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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The characterization and cloning of constitutive and inducible nitric oxide (NO)-synthesizing enzymes and the development of specific inhibitors of the L-arginine NO pathway have provided powerful tools to define the role of NO in renal physiology and pathophysiology. There is increasing evidence that endothelium-derived NO is tonically synthesized within the kidney and that NO plays a crucial role in the regulation of renal hemodynamics and excretory function. Bradykinin and acetylcholine induce renal vasodilation by increasing NO synthesis, which in turn leads to enhancement of diuresis and natriuresis. The blockade of basal NO synthesis has been shown to result in decreases of renal blood flow and sodium excretion. These effects are partly mediated by an interaction between NO and the renin angiotensin system. Intrarenal inhibition of NO synthesis leads to reduction of sodium excretory responses to changes in renal arterial pressure without an effect on renal autoregulation, suggesting that NO exerts a permissive or a mediatory role in pressure natriuresis. Nitric oxide released from the macula densa may modulate tubuloglomerular feedback response by affecting afferent arteriolar constriction. Nitric oxide produced in the proximal tubule possibly mediates the effects of angiotensin on tubular reabsorption. In the collecting duct, an NO-dependent inhibition of solute transport is suggested. The L-arginine NO pathway is also active in the glomerulus. Under pathologic conditions such as glomerulonephritis, NO generation is markedly enhanced due to the induction of NO synthase, which is mainly derived from infiltrating macrophages. An implication of NO in the mechanism of proteinuria, thrombosis mesangial proliferation, and leukocyte infiltration is considered. In summary, the data presented on NO and renal function have an obvious clinical implication. A role for NO in glomerular pathology has been established. Nitric oxide is the only vasodilator that closely corresponds to the characteristics of essential hypertension. Using chronic NO blockade, models of systemic hypertension will provide new insights into mechanisms of the development of high blood pressure.
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PMID:Nitric oxide in the kidney: synthesis, localization, and function. 751 25

The purpose of these experiments was to determine in normotensive rats the role of endogenous bradykinin, prostaglandins, and nitric oxide in glucose metabolism and blood pressure response to hyperinsulinemia. Normotensive Wistar rats were treated with two different bradykinin antagonists, indomethacin or N omega-nitro-L-arginine methyl ester, concurrently with a euglycemic clamp with insulin infusion rates of 3 or 6 mU/kg per minute. Glucose uptake, steady-state plasma insulin levels, and insulin sensitivity index were determined over 2 hours. Bradykinin inhibition dramatically reduced glucose uptake and insulin sensitivity index during both the lower and higher insulin infusion rates to 30% and 32%, respectively, of values observed in control rats. Inhibition of prostaglandins or nitric oxide did not alter glucose metabolism in these rats. Blood pressure remained unchanged in the control group throughout the clamp but increased significantly in rats submitted to inhibition of bradykinin, prostaglandins, or nitric oxide, suggesting that these vasodilator systems tend to counteract the hypertensive effect of hyperinsulinemia. The counterregulatory component attributable to bradykinin was about twice as great as that attributable to nitric oxide. These findings suggest that insulin infusion in normotensive Wistar rats fails to raise blood pressure because its effects are offset by mobilization of vasodilator mechanisms, such as bradykinin, prostaglandins, and nitric oxide. Bradykinin seems to play the most important homeostatic role under these conditions, because its inhibition significantly reduces insulin sensitivity and allows blood pressure to rise.
Hypertension 1995 May
PMID:Role of bradykinin in insulin sensitivity and blood pressure regulation during hyperinsulinemia. 773 6

Brief angiotensin-converting enzyme (ACE) inhibition in young spontaneously hypertensive rats (SHR) causes a persistent reduction in blood pressure. Bradykinin accumulation may contribute to these long-term effects, and to test this hypothesis we studied the consequences of bradykinin B2 receptor antagonism during ACE inhibitor treatment in young SHR. Male SHR were treated from 6 to 10 weeks of age with water, ramipril (1 mg/kg per day), Hoe 140 (0.5 mg/kg per day), or both ramipril and Hoe 140. Systolic blood pressure and body weight were measured each week from 6 to 20 weeks of age. During treatment, Hoe 140 treatment resulted in lower blood pressures than in controls. Rampiril caused a larger fall in blood pressure over the same period. The ramipril plus Hoe 140 group had the lowest blood pressures of any group during treatment. After treatment, the blood pressure of Hoe 140-treated SHR was similar to that of untreated SHR. After ramipril, blood pressure rose but plateaued significantly below values in controls. In contrast, withdrawal of combined ramipril and Hoe 140 treatment caused a rapid rise of systolic blood pressure to levels significantly higher than in ramipril-treated SHR but less than in controls. The antihypertensive effects of Hoe 140 during the development of genetic hypertension may represent a direct effect of the drug or some alteration in the normal relation between bradykinin and blood pressure. The antagonism by Hoe 140 of the long-term blood pressure reduction after ramipril withdrawal indicates that the persistent effects of ACE inhibitors may in part be due to the accumulation of bradykinin during a critical stage of development.
Hypertension 1995 Feb
PMID:Resetting blood pressure in spontaneously hypertensive rats. The role of bradykinin. 784 64

