Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The term vasopeptidase means any peptidase able to generate or to inactivate a vasoactive peptide. This term got a more definitive meaning when a new class of drugs, the vasopeptidase inhibitors, was introduced. These drugs are especially represented by the inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE is now primarily considered a kininase rather than an angiotensinase and ACE-inhibitors have been used successfully in the treatment of many cardiovascular diseases, including hypertension and heart failure. Preliminary results suggest that the use of NEP inhibitors could also contribute to improve prognosis of cardiovascular diseases. Vasopeptidase inhibitors simultaneously inhibiting both NEP and ACE have shown to be more effective than currently available ACE inhibitors. (Omapatrilat is at present the most clinically advanced in these drugs). However, many side-effects of vasopeptidase inhibitors have been reported, but the most dangerous is angioedema which is potentially life threatening. Since this complication is mediated by bradykinin, and both inhibition of ACE and NEP can produce bradykinin increasing, it has been suggested that the incidence of angioedema due to vasopeptidase inhibitors could be higher compared with that related to ACE-inhibitors. The FDA raised concern about this adverse effect, and the manufacturer decided to withdraw the application temporarily. In order to identify patients at risk of angioedema we have recently shown that low plasma levels of aminopeptidase P, another enzyme which cabolises bradykinin, could indicate a predisposition for development of angioedema in some patients treated with vasoinhibitor drugs.
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PMID:[Vasopeptidases and their inhibitors]. 1240 10

The last decade has witnessed an effervescence of research interest in the development of potent inhibitors of various aspartic peptidases. As an enzyme family, aspartic peptidases are relatively a small group that has received enormous interest because of their significant roles in human diseases like involvement of renin in hypertension, cathepsin D in metastasis of breast cancer, beta-Secretase in Alzheimer's Disease, plasmepsins in malaria, HIV-1 peptidase in acquired immune deficiency syndrome, and secreted aspartic peptidases in candidal infections. There have been developments on clinically active inhibitors of HIV-1 peptidase, which have been licensed for the treatment of AIDS. The inhibitors of plasmepsins and renin are considered a viable therapeutic strategy for the treatment of malaria and hypertension. Relatively few inhibitors of cathepsin D have been reported, partly because of its uncertain role as a viable target for therapeutic intervention. The beta-secretase inhibitors OM99-2 and OM003 were designed based on the substrate specificity information. The present article is a comprehensive state-of-the-art review describing the aspartic peptidase inhibitors illustrating the recent developments in the area. In addition, the homologies between the reported inhibitor sequences have been analyzed. The understanding of the structure-function relationships of aspartic peptidases and inhibitors will have a direct impact on the design of new inhibitor drugs.
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PMID:Aspartic peptidase inhibitors: implications in drug development. 1274 95

Elevated blood pressure is a risk factor for a variety of cardiovascular disorders, including coronary heart disease, peripheral vascular disease, cardiac failure and cerebrovascular disease. The prevailing view is that an elevated systolic rather than diastolic blood pressure is the major contributor in mortality and morbidity attributed to cardiovascular disorders. Isolated high systolic blood pressure, especially in the elderly, is a major risk factor and should undoubtedly be a target for drug treatment. In the general population, systolic and diastolic blood pressure are highly correlated, and thus it is difficult to dissociate the effects of these two components of the blood pressure and specifically ascribe cardiovascular risk factors to just elevated systolic blood pressure. Therefore, the goal in therapy of an individual with hypertension must be to reduce elevated systolic and diastolic blood pressure in order to reduce mortality and morbidity. ACE and neutral peptidase inhibitors are a new class of drugs that may be beneficial in the treatment of patients with hypertension and heart failure. They may also be useful in the treatment of diabetic patients with hypertension and/or heart failure. Drugs of this class are dual inhibitors of ACE and neutral endopeptidase, and are capable of affecting vascular tone and fluid balance. They are capable of producing vasodilatation by virtue of inhibiting the production of angiotensin II, degradation of natriuretic peptides and bradykinin. They also appear to promote natriuresis and diuresis by amplifying the actions of natriuretic peptidase and reducing aldosterone effects. In addition, they should also attenuate trophogenic actions of the renin angiotensin system and the sympathetic nervous system. Omapatrilat is one drug that appears to be at the advanced stages of clinical development. This drug has been shown to be quite effective in the treatment of hypertension. Evidence also seems to indicate that treatment with omapatrilat results in a higher tendency towards preventing death and worsening heart failure when compared with treatment with a pure ACE inhibitor in patients with advanced heart failure. Overall safety with omapatrilat appears to be good, but like other ACE inhibitors the incidence of cough is higher when compared with placebo. Other common adverse effects noted are headaches, facial flushing/warm sensation, dizziness, nausea and dyspnoea. Of greater concern is the occurrence of angio-oedema, the true incidence of which remains to be fully established as part of the published medical literature.
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PMID:Dual ACE and neutral endopeptidase inhibitors: novel therapy for patients with cardiovascular disorders. 1501 94

The chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension. This inhibition of NO production results in activation of the renin-angiotensin system, with increased activity of the carboxypeptidase angiotensin I-converting enzyme (ACE). Since chronic NO inhibition increases ACE activity, we hypothesized that this inhibition could also affect the activities of other peptidases involved in cardiovascular functions. To test this possibility, we examined the activities of aminopeptidase M (APM), dipeptidyl peptidase IV (DPP IV), metalloendopeptidase 24.15 (MEP 24.15) and neutral endopeptidase 24.11 (NEP 24.11) in rat brain, heart, kidney, liver, lung and thoracic aorta. Male Wistar rats were treated chronically with L-NAME (80mgkg(-1) per day) administered in the drinking water for 4 weeks and their organs then removed and processed for the determination of peptidase activities. Treatment with L-NAME did not significantly alter the activities of the four peptidases in brain, heart, kidney, liver and lung. In contrast, in aorta, the activity of APM was slightly but significantly reduced whereas those of DPP IV and MEP 24.15 were markedly enhanced; NEP 24.11 was not detected in this tissue. Immunoblotting for DPP IV and MEP 24.15 showed increased expression in aortic tissue. Neither L-NAME (1-100microM) nor the NO donors sodium nitroprusside and 3-morpholinosydnonimine (SIN-1; 1-100microM) had any consistent effect on the activity of recombinant MEP 24.15 or renal DPP IV. The importance of MEP 24.15 in peptide metabolism was confirmed in pentobartibal-anesthetized rats pretreated with the MEP 24.15 inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA2), which significantly potentiated the hypotensive response to bradykinin. The altered peptidase activities seen in aorta may contribute to modulating vascular responses in this model of hypertension.
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PMID:Peptidase activities in rats treated chronically with N(omega)-nitro-L-arginine methyl ester (L-NAME). 1519 92

Prostasin is a serine peptidase hypothesized to regulate epithelial sodium channel (ENaC) activity in animals or on in vitro cultured cells. We investigated whether urinary prostasin may be a candidate marker of ENaC activation in humans. We studied 10 healthy volunteers and 8 hypertensive patients with raised aldosterone-to-renin ratio before and after spironolactone or saline/Florinef suppression test, respectively. Four healthy subjects were also studied before and after saline. Urinary prostasin was evaluated by SDS-PAGE, 2D maps, and Western blotting. Every sample of normotensive individuals was compared with the corresponding sample of urine collected after spironolactone or saline; every sample of hypertensive patients was compared with the corresponding sample of urine collected after saline or Florinef. Prostasin was detectable in all subjects regardless of gender, dietary sodium intake, and spironolactone treatment. Spironolactone (100 mg) increased urinary Na+/K+ ratio and decreased urinary prostasin in normotensives in whom the renin/aldosterone axis was activated by a low Na+ intake, but it was ineffective in individuals with high Na+ intake. Saline infusion also reduced prostasin in normotensive subjects. In contrast, prostasin paradoxically increased in urine of patients affected by primary aldosteronism after volume expansion. By 2D immunoblotting, several protein isoforms were observed, some of them being overexpressed after inhibition tests in patients with primary aldosteronism. In addition to a "basal" aliquot of prostasin, constitutively released in human urine regardless of sodium balance and aldosterone activation, there exists a second "aldosterone-responsive" aliquot modulated by Na+ intake and potentially suitable as candidate marker of ENaC activation.
Hypertension 2005 Oct
PMID:Urinary prostasin: a candidate marker of epithelial sodium channel activation in humans. 1617 30

