trandolapril and Hypertrophy

In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade.. From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age.. High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta.. As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Cardiovascular Diseases; Drinking; Echocardiography; Fibrosis; Heart Rate; Hypertension; Hypertrophy; Indoles; Injections, Subcutaneous; Kidney; Kidney Diseases; Lisinopril; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Sodium, Dietary; Telemetry

We compared the chronic effects in spontaneously hypertensive rats (SHR) of low doses of an angiotensin converting enzyme inhibitor, trandolapril, a Ca2+ channel antagonist, verapamil, and their combination (trandolapril-verapamil), on arterial mechanical properties, arterial wall hypertrophy and extracellular matrix proteins. Four-week-old SHR were randomly allocated to oral treatment with verapamil (50 mg kg(-1) day(-1)), trandolapril (0.3 mg kg(-1) day(-1)), the combination of verapamil (50 mg kg(-1) day(-1)) plus trandolapril (0.3 mg kg(-1) day(-1)), or placebo for 4 months. A group of Wistar Kyoto (WKY) control rats received placebo for the same period of time. At the end of the treatment, mean blood pressure was lower in verapamil-trandolapril than in trandolapril SHR, but remained higher than in WKY. Verapamil had no effects on blood pressure. Equivalent reduction in aortic wall hypertrophy was obtained in all treated SHR. Trandolapril and verapamil-trandolapril combination produced a significant reduction of aortic collagen density compared with placebo SHR. Carotid total fibronectin, EIIIA fibronectin isoform and alpha5beta1 integrin, were higher in the media of placebo SHR than in WKY. EIIIA fibronectin isoform and alpha5beta1 integrin were reduced in verapamil-SHR compared with placebo-SHR and normalized in trandolapril and verapamil-trandolapril-SHR compared with WKY. SHR-placebo and SHR treated with either verapamil or trandolapril as single-drug treatment showed a 4-fold increase in total fibronectin compared to the WKY. Only SHR treated with verapamil-trandolapril combination had total fibronectin not significantly different from that of WKY. Carotid arterial distensibility increased only in verapamil-trandolapril treated rats. Multivariate analysis showed arterial distensibility to be negatively correlated to mean blood pressure (P < 0.0001) and total fibronectin (P < 0.01). In conclusion, chronic treatment with the verapamil-trandolapril combination significantly improved in vivo arterial distensibility in SHR. The most important effects of the combination on arterial mechanics compared to those of verapamil or trandolapril alone may have been the consequence of its stronger action on arterial pressure, arterial wall hypertrophy and total fibronectin density. However we suggest that, in addition to the structural effects, complete normalization of blood pressure is necessary to obtain normal arterial distensibility.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antigens, CD; Aorta, Thoracic; Arteries; Blood Pressure; Body Weight; Calcium Channel Blockers; Carotid Arteries; Fibronectins; Heart Rate; Hypertension; Hypertrophy; Indoles; Integrin alpha5; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Time Factors; Vascular Diseases; Verapamil

