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

Substance P and calcitonin gene-related peptide (CGRP) are colocalized in renal pelvic sensory nerves. Increasing renal pelvic pressure results in an increase in afferent renal nerve activity that is blocked by a substance P receptor antagonist but not by a CGRP receptor antagonist. CGRP potentiates the effects of substance P by preventing the metabolism of substance P. Therefore, we examined whether CGRP enhanced the afferent renal nerve activity responses to substance P and increased renal pelvic pressure, a stimulus known to increase substance P release. Combined administration of substance P and CGRP into the renal pelvis resulted in an increase in afferent renal nerve activity (1392+/-217%. s; area under the curve of afferent renal nerve activity versus time) that was greater (P<0.01) than that produced by substance P (620+/-156%. s) or CGRP (297+/-96%. s) alone. Likewise, CGRP enhanced the afferent renal nerve activity response to increased renal pelvic pressure. During renal pelvic administration of the neutral endopeptidase inhibitor thiorphan, the afferent renal nerve activity response to substance P plus CGRP was similar to that produced by either neuropeptide alone. Because these studies suggested that CGRP potentiated the afferent renal nerve activity responses to substance P, we examined whether the afferent renal nerve activity response to CGRP was blocked by a substance P receptor antagonist, RP67580. RP67580 blocked the afferent renal nerve activity response to CGRP by 85+/-12% (P<0.02). We conclude that CGRP activates renal pelvic sensory nerves by retarding the metabolism of substance P, thereby increasing the amount of substance P available for stimulation of substance P receptors.
Hypertension 1999 Jan
PMID:CGRP activates renal pelvic substance P receptors by retarding substance P metabolism. 993 Nov 54

Of the active fragments studied to-date, Ang-(l-7) is the most pleiotropic of the Ang I metabolities because it exerts effects that may be identical or opposite to those of Ang II. While much research remains to be done, accumulating evidence suggests that Ang-(1-7) stimulates the synthesis and release of vasodilator prostaglandins, augments the metabolic actions of bradykinin, and increases the release of nitric oxide. This explains why Ang-(1-7) activates antihypertensive mechanisms, particularly in situations of increased Ang II activity. In other words, Ang-(1-7) may act as a negative feedback hormone of the pressor and trophic actions of Ang II. The enzymes forming Ang-( 1-7) reinforce the idea that this peptide is a component of a vasodepressor system that regulates blood pressure. Both neprilysin and metalloendopeptidase 24.15 form Ang-(1-7) but also cleave bradykinin and atrial natriuretic peptide to smaller fragments. Our recent discovery that Ang-(1-7) is a major substrate for angiotensin converting enzyme (ACE) adds a new and important dimension to the understanding of the biochemical physiology of the renin angiotensin system. Moreover, these data explain why Ang-(1-7) augmentes the hypotensive effects of bradykinin and contributes to the antihypertensive actions of ACE inhibitors. While the bulk of the research in hypertension continues to emphasize the investigation of the cellular actions of Ang II, our research has introduced new concepts and uncovered new mechanisms through which angiotensin peptides control homeostasis and influence the pathogenesis of cardiovascular disease.
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PMID:Angiotension-(1-7) and antihypertensive mechanisms. 1004 92

Heart-transplant recipients (Htx) generally present with body fluid and sodium handling abnormalities and hypertension. To investigate whether neutral endopeptidase inhibition (NEP-I) increases endogenous atrial natriuretic peptide (ANP) and enhances natriuresis and diuresis after heart transplantation, ecadotril was given orally to 8 control subjects and 8 matched Htx, and levels of volume-regulating hormones and renal water, electrolyte, and cyclic guanosine monophosphate (cGMP) excretions were monitored for 210 minutes. Baseline plasma ANP, brain natriuretic peptide (BNP), and cGMP were elevated in Htx, but renin and aldosterone, like urinary parameters, did not differ between groups. NEP-I increased plasma ANP (Htx, 20.6+/-2.3 to 33.2+/-5.9 pmol/L, P<0.01; controls, 7.7+/-1. 2 to 10.6+/-2.6 pmol/L) and cGMP, but not BNP. Renin decreased similarly in both groups, whereas aldosterone decreased significantly only in Htx. Enhanced urinary sodium (1650+/-370% versus 450+/-150%, P=0.01), cGMP, and water excretions were observed in Htx and urinary cGMP positively correlated with natriuresis in 6 of the Htx subjects. Consistent with a normal circadian rhythm of blood pressure, without excluding a possible effect of NEP-I, mean systemic blood pressure increased similarly in both groups at the end of the study (6.9+/-2.0% versus 7.4+/-2.8% in controls and Htx). Thus, systemic hypertension, mild renal impairment, and raised plasma ANP levels are possible contributory factors in the enhanced natriuresis and diuresis with NEP-I in Htx. These results support a physiological role for the cardiac hormone after heart transplantation and suggest that long-term studies may be useful to determine the potential of NEP-I in the treatment of sodium retention and water retention after heart transplantation.
Hypertension 1999 Apr
PMID:Enhanced natriuretic response to neutral endopeptidase inhibition in heart-transplant recipients. 1020 32

