enalaprilat-anhydrous and icatibant

Angiotensin-converting enzyme (ACE) inhibition potentiates the tissue-type plasminogen activator (t-PA) response to exogenous bradykinin. This study tested the hypothesis that ACE inhibition increases endothelial t-PA release through endogenous bradykinin.. We measured the effect of intra-arterial enalaprilat (5 micro g/min) on forearm blood flow (FBF) and net t-PA release before and during intra-arterial infusion of bradykinin (25 to 400 ng/min) and methacholine (3.2 to 12.8 microg/min) in 24 smokers pretreated with bradykinin receptor antagonist HOE 140 (100 microg/kg intravenously) or vehicle. There was no specific effect of HOE 140 on FBF or forearm vascular resistance (FVR, 29.9+/-3.6 versus 29.7+/-3.6 mm Hg x mL(-1) x min(-1) x 100 mL(-1) after vehicle and HOE 140, respectively, P=0.956 between groups). Resting FVR decreased during enalaprilat compared with vehicle or HOE 140, but not compared with baseline, and the effect was similar in the 2 groups (22.0+/-2.7 and 24.1+/-2.9 mm Hg x mL(-1) x min(-1) x 100 mL(-1), respectively, P=0.610). In contrast, enalaprilat significantly increased resting net t-PA release (from 0.6+/-0.4 to 1.7+/-0.6 ng. min(-1) x 100 mL(-1), P=0.002); this effect was abolished by HOE 140 (0.1+/-0.3 ng x min(-1) x 100 mL(-1), P=0.036 versus enalaprilat alone). Enalaprilat increased the effect of exogenous bradykinin on FBF 60% (from 17.5+/-2.5 to 28.1+/-4.0 mL. min(-1) x 100 mL(-1) during 100 ng/min bradykinin, P=0.001) and on t-PA release 14-fold (from 21.2+/-7.9 to 317.4+/-118.9 ng x min(-1) x 100 mL(-1), P=0.024). Enalaprilat increased the t-PA response to bradykinin to a greater extent than the FBF response, shifting the relationship between net t-PA release and FBF (P=0.005). HOE 140 blocked these effects. There was no effect of enalaprilat or HOE 140 on the FBF or t-PA response to methacholine.. ACE inhibition increases constitutive endothelial t-PA release through endogenous bradykinin.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Bradykinin; Bradykinin Receptor Antagonists; Dose-Response Relationship, Drug; Enalaprilat; Endothelium, Vascular; Female; Fibrinolysis; Forearm; Humans; Infusions, Intra-Arterial; Male; Methacholine Chloride; Muscarinic Agonists; Regional Blood Flow; Smoking; Tissue Plasminogen Activator; Vascular Resistance

Angiotensin-(1-7) (Ang-(1-7)), a bioactive peptide in the renin-angiotensin system, has counterregulatory actions to angiotensin II (Ang II). However, the mechanism by which Ang-(1-7) enhances vasodepressor responses to bradykinin (BK) is not well understood. In the present study, the effects of Ang-(1-7) on responses to BK, BK analogs, angiotensin I (Ang I), and Ang II were investigated in the anesthetized rat. The infusion of Ang-(1-7) (55 pmol/min i.v.) enhanced decreases in systemic arterial pressure in response to i.v. injections of BK and the BK analogs [Hyp3, Tyr(Me)8]-bradykinin (HT-BK) and [Phe8psi (CH2-NH) Arg9]-bradykinin (PA-BK) without altering pressor responses to Ang I or II, or depressor responses to acetylcholine and sodium nitroprusside. The angiotensin-converting enzyme (ACE) inhibitor enalaprilat enhanced responses to BK and the BK analog HT-BK without altering responses to PA-BK and inhibited responses to Ang I. The potentiating effects of Ang-(1-7) and enalaprilat on responses to BK were not attenuated by the Ang-(1-7) receptor antagonist A-779. Ang-(1-7)- and ACE inhibitor-potentiated responses to BK were attenuated by the BK B2 receptor antagonist Hoe 140. The cyclooxygenase inhibitor sodium meclofenamate had no significant effect on responses to BK or Ang-(1-7)-potentiated BK responses. These results suggest that Ang-(1-7) potentiates responses to BK by a selective B2 receptor mechanism that is independent of an effect on Ang-(1-7) receptors, ACE, or cyclooxygenase product formation. These data suggest that ACE inhibitor-potentiated responses to BK are not mediated by an A-779-sensitive mechanism and are consistent with the hypothesis that enalaprilat-induced BK potentiation is due to decreased BK inactivation.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Carotid Artery, External; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Synergism; Enalaprilat; Male; Meclofenamic Acid; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Receptors, G-Protein-Coupled; Vasoconstrictor Agents; Vasodilator Agents

