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)

Human chymase forms angiotenin (ANG) I to ANG II, whereas the roles of ANG II generated by chymase and the effects of chymase inhibitors have been unclear. On the other hand, rat chymase could not convert ANG I to ANG II. In isolated rat arteries, the ANG I-induced vascular contraction was completely suppressed by angiotensin-converting enzyme (ACE) inhibitor only. However, 30% of ANG I-induced vascular contraction in isolated human arteries was suppressed by an ACE inhibitor, but the remainder was blocked by chymostatin. In hamster hypertensive models, ANG II formation by ACE, but not by chymase, in vascular tissues plays an important role in maintaining hypertension. ANG II formation also induces vascular remodeling such as neointima formation. After balloon injury of vessels in dog, chymase and ACE activities were significantly increased in the injured vessels. In this model, an ANG II receptor antagonist was effective in preventing neointimal formation after balloon injury of vessels in dog, but an ACE inhibitor was ineffective. In dog grafted veins, the activities of chymase and ACEmin the grafted vein were significantly increased 15- and 2-fold, respectively, compared with those in the symmetrical veins. The intimal area of the grafted vein was reduced by a chymase inhibitor. Therefore, chymase-dependent ANG II formation plays an important role in the proliferative response, and chymase inhibitors may appear useful for preventing vascular proliferation.
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PMID:[Pathophysiological roles of chymase and effects of chymase inhibitor]. 1062 53

Apart from ACE, various angiotensin II (Ang II)-forming serine proteinases (eg, chymase, kallikrein, and cathepsin G) are known to exist in human tissues, but their clinical significance or the regulatory mechanisms that control their activities are not well established. A recent clinical study has shown that chymase activity was significantly increased in human atherosclerotic or aneurysmal aorta. The association between vascular Ang II-forming activities (AIIFAs) in the human internal thoracic artery (ITA) and various clinical parameters was studied with the use of ITAs obtained from 32 patients who underwent coronary artery bypass graft surgery. Total and ACE- and chymase-dependent AIIFAs in homogenates of ITAs were determined. Total AIIFA was 8.67+/-0.86 (nmol Ang II formed. min(-1). mg protein(-1) [U]), and approximately 95% of the activities were due to chymase. Serum total cholesterol level, but no other risk factors, significantly correlated with chymase- (r=0. 60, P<0.001) and ACE- (r=0.35, P<0.05) dependent AIIFAs, respectively. LDL cholesterol level was also correlated with chymase-dependent AIIFAs (r=0.47, P<0.05). Mast cells identified through the use of toluidine blue or immunohistochemical staining appeared in the adventitia but not in the intima or media of ITAs. Our results suggest that an increased plasma LDL cholesterol level may induce increased arterial chymase and ACE activity.
Hypertension 2000 Jan
PMID:Increased chymase activity in internal thoracic artery of patients with hypercholesterolemia. 1064 75

The justification for clinical investigation has its roots in the fact that physiological mechanisms and disease pathogenesis in animal models replicate mechanisms and pathogenesis in humans only in part. In the case of the renin-angiotensin system, there is species variation in the anatomic distribution of the renin-angiotensin system, in the active site of the renin enzyme, and in the structure of angiotensin and the AT(1) receptor. The conversion of angiotensin I (Ang I) to angiotensin II (Ang II) may prove to be the most important aspect of species variation. In plasma, all the conversion occurs through a single enzyme, angiotensin-converting enzyme (ACE), and species variation in structure and function have not been reported. Non-ACE-dependent pathways, which occur only at the tissue level, show unambiguous, striking species variation. Specifically, chymase, the most important enzyme responsible for non-ACE conversion of Ang I to Ang II, shows striking species variation. In humans and a number of species, including the hamster, quantitatively important chymase-independent Ang II formation from Ang I occurs in the heart, arteries, and kidney. In rats and rabbits, on the other hand, chymase differs, is not active in the conversion of Ang I to Ang II, and indeed is involved in Ang II degradation. Consequently, one would anticipate that blockade of the system at the ACE step would be equivalent to that at the Ang II receptor in the rat. This has been widely reported. In humans, on the other hand, one would anticipate that the AT(1) receptor blockers will be more effective than ACE inhibitors. Again, preliminary evidence favors this possibility. The implications for therapeutics are clear.
Hypertension 2000 Jan
PMID:Implications of species difference for clinical investigation: studies on the renin-angiotensin system. 1064 91

