Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine whether vasoactive intestinal peptide (VIP) dilates resistance arterioles in the in situ systemic circulation and whether inhibitors of neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE), two membrane-bound metalloenzymes that are widely distributed in the microcirculation and cleave and inactive VIP, potentiate this response. Using intravital microscopy, we found that VIP (0.05 and 0.1 nmol) induced significant vasodilation in the hamster cheek pouch (13 +/- 1 and 20 +/- 2% increase from baseline, respectively; mean +/- SE; P < 0.05). These responses were significantly potentiated by topical application of phosphoramidon and thiorphan, two relatively selective NEP inhibitors, but not by captopril, a relatively selective ACE inhibitor. Furthermore, suffusion of a mixture of proteinase inhibitors consisting of leupeptin, Bestatin, and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid to inhibit serine proteinases, including mast cell tryptase, aminopeptidases, and carboxypeptidase N, respectively, had no significant effects on VIP-induced responses. These data indicate that VIP elicits vasodilation in the in situ systemic microcirculation and that NEP modulates this response.
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PMID:Neutral endopeptidase modulates VIP-induced vasodilation in hamster cheek pouch vessels in situ. 877 Jan 40

1. In patients with congestive cardiac failure, treatment with angiotensin converting enzyme (ACE) inhibitors results in peripheral vasodilatation and an increase in cardiac output without an increase in heart rate, which suggests a positive inotropic effect. This cannot be explained by changes in angiotensin II and bradykinin concentrations that occur. ACE has been suggested to also metabolise vasoactive intestinal peptide (VIP), which is a positive inotrope. As VIP is synthesized by the heart and acts locally to increase cardiac output, we postulated that ACE inhibition would increase the myocardial concentration of VIP. 2. Male Sprague-Dawley rats received enalapril (2 mg/kg per day) in their drinking water or no therapy for 7 days. On day 7 the rats were anaesthetized and blood was sampled. Hearts and kidneys were then harvested and snap frozen by immersion in liquid nitrogen. Concentrations of VIP in plasma and tissue extracts were measured by radioimmunoassay. 3. Plasma and renal concentrations of VIP did not change in enalapril-treated rats. However, the myocardial concentration of VIP increased significantly in rats receiving enalapril compared with control animals (P < 0.0005). 4. We conclude that treatment with ACE inhibitors results in increased myocardial VIP concentrations and suggest that this may contribute to the improvement in cardiac function that occurs with these agents.
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PMID:Increases in the myocardial concentration of vasoactive intestinal peptide may explain the positive inotropic effect of angiotensin converting enzyme inhibitors. 880 Jun 3

Phase I human studies can be used to differentiate a novel agent from existing drugs that influence the same pathway (eg, angiotensin-converting enzyme [ACE] inhibitors). Human forearm vasculature provides a useful experimental model for such studies because antagonism of local effects of agonists on resistance vasculature can be quantified, unconfounded by reflex cardiovascular responses to systemically applied agonists. In this model, inhibition of ACE with enalapril (given orally) or its active metabolite enalaprilat (given into the brachial artery) influences responses to some, but not all, vasoactive peptides that are substrates of ACE in vitro. Vasoconstrictor responses to angiotensin I (A I) are antagonized, while vasodilator responses to bradykinin are potentiated. Responses to vasoactive intestinal peptide (VIP), substance P (SP), and atrial natriuretic peptide (ANP) are unaltered by ACE inhibition. Vasodilator responses to bradykinin are antagonized by the B2-receptor icatibant and are blunted (but not abolished) by inhibition of the L-arginine/NO pathway with L-NG-monomethyl arginine. In contrast to inhibition of ACE with enalapril, blockade of the AT1 receptor with losartan results in similar inhibition of vasoconstrictor responses to both A I and angiotensin II but has no significant effect on the vasodilator action of bradykinin. The implication is that losartan provides more specific blockade of the renin-angiotensin pathway than does inhibition of ACE. The in vivo methods described in the study confirm the mechanistically relevant differentiation between AT1-receptor antagonism and ACE inhibition in humans.
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PMID:Angiotensin II-receptor (AT1) blockade in the human forearm. 891 43

