enalaprilat-anhydrous and candesartan

The adverse reactions in combination of angiotensin-converting enzyme inhibitors (ACEIs) and Ang II receptor blockers (ARBs) were severer than that in monotherapy for patients with nephropathy. The effect of candesartan on pharmacokinetics of enalaprilat in nephrotic rats was investigated to make references for the clinical therapy in patients with nephropathy to avoid related adverse effects.. Nephrotic rats were prepared by adriamycin injection. Control group and one nephrotic group received enalapril alone, another nephrotic group received enalapril and candesartan simultaneously. Blood samples were drawn at time points after a single oral administration. The concentration of enalaprilat was determined using LC-MS/MS.. Compared with control group and nephrotic group received enalapril alone respectively, Tmax of enalaprilat in nephrotic group received both enalapril and candesartan cilexetil prolonged about 21.43% and 6.224%, respectively; AUC(0-t) increased by 185.3% and 60.63%, respectively; Cmax increased by 219.4% and 56.64%, respectively; t1/2 increased by 163.7% and 30.05%, respectively; CL/F reduced by 65.12% and 40.78%, respectively. There were no significant differences of the V1/F of enalaprilat between three groups. The CL/F and t1/2 of enalaprilat showed significant correlations with serum creatinine (Scr) respectively (r = -0.7502; r = 0.5626).. The combination with candesartan in nephrotic rats significantly changed the pharmacokinetics of enalaprilat, showing increased accumulation and decreased elimination. In view of these findings, we should lower dosage and prolong dosing interval for nephrotic patients in the combination of enalapril and candesartan.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Drug Interactions; Enalaprilat; Female; Male; Nephrosis; Rats; Rats, Sprague-Dawley; Tetrazoles

Angiotensin II maintains renal cortical blood flow and renal oxygenation in the clipped kidney of early 2-kidney, 1-clip Goldblatt hypertensive (2K,1C) rats. The involvement of Ang II is believed to decline, whereas oxidative stress increases during the progression of 2K,1C hypertension. We investigated the hypothesis that the acute administration of drugs to inhibit reactive oxygen species (Tempol), angiotensin II type 1 receptors (candesartan), or angiotensin-converting enzyme (enalaprilat) lowers mean arterial pressure and increases kidney blood flow and oxygenation in the clipped kidney of chronic 2K,1C rats in contrast to sham controls. Twelve months after left renal artery clipping or sham, mean arterial pressure, renal cortical blood flow, and renal cortical and medullary oxygen tension were measured after acute administration of Tempol followed by enalaprilat or candesartan followed by enalaprilat. The mean arterial pressure of the 2K,1C rat was reduced by candesartan (-9%) and, more effectively, by Tempol (-35%). All of the applied treatments had similar blood pressure-lowering effects in sham rats (average: -21%). Only Tempol increased cortical blood flow (+35%) and cortical and medullary oxygen tensions (+17% and +94%, respectively) in clipped kidneys of 2K,1C rats. Administration of enalaprilat had no additional effect, except for a modest reduction in cortical blood flow in the clipped kidney of 2K,1C rats when coadministered with candesartan (-10%). In conclusion, acute administration of Tempol is more effective than candesartan in reducing the mean arterial blood pressure and improving renal blood perfusion and oxygenation in the clipped kidney of chronic 2K,1C rats.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cyclic N-Oxides; Disease Models, Animal; Enalaprilat; Glomerular Filtration Rate; Hypertension, Renovascular; Male; Organ Size; Oxygen Consumption; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Renal Circulation; Spin Labels; Tetrazoles; Vascular Resistance

