Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin-converting enzyme (ACE) is mainly responsible for converting angiotensin I (AI) to angiotensin II (AII), and ACE inhibitors prevent atherosclerosis in animal models. Neutral endopeptidase 24.11 (NEP) degrades substance P, kinins and atrial natriuretic peptide (ANP), and aortic wall NEP activity was found to be increased in atherosclerosis. In the present study, we have evaluated the effect of candoxatril, a NEP inhibitor, and of omapatrilat, a dual ACE and NEP inhibitor, on the development of fatty streak in apolipoprotein E (apoE)-deficient mice. Groups of ten male apoE-deficient mice were given either placebo, candoxatril 50 mg/kg per day, or omapatrilat 10, or 100 mg/kg per day for 4 months. None of the treatments influenced body weight, serum total or HDL-cholesterol. Compared with the placebo, candoxatril did not protect the mice from fatty streak deposit. In contrast, omapatrilat dose dependently inhibited the constitution of fatty streak in apoE-deficient mice. The precise advantages of the dual ACE and NEP inhibition versus the inhibition of only ACE should now be considered in the prevention of atherosclerosis as well as in the occurrence of its complications.
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PMID:Omapatrilat, a dual angiotensin-converting enzyme and neutral endopeptidase inhibitor, prevents fatty streak deposit in apolipoprotein E-deficient mice. 1125 98

In both diabetic and nondiabetic renal disease, reducing blood pressure with antihypertensive therapy has beneficial effects on renal function. The key role of the renin-angiotensin system in blood pressure and volume homeostasis has long been established, but its importance for the overall normal functioning of the kidney itself is also increasingly being recognized. Angiotensin-converting enzyme (ACE) inhibitors, widely and successfully used in the treatment of hypertension, may also provide renal protection independent of blood pressure reduction; however, their relatively nonspecific mode of action in blocking an early metabolic step entails major clinical disadvantages, such as accumulation of bradykinin and substance P, that may cause the characteristic ACE-inhibitor side effects of persistent dry cough and, more rarely, angioneurotic edema. Angiotensin II antagonists or receptor blockers, a new class of antihypertensive agent, selectively antagonize the AT1 receptor subtype and, because of greater specificity, do not give rise to the side effects associated with ACE inhibitors. More important, these new drugs may have mechanistic advantages over other antihypertensives, including ACE inhibitors.
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PMID:Valsartan and the kidney: review of preclinical and clinical data. 1144 69

Since adverse effects due to angiotensin-converting enzyme (ACE) inhibitors frequently occur in cutaneous locations, this review summarizes the spectrum of expected and unexpected adverse effects of these drugs, possible associated mechanisms, and their basic functions for dermatologists. ACE inhibitors block the activity of the metalloproteinase ACE by binding to its active site, thus displacing angiotensin I and preventing its conversion to vasopressive angiotensin II. Furthermore, ACE degrades bradykinin, substance P, enkephalins and some of the reproductive peptide hormones. The overall incidence of adverse effects to ACE inhibitors is estimated at 28%, approximately half of which occurs in the skin. General reactions are first-dose hypotension, hyperkalaemia and renal failure. Cutaneous reactions comprise life-threatening angioedema, pruritus, bullous eruptions, urticaria, other generalized rashes, photosensitivity and hair loss. ACE inhibitors thus mimic a broad variety of skin diseases, why these drugs should be thought of when sudden, unexplainable skin eruptions are observed.
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PMID:Angiotensin-converting enzyme inhibitors as inducers of adverse cutaneous reactions. 1180 Jan 36

