benazepril and candesartan

Evidence suggests that the effectiveness of angiotensin-converting enzyme (ACE) inhibition diminishes with time, resulting in increasing angiotensin II levels, the action of which can be inhibited by the addition of an angiotensin receptor blocker (ARB). In the present study, the renal protective effects of ACE inhibitors and ARBs were compared over a five-year period in a prospective, randomized, open-blind study in 68 nondiabetic Japanese patients with elevated serum creatinine levels.. Japanese patients with renal insufficiency were randomly assigned to receive either an ACE inhibitor (benazepril 1.25 to 5 mg daily or trandolapril 0.5 to 4 mg daily) or ARB (candesartan 2 to 8 mg daily or losartan 25 to 100 mg daily) at the Kidney Disease Center at Saitama Medical School Hospital. The primary study endpoint was a change in glomerular filtration rate (GFR) between the baseline value and the last available value obtained during the five-year treatment period, as estimated by the Cockcraft-Gault equation. Secondary endpoints included the annual changes in GFR, serum creatinine level, urinary protein excretion, and blood pressure, as well as the rate of development of endstage renal disease.. There were no significant differences in the primary endpoint between the two groups. However, after 4 years, the decline in GFR in patients treated with ARBs was significantly greater than that seen in patients treated with an ACE inhibitor (p<0.05). Furthermore, the rate of introduction of dialysis therapy was also significantly greater in the ARB-treated patients (52.7% in ACE inhibitor and 81.2% in ARB group at year 5. p<0.01).. While our data suggested that ARB, like ACE, treatment might slow the progression of renal dysfunction, it also pointed to the necessity to be alerted to the progression to endstage renal disease with longterm medication.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chronic Disease; Creatinine; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Indoles; Losartan; Male; Middle Aged; Prospective Studies; Renal Insufficiency; Tetrazoles

Benazepril, an angiotensin-converting enzyme inhibitor, and candesartan, an angiotensin receptor blocker, are common drugs for treating hypertension. This study aimed to investigate the enhanced attenuation of myocardial fibrosis in spontaneously hypertensive rats (SHRs) possibly induced by joint treatment with benazepril and candesartan and the possible involvement of transforming growth factor beta1 (TGF-beta1)-Smad signaling pathway. SHRs were treated with benazepril at 10 mg.kg.d, candesartan at 4 mg.kg.d, and a combination of 2 drugs at half dose, respectively, for 12 weeks. Echocardiography and histology indicated that joint treatment with 2 drugs more significantly inhibited myocardial fibrosis in SHRs than either monotherapy, as evidenced by the changes in cardiac structural parameters, ultrasonic integrated backscatters, collagen volume fraction, and perivascular collagen area. The collagen analyses further revealed that significant decreases in total collagen concentration, the ratio of collagen type I to type III, and collagen cross-linking were found after the enhanced attenuation of myocardial fibrosis. Western blot analysis showed that the protein expression of TGF-beta1 and Smad3 was significantly decreased after joint treatment with 2 drugs. We conclude that synergistic attenuation of myocardial fibrosis in SHRs is produced by combined use of benazepril and candesartan possibly through the modulation of TGF-beta/Smad signaling proteins.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Benzimidazoles; Biphenyl Compounds; Drug Synergism; Drug Therapy, Combination; Fibrosis; Myocardium; Rats; Rats, Inbred SHR; Tetrazoles

Many of the effects of angiotensin (Ang) II are mediated through specific plasma membrane receptors. However, Ang II also elicits biological effects from the interior of the cell (intracrine), some of which are not inhibited by Ang receptor blockers (ARBs). Recent in vitro studies have identified high glucose as a potent stimulus for the intracellular synthesis of Ang II, the production of which is mainly chymase dependent. In the present study, we determined whether hyperglycemia activates the cardiac intracellular renin-Ang system (RAS) in vivo and whether ARBs, ACE, or renin inhibitors block synthesis and effects of intracellular Ang II (iAng II).. Diabetes was induced in adult male rats by streptozotocin. Diabetic rats were treated with insulin, candesartan (ARB), benazepril (ACE inhibitor), or aliskiren (renin inhibitor).. One week of diabetes significantly increased iAng II levels in cardiac myocytes, which were not normalized by candesartan, suggesting that Ang II was synthesized intracellularly, not internalized through AT(1) receptor. Increased intracellular levels of Ang II, angiotensinogen, and renin were observed by confocal microscopy. iAng II synthesis was blocked by aliskiren but not by benazepril. Diabetes-induced superoxide production and cardiac fibrosis were partially inhibited by candesartan and benazepril, whereas aliskiren produced complete inhibition. Myocyte apoptosis was partially inhibited by all three agents.. Diabetes activates the cardiac intracellular RAS, which increases oxidative stress and cardiac fibrosis. Renin inhibition has a more pronounced effect than ARBs and ACE inhibitors on these diabetes complications and may be clinically more efficacious.

Topics: Amides; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Benzazepines; Benzimidazoles; Biphenyl Compounds; Diabetes Mellitus, Experimental; Endomyocardial Fibrosis; Fumarates; Insulin; Myocytes, Cardiac; Oxidative Stress; Rats; Renin; Tetrazoles

Although recent clinical studies have indicated that angiotensin II receptor blocker is as effective in treating heart failure as an angiotensin-converting enzyme inhibitor, it is unknown whether their effects are different. Dahl salt-sensitive rats were treated with an angiotensin-converting enzyme inhibitor benazepril, and an angiotensin II receptor blocker candesartan from 11 weeks old. We examined cardiac geometry and function by echocardiography, and histology and gene expression by high-density oligonucleotide arrays using Affymetrix U34 (Affymetrix, Santa Clara, CA, U.S.A.). Dahl salt-sensitive rats fed a high salt diet showed a marked increase in blood pressure and developed concentric hypertrophy at 11 weeks, followed by left ventricle dilation and congestive heart failure by 20 weeks after birth. Although both medications had only a mild antihypertensive effect, they strongly suppressed the development of cardiac hypertrophy, fibrosis and heart failure to the same extent. Gene expression pattern examined by Affymetrix GeneChip (Affymetrix) is quite different between the two drug groups, indicating that angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor prevent heart failure by different mechanisms.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Benzimidazoles; Biphenyl Compounds; Disease Models, Animal; Echocardiography; Fibrosis; Gene Expression; Gene Expression Profiling; Heart Failure; Hypertension; Hypertrophy, Left Ventricular; Infusions, Parenteral; Male; Oligonucleotide Array Sequence Analysis; Organ Size; Rats; Rats, Inbred Dahl; Receptors, Angiotensin; Sodium Chloride, Dietary; Subcutaneous Tissue; Tetrazoles; Time Factors; Ventricular Function, Left