Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to analyse quantitatively, on a cat gastrocnemius muscle preparation in vivo, the effects of local angiotensin-converting enzyme (ACE) inhibition by enalaprilat on total regional vascular resistance (tone) and its distribution to the large-bore arterial resistance vessels (> 25 microns), the small arterioles (< 25 microns) and the veins. Associated effects on capillary pressure and fluid exchange were also studied. Close-arterial infusion of enalaprilat (0.05-0.20 mg kg muscle tissue min-1) elicited a moderate dilator response in all three consecutive sections of the muscle vascular bed, an increase in capillary pressure and transcapillary fluid filtration. This dilation could be abolished by the selective bradykinin B2-receptor antagonist Hoe 140 (2 mg kg-1 min-1, i.a.), indicating that the dilator mechanism of ACE inhibition was an increased local concentration of bradykinin, and hardly at all a decreased concentration of angiotensin (AT) II. The generalized dilator response to ACE inhibition along the vascular bed suggested a relatively uniform distribution of ACE from artery to vein and this was further supported by the finding that a close-arterial infusion of AT I (0.04-0.32 microgram kg-1 min-1), which was vasoactive only after conversion to AT II by local ACE, elicited a generalized constrictor response in all three vascular sections. In contrast, infused AT II (0.01-0.16 microgram kg-1 min-1) constricted almost selectively the large-bore arterial vessels. The specific angiotensin AT1-receptor antagonist losartan (2 mg kg-1 min-1, i.a.) abolished the constrictor response to AT II but did not affect vascular tone under control conditions, indicating that AT II is not involved in the initiation of basal vascular tone in muscle. These results, taken together, indicate that under basal conditions vascular ACE contributes to the local control of vascular tone in skeletal muscle by degrading the endogenous dilator bradykinin, and not by converting AT I into vasoconstrictor AT II.
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PMID:Effects of angiotensin-converting enzyme inhibition on arterial, venous and capillary functions in cat skeletal muscle in vivo. 887 45

The present study was undertaken to determine whether trandolaprilat, an active form of angiotensin I converting enzyme (ACE) inhibitor, may improve ischemia/reperfusion-induced contractile dysfunction and metabolic derangement of isolated rat hearts. Ischemia (25 min) and subsequent 60-min reperfusion resulted in a small recovery of post-ischemic left ventricular developed pressure (LVDP), a sustained increase in left ventricular end-diastolic pressure, an increase in the release of creatine kinase and ATP metabolites from the perfused heart, and changes in myocardial sodium, potassium, calcium and magnesium contents. Treatment with 10-100 microM of trandolaprilat for the last 10 min of pre-ischemia recovered approximately 50-90% of pre-ischemic LVDP during reperfusion, whereas that with 30-100 microM of enalaprilat restored approximately 55-65% of the pre-ischemic LVDP. Treatment with either trandolaprilat or enalaprilat at these concentrations attenuated the release of creatine kinase and ATP metabolites into the perfusate during reperfusion. Treatment with 30 microM trandolaprilat suppressed ischemia/reperfusion-induced changes in myocardial ion content. Treatment with bradykinin during the last 10 min of pre-ischemia also resulted in a post-ischemic contractile recovery with a degree similar to that of the trandolaprilat-treated hearts. E4177, an AT1-antagonist, showed no effect on ischemia/reperfusion-induced changes in cardiac parameters. The enhancement of post-ischemic contractile recovery by the ACE inhibitor was abolished by treatment with either Hoechst 140, a bradykinin (BK2) antagonist, or diclofenac, a cyclooxygenase inhibitor. These results suggest that trandolaprilat is capable of attenuating ischemia/reperfusion injury of isolated perfused hearts and altered BK metabolism is, at least in part, involved in this effect.
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PMID:Beneficial effects of angiotensin I converting enzyme inhibitor on post-ischemic contractile function of perfused rat heart. 887 76