To assess the importance for vasoconstriction of in situ angiotensin (Ang) II generation, as opposed to Ang II delivery via the circulation, we determined forearm vasoconstriction in response to Ang I (0.1 to 10 ng. kg(-1). min(-1)) and Ang II (0.1 to 5 ng. kg(-1). min(-1)) in 14 normotensive male volunteers (age 18 to 67 years). Changes in forearm blood flow (FBF) were registered with venous occlusion plethysmography. Arterial and venous blood samples were collected under steady-state conditions to quantify forearm fractional Ang I-to-II conversion. Ang I and II exerted the same maximal effect (mean+/-SEM 71+/-4% and 75+/-4% decrease in FBF, respectively), with similar potencies (mean EC(50) [range] 5.6 [0.30 to 12.0] nmol/L for Ang I and 3.6 [0.37 to 7.1] nmol/L for Ang II). Forearm fractional Ang I-to-II conversion was 36% (range 18% to 57%). The angiotensin-converting enzyme (ACE) inhibitor enalaprilat (80 ng. kg(-1). min(-1)) inhibited the contractile effects of Ang I and reduced fractional conversion to 1% (0.1% to 8%), thereby excluding a role for Ang I-to-II converting enzymes other than ACE (eg, chymase). The Ang II type 1 receptor antagonist losartan (3 mg. kg(-1). min(-1)) inhibited the vasoconstrictor effects of Ang II. In conclusion, the similar potencies of Ang I and II in the forearm, combined with the fact that only one third of arterially delivered Ang I is converted to Ang II, suggest that in situ-generated Ang II is more important for vasoconstriction than circulating Ang II. Local Ang II generation in the forearm depends on ACE exclusively and results in vasoconstriction via Ang II type 1 receptors.
Hypertension 2000 Mar
PMID:Functional importance of angiotensin-converting enzyme-dependent in situ angiotensin II generation in the human forearm. 1072 May 92

The renin-angiotensin system has been studied and recognized as one of the major blood pressure-regulating systems for the past century. In the last quarter century, however, many alternative pathways of angiotensin II formation have been found, and among them, chymase has been a focus of interest because of its specificity and potency in the human cardiovascular system. Chymase evidently is not involved in functional regulation of blood pressure at least in the short term, but evidence is accumulating that it may be involved in structural remodeling of the cardiovascular system. We found increased vascular chymase activity in atherosclerotic lesions of the human aorta as well as in cardiac remodeling after myocardial infarction. We found a significant positive correlation between serum total or LDL cholesterol levels and arterial chymase-dependent angiotensin II-forming activity in patients who were undergoing coronary artery bypass operation, suggesting that high serum cholesterol may trigger upregulation of vascular chymase and facilitate the development of atherosclerosis. This hypothesis was tested in Syrian hamsters fed a high cholesterol diet containing 0.5% cholesterol: A marked lipid deposition in the aortic cusp developed and the plasma cholesterol levels were positively correlated with aortic chymase activity. An orally active nonpeptide chymase inhibitor almost canceled this lipid deposition. These clinical and experimental data indicated an association between cholesterol and vascular chymase upregulation that may facilitate the development of atherosclerosis.
Hypertension 2000 Oct
PMID:Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. 1104 Feb 50

While greater than 80% of angiotensin II (Ang II) formation in the human heart and greater than 60% in arteries appears to result from chymase activity, no cardiovascular cell-expressed chymase has been previously reported. We now describe the cloning of a full-length cDNA encoding a novel chymase from rat vascular smooth muscle cells. The cDNA encompasses 953 nucleotides, encodes 247 amino acids, and exhibits 74% and 80% homology in amino acid sequence to rat mast cell chymase I and II, respectively. Southern blot analysis indicates that the rat vascular chymase is encoded by a separate gene. This chymase was induced in hypertrophied rat pulmonary arteries, with 11-fold and 8-fold higher chymase mRNA levels in aortic and pulmonary artery smooth muscle cells from spontaneously hypertensive than in corresponding tissues from normotensive rats. We assayed the activity of the endogenous enzyme and of a recombinant, epitope-tagged chymase in transfected smooth muscle cells and showed that Ang II production from Ang I can be inhibited with chymostatin, but not EDTA or captopril. Spontaneously hypertensive rats show elevated chymase expression and increased chymostatin-inhibitable angiotensin-converting activity, suggesting a possible role for this novel enzyme in the pathophysiology of hypertension.
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PMID:A novel vascular smooth muscle chymase is upregulated in hypertensive rats. 1125 70

The development of pharmacological agents that block the renin-angiotensin system (RAS) specifically have helped to define all the components of the system and their contribution to blood-pressure control and to the pathogenesis of hypertension, congestive heart failure and chronic renal failure. The angiotensin converting-enzyme inhibitors (ACEi) are among all available drugs that interfere with the RAS, the most efficient, so far, in the treatment of several cardiovascular diseases, with comfortable posologic schemes and an acceptable safety profile. The most important difference between them are more related to pharmacokinetic profile rather than to pharmacodynamic characteristics. With the use of ACEi the interference with other neurohumoral systems is unavoidable and the controversy has been pharmacologically and clinically installed. With the advent of oral selective AT1 angiotensin II receptor blockers (ARB) the pharmacological interference became eventually much more selective. Their antihypertensive efficacy is identical and their tolerability is better than that showed by ACEi. The ARBs differ mainly in their pharmacokinetics and in their binding capacity to the AT1 angiotensin receptor. The results of several ongoing clinical trials will show if the ARBs as ACEi will be capable to protect target-organs and to promote a significant reduction in cardiovascular morbility and mortality. In parallel there is an intense experimental and clinical research with other groups of drugs which also markedly interfere with RAS: renin inhibitors, chymase inhibitors and simultaneous inhibitors of vasopeptidases (ACE, endothelin converting-enzyme, neutral endopeptidase). From the pharmacological point of view, it is now possible to block effectively RAS with some relevant clinical results that will be certainly widen in the near future.
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PMID:[Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists. Pharmacologic features]. 1130 8