Angiotensin-converting enzyme 2 (ACE2) is a newly discovered carboxy-peptidase responsible for the formation of vasodilatory peptides such as angiotensin-(1-7). We hypothesized that ACE2 is part of the brain renin-angiotensin system, and its expression is regulated by the other elements of this system. ACE2 immunostaining was performed in transgenic mouse brain sections from neuron-specific enolase-AT(1A) (overexpressing AT(1A) receptors), R(+)A(+) (overexpressing angiotensinogen and renin), and control (nontransgenic littermates) mice. Results show that ACE2 staining is widely distributed throughout the brain. Using cell-type-specific antibodies, we observed that ACE2 staining is present in the cytoplasm of neuronal cell bodies but not in glial cells. In the subfornical organ, an area lacking the blood-brain barrier and sensitive to blood-borne angiotensin II, ACE2 was significantly increased in transgenic mice. Interestingly, ACE2 mRNA and protein expression were inversely correlated in the nucleus of tractus solitarius/dorsal motor nucleus of the vagus and the ventrolateral medulla, when comparing transgenic to nontransgenic mice. These results suggest that ACE2 is localized to the cytoplasm of neuronal cells in the brain and that ACE2 levels appear highly regulated by other components of the renin-angiotensin system, confirming its involvement in this system. Moreover, ACE2 expression in brain structures involved in the control of cardiovascular function suggests that the carboxypeptidase may have a role in the central regulation of blood pressure and diseases involving the autonomic nervous system, such as hypertension.
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PMID:Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. 1694 85

Recent investigations point to an important role for peptidases in regulating transcellular ion transport by the epithelial Na(+) channel, ENaC. Several peptidases, including furins and proteasomal hydrolases, modulate ENaC maturation and disposal. More idiosyncratically, apical Na(+) transport by ENaC in polarized epithelia of kidney, airway, and gut is stimulated constitutively by one or more trypsin-family serine peptidases, as revealed by inhibition of amiloride-sensitive Na(+) transport by broad-spectrum antipeptidases, including aprotinin and bikunin/SPINT2. In vitro, the transporting activity of aprotinin-suppressed ENaC can be restored by exposure to trypsin. The prototypical channel-activating peptidase (CAP) is a type 1 membrane-anchored tryptic peptidase first identified in Xenopus kidney cells. Frog CAP1 strongly upregulates Na(+) transport when coexpressed with ENaC in oocytes. The amphibian enzyme's apparent mammalian orthologue is prostasin, otherwise known as CAP1, which is coexpressed with ENaC in a variety of epithelia. In airway cells, prostasin is the major basal regulator of ENaC activity, as suggested by inhibition and knockdown experiments. Other candidate regulators of mature ENaC include CAP2/TMPRSS4 and CAP3/matriptase (also known as membrane-type serine protease 1/ST14). Mammalian CAPs are potential targets for treatment of ENaC-mediated Na(+) hyperabsorption by the airway in cystic fibrosis (CF) and by the kidney in hypertension. CAPs can be important for mammalian development, as indicated by embryonic lethality in mice with null mutations of CAP1/prostasin. Mice with selectively knocked out expression of CAP1/prostasin in the epidermis and mice with globally knocked out expression of CAP3/matriptase exhibit phenotypically similar defects in skin barrier function and neonatal death from dehydration. In rats, transgenic overexpression of human prostasin disturbs salt balance and causes hypertension. Thus, several converging lines of evidence indicate that ENaC function is regulated by peptidases, and that such regulation is critical for embryonic development and adult function of organs such as skin, kidney, and lung.
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PMID:Regulation of the epithelial Na+ channel by peptidases. 1733 14