Previous studies have shown that sodium depletion is associated with an increase in renal kallikrein-kinin system activity. This system may play an important role in counterbalancing the renal effects of the renin-angiotensin system. In this study, we examined whether the renal renin-angiotensin system participates in the regulation of renal bradykinin (BK) levels during sodium depletion. We measured changes in renal excretory and hemodynamic function, renal interstitial fluid (RIF) BK, and RIF and urinary guanosine 3',5'-cyclic monophosphate (cGMP) and prostaglandin E2 (PGE2) in conscious uninephrectomized dogs (n = 5) in sodium metabolic balance (10 meq/day) in response to intrarenal arterial administration of the renin inhibitor ACRIP (0.2 microgram.kg-1.min-1) or angiotensin II AT1-receptor blocker losartan (100 ng.kg-1.min-1). ACRIP and losartan increased urine flow rate from 0.75 +/- 0.06 to 1.6 +/- 0.03 and 1.5 +/- 0.05 ml/min, respectively (each P < 0.001), and urine sodium excretion from 5.4 +/- 0.7 to 18.3 +/- 1.3 and 15.9 +/- 1.2 meq/min, respectively (each P < 0.001). Glomerular filtration rate and renal plasma flow increased only during losartan administration (P < 0.05). ACRIP decreased RIF BK by 48%, from 33.1 +/- 3.8 to 17.4 +/- 4.1 pg/min (P < 0.01). ACRIP decreased RIF cGMP by 38%, from 0.69 +/- 0.08 to 0.43 +/- 0.1 pmol/min (P < 0.01); urinary cGMP by 16%, from 0.63 +/- 0.05 to 0.53 +/- 0.02 pmol/min (P < 0.05); and RIF PGE2 by 46%, from 10.5 +/- 1.1 to 5.7 +/- 1.1 pg/min (P < 0.01). Urinary PGE2 was unchanged by ACRIP. Losartan decreased RIF PGE2 by 71%, from 10.8 +/- 0.6 to 3.1 +/- 0.6 pg/min (P < 0.01) but failed to change RIF BK, RIF cGMP, urinary cGMP, or urinary PGE2. These data suggest that the renin-angiotensin system tonically stimulates renal BK production and cGMP formation via a non-AT1 angiotensin receptor and renal PGE2 production via the AT1 receptor.
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PMID:Renin-angiotensin system modulates renal bradykinin production. 889 5

Several studies are reviewed in which behavioral aspects of angiotensin (Ang) II on fluid intake have been compared with induction of the immediate early gene product, Fos, as a marker of neuronal activation in rat bain. Either peripheral or central administration of Ang II induced Fos along the lamina terminalis (SFO, MnPO, AV3V) and in the magnocellular neurosecretory groups (SO, PVH). A similar pattern is seen with central injection of renin. Both pharmacological and antisense oligonucleotide probe studies indicate that an AT1 receptor is involved, probably with the initial transduction in the SFO. Treatments that induce sodium appetite all induce Fos along the lamina terminalis, but usually not in the SO or PVN. Kininase II inhibitors, such as captopril, acutely potentiate drinking to Ang I, but after chronic exposure they may inhibit water intake. In contrast, the dipsogenic effect of bradykinin which is manifest in the presence of acute captopril remains unaffected by chronic administration. This suggests that the sodium appetite that appears with chronic captopril treatment may depend in part on peptides other than Ang.
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PMID:Angiotensin-related induction of immediate early genes in rat brain. 889 88

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 receptor antagonists represent a new class of drugs for the treatment of patients with hypertension. Reduction of blood pressure in patients with essential hypertension requires increased activity of the renin-angiotensin system. Losartan, the first orally active, nonpeptide angiotensin antagonist, specifically competes with angiotensin II (Ang II) for the AT1 receptor and reversibly alters the receptor. Maximum blood pressure reductions occur after doses of approximately 50 mg, although some patients will require 100 mg; the parent compound and a metabolite are responsible for a smooth 24-hour effect on blood pressure. Once-daily dosing with losartan has been documented to be safe. The drug's safety has been evaluated in 4,058 patients; of these patients, more than 1,200 were treated for longer than 6 months and more than 800 were treated for longer than 1 year with doses of 10 mg to 150 mg. Overall, no hypertensive patients were withdrawn from treatment because of elevated serum creatinine or potassium levels, and there were no reports of angioedema. In addition, some reductions in plasma uric acid levels were noted. Cough occurred significantly less often in patients treated with losartan than in those treated with hydrochlorothiazide or lisinopril. In contrast to angiotensin-converting enzyme (ACE) inhibitors, losartan does not activate bradykinin-nitric oxide-prostanoid vasodilation.
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PMID:Losartan: first of a new class of angiotensin antagonists for the management of hypertension. 893 38

