fold), and ecNOS (5-fold) than in the 1 day old. MV showed approximately equal levels of COX-2, lower levels of COX-1 (4-fold), bNOS (5-fold), and higher levels of ecNOS (20-fold) in comparison to 4-day-old cerebral MV. A 4-day-old brain expressed lower levels of bNOS (5-fold), ecNOS (10-fold), and COX-1 (2-fold) than the 6-week-old pig. COX-2 protein was undetected in a 4-day-old pig brain, but present in great excess in MV. Purified MV showed lower ecNOS (14-fold), COX-1 (2-fold), and about equal levels of bNOS and COX-2 in comparison with MV from 6-week-old pigs. Reverse transcription polymerase chain reaction analyses confirmed these results. Treatment with noo-nitro-L-arginine (LNA), a NOS inhibitor, downregulated COX-1 expression in the newborn brain and both COX-1 and COX-2 cerebral MV expression. GBS infection (10(9) colony-forming units, 0.5 mL intracerebroventricular) of sedated newborn piglets induced the expression of tumor necrosis factor-alpha in the cerebrospinal fluid after 2 hours, upregulated bNOS expression in both brain and MVs, upregulated ecNOS in MVs, and downregulated COX-1, COX-2, and ecNOS in the brain. GBS did not trigger the expression of iNOS. Our data suggest that there is a net deficiency of NOS isoforms in the immature brain and microvasculature of the 4-day-old piglet and that the differences in expression lead to the immature control of NO and PG production, rendering newborns particularly susceptible to neurological damage because of the undeveloped nature of their response mechanisms. Moreover, the GBS-induced cascade deregulates the gene expression of interacting inflammatory mediators and may cause a net vasoconstrictor/vasodilator imbalance, leading to cerebral hypertension and edema in the early stages of infection. Pharmacological manipulations of the inflammatory cascade could lead to novel therapeutic approaches for the treatment of GBS meningitis.
 ...
PMID:Deregulation of cyclooxygenase and nitric oxide synthase gene expression in the inflammatory cascade triggered by experimental group B streptococcal meningitis in the newborn brain and cerebral microvessels. 1040 95

Pathophysiological implications of the vascular nitric oxide (NO)/cGMP pathway were investigated in various rat models of hypertension. The expression of brain and endothelial constitutive NO synthases (bNOS, ecNOS) was determined by Western blot analysis, and the biochemical activity of soluble and particulate guanylate cyclases (GC) was assessed by the amount of cGMP generated in the thoracic aortae of rats with deoxycorticosterone acetate (DOCA)-salt, two-kidney, one dip (2K1C), and spontaneous hypertension (SHR). Plasma nitrite/ nitrate levels were decreased in DOCA-salt and 2K1C hypertension, and increased in SHR. The vascular expression of bNOS as well as that of ecNOS was decreased along with tissue nitrite/nitrate contents in DOCA-salt and 2K1C hypertension. The expression of both bNOS and ecNOS was increased in SHR with concomitant changes of tissue nitrite/nitrate contents. The activity of soluble GC was decreased, and that of particulate GC was increased in DOCA-salt hypertension. The soluble GC activity was increased, while the particulate GC activity was not affected in 2K1C hypertension. The soluble GC activity was not significantly changed, but the particulate GC activity was decreased in SHR. These results indicate that the high blood pressure is associated with differentially-altered vascular NO/cGMP pathway in different models of hypertension.
 ...
PMID:Differentially-altered vascular guanylate cyclase isoforms in experimental hypertensive rats. 1048 17

Male mice with targeted deletion of the gene encoding the neuronal isoform of nitric oxide synthase (nNOS(-/-)) display increased aggressive behavior compared with wild-type (WT) mice. Specific pharmacological inhibition of nNOS with 7-nitroindazole also augments aggressive behavior. We report here that male mice with targeted deletion of the gene encoding endothelial NOS (eNOS(-/-)) display dramatic reductions in aggression. The effects are selective, because an extensive battery of behavioral tests reveals no other deficits. In the resident-intruder model of aggression, resident eNOS(-/-) males show virtually no aggression. Latency for aggression onset is 25-30 times longer in eNOS(-/-) males compared with WT males in the rare instances of aggressive behaviors. Similarly, a striking lack of aggression is noted in tests of aggression among groups of four mice monitored in neutral cages. Although eNOS(-/-) mice are hypertensive ( approximately 14 mmHg blood pressure elevation), hypertension does not appear responsible for the diminished aggression. Reduction of hypertension with hydralazine does not change the prevalence of aggression in eNOS(-/-) mice. Extensive examination of brains from eNOS(-/-) male mice reveals no obvious neural damage from chronic hypertension. In situ hybridization in WT animals reveals eNOS mRNA in the brain associated exclusively with blood vessels and no neuronal localizations. Accordingly, vascular eNOS in the brain appears capable of influencing behavior with considerable selectivity.
 ...
PMID:Elimination of aggressive behavior in male mice lacking endothelial nitric oxide synthase. 1049 75