Angiotensin-converting enzyme inhibitors (ACEIs) decrease the glomerular filtration rate and renal blood flow in the clipped kidneys of early 2-kidney, 1-clip Goldblatt hypertensive rats, but the consequences for oxygenation are unclear. We investigated the hypothesis that angiotensin II type 1 or angiotensin II type 2 receptors or NO synthase mediate renal oxygenation responses to ACEI. Three weeks after left renal artery clipping, kidney function, oxygen (O(2)) use, renal blood flow, renal cortical blood flow, and renal cortical oxygen tension (Po(2)) were measured after acute administration of an ACEI (enalaprilat) and after acute administration of ACEI following acute administration of an angiotensin II type 1 or angiotensin II type 2 receptor blocker (candesartan or PD-123,319) or an NO synthase blocker (N(G)-nitro-L-arginine methyl ester with control of renal perfusion pressure) and compared with mechanical reduction in renal perfusion pressure to the levels after ACEI. The basal renal cortical Po(2) of clipped kidneys was significantly lower than contralateral kidneys (35+/-1 versus 51+/-1 mm Hg; n=40 each). ACEI lowered renal venous Po(2), cortical Po(2), renal blood flow, glomerular filtration rate, and cortical blood flow and increased the renal vascular resistance in the clipped kidney, whereas mechanical reduction in renal perfusion pressure was ineffective. PD-123,319 and N(G)-nitro-L-arginine methyl ester, but not candesartan, reduced the Po(2) of clipped kidneys and blocked the fall in Po(2) with acute ACEI administration. In conclusion, oxygen availability in the clipped kidney is maintained by angiotensin II generation, angiotensin II type 2 receptors, and NO synthase. This discloses a novel mechanism whereby angiotensin can prevent hypoxia in a kidney challenged with a reduced perfusion pressure.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Enalaprilat; Enzyme Inhibitors; Glomerular Filtration Rate; Hypertension, Renovascular; Imidazoles; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxygen; Partial Pressure; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renal Circulation; Surgical Instruments; Tetrazoles; Vascular Resistance

To counteract the contribution of angiotensin II to shock-induced ischaemic organ damage pharmacologic blockade of the renin-angiotensin-system (RAS) is currently under investigation. To evaluate potential side-effects of RAS blockade regarding capillary leak, we studied alterations in microvascular permeability in various organs during haemorrhagic shock (HS) in rats pretreated with candesartan (AT(1)-receptor antagonism) or enalaprilat (ACE-inhibition).. Thirty-eight instrumented and anaesthetized animals received either candesartan, enalaprilat or placebo. Within each of the three groups 6-7 animals were exposed to HS and 6 animals of each group served as normovolaemic controls. After 30 min of shock, 50 mg kg(-1) Evans blue (EB) was injected i.v. followed by a distribution period of 20 min. Exsanguination was performed with saline, before harvesting organs to quantify albumin-bound EB extravasation.. To reduce cardiac output from 37.5 (1.3) to 20.4 (1.1) ml min(-1) [mean (SEM)] in the shock groups, withdrawal of 4.0 (0.25) ml [mean (SEM)] blood was necessary. Simultaneously mean arterial pressure decreased from 77.5 (3.2) to 36.1 (2) mm Hg. Serum lactate increased significantly from 1.3 (0.1) to 3.5 (0.24) mmol litre(-1). Treatment with candesartan increased EB extravasation in the kidney in normovolaemic controls. Specific AT(1) and ACE-blockade before acute non-resuscitated HS significantly increased EB extravasation in the rat ileum by 53 and 66%, respectively.. This observation of increased microvascular albumin extravasation should be borne in mind for any interventional use of candesartan or enalaprilat during circulatory stress.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Capillary Permeability; Coloring Agents; Enalaprilat; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Hemodynamics; Ileum; Kidney; Lactic Acid; Male; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Shock, Hemorrhagic; Tetrazoles

The study was designed to determine (i) whether the effects of angiotensin III (AngIII) are similar to those of angiotensin II (AngII) at identical plasma concentrations and (ii) whether AngIII operates solely through AT1- receptors.. Angiotensin II (3 pmol kg(-1) min(-1)-3.1 ng kg(-1) min(-1)) or AngIII (15 pmol kg(-1) min(-1)-14 ng kg(-1) min(-1)) was infused i.v. during acute inhibition of angiotensin converting enzyme (enalaprilate; 2 mg kg(-1)) and of aldosterone (canrenoate; 6 mg kg(-1) plus 1 mg kg(-1) h(-1)). Arterial plasma concentrations of angiotensins were determined by radioimmunoassay using a cross-reacting antibody to AngII. During ongoing peptide infusion, candesartan (2 mg kg(-1)) was administered to block the AT1-receptors.. Angiotensin immunoactivity in plasma increased to 60 +/- 10 pg mL(-1) during infusion of AngII or infusion of AngIII. AngII significantly increased mean arterial blood pressure (+14 +/- 4 mmHg) and plasma aldosterone by 79% (+149 +/- 17 pg mL(-1)) and reduced plasma renin activity and sodium excretion (-41 +/- 16 mIU L(-1) and -46 +/- 6 micromol min(-1) respectively). AngIII mimicked these effects and the magnitude of AngIII responses was statistically indistinguishable from those of AngII. All measured effects of both peptides were blocked by candesartan.. At the present arterial plasma concentrations, AngIII is equipotent to AngII with regard to effects on blood pressure, aldosterone secretion and renal functions, and these AngIII effects are mediated through AT1- receptors. The metabolic clearance rate of AngIII is five times that of AngII.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin III; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Dogs; Dose-Response Relationship, Drug; Enalaprilat; Female; Glomerular Filtration Rate; Metabolic Clearance Rate; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Tetrazoles

