UNIPROT:P20366 - FACTA Search

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)

Prolyl endopeptidase has been predominantly described as a cytosolic activity capable of cleaving a number of important neuropeptides (including TRH, LHRH, Bradykinin, Angiotensin, Substance P, Neurotensin, Oxytocin and Vasopressin) on the carboxy side of proline. In this paper, we report, for the first time, on the complete purification and characterization of a membrane-bound form of prolyl endopeptidase. This novel activity has been isolated from the synaptosomal (plasma membranes) membranes of bovine brain. Following gel filtration, hydroxylapatite and hydrophobic interaction chromatographies, the prolyl endopeptidase activity was purified 1400-fold with a 23% recovery of activity. The enzyme was shown to have a relative molecular mass of 87 kDa and a Km of 60 microM for its specific fluorimetric substrate, Z-GlyProMCA. The purified enzyme demonstrated a relatively broad substrate specificity and a relatively high affinity for proline-containing neuropeptides. It was shown to be inhibited by certain thiol-protease inhibitors and by the metal chelator, 1,10-phenanthroline, thus possibly classifying it as a 'thimet' activity. The purified particular form of proyl endopeptidase displayed a similar substrate specificity to the previously reported cytosolic forms of the enzyme. However, there were differences between the two forms in term of their sensitivity to inhibitors, their affinities for the peptide substrates and their relative molecular masses. The different subcellular location (i.e. the synaptosomal membrane) of the particulate prolyl endopeptidase is also of potential physiological significance given that here it is more likely to come in contact with the vesicle-bound neuropeptides than is its cytosolic counterpart.
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PMID:Purification and characterization of a novel membrane-bound form of prolyl endopeptidase from bovine brain. 902 55

Increases in arterial pressure and paraventricular nucleus vasopressin release in response to intracerebroventricular injections of angiotensin peptides are blunted in mRen2(27) renin transgenic [TG(+)] rats. Intraventricular injections of tachykinin peptides mimic several of the actions of angiotensin peptides, and angiotensin peptides evoke substance P release from hypothalamic brain slices. The present study assessed whether diminished substance P release occurs in response to angiotensin peptides in TG(+) rats. Systolic blood pressure at 8 to 12 weeks of age averaged 197 +/- 4 mm Hg (n = 20; P < .05) in TG(+) rats compared with 123 +/- 4 mm Hg in normotensive control [TG(-)] rats (n = 18). Body weight was lower in hypertensive than in normotensive rats (305 +/- 14 versus 344 +/- 13 g, respectively; P < .05). Brain slices from hypothalamus were perfused at 37 degrees C with oxygenated Krebs' bicarbonate buffer. Substance P was measured before (basal) and during perfusion with either Krebs' buffer (control) or 2 mumol/L angiotensin-(1-7) or angiotensin II. Basal substance P release was 92 +/- 10 pg/g wet tissue in TG(+) and 98 +/- 12 pg/g in TG(-) rats (P > .05). Angiotensin-(1-7) and angiotensin II significantly increased substance P release from hypothalamus of TG(-) rats (82% and 70% above control: P < .05) but not TG(+) rats. These studies further support the hypothesis that the cardiovascular effects of angiotensin peptides are mediated in part by substance P and that this relationship is blunted in a hypertensive model that results from excess tissue production of angiotensins.
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PMID:Hypothalamic substance P release. Attenuated angiotensin responses in mRen2(27) transgenic rats. 903 51

Angiotensin II stimulates release of substance P from medulla oblongata slices, and low doses of substance P or angiotensin II injected into the nucleus of the solitary tract (NTS) decrease heart rate and mean arterial pressure. In this study, angiotensin II (250 fmol in 30 nl) was injected into the NTS of halothane-anesthetized male Sprague-Dawley rats before and after NTS injections of the substance P antagonist [Leu11, psi CH2NH-(10-11)]substance P (600 fmol in 60 nl). The substance P antagonist blocked the angiotensin II-induced hypotension and bradycardia (-16 +/- 3 mmHg and -24 +/- 7 beats/min before versus -0.3 +/- 1 mmHg and -2 +/- 3 beats/min after; P < 0.05). The depressor and bradycardic effects of glutamate were not altered by the substance P antagonist. In vitro receptor autoradiography showed that the substance P antagonist (10 or 100 microM) did not compete for 125I-labeled angiotensin II binding in the dorsal medulla, suggesting that the substance P antagonist does not interact directly with angiotensin II receptors. We conclude that the cardiovascular effects of angiotensin II in the NTS are mediated at least in part by substance P.
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PMID:Acute depressor actions of angiotensin II in the nucleus of the solitary tract are mediated by substance P. 924 29

Angiotensin (Ang) II increases substance P (SP) efflux from perfused slices of medulla oblongata, and a peptide antagonist of SP, [Leu11,psiCH2NH10-11]SP, blocks the acute hypotension and bradycardia caused by Ang II injected into the nucleus tractus solitarii (nTS) of Harlan Sprague-Dawley (SD) rats. We investigated whether the same relationships exist in (mRen2)27 renin transgenic (TG) rats, which have chronic elevations of medullary tissue Ang II levels. Ang II increased SP efflux (48% above control; P<0.01) from slices of medulla prepared from 8- to 12-week old male TG rats. Injections of Ang II (250 fmol in 30 nL) into the nTS of chloralose-urethane anesthetized TG rats produced a significant increase in pressure of 7+/-2 mm Hg before a 13+/-3 mm Hg fall in pressure. Ang II induced similar depressor responses in Hannover SD rats but no increase in pressure. After nTS injection of the NK1-selective SP antagonist CP-96,345 (30 pmol in 60 nL), Ang II-induced hypotension was blocked in both groups, as was the pressor component in hypertensive rats. Hypotensive and bradycardic effects of glutamate (0.6 nmol in 30 nL) injected into the nTS were not altered by CP-96,345. In vitro receptor autoradiography showed that the SP antagonist (10 or 100 microM) did not compete for 125I-Ang II binding in the dorsal medulla, a result suggesting that it did not interact directly with Ang II receptors. Thus, the nTS cardiovascular effects of Ang II are mediated by SP in both normotensive rats and a model of hypertension with altered endogenous levels of Ang II. These findings link Ang II-induced effects on SP release from brain slices of the medulla oblongata to acute cardiovascular actions of the peptide through an NK1 receptor.
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PMID:NK1 receptor antagonist blocks angiotensin II responses in renin transgenic rat medulla oblongata. 945 48