Previous studies have suggested that salt-sensitive hypertension in humans and experimental animals may in part be due to dysregulation of the L-arginine/nitric oxide system. This study was conducted to determine the endothelial, inducible, and neuronal nitric oxide synthase expressions in the kidney, heart, aorta, and brain of salt-sensitive and salt-resistant Dahl rats. We studied salt-sensitive and salt-resistant Dahl rats maintained on high- (8%) and regular- (0.2%) salt diets for 3 weeks. Blood pressure was modestly elevated in both Dahl salt-sensitive and salt-resistant rats consuming regular diet and severely increased in sensitive but not resistant rats consuming the high-salt diet. The Dahl salt-sensitive animals showed a significant reduction in kidney, heart, and aorta inducible nitric oxide synthase protein abundance on the regular diet, with further reductions on the high-salt diet. In addition, the high-salt diet markedly downregulated endothelial nitric oxide synthase expression in the kidney and aorta but not in the heart of the Dahl salt-sensitive animals. The rise in blood pressure in the Dahl salt-sensitive rats on the high-salt diet was accompanied by a significant elevation of brain neuronal nitric oxide synthase protein. In contrast, salt-resistant animals showed no change in heart, kidney, and aorta endothelial or brain neuronal nitric oxide synthase and considerably less intense changes in inducible isotype than that seen in the salt-sensitive group in response to the high-salt diet. In conclusion, the study revealed a marked downregulation of inducible nitric oxide synthase in the Dahl salt-sensitive rats on the regular diet, with further reductions on the high-salt diet. Furthermore, Dahl salt-sensitive rats consuming the high-salt diet showed significant reductions of kidney and aorta endothelial nitric oxide synthase and an upregulation of brain neuronal nitric oxide synthase expression.
Hypertension 1999 Oct
PMID:Nitric oxide synthase isotype expression in salt-sensitive and salt-resistant Dahl rats. 1052 25

This study was designed to examine the contribution of cyclooxygenase-2 (COX-2) in the afferent arteriolar autoregulatory responses to increases in perfusion pressure and its relationship with neuronal nitric oxide synthase (nNOS). In rat kidneys, afferent arteriolar diameter responses to increases in perfusion pressure were assessed in vitro with the blood-perfused juxtamedullary nephron technique. Basal afferent arteriolar diameter at 100 mm Hg averaged 21.0+/-1.2 microm (n=7), and the vasoconstrictor response to increasing perfusion pressure to 160 mm Hg averaged 18.4+/-1.2%. Superfusion with the COX-2 inhibitor NS398 (10 micromol/L) did not influence basal diameters, but it did significantly enhance the vasoconstrictor response to the increase in perfusion pressure (32.9+/-4.0%). In contrast to previous findings that the nNOS inhibitor S-methyl-L-thiocitrulline (10 micromol/L) enhanced afferent arteriolar autoregulatory responses in normal rat kidneys, in this study, administration of 10 micromol/L S-methyl-L-thiocitrulline did not further modulate the vasoconstrictor response to increases in perfusion pressure in the NS398-treated kidneys of normal rats (31.8+/-4.7%). When tubuloglomerular feedback activity was interrupted by papillectomy and the addition of 50 micromol/L furosemide to the blood perfusate (n=5 for each), the afferent arteriolar constrictor responses to increasing perfusion pressure to 160 mm Hg averaged 7.9+/-0.9% and 10.7+/-0.7%, respectively, and they were significantly attenuated compared with the responses observed in control kidneys. NS398 treatment did not modulate the afferent arteriolar autoregulatory responses in papillectomized or furosemide-treated kidneys. These results indicate that COX-2-derived metabolites contribute to the nNOS modulation of pressure-mediated afferent arteriolar autoregulatory responses.
Hypertension 1999 Oct
PMID:Cyclooxygenase-2 modulates afferent arteriolar responses to increases in pressure. 1052 71

