Cilazapril increases plasma ghrelin concentration in obese patients with arterial hypertension.

INTRODUCTION: Ghrelin is a polypeptide hormone secreted mainly by the stomach cells, stimulating food intake and growth hormone release. Decreased plasma ghrelin concentration was found in obese subjects. Clinical and experimental data suggest that ghrelin also exerts a blood pressure lowering property. The influence of antihypertensive medication on plasma ghrelin concentration has not been studied, yet. MATERIAL AND METHODS: Plasma ghrelin concentration was estimated in 52 hypertensive obese (HA + O), 14 normotensive obese (O), and 15 lean healthy subjects in the fasting state, and after ingestion of a standard meal. HA + O patients were randomly allocated into 4 groups treated alternatively with: cilazapril, bisoprolol, amlodipine, or indapamide. After 6 weeks of antihypertensive monotherapy, the assessments were repeated. RESULTS: Similar fasting [HA + O - 780 (676-960) pg/ml; O - 751 (619-899) pg/ml] and postprandial plasma ghrelin concentrations were found in hypertensive and normotensive obese subjects. Plasma ghrelin concentrations in lean healthy subjects were significantly higher (987 (765-1366) pg/ml) in comparison to O and HA + O. Treatment with cilazapril was followed by a 28.0% increase of plasma ghrelin concentration (p = 0.04), while with bisoprolol, a 18.9% decrease (p = 0.01). No significant changes of ghrelinaemia were observed in HA + O treated with amlodipine or indapamide. No significant correlation between blood pressure and plasma ghrelin concentration before the therapy and their changes after 6 weeks of medication were found. CONCLUSIONS: 1. Our data do not support the major role of ghrelin in blood pressure regulation in obesity. 2. An increase of plasma ghrelin concentration after treatment with cilazapril was observed. (Pol J Endocrinol 2010; 61 (1): 21-27).

Impact of cilazapril on fibrinolytic system in hypertensive patients.

Impaired fibrinolysis is associated with thromboembolic complications in hypertensive patients. Cardiovascular morbidity/mortality rates have been reported high even after lowering the elevated blood pressure with antihypertensive drugs. We investigated the effects of clinically used dosages of cilazapril on the fibrinolytic system in hypertensive patients. The present study was performed among 30 hypertensive patients (22 women, eight men), who received 2.5-5.0 mg cilazapril daily for 1 month. Before and after the cilazapril treatment, patients' venous blood was drawn for fibrinolytic tests. The fibrinolytic activity was examined utilizing the euglobulin clot lysis time and fibrin plate methods. Using the fibrin plate method, as compared with the pretreatment group, we observed a 57% increased activity in the hypertensive patients receiving cilazapril (P < 0.001). When assessed by the euglobulin clot lysis time method, the activity due to cilazapril treatment was found to be relatively low, although highly significant (approximately 20%, P < 0.001). Changes in fibrinolytic activity were observed in 23 (77%) hypertensive patients after cilazapril treatment; however, their blood pressure remained normal. The remaining seven patients' (23%) blood pressures and fibrinolytic activity did not change significantly after cilazapril treatment. In conclusion, we suggest that the observed differential fibrinolytic activity between the pre and post cilazapril treatment values is due to the plasminogen activators released from the vascular endothelium, which may have been stimulated by cilazapril. It appears that cilazapril is not only an angiotensin-converting enzyme inhibitor but also a stimulator for fibrinolytic activity, which may be an added component in reducing thromboembolic complications in hypertensive patients.

Short-term effects of cilazapril and atenolol on P-wave dispersion in patients with hypertension.

INTRODUCTION: P-wave dispersion (PWD) has been shown to be a non-invasive electrocardiographic predictor for development of atrial fibrillation (AF). Thus, it may be possible to decrease AF risk through improvement in PWD. Our objective was to compare the effects of cilazapril and atenolol on P-wave duration and dispersion in patients with hypertension. METHODS: A total of 38 newly diagnosed hypertensive patients were enrolled in the study. The patients were randomly assigned to receive treatment with either cilazapril (5 mg) or atenolol (50 mg). Doppler echocardiographic examination, P-wave durations and PWD were measured before and 1 mo after treatment RESULTS: Both drugs reduced blood pressure significantly (P<0.001). Posttreatment heart rate was significantly lower in the atenolol group (P=0.01). The change in maximum P-wave duration was not significant. However, both agents decreased PWD (P=0.001 and P<0.001) and increased the minimum P-wave duration (P=0.004 and P=0.02). CONCLUSION: Both cilazapril and atenolol treatments resulted in improvement in PWD.

