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

---

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

Whether any class of antihypertensive drugs has specific renoprotective effects above and beyond lowering of blood pressure is still debatable. The renin-angiotensin system (RAS) is both localized and has many actions within the kidney, on intrarenal hemodynamics, on the mesangial cell, as well as stimulating growth factors and cytokines. Angiotensin converting enzyme (ACE) inhibitors have been shown to ameliorate the progression of renal failure. How much of this beneficial effect is due to their hemodynamic effects, how much to non-hemodynamic effects and how much to their effects on bradykinin and other putative ACE substrates is still unclear. Experimentally it can be shown that inhibiting ACE but preventing the fall in systemic blood pressure by salt loading abolishes renoprotection. Bradykinin has been implicated in both the beneficial and the adverse effects of ACE inhibitors. Because of this and because ACE inhibitors may not provide complete blockade of the RAS, angiotensin receptor (AT1R) antagonists have been developed. Experimentally AT1R antagonists have been shown to reproduce most of the beneficial effects of ACE inhibitors. The experience in humans is more limited but they have been demonstrated to be efficacious in hypertension, to reduce proteinuria, and produce a favorable hemodynamic effect in congestive cardiac failure with a low incidence of adverse effects and without cough. Calcium channel blockers (CCB) also have additional properties that may provide renoprotection beyond lowering blood pressure. However, as the different types of CCB block different calcium channels their effects may differ substantially. The inconsistency of the data in the renoprotective effect of CCB may reflect these differences. Quantitatively probably the most important factor in preventing the progress of renal failure by antihypertensive drugs is strict control of blood pressure. Lowering blood pressure by drugs is most likely effective by both reducing physical and sheer stress damage, as well as turning off the signal for the activation and production of vasoactive peptides and cytokines.
...
PMID:Comparison of renin-angiotensin to calcium channel blockade in renal disease. 940 14

Angiotensin-converting enzyme inhibitors block left ventricular hypertrophy in vivo. A component of this effect has been attributed to tissue accumulation of bradykinin. Little is known regarding the effect of bradykinin on cardiomyocytes. The objectives of the present study were to define the effects of bradykinin on isolated ventricular cardiomyocytes (from adult and neonatal rat hearts) and to determine the extent to which bradykinin blocks hypertrophy in vitro. Bradykinin was found to be a hypertrophic agonist, as defined by increased protein synthesis and atrial natriuretic peptide secretion and expression. Bradykinin (10 micromol/L) increased [3H]phenylalanine incorporation by 23+/-3% in adult and by 36+/-10% in neonatal cardiomyocytes. Constitutive atrial natriuretic peptide secretion by neonatal myocytes was increased 357+/-103%. All effects of bradykinin were abolished by the B2-kinin receptor antagonist Hoe 140. These increases were similar in magnitude to those observed with phenylephrine (20 micromol/L) and angiotensin II (1 micromol/L). However, in cardiomyocytes cocultured with endothelial cells, bradykinin did not increase protein synthesis. Angiotensin II increased [3H]phenylalanine incorporation by 24+/-3% in adult cardiomyocytes in monoculture and by 22+/-2% in adult rat cardiomyocytes cocultured with endothelial cells. Bradykinin abolished this angiotensin II-induced hypertrophy in myocytes cultured with endothelial cells but not in myocytes studied in the absence of endothelial cells. In conclusion, bradykinin has a direct hypertrophic effect on ventricular myocytes. The presence of endothelial cells is required for the antihypertrophic effects of bradykinin. The results suggest that the increase in local concentration of bradykinin associated with angiotensin-converting enzyme inhibition is an important mechanism by which hypertrophy can be blocked. Manifestation of this mechanism appears to require bradykinin-stimulated release of paracrine factor(s) from endothelial cells, which are also able to block the hypertrophic effects of Ang II.
Hypertension 1998 Jan
PMID:Bradykinin blocks angiotensin II-induced hypertrophy in the presence of endothelial cells. 944 88