There is a high prevalence of diabetes mellitus in the population of Saudi Arabia with the majority having non-insulin dependent diabetes mellitus (NIDDM). Random mid-day urine samples were obtained from 100 male [37 insulin dependants DM (IDDM) and 63 NIDDM] and 100 female (51 IDDM and 49 NIDDM) diabetic patients. Eighty-four patients were hypertensive (46 males and 28 females). One hundred and fifty-five subjects, not under medication and without clinical evidence of renal disease, hypertension, or diabetes mellitus were used as controls. Two urinary enzymes, N-acetyl-beta-D-glucosaminidase (NAG) and alanine amino-peptidase (AAP) were measured in the urine, together with total protein and creatinine concentration. Microalbuminuria, glucose and pH were measured using test strips. Increased levels of both NAG and AAP were found in the diabetic subjects. Increased excretion of both these enzymes as well as microalbuminuria was found in the hypertensive groups. The high levels of urinary enzymes found, suggest that renal complications were prevalent in the groups studied. Because of the high incidence of diabetes in Saudi Arabia, a screening program should be established which would include urinary biomarkers for the early detection of renal damage.
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PMID:Urinary enzymes and microalbuminuria as indicators of renal involvement in patients with diabetes mellitus in saudi arabia. 1820 62

The effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on ambulatory blood pressure was assessed in nondiabetic patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled, 3-period crossover study. Nineteen patients on stable treatment with antihypertensive agent(s) received sitagliptin 100 mg b.i.d., 50 mg b.i.d., or placebo for 5 days, with at least a 7-day washout interval between periods. Twenty-four-hour ambulatory blood pressure, including systolic blood pressure, diastolic blood pressure, and mean arterial pressure, were monitored on days 1 and 5. Relative to placebo on day 1, the mean difference in 24-hour systolic blood pressure was -0.9 mm Hg (90% confidence interval: -2.9 to 1.1; P = .46) with sitagliptin 50 mg b.i.d. and -2.8 mm Hg (90% confidence interval: -4.9 to -0.8; P < .05) with 100 mg b.i.d. On day 5, the mean difference in 24-hour systolic blood pressure was -2.0 mm Hg (90% confidence interval: -3.5 to -0.4; P < .05) with 50 mg b.i.d. and -2.2 mm Hg (90% confidence interval: -3.7 to -0.6; P < .05) with 100 mg b.i.d. relative to placebo. For 24-hour diastolic blood pressure, there were no between-group differences in mean 24-hour diastolic blood pressure on day 1. On day 5, sitagliptin 50 mg and 100 mg b.i.d significantly (P < .05) lowered mean 24-hour diastolic blood pressure by -1.8 mm Hg (90% confidence interval: -2.8 to -0.8) and -1.6 mm Hg (90% confidence interval: -2.6 to -0.7), respectively, relative to placebo. Sitagliptin produced small but statistically significant reductions of 2 mm Hg to 3 mm Hg in 24-hour ambulatory blood pressure measurements acutely (day 1) and at steady state (day 5), and was generally well tolerated in nondiabetic patients with mild to moderate hypertension.
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PMID:Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. 1835 96

Hypertension-induced myocardial metabolic, structural and electrophysiological remodeling deteriorates with aging and contributes to both heart failure and occurrence of malignant arrhythmias. It has been shown in clinical trials that n-3 polyunsaturated fatty acids (n-3 PUFA) reduce the incidence of cardiovascular diseases and sudden cardiac death. We investigated the cardioprotective effects of n-3 PUFA in aged spontaneously hypertensive rats (SHR) and possible cellular mechanisms involved. Male and female 14-moth-old SHR were fed with n-3 PUFA (Vesteralens, Norway, 20 mg/day for two months) and compared with untreated SHR. Results showed that n-3 PUFA supplementation led to 1) significant decline of blood pressure; 2) suppression of inducible ventricular fibrillation (VF) by 57 % (male) and 67 % (female), although the arrhythmogenic substrates, like fibrosis, hypertrophy and abnormal gap junctions distribution were not eliminated; 3) preservation of the cardiomyocytes and the integrity of their junctions; 4) enhancement of energetic metabolism enzyme activity; 5) augmentation of capillary density associated with increased alkaline phosphatase and decreased dipeptidyl peptidase-4 (DPP4) activity and 6/ increase in gap junction channel connexin-43 expression. Thus, aged male as well as female SHR benefit from n-3 PUFA supplementation that results in decrease in VF susceptibility, partly due to an improvement of myocardial metabolic state, cardiomyocyte and cell-to-cell junctions integrity and Cx43 up-regulation.
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PMID:Aged male and female spontaneously hypertensive rats benefit from n-3 polyunsaturated fatty acids supplementation. 1837 94


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