Effect of unilateral ureteral obstruction and anti-angiotensin II treatment on renal tubule and interstitial cell apoptosis in rats.

AIM: To investigate the effects of angiotensin-converting enzyme inhibitor (cilazapril) and angiotensin II type I receptor antagonist (losartan) on tubular and interstitial cell apoptosis and caspase-3 activity in rats with obstructive nephropathy after unilateral ureteral obstruction. METHODS: Rats with unilateral obstructive nephropathy and sham-operated rats were treated with cilazapril, losartan, or the vehicle (water). Tubular and interstitial cell apoptosis was detected morphologically on hematoxylin and eosin-stained renal specimens and by the terminal deoxynucleotidyl transferase-mediated nick end-labeling. Caspase-3 activity in whole-kidney tissue homogenates was measured colorimetrically. RESULTS: After unilateral ureter ligation, there was a significant increase in the number of apoptotic tubular and interstitial cells in the obstructed kidney (P=0.049 and P=0.036, respectively, vs sham-operated rats, 10 days after ligation). In rats with unilateral obstructive nephropathy, neither cilazapril nor losartan had an effect on tubular cell apoptosis. However, cilazapril caused a significant increase in the number of renal apoptotic interstitial cells (P=0.019). Caspase-3 activity was not significantly different in rats with unilateral obstructive nephropathy than in sham-operated rats. CONCLUSION: Rats with unilateral obstructive nephropathy had increased apoptosis of tubular and interstitial cells in comparison with sham-operated rats. Neither cilazapril nor losartan had an effect on tubular cell apoptosis, and cilazapril even increased interstitial cell apoptosis.

Angiotensin II type 1 receptor antagonist and angiotensin-converting enzyme inhibitor altered the activation of Cu/Zn-containing superoxide dismutase in the heart of stroke-prone spontaneously hypertensive rats.

Although angiotensin II type 1 (AT1) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors are known to reduce both reactive oxygen species (ROS) generated by activated NAD(P)H oxidase and vascular remodeling in hypertension, the effects of AT1 receptor antagonists or ACE inhibitors on ROS-scavenging enzymes remain unclear. We hypothesized that AT1 receptor antagonists or ACE inhibitors may modulate vascular remodeling via superoxide dismutase (SOD) in hypertension. Male stroke-prone spontaneously hypertensive rats (SHRSP) were treated for 6 weeks with a vehicle, an AT1 receptor antagonist (E4177; 30 mg/kg/day), or an ACE inhibitor (cilazapril; 10 mg/kg/day). We evaluated protein expression using immunoblots, determined SOD activities with a spectrophotometric assay, and measured NAD(P)H oxidase activity by a luminescence assay. The two drugs showed equipotent effects on blood pressure, left ventricular hypertrophy and fibrosis, and endothelial NO synthase in the SHRSP hearts. The wall-to-lumen ratio of the intramyocardial arteries and the NAD(P)H oxidase essential subunit p22(phox) and its activity were significantly reduced, whereas Cu/Zu-containing SOD (Cu/ZnSOD) expression and activity were significantly increased in the SHRSP hearts. Furthermore, E4177 reduced vascular remodeling more than did cilazapril not only by reducing p22(phox) expression and NAD(P)H oxidase activity but also by upregulating the Cu/ ZnSOD expression and its activity in the SHRSP hearts. Thus, both the AT1 receptor antagonist and the ACE inhibitor inhibited vascular remodeling and reduced ROS in SHRSP via not only a reduction in NAD(P)H oxidase but also an upregulation of Cu/ZnSOD.

[Effect of Cilazapril on endothelial cell function and fibrinolysis system in the canine atrial fibrillation models].