Cardiac fibrosis after myocardial infarction and in chronic hypertension involves an increase in the synthesis and deposition of collagen within the myocardium. Angiotensin-converting enzyme (ACE) inhibitors limit hypertrophy and fibrosis; their mechanism of action remains controversial, although kinins have been implicated to play a role. Because both bradykinin and prostaglandins (PG) have been shown to reduce collagen gene expression in cardiac fibroblasts, the goal of this study was to determine whether the bradykinin effect was mediated through enhanced prostaglandin formation by cardiac fibroblasts. Bradykinin increased [3H]arachidonic acid metabolite release 2.3-fold over control and stimulated a dose-dependent increase in 6-keto PGF1alpha (the stable metabolite of PGI2) release from these cells, in which 1 nmol/L bradykinin produced a 4-fold increase in 6-keto PGF1alpha release. Beraprost (a PGI2 analogue) reduced steady-state proalpha1(I) and proalpha1(III) collagen mRNA levels by 35.6+/-6.6% and 34.2+/-10.0%, respectively. Bradykinin-induced reductions in collagen type I and III gene expression were reversed by pretreatment with indomethacin. Our results indicate that one mechanism by which bradykinin modulates collagen biosynthesis via the rabbit cardiac fibroblast involves formation of arachidonic acid metabolites, particularly PGI2. The results of the present study argue that stabilization of endogenous kinins (as by ACE inhibitors) would enhance prostacyclin production and result in the attenuation of collagen gene expression, with potential implications for collagen synthesis and deposition within the myocardium.
Hypertension 1998 Jul
PMID:Bradykinin-induced reductions in collagen gene expression involve prostacyclin. 967 42

Bradykinin plays an important role in the regulation of renal hemodynamics. However, there have been few studies of the effect of bradykinin on isolated afferent arterioles, vascular segments that are important for the regulation of renal blood flow and glomerular filtration rate. Our purpose was to study (1) the effects of bradykinin on isolated perfused rabbit afferent arterioles and (2) the mechanisms of actions. Afferent arterioles dissected from rabbits were perfused in vitro at 60 mm Hg. In afferent arterioles preconstricted with phenylephrine, 10(-12) to 10(-10) mol/L bradykinin increased luminal diameter from 9.0+/-1.0 to 14.3+/-1.2 microm (P<0.003). In contrast, 10(-9) and 10(-8) mol/L bradykinin decreased luminal diameter to 10.8+/-1.4 and 9.7+/-1.2 microm, respectively (P<0.001). Bradykinin added to the bath had no effect on preconstricted afferent arterioles. The addition of [des-Arg9]-bradykinin (10(-9) and 10(-8) mol/L), a B1 receptor agonist, to the lumen decreased diameter from 9.7+/-1.2 to 6.7+/-1.2 microm at 10(-8) mol/L (P<0.002). Icatibant (Hoe 140), a B2 receptor antagonist, blocked both the vasodilation and vasoconstriction induced by bradykinin as well as the vasoconstriction induced by [des-Arg9]-bradykinin. L-NAME had no effect on bradykinin-induced dilation or constriction. Indomethacin blocked both the dilation induced by 10(-12) to 10(-10) mol/L bradykinin and the constriction induced by 10(-9) to 10(-8) mol/L bradykinin. In fact, in the presence of indomethacin, 10(-9) and 10(-8) mol/L bradykinin increased luminal diameter from 6.2+/-0.7 to 10.7+/-0.6 microm at 10(-8) mol/L (P<0.001), which was attenuated by L-NAME. Finally, in the presence of SQ29548, a prostaglandin H2/thromboxane A2 receptor antagonist, bradykinin caused dilation at all concentrations tested. In conclusion, bradykinin has a biphasic effect on afferent arterioles. Both dilation and constriction may be mediated by bradykinin B2 receptors. The mechanisms of vasodilation and vasoconstriction are due to cyclooxygenase products, not nitric oxide.
Hypertension 1998 Aug
PMID:Biphasic effect of bradykinin on rabbit afferent arterioles. 971 56