Urotensin II is a cyclic undecapeptide which activates the GPR14 receptor and exerts potent vasoconstrictor effects in some species of fish and mammals. The present study intended to investigate isolated vessels from various species in an attempt to find sensitive preparations to be used in studies of the human urotensin (hU-II)/GPR14 system. Contractile responses evoked by noradrenaline (NA), angiotensin II (Ang II), endothelin 1 (ET-1) and hU-II were measured in large vessels (aorta and some large arteries and veins) of rats, guinea pigs, rabbits, pigs and humans. Relaxing effects of hU-II, bradykinin (BK) and substance P (SP) were measured in pig coronary arteries contracted with KCl 30 mM. The rat mesenteric vasculature was investigated from the arterial and venous site to establish the function of ET-1 and hU-II receptors. Results indicate that the only preparation showing high sensitivity to hU-II (pEC(50)=8.27) is the rat aorta, whose contractions in response to hU-II develop slowly and persist for hours, similar to those of ET-1 (pEC(50)=8.35). Effects of NA (pEC(50)=8.12) and Ang II (pEC(50)=7.95) develop and reverse more rapidly. Tissues treated with ET-1 and hU-II show marked desensitization, in contrast to those treated with NA. Specific antagonists for alpha(1) (prazosin, p A(2)=10.46), AT(1) (EXP 3174, p A(2)=10.20), 5HT(2) (ketanserine, p A(2)=8.61) and ET(A)-ET(B) (bosentan, p A(2)=6.88) receptors were shown to block the effects of the respective agonists, while being inactive against hU-II. In some vessels, hU-II behaved as an highly potent but scarcely effective contractile agent. It is concluded that: the hU-II/GPR14 is not a functional contractile system in vessels of several species, in contrast with NA/alpha(1), Ang II/AT(1), 5HT/5HT(2) and ET-1/ET(A)-ET(B). The rat aorta appears however to be a sensitive and reliable preparation for evaluating biological activities of hU-II and related peptides.
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PMID:Effects of human urotensin II in isolated vessels of various species; comparison with other vasoactive agents. 1181 32

Angiotensin II (Ang II) plays an important role in the central control of blood pressure and baroreflexes. These effects are initiated by stimulation of Ang II type 1 (AT(1)) receptors on neurons within the hypothalamus and brain stem, and involve increasing the activity of noradrenergic, substance P, and glutamatergic pathways. The goal of this study is to investigate the intracellular signaling molecules, which are involved in mediating the Ang II-induced increases in neuronal activity. Using neurons in primary culture from newborn rat hypothalamus and brain stem, we have previously determined that Ang II elicits an AT(1) receptor-mediated inhibition of delayed rectifier K(+) current, a stimulation of Ca(2+) current, and a consequent increase in firing rate. In the present study we have demonstrated that this chronotropic action of Ang II in neuronal cultures involves activation of Ca(2+)-dependent signaling molecules. The Ang II-induced increase in firing rate was abolished by inhibition of phospholipase C with U73122 (10 micromol/L), and was attenuated by the protein kinase C inhibitor calphostin C (10 micromol/L) or by the calcium/calmodulin-dependent kinase II (CaMKII) inhibitor KN-93 (10 micromol/L). A combination of calphostin C and KN-93 completely inhibited this Ang II action. These results indicate that the AT(1) receptor-mediated increase in neuronal firing rate involves activation of both PKC and CaMKII, and suggest that these enzymes are potential targets for manipulating the central actions of Ang II.
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PMID:Chronotropic action of angiotensin II in neurons via protein kinase C and CaMKII. 1188 8

PgPepO is a homologue of endothelin-converting enzyme-1 (ECE-1), with which it shares 31% identity. PgPepO was isolated from the periodontal pathogen Porphyromonas gingivalis. Recent studies have suggested a link between periodontal and cardiovascular disease, and several groups have suggested that bacterial and viral infections may contribute to the latter. P. gingivalis possesses the ability to invade, and multiply within, aortic endothelial cells and has been localized to atherosclerotic plaques. PgPepO was expressed and purified to homogeneity and we have begun detailed functional analysis, in terms of substrate preference and inhibitor specificity, in order to provide active-site comparisons with other members of the neprilysin (NEP)/ECE family. PgPepO possesses similar substrate specificity to ECE-1 and has been shown to cleave big endothelin-1 (big ET-1), big ET-2 and big ET-3, converting the substrates into their respective mature endothelin peptides. Substance P, angiotensin I, angiotensin II and neurotensin are all cleaved at multiple sites by PgPepO and the kinetics of these reactions have been compared. The potent vasoconstrictor urotensin II is not hydrolysed by PgPepO. Cleavage of bradykinin by PgPepO occurs at the Pro(7)-Phe(8) bond and is inhibited by the NEP and ECE-1 inhibitor phosphoramidon in a pH-dependent fashion (IC(50) =10 microM at pH 7.0) but not by thiorphan, an NEP-specific inhibitor. PgPepO activity is completely inhibited by EDTA. Characterization of this enzyme is important in elucidating possible links between periodontal pathogens and cardiovascular disorders such as atherosclerosis, and provides an opportunity to gain structural information on a bacterial protein with striking similarity to human ECE-1.
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PMID:Characterization of PgPepO, a bacterial homologue of endothelin-converting enzyme-1. 1219 62