High plasma levels of angiotensin II are found in several pathologies such as hypertension, heart failure and myocardial infarction. The effect of high concentrations of angiotensin II on coronary circulation is not well defined. The aim of the present study was to assess coronary blood flow regulation during tachycardia in the presence of elevated coronary plasma levels of angiotensin II, and the changes induced by ACE inhibition and blockade of angiotensin II and endothelin-A receptors.. Left anterior coronary artery was catheterized in 38 pigs to infuse the study drugs. Saline was infused for 15 min. Then, the first atrial pacing was performed. The pigs were distributed to: Group 1 (n = 7) angiotensin II; Group 2 (n = 7) enalaprilat + angiotensin II; Group 3 (n = 9) the bradykinin B2 antagonist HOE 140 + enalaprilat + angiotensin II; Group 4 (n = 7) losartan + angiotensin II; and Group 5 (n = 8) endothelin-A receptor antagonist LU 135252 + angiotensin II. After giving these infusions, a second pacing was repeated.. The increase in coronary blood flow induced by pacing with angiotensin II was reduced from 181 +/- 21% to 116 +/- 37% (P = 0.006 vs. saline). Enalaprilat, losartan and LU 135252 restored the capacity of coronary blood flow to increase during pacing (151 +/- 39%, 162 +/- 35% and 161 +/- 16%, respectively; P = NS, vs. saline), while HOE 140 abolished the effect of enalaprilat.. Moderately elevated coronary concentrations of angiotensin II reduced coronary blood flow during pacing. Enalaprilat, losartan and LU 135252 restored the hyperaemic coronary flow to similar values observed with saline. The beneficial effect of ACE inhibition is mediated through an increase in bradykinin.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Bradykinin; Coronary Circulation; Enalaprilat; Female; Losartan; Male; Phenylpropionates; Pyrimidines; Swine

This study examined the proposition that kinins are involved in the renal hemodynamic effect of an ACE inhibitor in Goldblatt (GB) hypertension. The effects of the ACE inhibitor enalaprilat were compared in two groups of anesthetized two-kidney one-clip GB rabbits. One group (n = 11) was given enalaprilat (10 mg/kg, i.v.) while a second group (n = 10) received the kinin B2 receptor antagonist, icatibant (2.5-5 microg/kg/min, i.v.) prior to enalaprilat. Enalaprilat caused a 40% rise in renal blood flow and 11 mm Hg decrease in blood pressure in the untreated, but no significant renal effect in the icatibant-treated group. Blood pressure was reduced to the same degree in both groups. The results indicate that kinins play a major role in the renal hemodynamic, but not the blood pressure effect of ACE inhibition in the GB rabbit.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Drug Interactions; Enalaprilat; Hypertension, Renal; Kallikreins; Kidney; Organ Size; Rabbits; Receptor, Bradykinin B2; Renal Circulation

Angiotensin-converting enzyme (ACE) inhibitors have been shown to have beneficial effects on ischemic myocardium. We examined whether the ACE inhibitor, enalaprilat (EN), improves intracellular sodium homeostasis during myocardial ischemia and the relationship of this effect to bradykinin.. EN (3.2 nM) was administered to isolated rat hearts that were subjected to ischemia and reperfusion. Intracellular sodium and pH were monitored using magnetic resonance spectroscopy (MRS). The specific bradykinin B2 receptor antagonist, HOE 140 (10 nM), was administered with EN in some hearts to determine the effect of bradykinin blockade on EN-mediated effects.. EN blunted the rise in ischemic intracellular sodium, measured using MRS. With reperfusion, EN-treated hearts recovered 80% of their preischemic ventricular function, compared with negligible recover, in controls. These beneficial effects of EN were blocked when the bradykinin receptor antagonist, HOE 140, was coadministered with EN. HOE 140 also blocked EN-mediated attenuation of ischemic intracellular acidosis.. These results suggest that EN exerts beneficial effects on ischemic intracellular sodium and pH homeostasis via the bradykinin receptor. These effects of EN may provide a mechanism for the beneficial actions of this agent during ischemia.