Tissue kallikrein and low molecular weight kininogen are localized in the particular cells of the connecting tubules, indicating that kinin is immediately generated in the lumina of the lower nephrons. The role of the renal kallikreinkinin system was studied using mutant kininogen-deficient Brown NorwayKatholiek (BN-Ka) rats, and compared with that in normal BN-Kitasato rats of the same strain. Mutant BN-Ka rats showed no visible changes, but they were very sensitive to excess sodium ingestion and to the tendency of sodium to accumulate in the body by aldosterone released by angiotensin II, so that sodium was accumulated in erythrocytes and cerebrospinal fluid in BN-Ka rats and hypertension was induced. After four days infusion of 0.3 M NaCl solution to conscious and unrestrained mutant BN-Ka rats, the sensitivity of the vascular smooth muscle to norepinephrine and angiotensin II increased 30-fold and 10-fold, respectively. Bradykinin was degraded by neutral endopeptidase (NEP) and carboxypeptidase Y-like exopeptidase (CPY) in rat and human urine. Daily oral administration of a selective inhibitor of CPY, ebelactone B, or that of NEP, BP1O2, prevented development of deoxycorticosterone acetate-salt hypertension in Sprague-Dawley rats. These results indicate that: 1) the renal kallikrein-kinin system allows excretion of excess sodium in the body, 2) decreased sodium excretion due to reduced excretion of urinary kallikrein in patients with essential hypertension or in genetically hypertensive rats may cause hypertension, and 3) urine kininase inhibitors such as ebelactone B may emerge as a new antihypertensive drug.
...
PMID:Crucial suppressive role of renal kallikrein-kinin system in development of salt-sensitive hypertension. 983 May 1

In the kidney and colon 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) inactivates cortisol to cortisone, thereby protecting the non-selective mineralocorticoid receptor from cortisol. Deficiency of 11beta-HSD2 results in cortisol-mediated sodium retention and hypertension, suggesting that the physiological regulation of 11beta-HSD2 in mineralocorticoid target tissues may be important in modulating sodium homoeostasis and blood pressure control. Using the human epithelial colon cell line SW-620, reverse transcriptase-polymerase chain reaction and enzyme kinetic analysis indicated expression of only 11beta-HSD2 (Km for cortisol 66 nmol/l). Bradykinin (10(-8) to 10(-12) mol/l), frusemide (10(-4) to 10(-9) mol/l), benzamiloride hydrochloride (10(-5) to 10(-10) mol/l) and atrial natriuretic peptide (10(-6) to 10(-10) mol/l) had no effect on 11beta-HSD2 expression. Using a range of concentrations of angiotensin II (2x10(-8) to 2x10(-5) mol/l) a significant reduction in activity was seen but only at supra-physiological concentrations, [e.g. 2x10(-6) mol/l at 4 h pretreatment: 36.7+/-2.0 pmol cortisone. h-1.mg-1 (mean+/-S.E.M.) compared with 45.1+/-1.7 pmol.h-1.mg-1 in control; P<0.05]. The angiotensin-converting enzyme inhibitors captopril, enalapril, lisinopril, perindopril, quinapril and trandolapril at 10(-7) mol/l, but not fosinopril, significantly increased 11beta-HSD2 activity after pretreatment for 16 or 24 h (P<0.05-P<0.01 compared with control). No effects were seen at 4 h pretreatment. Hydrochlorothiazide (10(-7) mol/l) significantly decreased 11beta-HSD2 activity (P<0.05 compared with control) at 4 h pretreatment. Commonly used diuretics, atrial natriuretic peptide and physiological concentrations of angiotensin II and bradykinin do not alter 11beta-HSD2 activity. In contrast, a series of angiotensin-converting enzyme inhibitors significantly increase 11beta-HSD2 activity in vitro. This may explain how intrarenal infusions of angiotensin-converting enzyme inhibitors increase renal sodium excretion independent of circulating concentrations of angiotensin II. The interaction between angiotensin-converting enzyme inhibitors and 11beta-HSD2 may be an additional mechanism by which the former can lower blood pressure.
...
PMID:Regulation of 11beta-hydroxysteroid dehydrogenase type 2 by diuretics and the renin-angiotensin-aldosterone axis. 1033 75

