Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Crucial suppressive role of renal kallikrein-kinin system in development of salt-sensitive hypertension. 983 May 1

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

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.
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PMID:Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans. 1081 79

Endogenous peptidases participate in a major way in the formation of peptide pressor substances such as angiotensin II (A II) and endothelin (ET) as well as in the degradation of depressor substances, e.g. atrial natriuretic peptide (ANP) or bradykinin. They include on the one hand the angiotensin converting enzyme (ACE) and endothelin converting enzyme (ECE), on the other hand kinase II for bradykinin and neutral endopeptidase 24.11 (NEP) for ANP. Inhibition of these enzymatic reactions leads to a decline of vasopressors A II and ET and conversely delays the break-down of vasodilatating bradykinin and ANP. The main haemodynamic consequence of this double inhibition is a reduced peripheral vascular resistance and decline of the blood pressure. The concurrent block of both systems (dual inhibition) is more effective than the isolated block of one substance. The first dual endopeptidase inhibitors were ACE inhibitors blocking the conversion of angiotensin I to A II and inhibiting at the same time the degradation of bradykinin by kininase II which is identical with ACE. At present further substances were synthetized with a dual inhibitory effect e.g. on ECE and on NEP (phosphoramidone, thiorphan, ecadatril etc.). Under experimental conditions they have a long-term antihypertensive effect on the vascular wall and heart muscle. The development of another dual ACE and NEP inhibitor has reached already the stage of clinical tests and the first clinical studies. The preparation omapatrilate in amounts of 2.5-80 mg significantly reduced the BP in a dose-dependent way in mild and medium advanced essential hypertension. Normalization of the blood pressure, i.e. a drop below 140/90 mm Hg, was achieved with omapatrilate monotherapy in as many as 83% of patients with hypertension stage I and in 53% patients with essential hypertension stage II. The drop of blood pressure after 20-80 mg/day depended on the degree of hypertension and was comparable or better than monotherapy with lisonopril 20 mg/day or amlodipine 10 mg/day. Treatment with omapatrilate was well tolerated. Dual peptidase inhibitors interfering with the formation of pressor substances and with the degradation of depressor substances seem to be a perspective class of antihypertensives also useful in the treatment of other cardiovascular diseases (heart failure, primary pulmonary hypertension). Before its final inclusion in the therapeutic pattern, further comparative and clinical mortality studies must be implemented.
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PMID:[Dual endopeptidase inhibitors--a new direction in the development of hypertensive agents]. 1104 16

Omapatrilat was designed to inhibit simultaneously angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The ubiquitous involvement of the renin-angiotensin-aldosterone system, originally conceived as an axis of sodium and fluid metabolism in inflammation, thrombosis and cardiac and smooth muscle hypertrophy, is a major factor in disease progression for conditions as diverse as hypertension, heart failure, coronary artery disease and diabetes. Interruption of angiotensin II generation and bradykinin degradation by ACE inhibition is a major therapeutic advance in the management of these diseases. NEP metabolizes both bradykinin and the natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide, c-type natriuretic peptide and adrenomedullin). These peptides counter the adverse effects of angiotensin II by their vasodilator, natriuretic, diuretic and autonomic neural actions; by their antitrophic effects; and by suppressing plasma renin activity. These two systems can be considered key components of a cardiorenal axis that maintains blood pressure and cardiopulmonary blood volume within a stable range. This balance is compromised in the setting of heart failure and primary hypertension. The combination of ACE and NEP inhibition should augment the beneficial hemodynamic and tissue effects of bradykinin and the natriuretic peptides. Vasopeptidase inhibition, therefore, is a novel approach to cardiovascular therapy, with implications for hypertension, heart failure, renal function and ischemic heart disease.
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PMID:Vasopeptidase inhibition: a novel approach to cardiovascular therapy. 1187 87