We investigated the role of the renin-angiotensin system in neointima formation in a species in which converting enzyme inhibitors have been so far ineffective in suppressing abnormal vascular repair. The effects of converting enzyme inhibition by perindopril and selective blockade of angiotensin subtype 1 receptor by DuP 753 were assessed on neointima formation after balloon injury of rabbit carotid artery. Myointimal growth was measured by histomorphometric analysis. In rabbits treated 6 days before and for 14 days after injury, perindopril (2 mg/kg per day PO, n = 7) significantly reduced neointima formation (-51%, P < .01). DuP 753 (1 mg/d, n = 8) infused perivascularly for 14 days in the vicinity of injured carotid artery also markedly suppressed myointimal thickening (-60%, P < .01). To determine whether angiotensin subtype 2 receptor was implicated in this vascular response, we infused CGP 42112A, a specific subtype 2 receptor ligand, continuously for 14 days according to the same protocol of DuP 753 administration. CGP 42112A (1 mg/d) did not change the neointima-media ratio, indicating that angiotensin subtype 2 receptors were not involved in myointimal hyperplasia in rabbits. Thus in rabbits, the renin-angiotensin system plays a major role in neointima formation, and the protective effect of perindopril appears to be mediated mainly by inhibition of angiotensin II production, because blockade of the subtype 1 receptor reduced myointimal growth in a manner similar to that of converting enzyme inhibition and because intracarotid infusion of angiotensin II (500 ng/min) at the site of injury enhanced the vascular response (+39%, P < .05). Bradykinin (500 ng/min) administered in the same conditions as angiotensin II did not modify neointima formation.
Hypertension 1994 Dec
PMID:Role of the renin-angiotensin system in neointima formation after injury in rabbits. 799 23

Bradykinin-induced relaxation of precontracted, porcine coronary artery (PCA) rings is mediated by distinctly different endothelium-derived relaxing factors depending on the contractile agent used. Thus when contracted with KCl, bradykinin-induced relaxation of PCA rings is mediated solely by nitric oxide (NO), whereas when contracted with the thromboxane mimetic U46619, a small component of the relaxation is attributable to NO and a large component is attributable to a non-NO mechanism that is independent of cyclooxygenase activity. We hypothesized that the non-NO component was mediated by arachidonic acid (AA) or by a non-cyclooxygenase product of AA metabolism. Bradykinin-induced relaxations of PCA rings precontracted with U46619 in the presence of indomethacin (10 mumol/L) were moderately attenuated by the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 100 mumol/L), whereas when precontracted with KCl, L-NAME abolished the relaxations. AA produced endothelium-dependent relaxations of rings precontracted with U46619 that were unaffected by L-NAME, whereas AA did not relax rings precontracted with KCl. In rings precontracted with U46619, in the presence of L-NAME and indomethacin the phospholipase inhibitors quinacrine (50 mumol/L) and 4-bromophenacyl bromide (10 mumol/L) attenuated bradykinin- but not AA-induced relaxations. Inhibitors of both lipoxygenase (BW 755c [100 mumol/L] and nafazatrom [20 mumol/L]) and cytochrome P-450 (proadifen [10 mumol/L] and clotrimazole [10 mumol/L]) pathways did not eliminate bradykinin- or AA-induced relaxations, although clotrimazole partially attenuated AA-induced relaxations. These findings suggest that bradykinin-induced relaxation of PCA rings is mediated by AA through a mechanism that is not dependent on cyclooxygenase, lipoxygenase, or cytochrome P-450 pathways.
Hypertension 1994 Jun
PMID:Relaxation of porcine coronary artery to bradykinin. Role of arachidonic acid. 820 38

Prostaglandins (PGs) and bradykinin act as potent respiratory irritants in both normal and asthmatic subjects, but their sites of action are unknown. We compared the cardiorespiratory effects of bradykinin, PGE2, and PGF2 alpha nebulized into the isolated "in situ" larynx, inhaled into the tracheobronchial tree, and injected intravenously in anesthetized spontaneously breathing dogs. Laryngeal administration only resulted in a brief burst of rapid shallow breaths produced by bradykinin (1,000 micrograms/ml) in one of five dogs. Tracheobronchial administration of bradykinin (1,000 micrograms/ml) increased breathing rate and tidal volume (VT) in four of seven dogs without changing cardiovascular parameters, whereas PGE2 (500 micrograms/ml) caused similar effects in two of six dogs. Lower concentrations of both agents were essentially without effect. PGF2 alpha (50-500 micrograms/ml) inhaled into the lower airway increased breathing rate, reduced VT, and caused a concentration-dependent bronchoconstriction that was significantly reduced by atropine. Inhaled PGF2 alpha only slightly increased arterial blood pressure (5.8 +/- 2.8%) and heart rate (12.0 +/- 6.4%). Intravenous PGF2 alpha (5 micrograms/kg) increased upper and lower airway resistances, which were accompanied by a decrease in breathing rate and VT, hypertension, and bradycardia. Bradykinin (1 micrograms/kg) and PGE2 (1 and 3 micrograms/kg) produced apnea followed by rapid shallow breathing, bradycardia, and hypotension. These results indicate that the tracheobronchial tree is considerably more responsive to aerosolized bradykinin, PGE2, and PGF2 alpha than the laryngeal region. Moreover, the stronger effects produced by intravascular administration suggest a greater accessibility of rapidly adapting stretch receptors and C-fiber endings from the vascular bed than from the airway lumen.
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PMID:Respiratory and cardiovascular effects of inhaled and intravenous bradykinin, PGE2, and PGF2 alpha in dogs. 833 71