The role played by several vasoactive mediators that are synthesized and released by the pulmonary vascular endothelium in the regulation of hypoxic pulmonary vasoconstriction (HPV) remains unclear. As a potent vasoconstrictor, angiotensin II could be involved. We tested the hypothesis that angiotensin-converting enzyme inhibition by enalaprilat and type 1 angiotensin II receptor blockade by candesartan would inhibit HPV.. HPV was evaluated in anaesthetized dogs, with an intact pulmonary circulation, by examining the increase in the Ppa-Ppao gradient (mean pulmonary artery pressure minus occluded pulmonary artery pressure) that occurred in response to hypoxia (inspiratory oxygen fraction of 0.1) at constant pulmonary blood flow. Plasma renin activity and angiotensin II immunoreactivity were measured to determine whether activation or inhibition of the renin-angiotensin system was present.. Administration of enalaprilat and candesartan did not affect the Ppa-Ppao gradient at baseline or during hypoxia. Plasma renin activity and angiotensin II immunoreactivity increased during hypoxia, and subsequent measurements were consistent with effective angiotensin-converting enzyme inhibition after administration of enalaprilat, and with angiotensin receptor blockade after administration of candesartan.. These results suggest that, although the renin-angiotensin system was activated in hypoxia, angiotensin II is not normally involved in mediating acute HPV.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Dogs; Enalaprilat; Endothelium, Vascular; Hypertension, Pulmonary; Hypoxia; Lung; Models, Animal; Renin-Angiotensin System; Tetrazoles; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents

The role of local endogenous angiotensin II (Ang II) in endothelial function in resistance arteries was investigated using rabbit mesenteric resistance arteries. First, the presence of immunoreactive Ang II together with Ang II type-1 receptor (AT1R) and angiotensin converting enzyme (ACE) was confirmed in these arteries. In endothelium-intact strips, the AT1R-blocker olmesartan (1 microM) and the ACE-inhibitor temocaprilat (1 microM) each enhanced the ACh (0.03 microM)-induced relaxation during the contraction induced by noradrenaline (NA, 10 microM). Similar effects were obtained using CV-11974 (another AT1R blocker) and enalaprilat (another ACE inhibitor). The nitric-oxide-synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished the above effect of olmesartan. In endothelium-denuded strips, olmesartan enhanced the relaxation induced by the NO donor NOC-7 (10 nM). Olmesartan had no effect on cGMP production (1) in endothelium-intact strips (in the absence or presence of ACh) or (2) in endothelium-denuded strips (in the absence or presence of NOC-7). In beta-escin-skinned strips, 8-bromoguanosine 3',5' cyclic monophosphate (8-Br-cGMP, 0.01-1 microM) concentration dependently inhibited the contractions induced (a) by 0.3 microM Ca2+ in the presence of NA+GTP and (b) by 0.2 microM Ca2++GTPgammaS. Olmesartan significantly enhanced, while Ang II (0.1 nM) significantly inhibited, the 8-Br-cGMP-induced relaxation. We propose the novel hypothesis that in these arteries, Ang II localized within smooth muscle cells activates AT1Rs and inhibits ACh-induced, endothelium-dependent relaxation at least partly by inhibiting the action of cGMP on these cells.