Type 2 bradykinin (B2)-receptor antagonists have been used to define the role of endogenous kinin peptides. However, interpretation of the effects of B2-receptor antagonists has been limited by lack of information concerning the effects of these antagonists on endogenous kinin and angiotensin peptide levels. If kinin levels were subject to short-loop-feedback regulation mediated through B2 receptors, then a reactive increase in kinin levels might blunt the effects of B2-receptor antagonism and stimulate type 1 bradykinin receptors. Moreover, kinins have been implicated in the control of renin secretion. We investigated whether endogenous kinin levels are subject to short-loop-feedback regulation mediated by the B2 receptor and whether endogenous kinins acting through the B2 receptor influence plasma renin levels and circulating and tissue angiotensin peptide levels. The B2-receptor antagonist icatibant (1 mg/kg) was administered to rats by intraperitoneal injection, and circulating and tissue levels of angiotensin and kinin peptides were measured after 4 hours. Icatibant produced 75% occupancy of B2 receptors in the inner stripe of the renal medulla. Icatibant did not influence plasma levels of renin, angiotensinogen, angiotensin-converting enzyme, neutral endopeptidase, or circulating or tissue levels of angiotensin and bradykinin peptides. This study demonstrated that kinin levels are not subject to short-loop-feedback regulation mediated through B2 receptors and that endogenous kinin levels acting through the B2 receptor do not modulate the renin-angiotensin system.
Hypertension 1999 May
PMID:Type 2 bradykinin-receptor antagonism does not modify kinin or angiotensin peptide levels. 1033 17

Vasopeptidase inhibition is a new concept in cardiovascular therapy. It involves simultaneous inhibition with a single molecule of two key enzymes involved in the regulation of cardiovascular function, neutral endopeptidase (EC 24.11; NEP) and angiotensin-converting enzyme (ACE). Simultaneous inhibition of NEP and ACE increases natriuretic and vasodilatory peptides (including atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP] of myocardial cell origin, and C-type natriuretic peptide [CNP] of endothelial cell origin) and increases the half-life of other vasodilator peptides including bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide system, vasopeptidase inhibitors (VPIs) reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure. Omapatrilat, a heterocyclic dipeptide mimetic, is a novel vasopeptidase inhibitor and a single molecule that simultaneously inhibits NEP and ACE with similar inhibition constants. Unlike ACE inhibitors, omapatrilat demonstrates antihypertensive efficacy in low-, normal-, and high-renin animal models. Unlike NEP inhibitors, omapatrilat provides a potent and sustained antihypertensive effect in spontaneously hypertensive rats (SHR), a model of human essential hypertension. In animal models of heart failure, omapatrilat is more effective than ACE inhibition in improving cardiac performance and ventricular remodeling and prolonging survival. Omapatrilat effectively reduces blood pressure, provides target-organ protection, and reduces morbidity and mortality from cardiovascular events in animal models. Omapatrilat is the first VPI to enter advanced USA clinical trials. Omapatrilat appears to be a safe, well-tolerated and effective antihypertensive in humans. Vasopeptidase inhibition is a novel and efficacious strategy for treating cardiovascular disorders, including hypertension and heart failure, that may offer advantages over currently available therapies.
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PMID:Vasopeptidase inhibition: a new concept in blood pressure management. 1034 Aug 42