OBJECTIVE: To investigate the effect of cilazapril on endothelial cell function and fibrinolysis system in the canine atrial fibrillation (AF) models. METHODS: All canines were divided into three groups: (1) Control group, without atrial pacing; (2) Atrial pacing group, in which atrial fibrillation was established by rapid atrial pacing at 400 bpm for 6 weeks; (3) Atrial pacing together with cilazapril group, in which cilazapril was given before and after atrial pacing. Nitric oxide (NO) of atrial endocardium was measured with NO-specific microelectrode. The expression of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) protein in atrium was determined by Western Blot analysis and immunohistochemical staining. Plasma levels of von Willebrand Factor (vWF), PAI-1 and tPA were analyzed by enzyme-linked immunoadsorbent assay. RESULTS: NO production from atrial endocardium was significantly increased in atrial pacing together with cilazapril group than atrial pacing group [(42.6 +/- 9.9) nmol/L vs (23.4 +/- 5.8) nmol/L, P < 0.05], whereas the plasma levels of vWF were decreased [(75.4 +/- 12.8)% vs (125.9 +/- 20.6)%, P < 0.05]. Compared to controls, the expression of atrium tPA protein in atrial pacing together with cilazapril group was significantly upregulated (4052 +/- 857 vs 1936 +/- 421, P < 0.05) and PAI-1 protein was downregulated (2487 +/- 542 vs 3164 +/- 827, P < 0.05). Cilazapril also significantly increased tPA antigen and decreased PAI-1 antigen in plasma. CONCLUSION: Cilazapril can favorably improve endothelial function and resume the balance of fibrinolysis system in AF, which might be of beneficial to hypercoagulated state in AF.

Effects of a beta-blocker or a converting enzyme inhibitor on resistance arteries in essential hypertension.

Seventeen male untreated mild essential hypertensive patients aged 41 +/- 2 years agreed to participate in a double-blind randomized trial to test the effects of antihypertensive treatment on the structure and function of subcutaneous resistance arteries. Patients were treated with either 50 to 100 mg/d atenolol or 2.5 to 5 mg/d cilazapril. Blood pressure before treatment was 148 +/- 6/99 +/- 1 and 147 +/- 2/99 +/- 1 mm Hg, respectively. At 1 year of treatment blood pressure was 131 +/- 4/85 +/- 2 and 132 +/- 2/87 +/- 1 mm Hg, respectively. Resistance arteries (200 to 400 microns lumen diameter) dissected from subcutaneous gluteal biopsies obtained before treatment and at 1 year showed that the media-lumen ratio of arteries from patients treated with cilazapril was reduced to 6.31 +/- 0.21% from 7.54 +/- 0.31% before treatment (P < .05), still slightly but significantly larger (P < .05) than the media-lumen ratio of resistance arteries of normotensive control subjects (5.15 +/- 0.30%). In contrast, in arteries from patients treated with atenolol there was no significant change with treatment (7.97 +/- 0.60% before and 8.07 +/- 0.45% after 1 year of treatment). Active wall tension responses to endothelin-1 were blunted in hypertensive patients and normalized in the cilazapril-treated patients. Depressed active media stress responses to norepinephrine, arginine vasopressin, and endothelin-1 were accordingly normalized in the patients receiving cilazapril as the media width became thinner but were unchanged in those taking atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of cilazapril on cerebral vasodilatation in hypertensive rats.