We have previously demonstrated that nitric oxide (NO) exerts a greater modulatory influence on renal cortical blood flow in ANG II-infused hypertensive rats compared with normotensive rats. In the present study, we determined nitric oxide synthase (NOS) activities and protein levels in the renal cortex and medulla of normotensive and ANG II-infused hypertensive rats. Enzyme activity was determined by measuring the rate of formation of L-[(14)C]citrulline from L-[(14)C]arginine. Western blot analysis was performed to determine the regional expression of endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms in the renal cortex and medulla of control and ANG II-infused rats. Male Sprague-Dawley rats were prepared by the infusion of ANG II at a rate of 65 ng/min via osmotic minipumps implanted subcutaneously for 13 days and compared with sham-operated rats. Systolic arterial pressures were 127 +/- 2 and 182 +/- 3 mmHg in control (n = 13) and ANG II-infused rats (n = 13), respectively. The Ca(2+)-dependent NOS activity, expressed as picomoles of citrulline formed per minute per gram wet weight, was higher in the renal cortex of ANG II-infused rats (91 +/- 11) than in control rats (42 +/- 12). Likewise, both eNOS and nNOS were markedly elevated in the renal cortex of the ANG II-treated rats. In both groups of rats, Ca(2+)-dependent NOS activity was higher in the renal medulla than in the cortex; however, no differences in medullary NOS activity were observed between the groups. Also, no differences in medullary eNOS levels were observed between the groups; however, medullary nNOS was decreased by 45% in the ANG II-infused rats. For the Ca(2+)-independent NOS activities, the renal cortex exhibited a greater activity in the control rats (174 +/- 23) than in ANG II-infused rats (101 +/- 10). Similarly, cortical iNOS was greater by 47% in the control rats than in ANG II-treated rats. No differences in the activity were found for the renal medulla between the groups. There was no detectable signal for iNOS in the renal medulla for both groups. These data indicate that there is a differential distribution of NOS activity, with the Ca(2+)-dependent activity and protein expression higher in the renal cortex of ANG II-infused rats compared with control rats, and support the hypothesis that increased constitutive NOS activity exerts a protective effect in ANG II-induced hypertension to maintain adequate renal cortical blood flow.
 ...
PMID:Increased activity and expression of Ca(2+)-dependent NOS in renal cortex of ANG II-infused hypertensive rats. 1056 45

We recently reported that the rat thick ascending limb (THAL) possesses an active isoform of nitric oxide synthase (NOS) that is substrate-limited in vitro. NO produced by THAL NOS inhibits chloride flux. Protein and transcript for each of the primary NOS isoforms-endothelial (eNOS), inducible (iNOS), and neuronal (nNOS)-have been demonstrated in THALs. However, the NOS isoform that mediates NO-induced inhibition of chloride flux is unknown. We hypothesized that NO produced from eNOS in the THAL inhibits NaCl transport. THALs from male eNOS, iNOS, and nNOS knockout mice and C57BL/6J wild-type controls were perfused in vitro and the response of transepithelial chloride flux (J(Cl)) to L-arginine (L-Arg), the substrate for NOS, and spermine NONOate (SPM), an NO donor was measured. We first tested whether isolated mouse THALs could synthesize NO and whether this NO inhibits transport. Addition of 0. 5 mmol/L L-Arg to the bath decreased J(Cl) from 105.8+/-17.5 to 79. 2+/-15.8 pmol/mm per minute (P<0.01) in C57BL/6J wild-type mice, whereas addition of D-Arginine had no effects on J(Cl.) In contrast, addition of 0.5 mmol/L L-Arg to the bath did not alter J(Cl) of THALs from eNOS knockout mice. When 10 micromol/L SPM was added to the bath of eNOS knockout THALs, J(Cl) decreased from 89.1+/-8.6 to 74.8+/-7.5 pmol/mm/min (P<0.05). Thus the lack of responsiveness of eNOS knockout THALs to L-Arg was not due to an inability to respond to NO. We next evaluated the role of iNOS and nNOS in the response to L-Arg. Addition of 0.5 mmol/L L-Arg to the bath decreased J(Cl) in THALs from iNOS and nNOS knockout mice by 37.7+/-6.4% (P<0.05) and 31.8+/-8.3% (P<0.01), respectively. We conclude that eNOS is the active isoform of NOS in the THAL under basal conditions. Mouse THAL eNOS responds to exogenous L-Arg by increasing NO production, which, in turn, inhibits J(Cl).
Hypertension 2000 Jan
PMID:eNOS mediates L-arginine-induced inhibition of thick ascending limb chloride flux. 1064 18

