lisinopril and Hypertrophy

The somatic isozyme of ACE (angiotensin I-converting enzyme) comprises two distinct zinc-dependent catalytic domains with different substrate specificities for angiotensin I (cleaved selectively by the C-domain) and bradykinin (cleaved equally efficiently by both the N- and C-domains). Classical ACEIs (ACE inhibitors) target both domains, with side effects such as cough and angio-oedema being attributed, in part, to N-domain inhibition, probably through bradykinin accumulation. We questioned whether a novel C-domain-selective ACEI (lisW-S) has anti-hypertensive effects without influencing bradykinin status. AngII (angiotensin II)-dependent hypertension was studied in mice that express active human renin in the liver (TtRhRen). Compared with wild-type littermates, TtRhRen mice displayed cardiac hypertrophy and had significantly elevated SBP [systolic BP (blood pressure)] as determined by tail cuff sphygmomanometry (150±3 compared with 112±5 mmHg; P<0.05) and telemetry (163±3 compared with 112±2 mmHg; P<0.01). Treatment with the non-selective ACEI lisinopril (1 mg/kg of body weight per day via an osmotic mini-pump for 2 weeks) reduced SBP (127±3 compared with. 154±6; P<0.05). Similarly, treatment with the C-domain selective ACEI lisW-S (lisinopril-tryptophan; 3.6 mg/kg of body weight per day via an osmotic mini-pump for 2 weeks) reduced BP. Treatment with lisinopril or lisW-S significantly reduced levels of AngII in kidneys (~4-fold; P<0.001). Ang-(2-8) [angiotensin-2-8)] was significantly reduced by lisinopril, but not by lisW-S. Plasma bradykinin levels were significantly increased only in the lisinopril group. These data suggest that C-domain-selective ACEIs reduce BP and AngII levels similarly to classical ACEIs. C-domain-selective ACEIs have the potential to avoid undesirable effects on the bradykinin system common to classic ACEIs and may represent a novel approach to the treatment of hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Cardiomegaly; Chronic Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Hypertension; Hypertrophy; Kidney; Lisinopril; Mice; Mice, Transgenic

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

Ocular vasculopathy resulting from severe systemic hypertension affects retina, choroidea, and the optic nerve. While the pathologic changes of the arterial system, including luminal narrowing, are well documented, little is known about the ocular venous vessels in hypertension. Adult 18-week-old spontaneously hypertensive rats (SHRs) were untreated (control) or treated with lisinopril for 4 weeks; normotensive Wistar-Kyoto (WKY) rats were additional controls. The mean systemic blood pressure (MSP) was monitored chronically using telemetry. The ocular microvasculature was examined using scanning electron microscopy (SEM) of corrosion casts, histology of serial sections, and computer-based 3D reconstruction. The MSP in control SHRs (145 +/- 11.9 mmHg) was decreased to 68.1 +/- 4.9 mmHg (P < 0.001) following treatment, which was even below the baseline level of WKY (96.7 +/- 5.8) rats (P < 0.05). In addition to media thickening in arteries, the venous plexus of the choroidea in control SHRs revealed multiple tufts of smooth muscle cells (sphincters) that narrowed the lumen. Correlating to histology, SEM of casts and 3D reconstruction showed numerous constrictions and muscular tufts in veins of the choroidea, narrowing the vascular lumen up to 47%. Following antihypertensive treatment, the percentage of sphincter constriction was decreased to 6% (P < 0.001). The depth of venous sphincter contraction correlated significantly with MSP (r = 0.87). To our knowledge, these results indicate for the first time that venous sphincters occur in the choroidea of the SHRs, and that their muscularity correlates with MSP. Venous sphincters might be involved in the pathophysiology of hypertension-related ocular changes.

Topics: Animals; Aorta; Blood Pressure; Cardiotonic Agents; Choroid; Female; Hypertension; Hypertrophy; Lisinopril; Male; Microscopy, Electron, Scanning; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Retina; Veins