Topics: Animals; Bradykinin; Culture Techniques; Enalaprilat; Homeostasis; Intracellular Fluid; Magnetic Resonance Spectroscopy; Male; Myocardial Ischemia; Rats; Rats, Wistar; Receptors, Bradykinin; Sodium

To investigate further the relationship of angiotensin I-converting enzyme (ACE) inhibitors to activation of the B(2) bradykinin (BK) receptor, we transfected Chinese hamster ovary cells to stably express the human receptor and either wild-type ACE (WT-ACE), an ACE construct with most of the cytosolic portion deleted (Cyt-del-ACE), or ACE with a glycosylphosphatidylinositol (GPI) anchor replacing the transmembrane and cytosolic domains (GPI-ACE). BK or its ACE-resistant analogue were the agonists. All activities (arachidonic acid release and calcium mobilization) were blocked by the B(2) antagonist HOE 140. B(2) was desensitized by repeated administration of BK but resensitized to agonist by ACE inhibitors in the cells expressing both B(2) and either WT-ACE or Cyt-del-ACE. In GPI-ACE expressing cells, the B(2) receptor was still activated by the agonists, but ACE inhibitors did not resensitize. Pretreatment with filipin returned the sensitivity to inhibitors. In immunocytochemistry, GPI-ACE showed patchy, uneven distribution on the plasma membrane that was restored by filipin. Thus, ACE inhibitors were inactive as long as GPI-ACE was sequestered in cholesterol-rich membrane domains. WT-ACE and B(2) receptor in Chinese hamster ovary cells co-immunoprecipitated with antibody to receptor, suggesting an interaction on the cell membrane. ACE inhibitors augment BK effects on receptors indirectly only when enzyme and receptor molecules are sterically close, possibly forming a heterodimer.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arachidonic Acid; Bradykinin; Calcium; Cell Line; Cell Membrane; Dimerization; Enalaprilat; Filipin; Glycosylphosphatidylinositols; Humans; Immunohistochemistry; Kinetics; Membrane Proteins; Peptidyl-Dipeptidase A; Precipitin Tests; Receptor, Bradykinin B2; Receptors, Bradykinin; Recombinant Fusion Proteins; Transfection

We investigated the effect of angiotensin-converting enzyme inhibitors on glucose uptake regulation as well as the effect of bradykinin (BK) on glucose uptake and its regulation by using inhibitors of phospholipase C, BK B2 receptor, protein kinase C, phosphatidylinositol 3-kinase, tyrosine kinase, and intracellular Ca(2+). We measured 2-deoxyglucose uptake by using L(6) skeletal muscle cells. In the presence of 1 nmol/L of insulin, 1 micromol/L of enalaprilat enhanced insulin-induced glucose uptake from 89.2+/-8. 1 to 138.0+/-13.6 pmol/h per mg protein. The stimulation of glucose uptake with enalaprilat was blocked to 92.7+/-7.8 pmol/h per mg protein by 10 micromol/L HOE 140 (a BK B2 receptor antagonist). In the presence of 1 nmol/L of insulin, exposure to 10 micromol/L BK stimulated glucose uptake from 89.2+/-8.1 to 171.6+/-10.1 pmol/h per mg protein. However, in the absence of insulin, BK could not enhance glucose uptake. One hundred nanomoles per liter of tyrphostin A-23 and genistein, which are tyrosine kinase inhibitors, significantly decreased the BK-induced glucose uptake from 142.0+/-8.4 to 87.6+/-6. 4 and 85.2+/-7.3 pmol/h per mg protein, respectively. BK-induced glucose uptake was inhibited significantly by 10 micromol/L U73122 (a phospholipase C antagonist) from 142.0+/-8.4 to 95.7+/-9.5 pmol/h per mg protein. One and 20 micromol/L of TMB-8 (an intracellular calcium antagonist) significantly decreased BK-induced glucose uptake from 142.0+/-8.4 to 108.0+/-9.6 and 100.8+/-11.4 pmol/h per mg protein. Angiotensin-converting enzyme inhibitors enhanced insulin-induced glucose uptake via the BK B2 receptor. BK-stimulated glucose uptake is related to phospholipase C, tyrosine kinase, and an increase in intracellular calcium.

Topics: Androstadienes; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Calcium Channel Blockers; Cell Line; Deoxyglucose; Dose-Response Relationship, Drug; Enalaprilat; Enzyme Inhibitors; Gallic Acid; Genistein; Insulin; Muscle, Skeletal; Phosphoinositide-3 Kinase Inhibitors; Protein-Tyrosine Kinases; Tyrphostins; Wortmannin

Angiotensin I-converting enzyme (ACE/kininase II) inhibitors potentiated guinea pig ileum's isotonic contractions to bradykinin (BK) and its analogues, shifting the BK dose-response curve to the left. ACE inhibitors added at the peak of the contraction immediately enhanced it further (343 +/- 40%), although the ileum inactivated BK slowly (t(1/2) = 12-16 min). Chymotrypsin and cathepsin G also augmented the activity of BK up to three- or four-fold, but in a manner slower than that of ACE inhibitors. The BK B(2) receptor blocker HOE 140 inhibited all effects. Histamine and angiotensin II were not potentiated. ACE inhibitors potentiate BK independent of blocking its inactivation by inducing crosstalk between ACE and the BK B(2) receptor; proteases activate the receptor by different mechanism.

