icatibant and candesartan

Impaired flow-dependent, endothelium-mediated vasodilation is an early finding in patients with coronary artery disease (CAD). Experimental and some clinical studies observed that angiotensin type-1 receptor antagonists (AT1A) enhance endothelium-dependent relaxation in CAD. The present study was designed to determine whether AT1A improves flow-dependent dilation (FDD) in patients with CAD and, if so, whether bradykinin and NO are involved. High-resolution ultrasound was used to measure radial artery diameter at rest and during reactive hyperemia, causing endothelium-mediated vasodilation. Twenty patients with CAD were randomly assigned to receive intrabrachial infusion of candesartan (800 microg/min) with and without icatibant, a bradykinin B2-receptor antagonist (90 microg/min; group A) or N-monomethyl-l-arginine (L-NMMA), an NO-synthase inhibitor (7 micromol/min; group B). The AT1A candesartan improved FDD by >40%, an effect that was inhibited by icatibant (group A: control, 7.3+/-0.9; candesartan, 10.3+/-1.1; candesartan+icatibant, 5.0+/-0.5%). Similarly, L-NMMA blunted the beneficial effect of candesartan (group B: control, 6.3+/-0.6; candesartan, 8.9+/-0.6; candesartan+L-NMMA: 4.7+/-0.5%; each P<0.01). The angiotensin type-1 receptor antagonist candesartan improves flow-dependent, endothelium-mediated vasodilation in patients with CAD. This effect is inhibited by either icatibant and or L-NMMA, suggesting that both bradykinin and NO contribute to the vascular effects of AT1-receptor antagonists in this patient population.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Flow Velocity; Bradykinin; Bradykinin Receptor Antagonists; Coronary Artery Disease; Endothelium, Vascular; Enzyme Inhibitors; Humans; Infusions, Intra-Arterial; Middle Aged; Nitric Oxide Synthase; Nitroprusside; omega-N-Methylarginine; Radial Artery; Receptor, Angiotensin, Type 1; Receptor, Bradykinin B2; Receptors, Bradykinin; Tetrazoles

The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately connected and some of the cardioprotective effects of Losartan are abolished by blocking the bradykinin B2 receptor (B2R) signaling. In this study, we investigated the ability of six clinically available ARBs to specifically bind and activate the B2R. First, we investigated their ability to activate phosphoinositide (PI) hydrolysis in COS-7 cells transiently expressing the B2R. We found that only Losartan activated the B2R, working as a partial agonist compared to the endogenous ligand bradykinin. This effect was blocked by the B2R antagonist HOE 140. A competitive binding analysis revealed that Losartan does not significantly compete with bradykinin and does not change the binding affinity of bradykinin on the B2R. Furthermore, Losartan but not Candesartan mimicked the ability of bradykinin to increase the recovery of contractile force after metabolic stress in rat atrial tissue strips. In conclusion, Losartan is a partial agonist of the B2R through direct binding and activation, suggesting that B2R agonism could partly explain the beneficial effects of Losartan.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensins; Animals; Benzimidazoles; Binding, Competitive; Biphenyl Compounds; Bradykinin; Bradykinin B2 Receptor Antagonists; Chlorocebus aethiops; COS Cells; Hydrolysis; Kallikrein-Kinin System; Losartan; Myocardial Contraction; Phosphatidylinositols; Rats; Receptor, Angiotensin, Type 1; Receptor, Bradykinin B2; Renin-Angiotensin System; Signal Transduction; Tetrazoles

PURPOSE. To investigate the effects of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II antagonist against retinal ischemia-reperfusion injury in the rat retina. METHODS. Retinal ischemia was induced by increasing intraocular pressure to 130 mm Hg. Rats were treated with an ACE inhibitor (captopril), an angiotensin II type 1 receptor (AT1-R) antagonist (candesartan), an AT2-R antagonist (PD123319), bradykinin, or a bradykinin B2 receptor antagonist (icatibant). At 7 days after the ischemia, retinal damage was evaluated. Immunohistochemistry and image analysis were used to measure changes in the levels of reactive oxygen species (ROS) and the localization of AT1-R. Dark-adapted full-field electroretinography (ERG) was also performed. RESULTS. Pretreatment with captopril or candesartan significantly inhibited the ischemic injury of the inner retina. However, PD123319, bradykinin, or icatibant did not reduce the ischemic damage. In control retinas, retinal vessels were positive for AT1-R. In contrast, 12 hours after ischemia, immunohistochemical analysis detected numerous AT1-R-positive cells in the inner retina in vehicle-treated rats. After ischemia, the production of ROS was detected in retinal cells. However, pretreatment with captopril or candesartan suppressed the production of ROS. On the seventh postoperative day, the amplitudes of the ERG b-waves were significantly lower in the vehicle group than in the groups pretreated with captopril or candesartan. CONCLUSIONS. The present findings demonstrate that ischemic damage promotes the expression of AT1-R in the inner retina. Both the ACE inhibitor and the AT1-R antagonist that were examined can block the stimulation of the AT1-R and attenuate the subsequent ischemic damage in the rat retina.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Bradykinin; Bradykinin B2 Receptor Antagonists; Captopril; Cell Survival; Electroretinography; Enzyme-Linked Immunosorbent Assay; Female; Imidazoles; Immunoenzyme Techniques; Neuroprotective Agents; Pyridines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Reperfusion Injury; Retina; Retinal Diseases; Retinal Ganglion Cells; Tetrazoles