Angiotensin converting enzyme inhibitor therapy results in an increase in cardiac output without an increase in heart rate suggesting a positive inotropic effect. This cannot be explained by changes in angiotensin II and bradykinin concentrations. Angiotensin converting enzyme may also metabolise vasoactive intestinal peptide (VIP), a vasodilator and positive inotrope whose concentration in the heart declines in heart failure. We sought to determine whether changes in plasma VIP or its metabolism might explain the positive inotropic effect of angiotensin converting enzyme inhibitors. We also measured VIP in the heart to determine whether a local increase in VIP might explain this effect. Male Sprague-Dawley rats were randomised to control and enalapril groups (2 mg kg(-1) day(-1)). After 7 days, rats were anaesthetised and underwent metabolic clearance studies for VIP or had hearts, lungs and kidneys removed and snap frozen. VIP concentrations in plasma, infusate and tissue extracts were measured by radioimmunoassay. Plasma concentrations of VIP were unchanged by treatment with enalapril (control: 7.7 +/- 0.8 pmol l(-1); enalapril: 7.9 +/- 0.8 pmol l(-1) ), while the metabolic clearance rate of) VIP increased significantly (control: 10.4 +/- 1.4 ml min(-1) 100 g(-1); enalapril: 17.3 +/- 1.6 ml min(-1) 100 g(-1); p < 0.005). Secretion rate) also increased in enalapril treated rats (139.1 +/- 25.0 pmol min(-1) 100 g(-1) compared with controls (96.3 +/- 13.4 pmol min (-1) 100 g(-1); P< 0.01). VIP in the heart increased after enalapril (control: 208.4 +/- 39.0 pmol g (-1); enalapril: 928.9 +/- 123.6 fmol g(-1); P < 0.0005). Angiotensin converting enzyme inhibition increases the metabolism of VIP. However, the significant increase in the myocardial concentration of VIP may contribute to the beneficial haemodynamic inotrope effects of angiotensin converting enzyme inhibitors.
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PMID:Effects of enalapril on vasoactive intestinal peptide metabolism and tissue levels. 980 65

Vascular resistance in the mammalian pulmonary circulation is affected by many endogenous agents that influence vascular smooth muscle, right ventricular myocardium, endothelial function, collagen and elastin deposition, and fluid balance. When the balance of these agents is disturbed, e.g. by airway hypoxia from high altitude or pulmonary obstructive disorders, pulmonary hypertension ensues, as characterized by elevated pulmonary artery pressure (P(PA)). Among neuropeptides with local pulmonary artery pressor effects are endothelin-1 (ET-1), angiotensin II (AII), and substance P, and among mitigating peptides are calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), atrial natriuretic peptide (ANP), vasoactive intestinal peptide (VIP) and ET-3. Moreover, somatostatin28 (SOM28) exacerbates, whereas SOM14 decreases P(PA) in hypoxic rats, with lowering and increasing of lung CGRP levels, respectively. Pressure can also be modulated by increasing or decreasing plasma volume (VIP and ANP, respectively), or by induction or suppression of vascular tissue remodeling (ET-1 and CGRP, respectively). Peptide bioavailability and potency can be regulated through hypoxic up- and down- regulation of synthesis or release, activation by converting enzymes (ACE for AII and ECE for ET-1), inactivation by neutral endopeptidase and proteases, or by interaction with nitric oxide (NO). Moreover, altered receptor density and affinity can account for changed peptide efficacy. For example, upregulation of ET(A) receptors and ET-1 synthesis occurs in the hypoxic lung concomitantly with reduced CGRP release. Also, receptor activity modifying protein 2 (RAMP2) has been shown to confer ADM affinity to the pulmonary calcitonin-receptor-like receptor (CRLR). We recently detected the mRNA encoding for RAMP2, CRLR, and the CGRP receptor RDC-1 in rat lung. The search for an effective, lung selective treatment of pulmonary hypertension will likely benefit from exploring the imbalance and restoring the balance between these native modulators of intrapulmonary pressure. For example, blocking of the ET-1 receptor ET(A) and vasodilation by supplemental CGRP delivered i. v. or via airway gene transfer, have proven to be useful experimentally.
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PMID:The role of endogenous lung neuropeptides in regulation of the pulmonary circulation. 1119 57

The purpose of the present paper was to study at physiological pH the affinity between vasoactive intestinal peptide (VIP) and four poly(amidoamine) dendrimers (PAMAMs) designed for drug delivery. Therefore, a fast and reproducible CE method was first developed to analyze the strongly basic peptide. To allow an accurate determination of binding constant (K) values, the ability to suppress peptide adsorption onto the silica capillary of nonpermanent coatings (poly(ethylene oxide) (PEO), low and medium relative molecular masses poly(diallyldimethylammonium chloride) (PDDA)) or poly(acrylamide) permanent coating (PAA) was evaluated. Very good intraday repeatability of VIP migration times and peak areas (0.1-0.6 and 2.9-4.9% RSD, respectively) was obtained using two of the investigated coatings (PEO and PDDA with medium molecular mass). ACE combined with these dynamic coatings was then employed to evaluate K between VIP and two amine-terminated PAMAM dendrimers of generation 2 and 5 (G2.NH2, G5.NH2) and two carboxyl-terminated PAMAM derivatives of generation 2 and 5 (G2.COOH, G5.COOH). Binding constant of (6.7 +/- 1.1) x 10(4)/M could be determined for the couple VIP/G5.NH2, while no affinity was evidenced between VIP and all other dendrimers investigated. These results suggest that G5.NH2 might be an interesting carrier for the delivery of VIP.
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PMID:Determination of binding constants of vasoactive intestinal peptide to poly(amidoamine) dendrimers designed for drug delivery using ACE. 1755 62