Topics: Animals; Bradykinin; Cathepsin G; Cathepsins; Chymotrypsin; Dose-Response Relationship, Drug; Drug Synergism; Enalaprilat; Guinea Pigs; Hydrolysis; Ileum; Peptidyl-Dipeptidase A; Radioimmunoassay; Receptors, Bradykinin; Serine Endopeptidases

The relative roles of ANG II and bradykinin (BK) in the regulation of renal medullary circulation have remained unclear. We compared the contributions of ANG II and BK to the renal medullary blood flow (MBF) responses to angiotensin-converting enzyme (ACE) inhibition (enalaprilat, 33 micrograms . kg-1. min-1) in dogs maintained on a normal-salt diet (0.63%, 3 days, n = 14; group 1) with those fed a low-salt diet (0.01%, 5 days, n = 14; group 2), which upregulates both the kallikrein-kinin and the renin-angiotensin systems. MBF responses to ACE inhibition were evaluated either before (n = 7) or after (n = 7) treatment with the BK B2 receptor blocker icatibant (100-300 micergrams) in both groups. Laser-Doppler needle flow probes were used to determine relative changes in MBF and cortical blood flow (CBF). ACE inhibition increased MBF (group 1, 33 +/- 9%, P

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Diet, Sodium-Restricted; Dogs; Enalaprilat; Kidney Cortex; Kidney Medulla; Reference Values; Renal Circulation; Vasodilation

The interaction between angiotensin [Ang-(1-7)] and bradykinin (BK) was determined in the mesentery of anesthetized Wistar rats using intravital microscopy. Topical application of BK and Ang-(1-7) induced vasodilation that was abolished by the BK B2 receptor antagonist HOE-140 and the Ang-(1-7) antagonist A-779, respectively. BK (1 pmol)-induced vasodilation, but not SNP and ACh responses, was potentiated by Ang-(1-7) 10 pmol and 100 pmols. The effect of 100 pmol of Ang-(1-7) on BK-induced vasodilation was abolished by A-779, indomethacin, and L-nitroarginine methyl esther, whereas losartan was without effect. Enalaprilat treatment enhanced the BK- and Ang-(1-7)-induced vasodilation and the potentiating effect of Ang-(1-7) on BK vasodilation. The potentiation of BK-induced vasodilation by Ang-(1-7) is a receptor-mediated phenomenon dependent on cyclooxygenase-related products and NO release.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arterioles; Bradykinin; Bradykinin Receptor Antagonists; Drug Synergism; Enalaprilat; Mesenteric Arteries; Nitric Oxide; Peptide Fragments; Prostaglandins; Rats; Rats, Wistar; Receptor, Bradykinin B2; Vasodilation; Vasodilator Agents

Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10(-10)-10(-8) M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10(-6) M). Bradykinin (>10(-7) M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9[Leu8]bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.

Topics: 3-Mercaptopropionic Acid; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cilazapril; Cycloheximide; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Enalaprilat; Endothelium, Vascular; Enzyme Inhibitors; Iliac Artery; In Vitro Techniques; Indomethacin; Muscle Contraction; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Protease Inhibitors; Protein Synthesis Inhibitors; Receptors, Bradykinin; Swine; Vasoconstriction; Vasodilation

The effects of N-type calcium channel inhibition with omega-conotoxin GVIA (omega-CTX) on cardiovascular parameters and vagally mediated autonomic reflexes and the role of the renin-angiotensin system were assessed in conscious rabbits. Omega-CTX (10 microg/kg, i.v.) resulted in hypotension, tachycardia, and attenuation of the sympathetic and vagal components of the baroreceptor-heart rate reflex (baroreflex). In the control group (no pretreatment), the peak decrease in mean arterial pressure (MAP) of 13 +/- 3 mm Hg from 72 +/- 2 mm Hg occurred after 33 +/- 3 min, with a corresponding tachycardia of 80 +/- 20 beats/min (n = 6). The tachycardia was due to vagal withdrawal, as a similar increase in heart rate (84 +/- 8 beats/min) after omega-CTX was observed after pretreatment with the beta-adrenoceptor antagonist, propranolol (n = 6). Angiotensin-converting enzyme (ACE) inhibition with enalaprilat revealed a larger, more rapid decrease in MAP in response to omega-CTX (-19 +/- 4 mm Hg from 65 +/- 1 mm Hg after 18 +/- 2 min; n = 6) compared with the control group. Similar larger decreases in MAP were also observed in the presence of the AT1-receptor antagonist, losartan, or the bradykinin B2 receptor antagonist, HOE-140 (n = 5-6). Pretreatment with enalaprilat, losartan, or HOE-140 caused a 50% decrease in the reflex tachycardia after omega-CTX compared with that observed in the control group, and omega-CTX caused a greater attenuation of the vagal component of the baroreflex and a decrease in the bradycardia evoked by the Bezold-Jarisch-like reflex. Also, there was a significant decrease in the bradycardia induced by the nasopharyngeal reflex after omega-CTX in the presence of ACE inhibition and HOE-140. Thus in the conscious rabbit, angiotensin II and bradykinin have a role in attenuating and slowing the hypotensive effect of N-type calcium channel inhibition. Vagolytic effects of omega-CTX on the baroreflex are augmented, and on other vagal reflexes are unmasked, via inhibition of the renin-angiotensin system. The complexity and mechanism of the interaction between N-type calcium channels and the renin-angiotensin system remain to be elucidated.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Baroreflex; Blood Pressure; Bradykinin; Calcium Channel Blockers; Dose-Response Relationship, Drug; Enalaprilat; Heart Rate; Hypotension; Losartan; Nasopharynx; omega-Conotoxin GVIA; Peptides; Pressoreceptors; Propranolol; Rabbits; Renin-Angiotensin System