Bradykinin stimulates tissue plasminogen activator (tPA) release in isolated perfused animal tissues. The present study tests the hypothesis that bradykinin increases tPA release in humans through local effects on the vasculature. Graded doses of sodium nitroprusside (0.8 to 3.2 micrograms/min), acetylcholine (ACh) (7.5 to 60 micrograms/min), and bradykinin (100 to 400 ng/min) were administered intra-arterially in random order in 10 salt-depleted (10 mmol/d of Na) normotensive volunteers. None of the drugs altered mean arterial pressure or heart rate. Forearm blood flow (FBF) was measured by strain-gauge plethysmography. All 3 drugs caused a dose-dependent increase in FBF, although ACh was less potent than either nitroprusside or bradykinin (maximum FBF 7.5+/-2.4 versus 10.0+/-1.5 and 11.9+/-2.1 mL. 100 mL-1. min-1, respectively). Bradykinin caused a significant, dose-dependent increase in venous (effect of dose F=9. 9, P=0.028 by ANOVA), but not arterial (F=0.154, P=0.92) tPA antigen in the infused arm. Thus, net tPA release increased significantly in response to bradykinin (50.6+/-13.3 at the highest dose versus 0. 9+/-0.4 ng. 100 mL-1. min -1 at baseline, P=0.014). In contrast, bradykinin did not affect plasminogen activator inhibitor antigen. Neither nitroprusside nor ACh altered plasma levels of tPA or plasminogen activator inhibitor antigen. Bradykinin increased tPA release across the forearm in the absence of systemic effects. This effect could not be attributed to changes in blood flow because doses of equivalent potency of the vasodilator nitroprusside did not increase tPA. These data demonstrate that bradykinin stimulates tPA release in the human vasculature.
Hypertension 1999 Jun
PMID:Bradykinin stimulates tissue plasminogen activator release in human vasculature. 1037 28

Bradykinin is a nonapeptide, whose mechanism of vasodilation is mediated chiefly through the release of endothelium-derived relaxing factor (EDRF). Diminished vasodilatory response to EDRF has been demonstrated in many pathologic states such as hypertension, atherosclerosis, diabetes, and long-term, heavy smoking. We studied whether the diminished EDRF-mediated vasodilatory response seen in chronic diseases can be demonstrated in young, clinically healthy smokers. We used the dorsal hand-vein compliance technique, an in vivo technique used to measure response to local infusions of vasoactive substances. Full dose-response curves to bradykinin (dosing range, 0.5-500 ng/min) were generated in 11 young, healthy smokers and 11 young, healthy nonsmokers by using hand veins preconstricted with phenylephrine (dosing range, 20-6,800 ng/min). In addition, after a washout period, a single maximal dose of a non-endothelium-dependent vasodilator, isoproterenol (300 ng/min) was infused. Our results demonstrated that smokers had a greater maximal venodilation to bradykinin than did nonsmokers (106 +/- 40% vs. 69 +/- 49%; p < 0.05). The log of the dose that produced half-maximal response to bradykinin was smaller in smokers: -0.10 +/- 0.93 (0.79 ng/min) versus 0.75 +/- 0.84 (5.6 ng/min); p < 0.05. There was no difference in the maximal dilatory response to isoproterenol: 80 +/- 45% (smokers) versus 89 +/- 50% (nonsmokers), nor was there a difference in the log dose of phenylephrine necessary to produce 80% constriction of the hand vein (2.7 +/-0.7 vs. 2.7 +/- 0.9 ng/min) between the two groups. We conclude that young, otherwise healthy smokers have a paradoxic hyperactive response to the endothelium-dependent vasodilator, bradykinin, but maintain a similar response to the nonendothelium-dependent vasodilator, isoproterenol as compared with nonsmokers. Their reactivity to the alpha1-adrenergic agonist phenylephrine was found to be intact. It is possible that a hyperactive response to EDRF in young smokers contributes to endothelium damage seen in chronic disease. To our knowledge, this is the first report on increased reactivity to bradykinin in short-term smokers.
...
PMID:Paradoxically enhanced bradykinin-induced venodilation in young, healthy, short-term smokers. 1044 84