1. Male, Long Evans rats were instrumented chronically with pulsed Doppler probes and intravascular catheters to allow assessment of regional haemodynamic changes during i.v. infusion of lipopolysaccharide (LPS, 150 micrograms kg-1 h-1). 2. In the presence of the AT1-receptor antagonists, losartan (10 mg kg-1 + 10 kg-1 h-1), the initial (1-2 h) hypotensive and renal, mesenteric and hindquarters vasodilator responses to LPS were enhanced significantly. Thereafter these effects waned, but between 8-23 h after the onset of LPS infusion, a further fall in mean atrial blood pressure (MAP) and increases in renal and hindquarters flows and conductances occurred. All these changes were significantly greater than seen with losartan or LPS alone, and exceeded the sum of their effects. 3. In the presence of captopril (2 mg kg-1 + 2 mg kg-1 h-1), the initial hypotensive and renal vasodilator responses to LPS were enhanced, but less so than in the presence of losartan. However, the effects of LPS in the presence of losartan and captopril together were not different from those in the presence of losartan alone. These observations indicate that the ability of captopril to inhibit the degradation of bradykinin had no additional influence, and the differences between the effect of captopril and losartan on the initial effects of LPS were probably due to more effective suppression of the action of angiotensin II by losartan. 4. In the absence of LPS, co-infusion of losartan and the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 + 600 micrograms kg-1 h-1), caused a substantial, progressive hypotension (-25 +/- 2 mmHg at 24 h) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (31 +/- 13, 44 +/- 9 and 45 +/- 12%, respectively), indicating an involvement of angiotensin II and endothelin in the maintenance of normal cardiovascular status in conscious, Long Evans rats. 5. In the presence of losartan and SB 209670, the initial, LPS-induced fall in MAP (-42 +/- 2 mmHg) was not different from that in the presence of losartan (-39 +/- 4 mmHg), and the increases in renal, in mesenteric, and in hindquarters vascular conductances were similar in the two conditions. However, there was no recovery in MAP, and there were persistent renal, mesenteric and hindquarter vasodilatations. 6. In all experiments involving LPS, administration of the V1- receptor antagonist, d(CH2)5-O-Me-Tyr-AVP (10 micrograms kg-1), 23 h after the start of LPS infusion caused additional hypotension and mesenteric vasodilatation, particularly. This effect was most marked in animals pretreated with losartan and SB 209670. 7. The results indicate that the initial (1-2 h) depressor and dilator effects of LPS infusion in conscious Long Evans rats are opposed by the actions of angiotensins II, rather than endothelin. However, between 2-8 h after the onset of LPS infusion the involvement of endothelin develops and that of angiotensin II fades. By 24 h after the start of infusion of LPS, the pressor and vasoconstrictor actions of endothelin wane, and a role of vasopressin is apparent. At no stage is there clear evidence for an involvement of bradykinin in the haemodynamic sequelae of endotoxaemia in this model.
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PMID:Temporal differences between the involvement of angiotensin II and endothelin in the cardiovascular responses to endotoxaemia in conscious rats. 898 10

The presence of specific Ang II receptors in membrane fractions was investigated using 125I-labeled homologous Ang II ([Asn1, Pro3, Ile5]Ang II; df Ang II) in Triakis scyllia. Specific binding sites occurred in a variety of tissues, with highest binding in interrenal tissue (17.11 +/- 2.45 fmol Ang II/mg protein) and gill (6.26 +/- 0. 69 fmol Ang II/mg protein) and possible Ang II receptors in rectal gland and other tissues. 125I-[Asn1, Pro3, Ile5]Ang II (10(-10)M) binding to branchial cell membrane fraction (25 microg protein) in 5 mM MgCl2, 125 mM NaCl, 50 mM Tris-HCl, 0.2% bovine serum albumin at 28 degrees (1) is rapid and saturable; (2) increases as a function of membrane concentration and time; and (3) optimally fits to a two-site (high-and low-affinity) model. The equilibrium dissociation constant (0.11 +/- 0.01 nM) and binding site concentration (35.00 +/- 1.16 fmol/mg protein) are similar to those of mammalian and avian vascular Ang II receptors. Bound labeled ligand was not competitively displaced by dogfish Ang I, dogfish C-type natriuretic peptide, bradykinin, or the AT1 receptor antagonist, CV 11974. The AT2 receptor antagonist, CGP 42112, was much less potent at displacing the labeled ligand compared to the unlabeled ligand.
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PMID:The presence of angiotensin II receptors in elasmobranchs. 900 Apr 63