Roles of each angiotensin II producing enzymes of each of the angiotensin II-producing enzymes were reviewed based on experimental models. In vascular tissues, angiotensin II is potentially cleaved from angiotensin I by angiotensin converting enzyme (ACE) and chymase. It has been confirmed that vascular tissues of humans, monkeys, dogs and hamsters have a chymase-dependent angiotensin II-forming pathway. Much like other hypertensive models, hamster hypertensive models show high levels of vascular ACE activity, but not chymase activity. In hypertensive hamsters, administration of either an ACE inhibitor or an angiotensin II type 1 (AT1) receptor antagonist resulted in similar reductions in blood pressure, suggesting that chymase is not involved in the maintenance of high blood pressure in this model. In monkeys fed a high-cholesterol diet, ACE activity was increased in the atherosclerotic lesions, and an ACE inhibitor and an AT1 receptor antagonist prevented atherosclerosis to a similar degree, suggesting that ACE may be mainly involved in the development of atherosclerosis. After balloon injury in dog vessels, both ACE and chymase activities were locally increased about 3-fold in the injured arteries, and an AT1 receptor antagonist was effective in preventing the intimal formation, but an ACE inhibitor was ineffective. In dog grafted veins, the activities of chymase were increased 15-fold, but those of ACE were increased only 2-fold, and the intimal formation was suppressed by either an AT1 receptor antagonist or a chymase inhibitor. In the normal vascular tissues, ACE plays a crucial role for angiotensin II production, whereas chymase is stored in mast cells in an inactive form. Chymase acquires the ability to form angiotensin II following mast cells activation followed by mast cells activation by a strong stimulus such as occurs in catheter-injury or grafting. Together, these results indicate that chymase plays a major role in the vascular angiotensin II-generating system, particularly in cases of vascular injury.
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PMID:Local angiotensin II-generating system in vascular tissues: the roles of chymase. 1140 39

We cloned a rat vascular chymase (RVCH) from smooth muscle cells (SMCs) that converts angiotensin I to II and is up-regulated in SMC from spontaneously hypertensive vs. normotensive rats. To determine whether increased activity of RVCH is sufficient to cause hypertension, transgenic mice were generated with targeted conditional expression of RVCH to SMC, with the use of the tetracycline-controlled transactivator (tTA). We confirmed conditional expression of RVCH by mRNA, protein, and chymase activity in the absence, but not in the presence, of dietary doxycycline. The systolic blood pressure (mmHg), measured by carotid artery cannulation at 10-12 weeks of age, was higher in tTA+/RVCH+ mice than in nonbinary transgenic littermates (136 +/- 4 vs. 109 +/- 3) (P < 0.05), as were the diastolic and mean pressures. Hypertension was completely reversed by doxycycline, suggesting a causal link with chymase expression. Medial thickening of mesenteric arteries from tTA+/RVCH+ mice vs. littermates (0.82 +/- 0.1 vs. 0.42 +/- 0.02) (P < 0.05) was associated with increased SMC proliferation, as judged by positive immunoreactivity, with the use of an antibody to the proliferating cell nuclear antigen. These structural changes were prevented by doxycycline. Perfusion myography of mesenteric arteries from tTA+/RVCH+ mice also revealed increased vasoconstriction in response to phenylephrine and impaired metacholine-induced vasodilatation when compared with littermate controls or with the doxycyline-treated group. Our studies suggest that up-regulation of this vascular chymase is sufficient to cause a hypertensive arteriopathy, and that RVCH may be a candidate gene and a therapeutic target in patients with high blood pressure.
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PMID:Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice. 1141 17

Angiotensin Converting Enzyme (ACE) inhibitors represent a major advance in the treatment of: hypertension, and generally speaking, in cardiovascular prevention; myocardial infarction; cardiac failure. They have a cardio and vascular protective action by tending to correct hypertension, left ventricular hypertrophy and remodelling, endothelial dysfunction, arterial smooth muscle proliferation and thrombotic phenomena. However, besides the cough that this therapeutic class engenders, a major question remains unanswered: is there resistance to this family of drugs? In other words, does left ventricular remodelling and arterial smooth muscle proliferation continue with regular treatment at the prescribed dosages? The synthesis of angiotensin II does not only depend on the angiotensin converting enzyme but also on the quality of angiotensin I and the presence of other enzymes such as chymase. A secondary increase of angiotensin II with ACE inhibitor therapy may reflect insufficient blockade of the renin-angiotensin system or a synthesis of angiotensin II by an alternative pathway to the converting enzyme. In vivo measurement of ACE inhibition shows that blockade of the renin-angiotensin system is automatically limited due to the very accurate regulation of angiotensin II concentrations.
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PMID:[Resistance to ACE inhibitors. Myth or reality?]. 1160 63


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