Activation of the renin-angiotensin-aldosterone system (RAAS) in left ventricular systolic dysfunction is a critically important determinant in the pathophysiologic processes that lead to progression of heart failure and sudden death. Angiotensin II, acting at the specific angiotensin receptor (AT1-R), activates a series of intracellular signaling sequences which are ultimately expressed within the cardiovascular system as vasoconstriction and associated vascular hypertrophy and remodeling. Angiotensin converting enzyme (ACE) inhibition leads to increases in the vasodilatory peptides bradykinin and substance P and at least an initial reduction in angiotensin II concentrations. AT1-R blocking drugs prevent access of angiotensin II to the AT1-R and thus prevent cellular activation. ACE inhibitors have clearly been demonstrated through a large number of clinical trials to increase survival in congestive heart failure, primarily by reducing the rate of progression of left ventricular dilatation and decompensation. However, this beneficial effect diminishes over time. Preliminary short-term clinical studies evaluating the efficacy of AT1-R blocking drugs in the treatment of heart failure have suggested that they elicit similar hemodynamic and neuroendocrine effects as do the ACE inhibitors. The combination ACE inhibitors and AT1-R blocking drugs offer the theoretical advantage of increasing bradykinin while blocking the actions of angiotensin II, and thus possibly show a synergistic effect. Again, preliminary studies have yielded encouraging results that are difficult to interpret because neither ACE inhibitor nor the AT1-R blocking drug doses were titrated to tolerance. Pharmacological manipulation of the RAAS has led to better understanding of its role in heart failure and improved clinical outcomes.
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PMID:Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of heart failure caused by left ventricular systolic dysfunction. 1036 49

The renin-angiotensin system (RAS) plays an important role in regulating blood pressure, and maintaining fluid and electrolyte balance. Angiotensin II is the principal mediator of the RAS and has been implicated in the development of hypertension as well as other forms of cardiovascular and renal disease. Angiotensin II-receptor antagonists are a new class of drugs that inhibit the RAS by selectively blocking the AT(1) receptor. These compounds therefore provide more specific and thorough blockade of the RAS by inhibiting the deleterious actions of angiotensin II at the receptor level, irrespective of how this peptide is formed. The increased specificity of action of angiotensin II-receptor antagonists may also circumvent unwanted side-effects normally associated with angiotensin-converting enzyme (ACE) inhibitors (eg, cough and angioedema) as these agents do not interfere with the metabolism of other peptides (eg, bradykinin, substance P, etc.). There is still some concern with angiotensin II-receptor antagonists and the long-term effects of hyper-stimulation of the unopposed AT(2) receptor that is caused by elevated levels of angiotensin II. However, it appears that stimulation of the AT(2) receptor may actually contribute to the beneficial effects of angiotensin II-receptor antagonists by counteracting the effects mediated by the AT(1) receptor. Angiotensin II-receptor antagonists display great therapeutic promise in the field of cardiovascular medicine and are currently being exploited as new antihypertensive agents. These drugs have demonstrated safety, efficacy, and tolerability; however, morbidity and mortality data are still lacking. Nonetheless, it is likely that angiotensin II-receptor antagonists will become part of the medical arsenal against cardiovascular and renal disease, thus consideration should be given to their future use as first-line antihypertensive agents.
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PMID:Spectrum of use for the angiotensin-receptor blocking drugs. 1098 Oct 96

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

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

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

Angiotensin converting enzyme (ACE) is expressed in the central nervous system (CNS), where its primary function comprises degradation of neuropeptides including substance P (SP). Because of the possible antidepressant effects of SP antagonists, the influence of SP on both pathophysiology and mitigation of depression has been hypothesized. It was shown that ACE plasma concentration is determined by an insertion/deletion (I/D) polymorphism represented by the presence or absence of a 287 bp DNA fragment within the ACE gene. Because the D allele was associated with higher ACE levels this may have a positive impact on the therapeutic efficacy of antidepressant treatment. Thus, variations in CNS expression of ACE might influence the response to various antidepressant therapies. We could show a divergent clinical outcome in relation to different genotypes in 313 depressed patients who were treated with various antidepressants. A lower HAM-D17 score after 4 weeks of treatment in D/D and I/D in comparison to I/I genotypes was detected; the duration of hospitalization was shorter in D allele carriers. The D allele seems to be a predictor for a faster onset of different antidepressant therapies. The patients' gender influences these outcome effects significantly. After subdivision of the patients according to their gender only female patients contributed significantly to the genotype dependent therapeutic outcome. Our investigation gives the first hint that the speed of onset of antidepressant therapies may be dependent on both variants of the ACE genes and the gender of the patients.
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PMID:The angiotensin I converting enzyme insertion/deletion polymorphism influences therapeutic outcome in major depressed women, but not in men. 1515 92

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