Topics: Acetylcholine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Cell Membrane Permeability; Cyclic GMP; Enalaprilat; Endothelium, Vascular; In Vitro Techniques; Kinetics; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Nitroarginine; Rabbits; Receptor, Angiotensin, Type 1; Tetrazoles; Thiazepines; Vasodilation

The existence of tubulointerstitial damage in most cases of progressive human glomerular disease suggests that this compartment of the kidney is likely to be targeted by renoprotective agents which slow the progression of disease. Angiotensin-converting enzyme (ACE) inhibitors have become the cornerstone of renal protection. Since we have proposed that perturbation of the interstitial capillary circulation with consequent chronic hypoxia could be critical to the progressive nature of many renal diseases, we developed a dynamic method of measuring renal cortical pO(2) and sought to determine whether agents which block the renal effects of angiotensin II (AII) could affect interstitial microvascular oxygenation in the normal rat kidney.. Instrumented, anaesthetised adult male Sprague-Dawley rats were studied. Cortical microvascular pO(2 )was measured on the surface of the exposed kidney using protoporphyrin phosphorescence. Blood pressure and renal artery blood flow (Doppler flowmetry) were measured concurrently over a 180-min experimental period. Animals received non-hypotensive doses of enalaprilat (100 microg/kg i.v.) or candesartan (40 microg/kg i.v.) either at the beginning of the experimental period or after an initial decline in cortical microvascular pO(2).. After a 30-min stabilisation period there was a slow decline in pO(2 )from 48.6 +/- 4.1 to 38.5 +/- 6.9 mm Hg in control animals over the 180-min experimental period. Administration of the ACE inhibitor, enalaprilat at the beginning of the experimental period, completely abrogated this decline and protected pO(2) levels throughout this period with no effect on blood pressure or renal blood flow. In separate experiments, administration of enalaprilat after microvascular pO(2) had fallen by 5 mm Hg, resulted in a rise in RBF and pO(2 )within 15 min with pO(2) remaining elevated for up to 60 min post-injection. The angiotensin II AT(1) receptor antagonist, candesartan, had a similar effect to enalaprilat, inducing a rapid and sustained elevation in cortical pO(2).. These studies indicate that blockade of AII raises pO(2 )in the interstitial microvascular compartment of the normal rat kidney. This effect may contribute to the renoprotective action of ACE inhibitors and AII receptor antagonists in slowing the progression of chronic renal diseases.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Enalaprilat; Hypertension; Hypoxia; Kidney Cortex; Male; Microcirculation; Oxygen; Oxygen Consumption; Partial Pressure; Pilot Projects; Porphyrins; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Tetrazoles

Hemodynamic responses to angiotensin II and the role of AT(1) and AT(2) receptors and the autonomic nervous system in mediating acute responses to angiotensin II were investigated in anesthetized CD1 mice. Injections of angiotensin II caused dose-related increases in systemic arterial pressure that were antagonized by candesartan. Pressor responses to angiotensin II were not altered by PD-123,319 in doses up to 25 mg/kg iv. At the lowest dose studied (20 microgram/kg iv), the inhibitory effects of candesartan were competitive, whereas at the highest dose (100 microgram/kg iv) the dose-response curve for angiotensin II was shifted to the right in a nonparallel manner with inhibitory effects that could not be surmounted. The inhibitory effects of candesartan were selective and were similar in animals pretreated with enalaprilat (1 mg/kg iv) to reduce endogenous angiotensin II production. Acute pressor responses to angiotensin II were not altered by propranolol (200 microgram/kg iv), phentolamine (200 microgram/kg iv), or atropine (1 mg/kg iv) but were enhanced by hexamethonium (5 mg/kg iv). Increases in total peripheral resistance induced by angiotensin II were inhibited by the AT(1)-receptor antagonist but were not altered by AT(2)-, alpha-, or beta-receptor antagonists. These results suggest that acute pressor responses to angiotensin II are mediated by AT(1) receptors, are buffered by the baroreceptors, and are not modulated by effects on AT(2) receptors and that activation of the sympathetic nervous system plays little if any role in mediating rapid hemodynamic responses to the peptide in anesthetized CD1 mice.

Topics: Adrenergic beta-Antagonists; Anesthesia; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Atropine; Autonomic Nervous System; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Enalaprilat; Heart Rate; Hexamethonium; Imidazoles; Mice; Mice, Inbred Strains; Parasympatholytics; Phentolamine; Propranolol; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tetrazoles; Vascular Resistance; Vasoconstrictor Agents