1. Bradykinin and related kinins may act on four types of receptors designated as B1, B2, B3 and B4. It seems that the B2 receptors are most commonly found in various vascular and non-vascular smooth muscles, whereas B1 receptors are formed in vitro during trauma, and injury, and are found in bone tissues. 2. These BK receptors are involved in the regulations of various physiological and pathological processes. 3. The mode of kinin actions are based upon the interactions between the kinin and their specific receptors, which can lead to activation of several second-messenger systems. 4. Recently, numerous BK receptors antagonists have been synthesized with prime aim to treat diseases caused by excessive kinin production. 5. These diseases are RA, inflammatory diseases of the bowel, asthma, rhinitis and sore throat, allergic reactions, pain, inflammatory skin disorders, endotoxin and anaphylactic shock and coronary heart diseases. 6. On the other hand, BK receptor antagonists could be contraindicated in hypertension, since these drugs may antagonize the antihypertensive therapy and/or may trigger the hypertensive crisis. 7. It is worth suggesting that the BK receptor agonists might be useful antihypertensive drugs.
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PMID:Therapeutic prospects of bradykinin receptor antagonists. 838 49

In normotensive rats, renal sensory receptor activation by increased ureteral pressure results in increased ipsilateral afferent renal nerve activity, decreased contralateral efferent renal nerve activity, and contralateral diuresis and natriuresis, a contralateral inhibitory renorenal reflex response. In spontaneously hypertensive rats (SHR), increasing ureteral pressure fails to increase afferent renal nerve activity. The nature of the inhibitory renorenal reflexes indicates that an impairment of the renorenal reflexes would contribute to the increased efferent renal nerve activity in SHR. We therefore examined whether there was a general decrease in the responsiveness of renal sensory receptors in SHR by comparing the afferent renal nerve activity responses to bradykinin in SHR and Wistar-Kyoto rats (WKY). In WKY, renal pelvic perfusion with bradykinin at 4, 19, 95, and 475 micromol/L increased afferent renal nerve activity by 1066 +/- 704, 2127 +/- 1121, 3517 +/- 1225, and 4476 +/- 1631% x second (area under the curve of afferent renal nerve activity versus time). In SHR, bradykinin at 4 to 95 micromol/L failed to increase afferent renal nerve activity. Bradykinin at 475 micromol/L increased afferent renal nerve activity in only 6 of 10 SHR. In WKY, renal pelvic perfusion with the phorbol ester 4beta-phorbol 12,13-dibutyrate, known to activate protein kinase C, resulted in a peak afferent renal nerve activity response of 24 +/- 4%. However, 4beta-phorbol 12,13-dibutyrate failed to increase afferent renal nerve activity in SHR. These findings demonstrate decreased responsiveness of renal pelvic sensory receptors to bradykinin in SHR. The impaired afferent renal nerve activity responses to bradykinin in SHR may be due to a lack of protein kinase C activation or a defect in the intracellular signaling mechanisms distal to protein kinase C activation.
Hypertension 1996 Mar
PMID:Bradykinin and protein kinase C activation fail to stimulate renal sensory neurons in hypertensive rats. 861 11

Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions.
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PMID:Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough. 867 30

Angiotensin II can raise blood pressure rapidly by inducing direct vasoconstriction and by activating the sympathetic nervous system via central and peripheral mechanisms. In addition, this peptide may act as a growth factor to cause vascular and cardiac hypertrophy (CVH). The structural changes caused by hypertension can therefore be amplified by angiotensin II. Blockade of angiotensin II generation with angiotensin-converting enzyme (ACE) inhibitors appears to be particularly effective in preventing the development of cardiovascular hypertrophy. This beneficial effect might be related to some extent to local accumulation of bradykinin. ACE is one of the enzymes physiologically involved in bradykinin degradation. Treatment of hypertensive rats with a selective bradykinin antagonist can attenuate the blood pressure-lowering effect of ACE inhibition and render less effective the prevention of intimal thickening after endothelial removal from the rat carotid artery. Bradykinin is a vasodilator that acts by increasing the release of endothelium-derived factors such as nitric oxide and prostacyclin, which may have antiproliferative activity. However, blockade of the renin-angiotensin system with an angiotensin II subtype 1-receptor antagonist is also effective in preventing cardiac hypertrophy and neointimal proliferation after endothelial injury. Therefore, the exact contribution of bradykinin to the beneficial effects of ACE inhibition on cardiovascular hypertrophy remains to be further explored.
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PMID:Cardiovascular hypertrophy: role of angiotensin II and bradykinin. 872 98


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