Vasopeptidase inhibitors represent a new class of cardiovascular drugs. They function as a combined angiotensin-converting enzyme (ACE) inhibitor and neutral endopeptidase (NEP) inhibitor, the latter of which potentiates the actions of atrial natriuretic peptide (ANP) by minimizing its degradation in the circulation. The consequence of such dual inhibition is a synergistic reduction of vasoconstriction and enhancement of vasodilation, thereby serving to more effectively reduce blood pressure. Furthermore, inhibition of the renin-angiotensin-aldosterone system (RAAS) prevents physiologic compensatory responses in vivo seen with NEP inhibition alone. Vasopeptidase inhibitors have also shown to potentiate bradykinin and adrenomedullin, which additionally contribute to cardiovascular regulation. The most extensively researched and promising agents within the class of VP inhibitors is omapatrilat, a mercaptoacyl derivative of a bicyclic thiazepinone dipeptide. It is a single molecule with equal potency and affinity for ACE and NEP inhibition. Although ACE inhibition tends to more selectively benefit high-renin models of hypertension, vasopeptidase inhibition has been shown to be equally efficacious in low-, normal-, and high-renin models. Contrary to NEP inhibition alone, omapatrilat has also demonstrated the ability to significantly reduce blood pressure in spontaneously hypertensive rats, the equivalent of essential hypertension in humans. Studies also suggest that omapatrilat has cardioprotective properties, especially in the setting of congestive heart failure. More specifically, animal models have demonstrated omapatrilat to be more effective than ACE inhibition alone in remodeling the heart and improving its contractile function. Human studies have documented the efficacy of omapatrilat in the treatment of both hypertension and, to a lesser extent, heart failure. Safety concerns (specifically angioedema) are currently being addressed before the widespread utilization of this promising new agent.
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PMID:Vasopeptidase inhibitors, neutral endopeptidase inhibitors, and dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase. 1197 22

Sampatrilat is a dual inhibitor of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE), which is under development by Pfizer and Shire (previously Roberts Pharmaceutical) for the potential treatment of hypertension. As of 1995, Pfizer had taken the compound into phase II clinical trials [179233]. In April 1997, Roberts Pharmaceutical, through its wholly owned subsidiary Roberts Laboratories Inc, received an exclusive license from Pfizer to develop and market sampatrilat for the treatment of essential hypertension and congestive heart failure. The agreement provided for transfer of data and the awarding of patent rights to Roberts [240809]. Although in June 2000, Shire confirmed it had discontinued all development of this drug [372652], by December 2000 it had recommenced studies with a reformulation of sampatrilat that achieved a 4-fold increase in oral bioavailability. A clinical trial with the new formulation was to be initiated in 2001, with results expected during the second quarter of 2001. The company also revealed that it was seeking a licensing partner at this time [394238]. In November 2001, Shire confirmed that while the project was undergoing further development with a view to outlicensing, it was unlikely to take this project into phase II alone [429562].
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PMID:Sampatrilat Shire. 1209 Jul 27

SLV-306 is an orally active mixed neutral endopeptidase/endothelin converting enzyme inhibitor under development by Solvay SA for the potential treatment of essential hypertension and congestive heart failure. The compound is currently undergoing phase II clinical trials in Belgium.
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PMID:SLV-306. Solvay. 1273 34

In humans, the endothelins (ETs) comprise a family of three 21-amino-acid peptides, ET-1, ET-2 and ET-3. ET-1 is synthesised from a biologically inactive precursor, Big ET-1, by an unusual hydrolysis of the Trp21 -Val22 bond by the endothelin converting enzyme (ECE-1). In humans, there are four isoforms (ECE-1a-d) derived from a single gene by the action of alternative promoters. Structurally, they differ only in the amino acid sequence of the extreme N-terminus. A second enzyme, ECE-2, also exists as four isoforms and differs from ECE-1 in requiring an acidic pH for optimal activity. Human chymase can also cleave Big ET-1 to ET-1, which is cleaved, in turn, to the mature peptide as an alternative pathway. ET-1 is the principal isoform in the human cardiovascular system and remains one of the most potent constrictors of human vessels discovered. ET-1 is unusual in being released from a dual secretory pathway. The peptide is continuously released from vascular endothelial cells by the constitutive pathway, producing intense constriction of the underlying smooth muscle and contributing to the maintenance of endogenous vascular tone. ET-1 is also released from endothelial cell-specific storage granules (Weibel-Palade bodies) in response to external stimuli. ETs mediate their action by activating two G protein-coupled receptor sub-types, ETA and ET(B). Two therapeutic strategies have emerged to oppose the actions of ET-1, namely inhibition of the synthetic enzyme by combined ECE/neutral endopeptidase inhibitors such as SLV306, and receptor antagonists such as bosentan. The ET system is up-regulated in atherosclerosis, and ET antagonists may be of benefit in reducing blood pressure in essential hypertension. Bosentan, the first ET antagonist approved for clinical use, represents a significant new therapeutic strategy in the treatment of pulmonary arterial hypertension (PAH).
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PMID:Endothelin. 1699 23