ACE inhibitors potentiate kinin-nitric oxide (NO)-dependent coronary vascular dilation, and NO can modulate myocardial oxygen consumption. Whether ACE inhibitors also affect myocardial O2 consumption has not been established.. Production of nitrite, a metabolite of NO in aqueous solution, in coronary microvessels and O2 consumption in myocardium were quantified with the use of in vitro tissue preparations, the Greiss reaction, and a Clark-type O2 electrode. In coronary microvessels, kininogen (the precursor of kinin; 10 micrograms/mL) and three ACE inhibitors (captopril, enalaprilat, or ramiprilat; 10(-8) mol/L) increased nitrite production from 76 +/- 6 to 173 +/- 15, 123 +/- 12, 125 +/- 12, and 153 +/- 12 pmol/mg, respectively (all P < .05). In myocardium, kininogen (10 micrograms/mL) and captopril, enalaprilat, or ramiprilat (10(-4) mol/L) reduced cardiac O2 consumption by 41 +/- 2%, 19 +/- 3%, 25 +/- 2%, and 35 +/- 2%, respectively. The changes in both nitrite release and O2 consumption in vitro were blocked by N omega-nitro-L-arginine methyl ester or N omega-nitro-L-arginine, inhibitors of endogenous NO formation. The effects were also blocked by HOE 140, which blocks the bradykinin B2-kinin receptor, and serine protease inhibitors, which inhibit local kinin formation.. Our data indicate that stimulation of local kinin formation by use of a precursor for kinin formation or inhibition of kinin degradation by use of ACE inhibitors increases NO formation and is important in the control of cardiac O2 consumption. Vasodilation and control of myocardial O2 consumption by NO may contribute importantly to the therapeutic actions of ACE inhibitors in cardiac disease states.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Captopril; Coronary Vessels; Culture Techniques; Dogs; Enalaprilat; Kallikrein-Kinin System; Kininogens; Male; Microcirculation; Myocardium; Nitric Oxide; Nitrites; Oxygen Consumption; Ramipril

Responses to T-kinin, a peptide formed from the acute-phase substrate T-kininogen, were investigated in the hindlimb vascular bed of the cat. Under constant-flow conditions, injections of T-kinin into the perfusion circuit in doses of 0.03-1 nmol induced rapid dose-related decreases in perfusion pressure. Responses to T-kinin were similar in time course and magnitude to responses to bradykinin and kallidin and were inhibited by the kinin B2-receptor antagonist, Hoe-140. Responses to T-kinin were attenuated by an inhibitor of nitric oxide synthase and by tetraethylammonium chloride and were enhanced in duration by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor zaprinast. Responses to T-kinin were not altered by inhibitors of K+(ATP) channels, by the cyclooxygenase pathway, or by muscarinic or beta-adrenergic-receptor antagonists. These data suggest that vasodilator responses to T-kinin are mediated by kinin B2-receptor-stimulated release of nitric oxide from the endothelium and increased smooth muscle cGMP levels. These results indicate that activation of K+(ATP) channels and muscarinic or beta-adrenergic receptors and the release of vasodilator prostaglandins are not involved in mediating the response to T-kinin in the hindlimb circulation of the cat.