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT(1)) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT(1) receptors (postsynaptically) and at presynaptic AT(1) receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.
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PMID:Eprosartan for the treatment of hypertension. 1251 47

A rapid method for the simultaneous assay of 7 peptide mixture, including angiotensin I, II, III, substance P, neurokinin, somatostatin and neurotensin, by high performance capillary electrophoresis has been established. The nature, pH and concentration of buffer, running voltage, detection wavelength, injection time and the effective length of amino-coated capillary were defined with the results of experiment. With 50 mmol/L ammonium acetate (pH 4.5) as running buffer and siphonage injection for 10 seconds, the measurements were carried out at 25 degrees C and 10 kV running voltage [(-)-->(+)] applied to a 57 cm x 75 microns i.d. (50 cm effective length) amino-coated capillary. The 7 peptide mixture was determined by a UV detector at 214 nm. The total time for separation and determination was within 8 min. The recoveries ranged from 95% to 98% with RSD from 2.9% to 4.2%. It has been found that the 75 microns i.d. capillary has higher sensitivity than 50 microns, but its efficiency and Rs were worse.
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PMID:[Study on the determination of peptide mixture by HPCE]. 1254 65

This review summarizes some basic properties and distribution of angiotensin I converting enzyme (ACE). ACE is one of several biologically important ectoproteins that exists in both membrane-bound and soluble forms. Localized on the surface of various cells, ACE is inserted at the cell membrane via its carboxyl terminus. Human plasma ACE originates from endothelial cells while other body fluids may contain ACE that originates from epithelial, endothelial or germinal cells. The two isoforms of ACE, the two-domain somatic form and the single domain germinal form, convert angiotensin I to angiotensin II, and metabolize kinins and many other biologically active peptides, including substance P, chemotactic peptide and opioid peptides. The broad spectrum of substrates for ACE and its wide distribution throughout the body indicates that this enzyme, in addition to an important role in cardiovascular homeostasis, may be involved in additional physiologic processes such as neovascularization, fertilization, atherosclerosis, kidney and lung fibrosis, myocardial hypertrophy, inflammation and wound healing. Future research should explore the possible functions of tissue ACE and its systemic role as a pressor agent. ACE inhibitors have achieved widespread use in the treatment of hypertension and the protection of end-organ damage in cardiovascular and renal diseases. Potential problems related to side effects and compliance of such therapy need to be addressed. A safer way of producing therapeutic effects is promised by the delivery of the ACE antisense sequences by a vector producing a permanent inhibition of ACE and long-term control of blood pressure in hypertensive patients.
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PMID:Properties and distribution of angiotensin I converting enzyme. 1257 Jul 87

Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxypeptidase, which cleaves dipeptides and, in some instances, dipeptide or tripeptide amides from the C-terminus of regulatory peptides (e.g. angiotensin I, bradykinin and substance P). The expression of ACE is highly regulated in insects, where it is thought to have a role in the metabolism of peptide hormones involved in regulating reproduction. After a blood meal, ACE activity in the female mosquito Anopheles stephensi, increases four-fold with much of the enzyme finally accumulating in the ovary. In the present study, we have studied the effect on reproduction of adding two selective inhibitors of ACE, captopril and lisinopril, to the blood meal. Both ACE inhibitors reduced the size of the batch of eggs laid by females in a dose-dependent manner, with no observable effects on the behaviour of the adult insect. The almost total failure to lay eggs after feeding on either 1 mM captopril or 1 mM lisinopril, did not result from interference with the development of the primary follicle, but was due to the inhibition of egg-laying. Since very similar effects on the size of the egg-batch were observed with two selective ACE inhibitors, belonging to different chemical classes, we suggest that these effects are mediated by the selective inhibition of the induced mosquito ACE, a peptidase probably involved in the activation/inactivation of a peptide regulating egg-laying activity in A. stephensi.
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PMID:ACE inhibitors reduce fecundity in the mosquito, Anopheles stephensi. 1267 Jul 86


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