Endothelium-dependent dilatation of cerebral arterioles is impaired during chronic hypertension. The goal of this study was to determine the effects of an angiotensin converting enzyme inhibitor, cilazapril, on endothelium-dependent dilatation in pial arterioles. Four-month-old Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP) received cilazapril in their drinking water (500 mg/L) for 3 to 6 months. Treatment with cilazapril reduced mean arterial pressure in both WKY rats and SHRSP and had no significant effect on baseline diameter of pial arterioles measured with a cranial window. Responses to bradykinin and A23187, but not to nitroglycerin and adenosine, were impaired in SHRSP. Cilazapril did not affect responses to bradykinin (3 x 10(-7) M) and A23187 (10(-5) M) in WKY rats but significantly increased cerebral vasodilatation in response to bradykinin (52 +/- 4% vs 27 +/- 5%) and A23187 (19 +/- 3% vs 8 +/- 3%) in SHRSP. Cilazapril also tended to increase dilator responses to nitroglycerin and adenosine in SHRSP. In another group of SHRSP, treatment with cilazapril for 4 days produced a moderate reduction in blood pressure and increased cerebral vasodilatation in response to bradykinin, A23187, and adenosine. Topical application of the active form of cilazapril (cilazaprilat) for 40 minutes also increased cerebral vasodilatation in response to bradykinin, A23187, and nitroglycerin in SHRSP. The data indicate that an angiotensin converting enzyme inhibitor enhances cerebral vasodilatation in response to endothelium-dependent agonists in SHRSP and may also increase responses to endothelium-independent agonists.

Renal response to angiotensin after short-term angiotensin converting enzyme inhibition.

In 13 normotensive subjects on a normal sodium diet, we studied hormonal, blood pressure, and renal vascular changes and dextran sieving profiles induced by infusion of exogenous angiotensin II (Ang II) (5 ng.kg-1.min-1). during baseline conditions and after 5 days of administration of the angiotensin converting enzyme inhibitor cilazapril. Cilazapril induced a renal vasodilative effect without affecting supine blood pressure and glomerular filtration rate. Fractional dextran clearances were significantly decreased for dextran of effective radius ranging from 3.0 to 4.0 nm. This shift was primarily related to an increase in glomerular capillary plasma flow, because no change was observed in the transcapillary glomerular pressure gradient, the ultrafiltration coefficient, or the membrane parameters. Ang II elicited a slight pressor response accompanied by hormonal, antinatriuretic, and renal hemodynamic changes that were similar during and before short-term angiotensin converting enzyme inhibition. Dextran sieving curves were unchanged by a low dose of Ang II. However, the transcapillary glomerular pressure gradient and the ultrafiltration coefficient were computed to increase by 19.4% and to decrease by 44.2%, respectively, whereas membrane parameters were unaffected. When superimposed onto short-term angiotensin converting enzyme inhibition, glomerular response to this unique dose of Ang II was similar to that induced by Ang II alone. These findings indirectly suggest that most, if not all, of the renal effects of cilazapril are mediated through suppression of Ang II formation.

Altered cerebrovascular response to a potassium channel opener in hypertensive rats.

We examined whether the effect of Y-26763, an ATP-sensitive potassium channel opener, on cerebral blood flow is altered in stroke-prone spontaneously hypertensive rats (SHRSP) and, if altered, whether long-term antihypertensive treatment with cilazapril, an angiotensin-converting enzyme inhibitor, is capable of preventing the change. Cerebral blood flow during intracarotid infusion of Y-26763 was measured in anesthetized SHRSP and normotensive Wistar-Kyoto rats (WKY) as control. Y-26763 increased cerebral blood flow in a dose-dependent manner in WKY, and glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, inhibited the Y-26763-induced increase in cerebral blood flow. In contrast, the response to Y-26763 in SHRSP was significantly impaired compared with that in WKY. Antihypertensive treatment with cilazapril lowered blood pressure toward normal and prevented the impaired response in cerebral blood flow to Y-26763 in SHRSP. These findings suggest that (1) ATP-sensitive potassium channels contribute to the regulation of cerebral blood flow in rats, (2) the response to an ATP-sensitive potassium channel opener is markedly diminished in hypertensive rats, and (3) the altered response to an ATP-sensitive potassium channel opener during chronic hypertension can be prevented by long-term antihypertensive treatment.

Role of Ca2+-activated K+ channels in the protective effect of ACE inhibition against ischemic myocardial injury.