Topics: Acetylcholine; Albuterol; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cats; Enalaprilat; Endothelium, Vascular; Female; Hindlimb; Hydrazines; Kallidin; Male; Muscle, Skeletal; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitrogen Oxides; Penicillamine; Regional Blood Flow; S-Nitroso-N-Acetylpenicillamine; Tetraethylammonium; Tetraethylammonium Compounds; Vasodilation; Vasodilator Agents

The effects of enalaprilate on duodenal mucosal alkaline secretion (in situ titration) and mean arterial blood pressure were investigated in chloralose-anesthetized male rats. A bolus injection of enalaprilate (0.7 mg/kg intravenously) increased alkaline secretion by about 60%, and this response was resistant to guanethidine (5 mg/kg intravenously), splanchnicotomy, and vagotomy. Furthermore, angiotensin II infusion (0.25-2.5 microg/kg/hr intravenously) following the administration of enalaprilate failed to influence this response. Bradykinin (10(-6)-10(-4) M) applied topically to the serosal surface of the duodenal segment under study increased dose-dependently the duodenal mucosal alkaline secretion, an effect that could be blocked by the selective bradykinin receptor subtype-2 antagonist HOE140 (100 nmol/kg intravenously). HOE140 also antagonized the response to enalaprilate. These data suggest that enalaprilate increases duodenal mucosal alkaline secretion via a local bradykinin pathway involving receptors of the bradykinin receptor subtype-2 antagonist, rather than by blockade of endogenous angiotensin II or by central autonomic neural regulation.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Bicarbonates; Bradykinin; Bradykinin Receptor Antagonists; Dose-Response Relationship, Drug; Duodenum; Enalaprilat; Intestinal Mucosa; Male; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin; Stimulation, Chemical

1. Heterozygous, male, hypertensive, transgenic ((mRen-2)27) rats (350-450 g) were instrumented for the measurement of regional or cardiac haemodynamics (n = 16, in both groups). Animals were given continuous i.v. infusions of the angiotensin-converting enzyme inhibitor, enalaprilat, or the dual metallopeptidase inhibitor, MDL 100,240 (both at 3 mg kg-1, 3 mg kg-1 h-1; n = 8 for regional and cardiac haemodynamics), for 32 h. Twenty four hours after the onset of infusion of enalaprilat or MDL 100,240, the bradykinin (B2)-receptor antagonist, Hoe 140 (1 mg kg-1, i.v.), was given and measurements were continued for a further 8 h, to assess any possible involvement of bradykinin. 2. Over the first 8 h of infusion, both enalaprilat and MDL 100,240 had significant antihypertensive effects, accompanied by similar regional vasodilatations. However, the blood pressure lowering effect of MDL 100,240 (-54 +/- 9 mmHg) was greater than that of enalaprilat (-38 +/- 4 mmHg), because the former caused a significantly greater reduction in cardiac index. 3. Between 8-24 h after the onset of infusion, there was a reduction in the effect of enalaprilat on blood pressure, because cardiac index rose, with no further increase in total peripheral conductance. In contrast, the antihypertensive effect of MDL 100,240 persisted, in spite of a recovery in cardiac index, because there was further vasodilatation, particularly in the mesenteric and hindquarters vascular beds. 4. There were no apparent haemodynamic changes associated with the injection of Hoe 140, and over the following 8 h, the difference between the haemodynamic effects of enalaprilat and MDL 100,240 persisted; there was little evidence of suppression of the effects of either drug. 5. These results are more consistent with the antihypertensive effects of enalaprilat or MDL 100,240 in transgenic ((mRen-2)27) rats being due to suppression of angiotensin II production, than due to inhibition of bradykinin degradation. The additional effects of MDL 100,240 may be accounted for by inhibition of the degradation of natriuretic peptides reducing cardiac output, initially, and decreasing vascular tone, subsequently. Alternatively, the additional increase in vascular conductance following treatment with MDL 100,240 may represent an autoregulatory response to the reduced pressure.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Benzazepines; Bradykinin; Enalaprilat; Hemodynamics; Hypertension; Male; Metalloendopeptidases; Protease Inhibitors; Pyridines; Rats

To determine the role of the renin-angiotensin system and the bradykinin pathway in the mechanism of action of angiotensin-converting enzyme inhibitors in heart failure, the acute effects of enalaprilat (1 mg/kg) were compared with those of a renin inhibitor (ciprokiren, 1 mg/kg i.v.) in 10 chronically instrumented conscious dogs with heart failure induced by right ventricular pacing (3 wk, 240 beats/min). The effects of enalaprilat and ciprokiren on bradykinin infusion (3, 10, and 30 micrograms/min) and the effects of enalaprilat in the presence of the bradykinin B2 receptor antagonist Hoe-140 (10 micrograms/kg i.v.) were also examined. Both inhibitors significantly decreased mean aortic pressure and increased cardiac output. However, enalaprilat induced significantly greater hemodynamic effects than ciprokiren (mean aortic pressure, -13 +/- 3 vs. -6 +/- 1 mmHg; cardiac output, 0.4 +/- 0.1 vs. 0.15 +/- 0.1 l/min). Bradykinin infusion led to dose-dependent decreases in mean aortic pressure and increases in cardiac output that were not modified by pretreatment with ciprokiren but were potentiated 10-fold by enalaprilat. Hoe-140 significantly reduced the hemodynamic effects of enalaprilat. Thus endogenous bradykinin is involved in the acute hemodynamic effects of enalaprilat in experimental heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cardiac Output, Low; Dogs; Enalaprilat; Female; Hemodynamics; Hormones; Imidazoles; Male; Renin; Time Factors

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.