Angiotensin-converting enzyme (ACE) inhibitor enhances the liver regeneration in rats after partial hepatectomy (PH), though the precise mechanisms are unknown. To determine the roles of bradykinin and angiotensin II in the ACE inhibitor-induced enhancement of liver regeneration, we investigated effects of lisinopril (ACE inhibitor), candesartan and losartan (angiotensin II type 1 (AT1) receptor antagonists) and icatibant (bradykinin B2 receptor antagonist) on the hepatic regenerative response to 70% PH in the rat. The liver regeneration was evaluated by measuring the frequency of 5-bromo-2'-deoxyuridine (BrdU) incorporation into hepatocyte nuclei 48 h after PH. We found that administration of candesartan or losartan, as well as lisinopril, enhanced BrdU incorporation after PH, and the lisinopril-induced enhancement was inhibited in part (40%) by icatibant. PH induced the expression of hepatocyte growth factor (HGF) mRNA in remnant liver, and this PH-induced up-regulation of HGF mRNA was further enhanced not only by lisinopril but also by candesartan and losartan. Administration of icatibant inhibited up to 40% of the lisinopril-induced up-regulation of HGF mRNA. These results suggest that the blockade of the renin-angiotensin system by either ACE inhibitor or AT1 receptor antagonist enhances the hepatic regenerative response to PH, probably through an augmentation of hepatic HGF production. In addition to this mechanism, the activation of B2 receptors may also be involved in the ACE inhibitor-induced enhancement of hepatic regenerative response.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Bradykinin; Bradykinin B2 Receptor Antagonists; Bromodeoxyuridine; Dose-Response Relationship, Drug; Hepatectomy; Hepatocyte Growth Factor; Hepatocytes; Lisinopril; Liver Regeneration; Losartan; Male; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazoles; Time Factors

Renal volume regulation is modulated by the action of cyclooxygenases (COX) and the resulting generation of prostanoids. Epithelial expression of COX isoforms in the cortex directs COX-1 to the distal convolutions and cortical collecting duct, and COX-2 to the thick ascending limb. Partly colocalized are prostaglandin E synthase (PGES), the downstream enzyme for renal prostaglandin E(2) (PGE(2)) generation, and the EP receptors type 1 and 3. COX-1 and related components were studied in two kidney-one clip (2K1C) Goldblatt hypertensive rats with combined chronic ANG II or bradykinin B(2) receptor blockade using candesartan (cand) or the B(2) antagonist Hoechst 140 (Hoe). Rats (untreated sham, 2K1C, sham + cand, 2K1C + cand, sham + Hoe, 2K1C + Hoe) were treated to map expression of parameters controlling PGE(2) synthesis. In 2K1C, cortical COX isoforms did not change uniformly. COX-2 changed in parallel with NO synthase 1 (NOS1) expression with a raise in the clipped, but a decrease in the nonclipped side. By contrast, COX-1 and PGES were uniformly downregulated in both kidneys, along with reduced urinary PGE(2) levels, and showed no clear relations with the NO status. ANG II receptor blockade confirmed negative regulation of COX-2 by ANG II but blunted the decrease in COX-1 selectively in nonclipped kidneys. B(2) receptor blockade reduced COX-2 induction in 2K1C but had no clear effect on COX-1. We suggest that in 2K1C, COX-1 and PGES expression may fail to oppose the effects of renovascular hypertension through reduced prostaglandin signaling in late distal tubule and cortical collecting duct.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Cyclic GMP; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Hypertension, Renovascular; Kidney Cortex; Kidney Tubules, Collecting; Kidney Tubules, Distal; Loop of Henle; Male; Membrane Proteins; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Surgical Instruments; Tetrazoles