Angiotensin-converting enzyme (ACE) inhibitors increase the production of nitric oxide (NO) and prostacyclin and open Ca2+-activated K+ channels. The effects of these actions of ACE inhibitors on infarct size were investigated in open-chest dogs subjected to myocardial ischemia and reperfusion. Infarct size was assessed 6 hours after the onset of reperfusion, subsequent to 90 minutes of occlusion of the left anterior descending coronary artery. The ACE inhibitor cilazaprilat was administered into the coronary artery 10 minutes before coronary occlusion, and infusion was continued until 1 hour after reperfusion. The bradykinin and NO concentrations in coronary venous blood 10 minutes after the onset of reperfusion were significantly higher in dogs treated with cilazaprilat (3 microg x kg(-1) x min(-1)) than in control animals. Although there were no significant differences in collateral flow during ischemia, infarct size in the cilazaprilat group was smaller than that in the control group (15.1+/-3.0% versus 46.7+/-4.2% of the area at risk, P<0.0001). The infarct size-limiting effect of cilazaprilat was partially reduced by either N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase) or iberiotoxin (a blocker of Ca2+-activated K+ channels) and was abolished by N(G)-nitro-L-arginine methyl ester plus iberiotoxin. Indomethacin (an inhibitor of cyclooxygenase) had no effect on the beneficial action of cilazaprilat. Inhibition of ACE thus reduced myocardial infarct size, an effect that was mediated by NO and the opening of Ca2+-activated K+ channels in canine hearts.

Transforming growth factor-beta 1 expression and phenotypic modulation in the kidney of hypertensive rats.

We have previously reported that renal mRNA levels for transforming growth factor-beta 1, fibronectin, and collagens were increased in 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) with severe nephrosclerosis. To elucidate the mechanism of hypertension-induced nephrosclerosis, we examined gene expression and localization of transforming growth factor-beta 1 and cellular phenotype in the kidney of 25-week-old SHRSP with moderate renal damage. Renal mRNA was measured by Northern blot analysis. The localization of transforming growth factor-beta 1 and cellular phenotype was determined by immunohistochemistry. In the kidney of 25-week-old SHRSP, renal transforming growth factor-beta 1 mRNA was elevated compared with Wistar-Kyoto rats (WKY), whereas renal collagen mRNAs of SHRSP were not increased. Immunoreactive transforming growth factor-beta 1 in SHRSP was mainly localized in glomerular cells. Furthermore, alpha-smooth muscle actin and desmin were significantly expressed in SHRSP glomerular cells, in contrast to negligible expression of these proteins in WKY. alpha-Smooth muscle actin staining was also observed in interstitial cells, and vimentin, another phenotypic marker, was expressed in atrophic tubular cells of SHRSP, despite no staining of these proteins in WKY. Furthermore, all these phenotypic changes in SHRSP were associated with increased cell proliferation, as shown by the increased number of proliferating cell nuclear antigen-positive cells. Treatment of SHRSP with cilazapril and nifedipine (from the age of 13 to 25 weeks) prevented the increase in transforming growth factor-beta 1 expression and the cellular phenotypic modulation and was accompanied by a reduction of urinary albumin excretion and inhibition of cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of an angiotensin-converting enzyme inhibitor, a calcium antagonist, and an endothelin receptor antagonist on renal afferent arteriolar structure.

Narrowed afferent arteriolar diameter in young, spontaneously hypertensive rats (SHR) may be a contributor to later development of high blood pressure. Thus, treatment that causes dilation of the afferent arterioles in SHR may inhibit the redevelopment of high blood pressure when treatment is withdrawn. We treated SHR with an ACE inhibitor (cilazapril, 5 to 10 mg/kg per day, high; 1 mg/kg per day, low), a calcium antagonist (mibefradil, 20 to 30 mg/kg per day), and an endothelin receptor antagonist (bosentan, 100 mg/kg per day) from age 4 to 20 weeks. Untreated SHR and Wistar-Kyoto rats were also investigated. At 20 weeks, the rats were killed, and morphology of the afferent arterioles was studied. Other SHR (untreated, high cilazapril, low cilazapril, mibefradil) were treated in exactly the same way and then followed to 32 weeks without treatment. The morphometric studies showed that cilazapril increased the lumen diameter in the afferent arterioles and decreased the media-lumen ratio in a dose-dependent manner. On withdrawal of cilazapril treatment, the reduction in blood pressure persisted. Mibefradil tended to increase afferent arteriolar diameter, whereas it did not alter media-lumen ratio. The persistent effect on blood pressure was only moderate after withdrawal of mibefradil. Bosentan had no effect on renal afferent arteriolar structure or blood pressure. In conclusion, cilazapril was more effective than mibefradil in altering afferent arteriolar structure and caused the most persistent effect on blood pressure after treatment withdrawal. The association of increased afferent arteriolar diameter and lower blood pressure level after withdrawal of treatment may suggest a pathogenic role for afferent arteriolar diameter in the development of high blood pressure in SHR.