The aim of this study was to determine whether bradykinin, the angiotensin-converting enzyme inhibitor ramiprilat, and the calcium-channel antagonist amlodipine reduce myocardial oxygen consumption (MV(O2)) via a B(2)-kinin receptor/nitric oxide-dependent mechanism. Left ventricular free wall and septum were isolated from normal and B(2)-kinin receptor knockout (B(2) -/-) mice. Myocardial tissue oxygen consumption was measured in an airtight chamber with a Clark-type oxygen electrode. Baseline MV(O2) was not significantly different between normal (239+/-13 nmol of O(2). min(-1). g(-1)) and B(2) -/- (263+/-24 nmol of O(2). min(-1). g(-1)) mice. S-nitroso-N-acetyl-penicillamine (10(-7) to 10(-4) mol/L) reduced oxygen consumption in a concentration-dependent manner in both normal (maximum, 36+/-3%) and B(2) -/- mice (28+/-3%). This was also true for the endothelium-dependent vasodilator substance P (10(-10) to 10(-7) mol/L; 22+/-7% in normal mice and 20+/-4% in B(2) -/- mice). Bradykinin (10(-7) to 10(-4) mol/L), ramiprilat (10(-7) to 10(-4) mol/L), and amlodipine (10(-7) to 10(-5) mol/L) all caused concentration-dependent decreases in MV(O2)in normal mice. At the highest concentration, tissue O(2) consumption was decreased by 18+/-3%, 20+/-5%, and 28+/-3%, respectively. The reduction in MV(O2) to all 3 drugs was attenuated in the presence of N(G)-nitro-L-arginine-methyl ester. However, in the B(2) -/- mice, bradykinin, ramiprilat, and amlodipine had virtually no effect on MV(O2). Therefore, nitric oxide, through a bradykinin-receptor-dependent mechanism, regulates cardiac oxygen consumption. This physiological mechanism is absent in B(2) -/- mice and may be evidence of an important therapeutic mechanism of action of angiotensin-converting enzyme inhibitors and amlodipine.
Hypertension 1999 Oct
PMID:Role of nitric oxide in the control of cardiac oxygen consumption in B(2)-kinin receptor knockout mice. 1052 27

We have developed a novel inhibitor of the metalloendopeptidases EC 3.4.24.15 (EP24.15) and EC 3.4.24.16 (EP24.16), N-[1-(R, S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA2), in which alpha-aminoisobutyric acid (Aib) is substituted for an alanine in a well-described but unstable inhibitor, cFP-AAY-pAB. This substitution increases the resistance of the inhibitor to degradation without altering potency. In the present study, we investigated the effects of JA2 (5 mg/kg) on the responses of mean arterial pressure to bradykinin, angiotensin I, and angiotensin II in conscious rabbits. The depressor responses to both low (10 ng/kg) and high (100 ng/kg) doses of bradykinin were increased 7.0+/-2. 7-fold and 1.5+/-0.3-fold, respectively, during the 30 minutes after JA2 administration (mean+/-SEM, n=8). Bradykinin potentiation was undiminished 4 hours after JA2 injection. In contrast, the hypertensive effects of angiotensins I and II were unaltered, indicating that the bradykinin-potentiating effects were not due to angiotensin-converting enzyme inhibition. These data suggest that JA2 is not only a potent and specific inhibitor of EP24.15 and EP24. 16 but is also stable in vivo. Furthermore, the potentiation of bradykinin-induced hypotension by JA2 suggests for the first time a role for one or both of these peptidases in the metabolism of bradykinin in the circulation.
Hypertension 2000 Feb
PMID:A novel stable inhibitor of endopeptidases EC 3.4.24.15 and 3.4.24.16 potentiates bradykinin-induced hypotension. 1067 8


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

---