Studies in experimental models of chronic renal failure suggest an important role for the endothelin system in the development of renal scarring. Endothelin receptor (ETR) anatagonists interfere with progression, but it has not been resolved (i) whether this is true for all models of renal damage, (ii) to what extent the effect is modulated by systemic blood pressure and (iii) whether the effect is similar for ETAR and ETA/ETBR antagonists.. 5/6 subtotal nephrectomy (SNX) by surgical ablation in male Sprague-Dawley rats. Comparison of ACE inhibitor Trandolapril (0.1 mg/kg/day), ETAR antagonist BMS 182874 (30 mg/kg/day) and ETAR/ETBR antagonist Ro 46-2005 (30 mg/kg/day) by gavage. Duration of the experiment eight weeks.. Systolic blood pressure by tail plethysmography. Perfusion fixation of kidneys and morphometric analysis ET-1 and ETA/ETBR by quantitative PCR.. SNX caused a significant (P < 0.01) increase of systolic blood pressure (170 +/- 8.6 mmHg) compared to sham operated controls (131 +/- 5.3 mmHg). Blood pressure was significantly (P < 0.001) lower with Trandolapril (128 +/- 5.3 mmHg), but not with BMS 182874 (153 +/- 5.9 mmHg) or Ro 46-2005 (167 +/- 7.6 mmHg). Compared to sham operated rats (0.03 +/- 0.01) glomerulosclerosis index (GSI) was significantly (P < 0.01) higher in the untreated SNX group (0.9 +/- 0.15). Significantly lower GSI was found in Trandolapril treated (0.29 +/- 0.04), BMS 182874 treated (0.36 +/- 0.05), and Ro 46-2005 treated animals (0.45 +/- 0.11). The effect of BMS 182874 was accompanied by lower tubulointerstitial damage index. Mean glomerular volume was dramatically increased (P < 0.001) in SNX rats as compared to sham operated animals. This glomerular enlargement was partially prevented by Trandolapril (P < 0.05), but not by either ETR antagonist. ET-1 mRNA tended to be higher in SNX irrespective of treatment, while ETAR and ETBR mRNA were significantly lower.. Both specific (ETAR) and non-specific (ETA/ETBR) endothelin antagonists interfere with development of glomerulosclerosis by mechanisms which are, at least in part, independent of systemic blood pressure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Base Sequence; Blood Pressure; Dansyl Compounds; DNA Primers; Endothelin Receptor Antagonists; Endothelins; Glomerulosclerosis, Focal Segmental; Hypertrophy; Indoles; Kidney Glomerulus; Male; Molecular Sequence Data; Nephrectomy; Polymerase Chain Reaction; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; RNA, Messenger; Sulfonamides

The effects of the angiotensin-converting enzyme inhibitor trandolapril were studied using a Goldblatt (two-kidney, one-clip) rat model of renovascular hypertension after 4 weeks of oral treatment at 0.3 or 1 mg/kg/day. The effects of trandolapril on blood pressure and on cardiac and vascular hypertrophy were analyzed in comparison with the control group. Trandolapril produced a rapid, dose-dependent decrease in blood pressure, which plateaued after 2 weeks of treatment. Complete normalization of blood pressure was observed at a daily dose of 1 mg/kg. Dose-dependent inhibition of cardiac hypertrophy was also observed, heart:body weight ratio being decreased by 17 and 30% at 0.3 and 1 mg/kg, respectively, leading to a normalization of this parameter at the higher dose compared with normotensive controls. Similarly, trandolapril produced a marked decrease in vascular wall hypertrophy in both the mesenteric artery and the aorta. Indeed, complete normalization of media thickness was observed, compared with the normotensive control group, at 1 mg/kg of trandolapril. These results show that short-term treatment with trandolapril can induce complete regression of cardiac and vascular hypertrophy, which is associated with the development of renal hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Vessels; Cardiomegaly; Hypertension, Renovascular; Hypertrophy; Indoles; Male; Rats; Rats, Wistar

The aim of this study was to determine the morphologic and functional vascular changes occurring following 4 weeks of treatment with the angiotensin-converting enzyme inhibitor trandolapril in the spontaneously hypertensive rat (SHR) in the established phase of hypertension. At the dosage used, 0.4 mg/kg orally, trandolapril decreased blood pressure of the SHR by 15-18% compared with that of the control animals. Immediately before the end of treatment, the following changes from control values were observed: (1) 9, 11, and 12% reductions for myocardial hypertrophy and the media thickness of the thoracic aorta and femoral arteries, respectively; and (2) an increase in the compliance of the resistance arteries, demonstrated by a shift to the right of the in vitro tension-diameter curves and a significant 22% increase in their normalized internal diameter, while their maximum contractile ability was significantly decreased. Following discontinuation of treatment, blood pressure levels remained significantly lower in the treated versus the control groups for up to 4 weeks after the last administration. At that time measurement of the studied parameters showed: (1) a rapid reversion to control values of the compliance of the resistance vessels; and (2) a slower progression, but in the same direction, in the parameters of cardiac and vascular hypertrophy. Thus, trandolapril, administered for a short period in the adult SHR, was able to reverse the cardiac and vascular morphologic changes present in this model of hypertension. Like the effect on blood pressure, these effects were slowly reversible at the end of treatment, whereas the functional consequences at the resistance artery level seemed to display a more rapid reversibility.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arteries; Cardiomegaly; Hemodynamics; Hypertension; Hypertrophy; Indoles; Male; Rats; Rats, Inbred SHR