Diabetes is associated with alterations in nitric oxide-mediated vasomotor function. The role of nitric oxide generated via the neuronal nitric oxide synthase pathway in the control of systemic and renal hemodynamics in diabetes has not been studied. To explore the hypothesis that diabetic vascular dysfunction is in part caused by altered neuronal nitric oxide synthase activity, systemic and renal hemodynamics were assessed before and after acute inhibition of this enzyme with a specific inhibitor, S-methyl-L-thiocitrulline, in control and diabetic rats. The interaction of this pathway and the renin-angiotensin system was studied in separate groups of rats pretreated with the angiotensin II receptor blocker losartan; these rats were compared with rats treated with losartan alone. Diabetic animals demonstrated higher baseline glomerular filtration rates and filtration fractions. At a low dose, the neuronal nitric oxide synthase inhibitor induced similar dose-dependent pressor responses in control and diabetic rats. Losartan abolished the pressor response in both groups. No changes in renal plasma flow or renal vascular resistance occurred in control rats. In contrast, diabetic rats responded with significant renal vasoconstriction. At a high dose, the renal vasoconstriction was similar in both groups and was not affected by losartan. In conclusion, neuronal nitric oxide synthase-derived nitric oxide plays a role in the control of systemic and renal hemodynamics in normal and diabetic rats. Diabetic rats are more sensitive to the inhibitor, suggesting increased activity of this pathway in the diabetic kidney. Furthermore, renal responses in diabetic rats were attenuated by angiotensin II receptor blockade, whereas losartan alone induced hemodynamic changes that were opposite those seen with neuronal nitric oxide synthase inhibition. This observation implicates angiotensin II as an important modulator of this nitric oxide pathway in diabetes.
Hypertension 2000 Feb
PMID:Effects of systemic inhibition of neuronal nitric oxide synthase in diabetic rats. 1067 13

The juxtaglomerular apparatus (JGA) has the very important functions of detecting the fluid flow rate to the distal tubule and thus controlling the glomerular filtration rate (GFR) (tubuloglomerular feedback mechanism [TGF]) and renin release from the afferent arteriole. In studies of the TGF it has been evident that the sensitivity of this mechanism can be reset. Volume expansion will reset it to a low sensitivity leading to a high GFR and urine excretion rate, while dehydration will sensitize the TGF mechanism, giving rise to a low GFR and low urine excretion rate. Furthermore, we have found that in animals that spontaneously develop hypertension there is initially a sensitization of the TGF, leading to a reduced GFR and urine excretion rate, with fluid volume retention in the body and a consequent rise in blood pressure. When the pressure is raised, the TGF characteristics are normalized. In the macula densa (MD) cells in the JGA, there is a large production of NO from neuronal NOS. This production continuously reduces TGF sensitivity and is apparently impaired in animals that spontaneously develop hypertension. When we added an nNOS inhibitor to the drinking water for several weeks while measuring blood pressure, we found an increase in blood pressure after 3-4 weeks of treatment. This effect was abolished by a high salt diet. From these investigations, it also appeared as if nNOS-derived NO inhibited renin release. Experiments have also indicated that NO may resensitize inhibited G-protein coupled purinergic receptors.
 ...
PMID:Renal NO production and the development of hypertension. 1069 96

1. Accumulating animal and human data suggest that nitric oxide (NO) is important for both coronary and peripheral haemodynamic control and metabolic regulation during performance of exercise. 2. While still controversial, NO of endothelial origin is thought to potentiate exercise-induced hyperaemia, both in the peripheral and coronary circulations. The mechanism of release may include both acetylcholine derived from the neuromuscular junction and vascular shear stress. 3. A splice variant of neuronal nitric oxide synthase (NOS), nNOSmicro, incorporating an extra 34 amino acids, is expressed in human skeletal muscle. In addition to being a potential modulator of blood flow, skeletal muscle-derived NO is an important regulator of muscle contraction and metabolism. In particular, recent human data indicate that NO modulates muscle glucose uptake during exercise, independently of blood flow. 4. Exercise training in healthy individuals promotes adaptations in the various NO systems, which can increase NO bioavailability through a variety of mechanisms, including increased NOS enzyme expression and activity. Such adaptations likely contribute to increased exercise capacity and protection from cardiovascular events. 5. Cardiovascular risk factors, including hypercholesterolaemia, hypertension, diabetes and smoking, as well as established disease, are associated with impairment of the various NO systems. Given that NO is an important signalling mechanism during exercise, such impairment may contribute to limitations in exercise capacity through inadequate coronary or peripheral blood delivery and via metabolic effects. 6. Exercise training in individuals with elevated cardiovascular risk or established disease can increase NO bioavailability and may represent an important mechanism by which exercise training provides benefit in the setting of secondary prevention.
 ...
PMID:Nitric oxide as a metabolic regulator during exercise: effects of training in health and disease. 1077 20


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