The vascular kallikrein-kinin system contributes to about one third of flow-dependent dilation in mice carotid arteries, by activating bradykinin B2 receptors coupled to endothelial nitric oxide (NO) release. Because the bradykinin/NO pathway may mediate some of the effects of angiotensin II AT2 receptors, we examined the possible contribution of AT2 receptors to the kinin-dependent response to flow. Changes in outer diameter after increases in flow rate were evaluated in perfused arteries from wild-type animals (TK+/+) and in tissue kallikrein-deficient mice (TK-/-) in which the presence of AT2 receptor expression was verified. Saralasin, a nonselective angiotensin II receptor antagonist, impaired significantly flow-induced dilation in TK+/+, whereas it had no effect in TK-/- mice. In both groups, blockade of AT1 receptors with losartan or candesartan did not affect the response to flow. Inhibition of AT2 receptors with PD123319 reduced significantly flow-induced dilation in TK+/+ mice, but had no significant effect in TK-/- mice. Combining PD123319 with the bradykinin B2 receptor antagonist HOE-140 had no additional effect to AT2 receptor blockade alone in TK+/+ arteries. Flow-dependent-dilation was also impaired in AT2 receptor deficient mice (AT2-/-) when compared with wild-type littermates. Furthermore, HOE-140 significantly reduced the response to flow in the AT2+/+, but not in AT2-/- mice. In conclusion, this study demonstrates that the presence of functional AT2 receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Bradykinin; Bradykinin B2 Receptor Antagonists; Carotid Arteries; Hemorheology; Imidazoles; Losartan; Male; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenylephrine; Pyridines; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Tetrazoles; Tissue Kallikreins; Vasodilation; Vasodilator Agents

The effects of blockade of the renin-angiotensin system on the renal metabolism of arachidonic acid (AA) were examined. Male Sprague-Dawley rats were treated with vehicle, captopril (25 mg x kg(-1) x day(-1)), enalapril (10 mg x kg(-1) x day(-1)), or candesartan (1 mg x kg(-1) x day(-1)) for 1 wk. The production of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) by renal cortical microsomes increased in rats treated with captopril by 59 and 24% and by 90 and 58% in rats treated with enalapril. Captopril and enalapril increased 20-HETE production in the outer medulla by 100 and 143%, respectively. In contrast, blockade of ANG II type 1 receptors with candesartan had no effect on the renal metabolism of AA. Captopril and enalapril increased cytochrome P-450 (CYP450) reductase protein levels in the renal cortex and outer medulla and the expression of CYP450 4A protein in the outer medulla. The effects of captopril on the renal metabolism of AA were prevented by the bradykinin-receptor antagonist, HOE-140, or the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester. These results suggest that angiotensin-converting enzyme inhibitors may increase the formation of 20-HETE and EETs secondary to increases in the intrarenal levels of kinins and NO.

Topics: 8,11,14-Eicosatrienoic Acid; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arachidonic Acid; Benzimidazoles; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Captopril; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Desoxycorticosterone; Enalapril; Enzyme Inhibitors; Hydroxyeicosatetraenoic Acids; Kidney; Kidney Cortex; Kidney Medulla; Male; Microsomes; Mixed Function Oxygenases; NADPH-Ferrihemoprotein Reductase; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Spironolactone; Tetrazoles

The combination therapy with ACE inhibitors, angiotensin II type 1 (AT(1)) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal alpha-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-beta receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-beta receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT(1) receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT(1) receptor antagonist or monotherapy with each agent.

Topics: Adrenergic beta-Antagonists; Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Antihypertensive Agents; Aorta; Atrial Natriuretic Factor; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Calcium; Calcium Channel Blockers; Drug Therapy, Combination; ErbB Receptors; Gene Expression; Heart Ventricles; Hypertension; Myocardium; Organ Size; Perindopril; Phosphorylation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Receptors, Platelet-Derived Growth Factor; RNA, Messenger; Stroke; Tetrazoles

The relative contributions of ANG II and bradykinin (BK) to the renal regional blood flow responses during angiotensin-converting enzyme (ACE) inhibition remain unclear. This study was performed to evaluate renal cortical (CBF) and medullary blood flow (MBF) responses to intrarterial administration of enalaprilat (33 microg. kg(-1). min (-1)) after blockade of the ANG II AT(1 )receptors with candesartan (100 microg) in 7 dogs fed a low-salt diet (0.01%) for 5 days. Laser-Doppler flowmetry was used to measure relative changes in CBF and MBF. Candesartan alone increased CBF (+20 +/- 2%) and MBF (+22 +/- 7%). Enalaprilat infusion after candesartan administration resulted in further increases in both CBF (+21 +/- 5%) and MBF (+41 +/- 8%). However, the relative changes in MBF were significantly greater (P < 0.01) than those in CBF. Administration of the BK B(2) receptor blocker icatibant (300 microg) after enalaprilat returned CBF and MBF to values seen with candesartan alone. These data support a substantive role for BK potentiation during ACE inhibitor-induced renal vasodilation in dogs maintained on a low-sodium diet, with a relatively greater effect on MBF compared to CBF.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Bradykinin; Diet, Sodium-Restricted; Dogs; Laser-Doppler Flowmetry; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renal Circulation; Sodium; Tetrazoles