Topics: Adrenergic beta-2 Receptor Antagonists; Adrenergic beta-Antagonists; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Capillaries; Cats; Enalaprilat; Male; Muscle Tonus; Muscle, Skeletal; Muscle, Smooth, Vascular; Regional Blood Flow; Sympathectomy; Vascular Resistance

These experiments compare the effects of a neutral endopeptidase inhibitor, retrothiorphan, 1-[(1-mercaptomethyl-2-phenyl)ethyl]amino-1-oxopropanoic acid, a converting enzyme inhibitor, enalaprilat, and the combination of the two inhibitors on changes in blood pressure and renal function induced by exogenous and endogenous bradykinin in deoxycorticosterone acetate (DOCA)-salt rats. Enalaprilat potentiated the exogenous bradykinin-induced hypotensive responses while retrothiorphan potentiated the effects on urinary cyclic-GMP (cGMP) and bradykinin. The combination potentiated the exogenous bradykinin-induced hypotensive effects and the bradykinin-induced urinary excretion of cGMP, bradykinin and prostaglandin. The bradykinin B2 receptor antagonist, Hoe 140, had no effect on the enalaprilat- and retrothiorphan-induced changes in blood pressure and renal function. In conclusion, while angiotensin-converting enzyme and neutral endopeptidase are involved in the vascular and renal catabolism of exogenous bradykinin, the effects of the peptidase inhibitors do not appear to depend on the protection of endogenous bradykinin under acute conditions in DOCA-salt rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cyclic GMP; Enalaprilat; Hypertension; Kidney; Male; Neprilysin; Rats; Rats, Wistar; Thiorphan

We have previously shown that the natriuretic response to DA-1 receptor agonist fenoldopam is markedly potentiated by angiotensin converting enzyme inhibitor captopril. Since inhibition of angiotensin converting enzyme can lead to decreased production of angiotensin-II and increased levels of kinins (e.g., bradykinin), it is likely that both of these mechanisms might be involved in this phenomenon. However, it is not known whether and to what degree the accumulation of kinins contributes to the overall potentiation of natriuretic response to fenoldopam seen during angiotensin converting enzyme inhibition. In the present study, we have examined the effect of angiotensin converting enzyme inhibitor enalaprilat and angiotensin-II receptor antagonist losartan as well as bradykinin-2 receptor antagonist HOE 140 on fenoldopam-induced natriuresis. Intravenous infusion of fenoldopam (1 microgram/kg/min) for 30 min produced significant increases in urine output and urinary sodium excretion without causing any changes in glomerular filtration rate, renal blood flow and mean arterial blood pressure, a phenomenon suggestive of a direct tubular site of action. In animals treated with either the angiotensin converting enzyme inhibitor enalaprilat or angiotensin-II receptor antagonist losartan, the diuretic and natriuretic effects of fenoldopam were potentiated to a similar degree. Whereas no significant changes in glomerular filtration rate occurred when fenoldopam alone was given to control rats, in animals treated with either enalaprilat or losartan, fenoldopam produced a modest but significant increase in glomerular filtration rate. In a separate group of animals, the effects of bradykinin-2 receptor antagonist HOE 140 on potentiation of fenoldopam-induced natriuresis by enalaprilat was examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Bradykinin; Diuresis; Dopamine Agonists; Drug Synergism; Enalaprilat; Fenoldopam; Glomerular Filtration Rate; Imidazoles; Kidney; Losartan; Male; Natriuresis; Rats; Rats, Sprague-Dawley; Tetrazoles