Comparative effects of three different potent renin inhibitors in primates.

The goal of the present study was to compare the effects of three potent reference renin inhibitors (remikiren, CGP 38560A, and enalkiren) in sodium-depleted normotensive squirrel monkeys. In these monkeys, arterial pressure was measured in the conscious state with a telemetry system. Oral and intravenous maximal effective doses of the three renin inhibitors were compared in parallel groups of monkeys. In additional experiments, remikiren was given on top of either CGP 38560A or enalkiren in the same animals. Finally, the three drugs were compared with the angiotensin converting enzyme inhibitor cilazapril. The effects of the three drugs on the plasma components of the renin-angiotensin system (plasma renin activity, immunoreactive renin, and immunoreactive angiotensin II concentrations) were also measured. Our results show that remikiren was as effective as cilazapril and markedly more effective than CGP 38560A or enalkiren in reducing arterial pressure in our monkey model. Interestingly, these differences in arterial pressure could not be explained by differences of in vitro potency or different biochemical changes of the plasma components of the renin-angiotensin system, because the inhibitors all reduced immunoreactive angiotensin II to similarly low levels. One possible explanation is that, in our model, remikiren in contrast to CGP 38560A and enalkiren is able to inhibit renin in a functionally important extraplasmatic compartment.

Effects of candesartan and cilazapril on rats with myocardial infarction assessed by echocardiography.

The purpose of this study was to compare the angiotensin II type 1 receptor antagonist candesartan cilexitil (candesartan) and the angiotensin-converting enzyme inhibitor cilazapril on cardiac function, assessed by Doppler echocardiography and cardiac gene expression associated with cardiac remodeling, in rats with myocardial infarction. Candesartan or cilazapril was administered after myocardial infarction. At 1 and 4 weeks after myocardial infarction, cardiac function and mRNA expression in noninfarcted myocardium were analyzed. Candesartan and cilazapril equally prevented increases in hypertrophy in noninfarcted myocardium, left ventricular dilatation, and ejection fraction at 4 weeks. The E-wave/A-wave velocity ratio and the rate of E-wave deceleration, measures of diastolic function, increased to 9.2+/-0.6 and 26.3+/-2. 6 m/s2 at 1 week after myocardial infarction. Candesartan and cilazapril, administered at a dose of 1 mg/kg per day, prevented increases in E-wave/A-wave velocity ratio and E-wave deceleration at 1 and 4 weeks. Candesartan and cilazapril significantly suppressed increased mRNA expression of beta-myosin heavy chain, alpha-skeletal actin, and atrial natriuretic peptide in noninfarcted ventricle at 1 and 4 weeks and expression of collagen I and III at 4 weeks to a similar extent. When given at a dose of 10 mg/kg per day, both candesartan and cilazapril prevented cardiac dysfunction and gene expression to the same extent as when given at 1 mg/kg per day. In conclusion, Doppler echocardiography showed that candesartan and cilazapril equally improved systolic and diastolic function and that ventricular remodeling accompanied modulation of cardiac gene expression.

Comparison of effect of endothelin antagonism and angiotensin-converting enzyme inhibition on blood pressure and vascular structure in spontaneously hypertensive rats treated with N omega-nitro-L-arginine methyl ester. Correlation with topography of vascular endothelin-1 gene expression.