Although ACE inhibitors can protect myocardium against ischemia/reperfusion injury, the mechanisms of this effect have not yet been characterized at the cellular level. The present study was designed to examine whether an ACE inhibitor, cilazaprilat, directly protects cardiac myocytes against hypoxia/reoxygenation (H/R) injury.. Neonatal rat cardiac myocytes in primary culture were exposed to hypoxia for 5.5 hours and subsequently reoxygenated for 1 hour. Myocyte injury was determined by the release of creatine kinase (CK). Both cilazaprilat and bradykinin significantly inhibited CK release after H/R in a dose-dependent fashion and preserved myocyte ATP content during H/R, whereas CV-11974, an angiotensin II receptor antagonist, and angiotensin II did not. The protective effect of cilazaprilat was significantly inhibited by Hoe 140 (a bradykinin B2 receptor antagonist), NG-monomethyl-L-arginine monoacetate (L-NMMA) (an NO synthase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) but not by staurosporine (a protein kinase C inhibitor), aminoguanidine (an inhibitor of inducible NO synthase), or indomethacin (a cyclooxygenase inhibitor). Cilazaprilat significantly enhanced bradykinin production in the culture media of myocytes after 5.5 hours of hypoxia but not in that of nonmyocytes. In addition, cilazaprilat markedly enhanced the cGMP content in myocytes during hypoxia, and this augmentation in cGMP could be blunted by L-NMMA and methylene blue but not by aminoguanidine.. The present study demonstrates that cilazaprilat can directly protect myocytes against H/R injury, primarily as a result of an accumulation of bradykinin and the attendant production of NO induced by constitutive NO synthase in hypoxic myocytes in an autocrine/paracrine fashion. NO modulates guanylate cyclase and cGMP synthesis in myocytes, which may contribute to the preservation of energy metabolism and cardioprotection against H/R injury.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Bradykinin; Cell Hypoxia; Cells, Cultured; Cilazapril; Creatine Kinase; Cyclic GMP; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Guanidines; Indomethacin; Methylene Blue; Muscle Fibers, Skeletal; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Oxygen; Rats; Rats, Wistar; Staurosporine; Tetrazoles

The renin-angiotensin system is thought to be involved in the progression of glomerulonephritis (GN) into end-stage renal failure (ESRF) because of the observed renoprotective effects of angiotensin-converting enzyme inhibitors (ACEIs). However, ACEIs have pharmacological effects other than ACE inhibition that may help lower blood pressure and preserve glomerular structure. We previously reported a new animal model of progressive glomerulosclerosis induced by a single intravenous injection of an anti-Thy-1 monoclonal antibody, MoAb 1-22-3, in uninephrectomized rats. Using this new model of progressive GN, we examined the hypothesis that ACEIs prevent the progression to ESRF by modulating the effects of angiotensin II (Ang II) on the production of transforming growth factor-beta (TGF-beta) and extracellular matrix components.. We studied the effect of an ACEI (cilazapril) and an Ang II type 1 receptor antagonist (candesartan) on the clinical features and morphological lesions in the rat model previously reported. After 10 weeks of treatment with equihypotensive doses of cilazapril, cilazapril plus Hoe 140 (a bradykinin receptor B2 antagonist), candesartan, and hydralazine, we examined systolic blood pressure, urinary protein excretion, creatinine clearance, the glomerulosclerosis index, and the tubulointerstitial lesion index. We performed a semiquantitative evaluation of glomerular immunostaining for TGF-beta and collagen types I and III by immunofluorescence study and of these cortical mRNA levels by Northern blot analysis.. Untreated rats developed massive proteinuria, renal dysfunction, and severe glomerular and tubulointerstitial injury, whereas uninephrectomized control rats did not. There was a significant increase in the levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III in untreated rats. Cilazapril and candesartan prevented massive proteinuria, increased creatinine clearance, and ameliorated glomerular and tubulointerstitial injury. These drugs also reduced levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III. Hoe 140 failed to blunt the renoprotective effect of cilazapril. Hydralazine did not exhibit a renoprotective effect.. These results indicate that ACEIs prevent the progression to ESRF by modulating the effects of Ang II via Ang II type 1 receptor on the production of TGF-beta and collagen types I and III, as well as on intrarenal hemodynamics, but not by either increasing bradykinin activity or reducing blood pressure in this rat model of mesangial proliferative GN.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Cilazapril; Collagen; Disease Models, Animal; Glomerulonephritis, Membranoproliferative; Hydralazine; Kidney Failure, Chronic; Male; Proteinuria; Rats; Rats, Wistar; Renal Circulation; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta

Although bradykinin is thought to contribute to the effects of ACE inhibitors on the cardiovascular system, its precise role remains to be elucidated. Evidence suggests that bradykinin might be important in the upregulation of beta-adrenergic receptors (beta-ARs) induced by ACE inhibitors, and the role of bradykinin in this effect has now been investigated with cultured neonatal rat cardiac myocytes.. The density of beta-ARs on the myocyte surface was determined with a binding assay with [3H]CGP-12177. Incubation of cultured myocytes for 24 hours with the ACE inhibitor captopril (1 micromol/L) increased beta-AR density by 35% and enhanced the response of cells to isoproterenol but not to forskolin. Neither an angiotensin-II type 1 (AT1) receptor antagonist, CV-11974, nor angiotensin-I affected beta-AR density. However, the bradykinin B2 receptor antagonist Hoe 140 abolished the effect of captopril on beta-AR upregulation in a dose-dependent manner. The protein kinase C inhibitor staurosporine (20 nmol/L) but neither indomethacin nor L-NAME also inhibited captopril-induced upregulation of beta-ARs. Exogenous bradykinin increased the spontaneous beating frequency of cultured myocytes and Hoe 140 abolished this effect. Bradykinin level in the medium increased 1.4-fold by the treatment of cultured myocytes with captopril for 24 hours.. The results suggest that captopril enhances beta-AR responsiveness by inducing beta-AR upregulation and that the latter effect is mediated by activation of bradykinin B2 receptors and protein kinase C. These observations also offer insight into the different roles of ACE inhibitors and AT1 receptor antagonists in the treatment of heart failure.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Benzimidazoles; Biphenyl Compounds; Bradykinin; Captopril; Cells, Cultured; Female; In Vitro Techniques; Isoproterenol; Male; Myocardium; Protein Kinase C; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Receptors, Bradykinin; Tetrazoles; Up-Regulation

We studied the effect of the angiotensin II type 1 (AT1)-receptor antagonist candesartan on infarct size resulting from regional myocardial ischemia in pigs.. The effects of AT1-receptor blockade on infarct size in different species remain controversial and its potential cardioprotective mechanisms are still unclear. In pigs, infarct development closely resembles that observed in humans.. A total of 62 enflurane-anesthetized pigs underwent a protocol of 90-min low-flow ischemia and 120-min reperfusion. Systemic hemodynamics (micromanometer), regional myocardial function (sonomicrometry), regional myocardial blood flow (microspheres) and infarct size (TTC [triphenyl tetrazolium chloride]-staining) were determined.. Left ventricular peak pressure decreased with candesartan (1 mg/kg i.v.) from 97+/-2 standard error of the mean (SEM) to 86+/-5 mm Hg and was then readjusted by aortic banding. In placebo pigs (n=9), infarct size was 21.8+/-4.8% of the area at risk. Candesartan (n=7) reduced infarct size to 9.7+/-2.5% (p < 0.05). Pretreatment with the AT2-receptor antagonist PD123319 (3 microg/kg/min intracoronarily [i.c.]; n=8), the bradykinin B2-receptor antagonist HOE140 (0.01 microg/kg/min i.c.; n=8) or the cyclooxygenase inhibitor indomethacin (10 mg/kg i.v.; n= 8) per se did not affect infarct size but did abolish the reduction of infarct size achieved by candesartan (PD123319 + candesartan (n=7): 23.2+/-4.7%; HOE140 + candesartan (n=7): 18.2+/-4.0%; indomethacin + candesartan (n=8): 21.1+/-5.2%). Hemodynamics, regional myocardial blood flow during ischemia and the area at risk were comparable among all groups of pigs.. Reduction of infarct size by the AT1-receptor antagonist candesartan in pigs involves angiotensin II type 2 receptor (AT2) activation, bradykinin and prostaglandins.

Topics: Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Cyclooxygenase Inhibitors; Drug Combinations; Female; Imidazoles; Indomethacin; Male; Myocardial Infarction; Prostaglandins; Pyridines; Receptors, Angiotensin; Signal Transduction; Swine; Swine, Miniature; Tetrazoles