Hypertension remains uncontrolled worldwide despite the availability of several classes of antihypertensive agents. There is an increased risk of serious cardiovascular, cerebrovascular, and renal events if the disease goes untreated or is poorly treated. Thus, the high incidence of hypertension coupled with its poor control make it imperative that more effective and well-tolerated treatments that exhibit target-organ protection be developed. Vasopeptidase inhibitors are a new class of cardiovascular agents that simultaneously inhibit neutral endopeptidase and angiotensin converting enzyme. They enhance peptides with vasodilatory and possibly organ-protective properties and also inhibit the production of the vasoconstrictor angiotensin II. In preclinical studies, omapatrilat has shown blood pressure-lowering effects independent of renin status and has increased survival in an animal model of congestive heart failure. Human studies with omapatrilat, the most clinically advanced vasopeptidase inhibitor, administered orally once daily have demonstrated powerful dose-dependent reduction of systolic and diastolic blood pressures, regardless of age, race, or gender. Omapatrilat is particularly effective in lowering systolic blood pressure; this article summarizes data from recent clinical trials. This drug is well tolerated, with adverse effects comparable to those of currently available antihypertensive agents. Omapatrilat and other vasopeptidase inhibitors have potential applications in the treatment of hypertension, heart failure, and other cardiac and vascular disorders.
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PMID:Emerging treatments for hypertension: potential role for vasopeptidase inhibition. 1059 65

The results of recent studies have demonstrated that angiotensin (Ang)-(1-7) contributes to the antihypertensive actions of either combined ACE/Ang II type 1 receptor blockade or ACE inhibition alone. The vasculature is a key site of action for either drug regimen, and evidence favors a local Ang system within these tissues. Because ACE may degrade Ang-(1-7), we determined whether ACE inhibition alters Ang-(1-7) release from the rat hindlimb perfused with Krebs-Ringer buffer containing Ficoll. Ang-(1-7) release averaged 36+/-13 fmol (period 1, 15-minute collection) and 44+/-11 fmol (period 2) in the control buffer. The addition of the ACE inhibitor lisinopril to the perfusion buffer augmented levels of Ang-(1-7) in periods 3 (144+/-39 fmol) and 4 (163+/-35 fmol; P<0.05 versus 1 or 2, n=8). HPLC and radioimmunoassay of effluent from control or lisinopril treatment demonstrated a single immunoreactive peak with a retention time identical to that of Ang-(1-7). The addition of the neprilysin inhibitor SCH 39370 reduced Ang-(1-7) release in the lisinopril buffer from 177+/-32 (period 1) and 173+/-39 (period 2) fmol to 112+/-24 (period 3) and 87+/-23 fmol (period 4; P<0.05 versus 1 or 2, n=6). Ang I metabolism in the collected perfusate revealed the formation of Ang-(1-7) that was sensitive only to thimet oligopeptidase inhibition; Ang II generation was not detected. The present study demonstrates the recovery of endogenous Ang-(1-7) from the perfused hindlimb. The release of Ang-(1-7) is significantly influenced by inhibition of ACE, which may reflect both increased substrate (Ang I) levels and reduced metabolism of the peptide. Neprilysin inhibition reduced but did not abolish Ang-(1-7) release, which suggests that other endopeptidases may contribute to the release of the peptide.
Hypertension 2000 Jan
PMID:Release of angiotensin-(1-7) from the rat hindlimb: influence of angiotensin-converting enzyme inhibition. 1064 23

1. To determine whether the antihypertensive response in deoxycorticosterone acetate (DOCA) salt-treated rats was mediated by kinins on the luminal side of renal tubules or in the circulation, selective urinary kininase inhibitors were administered to normal Brown Norway Kitasato (BN-Ki) rats and kininogen-deficient Brown Norway Katholiek (BN-Ka) rats. 2. Kinins were degraded by neutral endopeptidase (NEP) and carboxypeptidase Y-like kininase (CPY) in urine, but were inactivated mainly by angiotensin-converting enzyme (ACE) in the plasma. 3. Ebelactone B inhibited CPY, while poststatin inhibited CPY and NEP. 4. Daily administration of poststatin (5 mg/kg per day, s.c.) for 3 days reduced blood pressure (BP) in DOCA salt-treated BN-Ki rats, but not in BN-Ka rats. 5. Ebelactone B (5 mg/kg per day, s.c.) also reduced BP in BN-Ki rats, which was accompanied by increased urinary sodium excretion, but had no effect on BP in BN-Ka rats. 6. Lisinopril (5 mg/kg per day, s.c.) had no effect on BP in either rat strain. 7. Arterial kinin levels in BN-Ki rats increased significantly (2.2-4.6 pg/mL) with captopril (10 mg/kg, s.c.). However, arterial kinin levels that induced hypotension following the infusion of bradykinin (1000 ng/kg per min, i.v.) were 110-fold higher than endogenous arterial kinin levels attained following captopril. 8. These results suggest that inhibition of kinin degradation on the luminal side of the renal tubules may effectively attenuate hypertension.
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PMID:Inhibition of kinin degradation on the luminal side of renal tubules reduces high blood pressure in deoxycorticosterone acetate salt-treated rats. 1069 33