Neutral endopeptidase inhibition (NEP-I) and angiotensin converting enzyme inhibition (ACE-I) act synergistically to produce acute beneficial hemodynamic effects in models of heart failure. Blockade of the formation of angiotensin II (Ang II) acting together with potentiation of the natriuretic peptides, bradykinin and other vasoactive peptides may mediate the interaction of dual enzyme inhibition. In this study, the potential roles of Ang II repression and bradykinin potentiation were evaluated in conscious cardiomyopathic hamsters with compensated heart failure. The Ang II AT1 receptor antagonist, SR 47436 (BMS-186295), was administered at 30 mumol/kg, i.v. followed by i.v. infusion at 1 mumol/kg/min in combination with NEP-I (SQ-28603 at 30 mumol/kg i.v.). Cardiac preload (left ventricular end diastolic pressure) and afterload (left ventricular systolic pressure) decreased significantly more after the combination of Ang II blockade and NEP-I than after either treatment alone. This indicated that repression of Ang II contributes importantly to the NEP-I/ACE-I interaction. Bradykinin B2 receptor antagonism by Hoe 140 at 100 micrograms/kg, i.v. significantly blunted the decrease in left ventricular end diastolic pressure but not the decrease in left ventricular systolic pressure after dual NEP-I/ACE-I (SQ-28603 and enalaprilat each at 30 mumol/kg, i.v.). This suggests that bradykinin potentiation contributes to the preload-reducing, but not the afterload-reducing, acute effects of NEP-I/ACE-I. Hence, both Ang II repression and bradykinin potentiation are factors contributing to the synergistic hemodynamic effects of combined NEP-I and ACE-I in hamsters with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alanine; Angiotensin II; Animals; Biphenyl Compounds; Blood Pressure; Blood Volume; Bradykinin; Cricetinae; Drug Synergism; Enalaprilat; Heart Failure; Irbesartan; Male; Neprilysin; Tetrazoles; Vasodilation; Ventricular Function, Left

The mechanisms and receptor subtype mediating vasodilator responses to bradykinin were investigated in the hindquarters vascular bed of the cat under constant flow conditions. Intraarterial injections of bradykinin in doses of 10-1,000 ng into the hindquarters vascular bed caused dose-related decreases in perfusion pressure that were inhibited by Hoe-140, a bradykinin B2-receptor antagonist. Injections of des-Arg9-bradykinin (in doses 10-fold higher than for bradykinin) caused smaller dose-related decreases in hindquarters perfusion pressure that were not blocked by Hoe-140. Administration of atropine, glibenclamide, or cyclooxygenase inhibitors did not alter vasodilator responses to bradykinin, suggesting that activation of muscarinic receptors, ATP-sensitive K+ channels, or prostaglandin release is not involved in the response to the peptide. Administration of N omega-nitro-L-arginine and its methyl ester reduced vasodilator responses to bradykinin, acetylcholine, and substance P, whereas responses to endothelium-independent vasodilator agents were not attenuated. Decreases in systemic arterial pressure and in hindquarters perfusion pressure in response to bradykinin were enhanced by the angiotensin-converting enzyme inhibitors captopril and enalaprilat. These results suggest that hindquarters vasodilator responses to bradykinin are mediated by activation of kinin B2 receptors and in part by the release of nitric oxide. These data also suggest the presence of bradykinin B1 receptors, mediating vasodilation in the hindquarters vascular bed. These results indicate that bradykinin is rapidly inactivated by angiotensin-converting enzyme in the lung and in the hindquarters vascular bed of the cat.

Topics: Animals; Atropine; Blood Pressure; Blood Vessels; Bradykinin; Captopril; Cats; Cyclooxygenase Inhibitors; Enalaprilat; Female; Glyburide; Hindlimb; Male

The interaction of angiotensin-converting enzyme (ACE) inhibitors and bradykinin was investigated in isolated bovine and human coronary arteries. Rings with and without endothelium were mounted in organ chambers for measurement of isometric force. The effects of the ACE inhibitors lisinopril, enalaprilat, fosinoprilat, ramiprilat, and captopril were determined during submaximal stimulation with bradykinin or other vasodilators. Lisinopril and captopril alone did not affect vascular tone; however, in rings with endothelium partially relaxed with bradykinin (> or = 10(-10) M), all ACE inhibitors caused further relaxations. Lisinopril did not affect bradykinin concentrations in the incubation medium. Mechanical removal of the endothelium or incubation with nitro-L-arginine or the bradykinin2-receptor antagonist Hoe 140 prevented the relaxations to bradykinin and lisinopril. Other vasodilators including acetylcholine, adenosine diphosphate, substance P, or SIN-1 did not prime the rings to respond to ACE inhibitors. Endothelium-dependent relaxations to lisinopril were also observed in human coronary arteries treated with bradykinin (> or = 10(-7) M). Thus, ACE inhibitors potentiate endothelium-dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries. This local mechanism occurs regardless of elevated bradykinin concentrations in the blood and reduced angiotensin II generation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Captopril; Cattle; Coronary Vessels; Dipeptides; Enalaprilat; Endothelium, Vascular; Fosinopril; Humans; In Vitro Techniques; Lisinopril; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroarginine; Ramipril; Receptors, Bradykinin; Receptors, Neurotransmitter; Vasodilation; Vasodilator Agents