benazeprilat and Disease-Models--Animal

Diabetes-induced organ damage is significantly associated with the activation of the renin-angiotensin system (RAS). Recently, several studies have demonstrated a change in the RAS from an extracellular to an intracellular system, in several cell types, in response to high ambient glucose levels. In cardiac myocytes, intracellular angiotensin (ANG) II synthesis and actions are ACE and AT1 independent, respectively. However, a role of this system in diabetes-induced organ damage is not clear.. To determine a role of the intracellular ANG II in diabetic cardiomyopathy, we induced diabetes using streptozotocin in AT1a receptor deficient (AT1a-KO) mice to exclude any effects of extracellular ANG II. Further, diabetic animals were treated with a renin inhibitor aliskiren, an ACE inhibitor benazeprilat, and an AT1 receptor blocker valsartan.. AT1a-KO mice developed significant diastolic and systolic dysfunction following 10 wks of diabetes, as determined by echocardiography. All three drugs prevented the development of cardiac dysfunction in these animals, without affecting blood pressure or glucose levels. A significant down regulation of components of the kallikrein-kinin system (KKS) was observed in diabetic animals, which was largely prevented by benazeprilat and valsartan, while aliskiren normalized kininogen expression.. These data indicated that the AT1a receptor, thus extracellular ANG II, are not required for the development of diabetic cardiomyopathy. The KKS might contribute to the beneficial effects of benazeprilat and valsartan in diabetic cardiomyopathy. A role of intracellular ANG II is suggested by the inhibitory effects of aliskiren, which needs confirmation in future studies.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Down-Regulation; Fumarates; Kallikreins; Kininogens; Kinins; Mice; Mice, Knockout; Myocytes, Cardiac; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Tetrazoles; Ultrasonography; Valine; Valsartan

To investigate the chronic effects of combined administration of an angiotensin II receptor antagonist (valsartan) and an angiotensin converting enzyme inhibitor (benazeprilat) on blood pressure and heart rate in conscious telemetered spontaneously hypertensive rats.. Blood pressure and heart rate were monitored (by radiotelemetry) during 2-week infusions of 0.5-10 mg/kg valsartan per day and 0.5-10 mg/kg benazeprilat per day, alone or in combination, into conscious spontaneously hypertensive rats. Also, responses of blood pressure in conscious spontaneously hypertensive rats to exogenous angiotensin I and II were determined.. Synergistic antihypertensive effects were observed when valsartan and benazeprilat were coadministered at submaximal monotherapy doses in the range 0.5-1.5 mg/kg per day. For all combination groups, the area over the curve (mmHg x days) for lowering of blood pressure was significantly greater (synergy) than that predicted from the sum of the monotherapy responses. Combination therapy abrogated pressor responses to angiotensin I more effectively than did comparable doses of the monotherapies.. These results demonstrate that combination therapy aimed at interrupting operation of the renin-angiotensin system simultaneously at multiple sites can prevent the partial escape which occurs during chronic angiotensin converting enzyme inhibitor monotherapy. Furthermore, multiple-site intervention results in a more efficacious antihypertensive response than that achieved with high doses of the individual monotherapies.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Heart Rate; Hypertension; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Telemetry; Tetrazoles; Treatment Outcome; Valine; Valsartan

Past studies have shown that angiotensin-converting enzyme inhibition (ACEI) alone, angiotensin AT1 receptor blockade (AT1 block) alone, and combined treatment have differential effects on left ventricular (LV) function and geometry with developing congestive heart failure (CHF). The purpose of this study was to more carefully examine the cellular basis for these differential effects by using a model of pacing CHF.. Pigs were randomly assigned to five groups: (1) rapid pacing (240 bpm) for 3 weeks (n = 9), (2) concomitant ACEI (benazeprilat, 0.187 mg/kg/day) and pacing (n = 9), (3) concomitant AT1 block (valsartan, 3 mg/kg/day) and pacing (n = 9), (4) concomitant ACEI and AT1 receptor blockade (benazeprilat/valsartan, 0.05/3 mg/kg/day, respectively) and pacing (n = 9), and (5) sham controls (n = 10). The dosage protocol was based on obtaining a 50% reduction in angiotensin I and angiotensin II pressor response with no significant effects on mean basal arterial pressure. In the pacing group, LV fractional shortening (LVFS) fell compared with control group (13.4+/-1.4 v 39.1+/-1.0%, P < .05). With AT1 block, LVFS was unchanged from pacing only. ACEI and combined treatment increased LVFS from pacing values (25.2+/-0.9 v 20.9+/-1.9%, respectively, P < .05). LV myocyte shortening velocity was reduced with chronic pacing compared with control group (27.2+/-0.6 v 58.6+/-1.2 microm/s, P < .05) and remained reduced with AT1 block (28.0+/-0.5 microm/s, P < .05). Myocyte shortening velocity increased with ACEI or combination treatment (36.9+/-0.7 v 42.3+/-0.8 microm/s, respectively, P < .05). Concomitant treatment with either ACEI or AT1 blockade normalized myocyte action potential duration. In the combined ACEI and AT1 blockade group, all parameters of the myocyte action potential were unchanged from control values.. This study showed that combined ACEI and AT1 receptor blockade produced beneficial effects on myocyte contractility and electrophysiology when compared with either monotherapy alone and therefore may provide unique benefits with CHF.

Topics: Action Potentials; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Cardiac Pacing, Artificial; Disease Models, Animal; Drug Therapy, Combination; Evaluation Studies as Topic; Heart Failure; Myocardium; Random Allocation; Swine; Ventricular Function, Left

The goal of this study was to determine the effects of ACE inhibition (ACEI) alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade on LV function, systemic hemodynamics, and neurohormonal system activity in a model of congestive heart failure (CHF).. Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) AT1 Ang II receptor blockade (valsartan, 3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (4) ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). In the pacing group, LV fractional shortening (LVFS) fell (13.4+/-1.4% versus 39.1+/-1.0%) and end-diastolic dimension (LVEDD) increased (5.61+/-0.11 versus 3.45+/-0.07 cm) compared with control (P<.05). With AT1 Ang II blockade and rapid pacing, LVEDD and LVFS were unchanged from pacing-only values. ACEI reduced LVEDD (4.95+/-0.11 cm) and increased LVFS (20.9+/-1.9%) from pacing-only values (P<.05). ACEI and AT1 Ang II blockade reduced LVEDD (4.68+/-0.07 cm) and increased LVFS (25.2+/-0.9%) from pacing only (P<.05). Plasma norepinephrine and endothelin increased by more than fivefold with chronic pacing and remained elevated with AT1 Ang II blockade. Plasma norepinephrine was reduced from pacing-only values by more than twofold in the ACEI group and the combination group. ACEI and AT1 Ang II receptor blockade reduced plasma endothelin levels by >50% from rapid-pacing values.. These findings suggest that the effects of ACEI in the setting of CHF are not solely due to modulation of Ang II levels but rather to alternative enzymatic pathways and that combined ACEI and AT1 Ang II receptor blockade may provide unique benefits for LV pump function and neurohormonal systems in the setting of CHF.

Topics: Aldosterone; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Blood Pressure; Cardiac Output; Cardiac Pacing, Artificial; Diastole; Disease Models, Animal; Endothelins; Epinephrine; Heart Failure; Heart Rate; Hemodynamics; Norepinephrine; Pulmonary Artery; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Swine; Tetrazoles; Valine; Valsartan; Ventricular Function, Left