A local renin-angiotensin system (RAS) is present in the vasculature and might have an important role in the control of vascular resistance. In order to assess its functional role in the control of vasomotor tone, we investigated the effect of the RAS of a donor vessel (rat carotid artery) on the diameter of a recipient rat mesenteric resistance artery. Arteries were perfused in series in an arteriograph at a rate of 100 microL/min, under a pressure of 100 mm Hg. The two vessels were superfused in separate organ chambers to which drugs were added. Recipient artery internal diameter was measured continuously. Phenylephrine (0.1 mumol/L) was present in the organ baths throughout the experiments, ensuring a preconstriction of the recipient artery (236 +/- 4 to 174 +/- 3 microns, n = 65 arterial segments from 34 rats). The angiotensin I-converting enzyme inhibitors (ACEIs) cilazapril (1 mumol/L) and captopril (10 mumol/L) inhibited phenylephrine-induced constriction by 30 +/- 12% (n = 7, P < .001) and 20 +/- 8% (n = 5, P < .01), respectively. Addition of cilazapril (1 mumol/L) or captopril (10 mumol/L) to the donor vessel chamber further inhibited the constriction by 8 +/- 3% (n = 7, P < .01) and 31 +/- 10% (n = 5, P < .05), respectively. The angiotensin II receptor (AT1) antagonist losartan (10 mumol/L) prevented, in part, the relaxation due to the ACEI. The association of losartan (10 mumol/L) with the bradykinin B2 receptor antagonist HOE 140 (1 mumol/L) totally prevented the relaxation due to the ACEI. Finally, angiotensin II was measured in the perfusate of the carotid artery and was found to be released at a rate of 11.9 +/- 2.2 pg in 60 minutes (n = 8), which was significantly decreased to 1.4 +/- 0.4 pg in 60 minutes (n = 4) by cilazapril (1 mumol/L). This study provides functional evidence that tissue-generated angiotensin II and bradykinin, produced locally and in upstream arteries, control the diameter of a resistance mesenteric artery.
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PMID:In vitro modulation of a resistance artery diameter by the tissue renin-angiotensin system of a large donor artery. 901 41

Recent studies have shown that angiotensin-(1-7) [Ang-(1-7)] interacts with kinins and augments bradykinin (BK)-induced vasodilator responses by an unknown mechanism. In this study, we evaluated whether the potentiation of the BK-induced vasodilation by Ang-(1-7) may be attributable to inhibition of BK metabolism, release of nitric oxide, or both. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers. 125I-[Tyr0]-BK metabolism was determined in vascular rings by assessing the degradation of the peptide by high-performance liquid chromatography. Ang-(1-7) augmented the vasodilation induced by BK in a concentration-dependent manner in rings preconstricted with the thromboxane analog U46619. The EC50 of BK (2.45 +/- 0.51 nmol/L versus 0.37 +/- 0.08 nmol/L) was shifted leftward by 6.6-fold in the presence of 2 mumol/L concentration of Ang-(1-7). The response was specific for BK. since Ang-(1-7) did not augment the vasodilation induced by either acetylcholine (0.05 mumol/L) or sodium nitroprusside (0.1 mumol/L). Moreover, neither angiotensin I nor angiotensin II (Ang II) duplicated the augmented BK response of Ang-(1-7). Pretreatment of vascular rings with the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NA; 100 mumol/L) completely abolished the effects of Ang-(1-7) on BK-induced vasodilation whereas pretreatment with indomethacin (10 mumol/L) was without effect. The potent specific BK B2 receptor antagonist, Hoe 140. nearly abolished the BK and the Ang-(1-7) potentiated responses at 2 mumol/L, whereas at a lower concentration (20 nmol/L) Hoe 140 shifted the response curve to the right for both Ang-(1-7) and vehicle; however, the augmented response to Ang-(1-7) persisted. Preincubation of vascular rings with 20 mumol/L of the AT1 (CV11974), AT2 (PD123319), or nonselective (Sar1 Thr8-Ang II) receptor antagonists had no significant effect on the Ang-(1-7)-enhanced vasodilator response to BK. Lisinopril (2 mumol/L) significantly enhanced the BK-induced vasodilator response while at the same time it abolished the synergistic action of Ang-(1-7) on BK. In addition, pretreatment with 2 mumol/L Ang-(1-7) significantly inhibited the degradation of 125I-[Tyr0]-BK and the appearance of the BK-(1-7) and BK-(1-5) metabolites in coronary vascular rings. Ang-(1-7) inhibited purified canine angiotensin converting enzyme activity with an IC50 of 0.65 mumol/L. In conclusion. Ang-(1-7) acts as a local synergistic modulator of kinin-induced vasodilation by inhibiting angiotensin converting enzyme and releasing nitric oxide.
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PMID:Angiotensin-(1-7) augments bradykinin-induced vasodilation by competing with ACE and releasing nitric oxide. 903 33


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