Despite progress in recent years in the prevention, detection, and treatment of high blood pressure (BP), hypertension remains an important public health challenge. Hypertension affects approximately 1 billion individuals worldwide. High BP is associated with an increased risk of mortality and morbidity from stroke, coronary heart disease, congestive heart failure, and end-stage renal disease; it also has a negative impact on the quality of life. Hypertension cannot be eliminated because there are no vaccines to prevent the development of hypertension, but, its incidence can be decreased by reducing the risk factors for its development, which include obesity, high dietary intake of fat and sodium and low intake of potassium, physical inactivity, smoking, and excessive alcohol intake. For established hypertension, efforts are to be directed to control BP by lifestyle modification (LSM). However, if BP cannot be adequately controlled with LSM, then pharmacotherapy can be instituted along with LSM. Normalization of BP reduces cardiovascular risk (for cardiovascular death, myocardial infarction, and cardiac arrest), provides renoprotection (prevention of the onset or slowing of proteinuria and progression of renal dysfunction to end-stage renal disease in patients with hypertension, diabetes mellitus types 1 and 2, and chronic renal disease), and decreases the risk of cerebrovascular events (stroke and cognition impairment), as has been amply demonstrated by a large number of randomized clinical trials. In spite of the availability of more than 75 antihypertensive agents in 9 classes, BP control in the general population is at best inadequate. Therefore, antihypertensive therapy in the future or near future should be directed toward improving BP control in treated hypertensive patients with the available drugs by using the right combinations at optimum doses, individually tailored gene-polymorphism directed therapy, or development of new modalities such as gene therapy and vaccines. Several studies have shown that BP can be reduced by lifestyle/behavior modification. Although, the reductions appear to be trivial, even small reductions in systolic BP (for example, 3-5 mm Hg) produce dramatic reduction in adverse cardiac events and stroke. On the basis of the results of clinical and clinical/observational studies, it has been recommended that more emphasis be placed on lifestyle/behavior modification (obesity, high dietary intake of fat and sodium, physical inactivity, smoking, excessive alcohol intake, low dietary potassium intake) to control BP and also to improve the efficacy of pharmacologic treatment of high BP. New classes of antihypertensive drugs and new compounds in the established drug classes are likely to widen the armamentarium available to combat hypertension. These include the aldosterone receptor blockers, vasodilator beta-blockers, renin inhibitors, endothelin receptor antagonists, and dual endopeptidase inhibitors. The use of fixed-dose combination drug therapy is likely to increase. There is a conceptual possibility that gene therapy may yield long-lasting antihypertensive effects by influencing the genes associated with hypertension. But, the treatment of human essential hypertension requires sustained over-expression of genes. Some of the challenging tasks for successful gene therapy that need to be mastered include identification of target genes, ideal gene transfer vector, precise delivery of genes into the required site (target), efficient transfer of genes into the cells of the target, and prompt assessment of gene expression over time. Targeting the RAS by antisense gene therapy appears to be a viable strategy for the long-term control of hypertension. Several problems that are encountered in the delivery of gene therapy include 1) low efficiency for gene transfer into vascular cells; 2) a lack of selectivity; 3) problem in determining how to prolong and control transgene expression or antisense inhibition; and 4) difficulty in minimizing the adverse effects of viral or nonviral vectors. In spite of the hurdles that face gene therapy administration in humans, studies in animals indicate that gene therapy may be feasible in treating human hypertension, albeit not in the near future. DNA testing for genetic polymorphism and determining the genotype of a patient may predict response to a certain class of antihypertensive agent and thus optimize therapy in individual patients. In this regard, there are some studies that report the effectiveness of antihypertensive therapy based upon the genotype of selected patients. Treatment of human hypertension with vaccines is feasible but is not likely to be available in the near future.
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PMID:The future of antihypertensive treatment. 1741 79


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