The aim of this study was to assess the antihypertensive activity of fasidotril, a dual inhibitor of neprilysin (NEP) and angiotensin I-converting enzyme (ACE), in various models of hypertension in rats (spontaneously hypertensive rats [SHR]; renovascular Goldblatt 2-kidney, 1-clip rats; and deoxycorticosterone acetate [DOCA]-salt hypertensive rats) and in patients with mild-to-moderate essential hypertension. Fasidotril treatment (100 mg/kg PO twice daily for 3 weeks) resulted in a progressive and sustained decrease in systolic blood pressure (-20 to -30 mm Hg) in SHR and Goldblatt rats compared with vehicle-treated rats and prevented the progressive rise in blood pressure in DOCA-salt hypertensive rats. After a 4-week placebo run-in period, 57 patients with essential hypertension were included in a randomized double-blind, placebo-controlled, parallel-group study and received orally either fasidotril (100 mg twice daily) or placebo for 6 weeks. Blood pressure was measured during the 6 hours after the first intake and then at trough (12 hours after the last intake) on days 7, 28, and 42. The first dose of fasidotril had no significant effect on blood pressure. After 42 days, compared with placebo, fasidotril lowered supine systolic and diastolic blood pressures by 7.4/5.4 mm Hg and standing blood pressure by 7.6/6.8 mm Hg. Fasidotril, a dual NEP/ACE inhibitor, was an effective oral antihypertensive agent during chronic treatment in high-renin renovascular rats, normal-renin SHR, and low-renin DOCA-salt hypertensive rats and in patients with essential hypertension.
Hypertension 2000 May
PMID:Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans. 1081 79

The antihypertensive agent omapatrilat represents a novel approach to antihypertensive therapy, namely vasopeptidase inhibition. Omapatrilat (BMS-186716) concomitantly inhibits neutral endopeptidase and angiotensin-converting enzyme, leading to protection from degradation of natriuretic and other hypotensive peptides in addition to interruption of the renin-angiotensin system. Although the potency of omapatrilat on reduction of blood pressure has been reported, its effects on resistance artery structure and function were unknown. We tested omapatrilat in stroke-prone spontaneously hypertensive rats (SHRSP), a malignant model of hypertension, with the hypothesis that it would improve the structure and endothelial function of mesenteric resistance arteries. Ten-week-old SHRSP were treated orally for 10 weeks with omapatrilat (40 mg/kg per day). Mesenteric arteries (lumen <300 microm) were studied on a pressurized myograph. After 10 weeks, untreated SHRSP had a systolic blood pressure of 230+/-2 mm Hg that was significantly reduced (P<0.05) by omapatrilat (145+/-3 mm Hg). Omapatrilat treatment improved endothelium-dependent relaxation of resistance arteries as elicited by acetylcholine (10(-5) mol/L) but had no significant effect on endothelium-independent relaxation produced by a nitric oxide donor (sodium nitroprusside). This suggested that there existed endothelial dysfunction in SHRSP that was corrected by vasopeptidase inhibition, probably in part caused by the potent blood pressure-lowering effect of omapatrilat. Media width and media/lumen ratio were significantly decreased (P<0.05) by omapatrilat, and a trend (P=0.07) to increase lumen diameter was observed. Vascular stiffness (slope of the elastic modulus versus stress curve) was unaltered by omapatrilat. In conclusion, omapatrilat, acting as a potent antihypertensive agent, may improve structure and endothelial function of resistance arteries in SHRSP, a severe form of genetic hypertension.
Hypertension 2000 Jun
PMID:Vasopeptidase inhibition has potent effects on blood pressure and resistance arteries in stroke-prone spontaneously hypertensive rats. 1085 67


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