Inhibition of nitric oxide synthase by L-arginine analogues such as N omega-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR) is associated with malignant hypertension and enhanced expression of the endothelin-1 gene in some blood vessels. In this study, SHR treated chronically with L-NAME (SHR-L-NAME) were given the angiotensin I-converting enzyme inhibitor cilazapril or the endothelin-A/endothelin-B receptor antagonist bosentan for 3 weeks. Systolic pressure was lowered slightly by cilazapril (213 +/- 2 versus 229 +/- 2 mm Hg in untreated SHR-L-NAME, P < .01) but was not significantly lowered by bosentan (223 +/- 2 mm Hg). Hypertrophy of aorta and small arteries (coronary, renal, mesenteric, and femoral) was decreased by cilazapril treatment and unaffected by bosentan. Expression of the endothelin-1 gene was evaluated in SHR-L-NAME by in situ hybridization histochemistry, which showed that endothelin-1 expression was enhanced in the endothelium of aorta but not in small mesenteric arteries in these rats. The absence of enhancement of endothelin-1 gene expression in small arteries may account for the absence of increased severity of hypertrophy of small vessels in SHR-L-NAME and may be a mechanism whereby L-NAME inhibits cardiovascular growth. These results suggest that in the absence of enhanced small-artery endothelin-1 expression, endothelin antagonism does not lower blood pressure. The blood pressure-lowering effect of angiotensin I-converting enzyme inhibition suggests a role for the renin-angiotensin system in the malignant form of hypertension that develops in SHR treated with L-NAME.

Prevention of renal damage by angiotensin II blockade, accompanied by increased renal hepatocyte growth factor in experimental hypertensive rats.

Hepatocyte growth factor (HGF) is a unique growth factor that has many protective functions against renal damage. Our previous study demonstrated that HGF stimulated the growth of endothelial and epithelial cells without the replication of mesangial cells. Moreover, angiotensin (Ang) II significantly decreased local HGF production in mesangial cells. Therefore, we examined the effects of Ang II blockade on renal HGF expression and renal damage in experimental hypertensive rats. An angiotensin-converting enzyme inhibitor (cilazapril; 10 mg. kg(-1). d(-1)), an Ang II type 1 receptor antagonist (E-4177; 30 mg. kg(-1). d(-1)), hydralazine (8 mg. kg(-1). d(-1)), and vehicle were administered to 16-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) for 3 weeks. Renal damage was evaluated with a computer analysis system, and renal HGF mRNA was measured by Northern blot analysis. Blood pressure of SHR-SP was significantly decreased by all drug treatments compared with vehicle. Moreover, cilazapril, E-4177, and hydralazine significantly decreased the thickening and necrosis of blood vessels compared with vehicle. Similarly, degeneration and necrosis of glomeruli were also markedly improved by cilazapril and E-4177 (P<0.01). We next examined the effects of Ang II blockade on renal HGF expression in SHR-SP. Renal HGF mRNA was markedly decreased in SHR-SP compared with Wistar-Kyoto rats, although Ang II blockade by cilazapril and E-4177 but not hydralazine significantly increased renal HGF mRNA in SHR-SP. Ang II blockade significantly increased renal HGF (a protective growth factor for tubular epithelial cells); thus, we examined tubular histological appearance. Degeneration and necrosis of tubules were significantly improved by cilazapril and E-4177 treatment (P<0.01). In addition, cell infiltration into the glomeruli and hemorrhage were also significantly reduced in SHR-SP treated with cilazapril or E-4177. The present data demonstrated the prevention of renal damage by Ang II blockade in SHR-SP, which was accompanied by a significant increase in renal HGF mRNA. Given the strong mitogenic activity and antiapoptotic actions of HGF on endothelial and epithelial cells, we believe that increased local HGF production by the blockade of Ang II may improve renal function in hypertension.

Experimental intimal thickening studies using the photochemically induced thrombosis model in the guinea-pig femoral artery.

We have used the photochemically induced thrombosis model to study intimal thickening in the guinea-pig femoral artery. The femoral artery was occluded by a combination of rose bengal and green light which caused endothelial cell damage followed by formation of platelet rich thrombus at the site of endothelial damage. Thrombolysis was then achieved by administration of tissue-type plasminogen activator. Intimal thickening in the femoral arteries was histologically measured at 0, 1, 3, 6 and 9 weeks after the treatment. The neointimal areas gradually increased until 3 weeks and then remained unchanged up to 9 weeks. Cells in the neointima were identified as smooth muscle cells by immunohistochemical staining with an actin-specific antibody, HHF35. Cell proliferation in the media begun within 48 h after the thrombolysis and bromodeoxyuridine labeled cells appeared to migrate to the intima within 1 week after the thrombolysis. Administration of an angiotensin converting enzyme inhibitor, cilazapril (30 mg/kg/day, p.o.) for 3 weeks, suppressed intimal thickening and decreased the medial area in the femoral artery. These observations suggest that in this model cell proliferation and migration characteristics of pathological intimal thickening occur and this model is useful for investigating the effect of pharmacological preparations on intimal thickening.

Effects of the blockade of the renin-angiotensin system in cyclosporin-induced hypertension.

OBJECTIVE: To compare the acute hypotensive effects of three different methods of inhibiting the renin-angiotensin system in a primate model of cyclosporin-induced hypertension. DESIGN: The effects of maximally effective doses of an angiotensin I converting enzyme inhibitor, antihuman renin antibodies or a renin inhibitor (Ro 42-5892) on arterial pressure were evaluated in cyclosporin-treated monkeys. METHODS: Squirrel monkeys were made hypertensive by a 4-week treatment with oral cyclosporin (30 mg/kg) and were equipped with a telemetry system in order to measure arterial blood pressure in the conscious state. RESULTS: Each inhibitor induced a complete suppression of plasma angiotensin II 1 h after administration. The renin antibodies did not decrease blood pressure. Cilazapril decreased blood pressure and Ro 42-5892 was more effective than cilazapril. Moreover, when the renin inhibitor was administered after injection of renin antibodies (rabbit antiserum, 0.4 ml intravenously) or after cilazapril (10 mg/kg orally), it induced a supplementary fall in blood pressure. CONCLUSIONS: These data demonstrate that in this experimental model of hypertension the three different methods of maximal inhibition of the renin-angiotensin system do not lead acutely to the same blood pressure decrease. The results also suggest that renin inhibition might be more effective than angiotensin converting enzyme inhibition in certain forms of hypertension.

Effects of angiotensin converting enzyme inhibitor on renal haemodynamics during mental stress.

OBJECTIVE: To examine the effects of angiotensin converting enzyme (ACE) inhibition on renal and systemic haemodynamics as well as on humoral regulators, under resting conditions and during mental stress in 20 normotensive and 20 mildly hypertensive subjects. METHODS: All of the subjects received either 25 mg cilazapril or placebo once a day, in a randomized, double-blind, cross-over trial for 1 week, followed by a 2-week washout period before the alternative regimen was given. We measured renal blood flow with para-aminohippuran, glomerular filtration rate with inulin, cardiac output by impedance cardiography and blood pressure and heart rate by an oscillometric method. We also monitored effects on plasma renin activity, aldosterone, catecholamines and atrial natriuretic peptide. Mental stress consisted of a long-lasting, time-reaction device, thereby provoking activation of the sympathetic nervous system. RESULTS: At rest ACE inhibition lowered mean arterial pressure (92 +/- 10 versus 98 +/- 9 mmHg), increased renal blood flow (803 +/- 109 versus 707 +/- 93 ml/min) and the renal fraction of cardiac output (25.9 +/- 2.5 versus 23.5 +/- 2.5%) and decreased the filtration fraction (17.9 +/- 2.5 versus 19.8 +/- 2.7%) in hypertensive but not in normotensive subjects. Sympathetic activation by mental stress leading to a transient increase in blood pressure did not alter significantly the effects of ACE inhibition on renal and systemic haemodynamics, in normotensive or in hypertensive subjects, although a tendency towards attenuation of the rise in glomerular filtration rate was noted in hypertensives (7.2 +/- 1.0 versus 5.1 +/- 0.8%). ACE inhibition led to increased plasma noradrenaline at rest but not during mental stress in hypertensive patients. CONCLUSION: ACE inhibition in patients with mild hypertension increased selectively renal perfusion, which is conserved during mental stress without persistent effects on the sympathetic nervous system. Thus, mental stress as a correlate of daily life stress appeared not to confound the selective renal vasodilatory effect of ACE inhibitors.