Proliferation of aortic smooth muscle cells and renin-angiotensin system in SHR rats.
(25/1305)
AIM: To study the relationship between the enhanced proliferation and renin-angiotensin system (RAS) of aortic smooth muscle cells (ASMC) from SHR rats. METHODS: To measure the effects of angiotensin II (Ang), captopril (Cap), saralasin (Sar) on proliferation, Ang and angiotensin converting enzyme (ACE) levels in cultured ASMC from WKY and SHR rats. RESULTS: Ang was a bifunctional growth factor, which induced SHR ASMC hyperplasia in 2% FCS-RPMI 1640 medium, but not in serum free (SF)-medium. SHR ASMC had stronger proliferative ability compared with WKY while SHR ASMC RAS was activated. Enhanced proliferation of SHR ASMC and ACE activity were obviously inhibited by long-term treatment (4-wk) of both Cap and Sar, while Ang content decreased in Cap treatment group and increased in Sar treatment group. The antiproliferative effect of Cap and Sar on SHR ASMC was stronger than that on WKY. SHR, WKY ASMC RAS were not influenced by short-term (24 h) treatment of Cap. CONCLUSION: Long-term treatment of Cap and Sar suppressed SHR ASMC growth through inhibition of Ang generation or blockade of Ang binding to its receptor. (+info)
Bradykinin B2 receptor antagonist icatibant reduces inhibitory effect of captopril on growth of cultured neonatal rat cardiomyocytes.
(26/1305)
AIM: To study whether endogenous kinins are negative modulators in the growth of cardiomyocytes and their possible cellular and molecular mechanisms. METHODS: Cultured neonatal rat cardiomyocytes were used. Intracellular RNA and protein synthesis were measured by [3H]uridine incorporation and [3H]leucine incorporation, respectively. The expression level of proto-oncogene c-myc, c-fos mRNA was observed by Northern blotting. RESULTS: Exposure of cardiomyocytes to captopril (Cap, 100 mumol.L-1) for 48 h inhibited the rates of [3H]Urd and [3H]Leu incorporations by 25% and 26%, respectively, and for 2 h inhibited c-myc, c-fos mRNA expression by 75% and 55%, respectively. Treatment of angiotensin II (Ang II, 1 mumol.L-1) for 48 h significantly increased the rates of [3H]Urd and [3H]Leu incorporations and for 1 h induced c-myc, c-fos mRNA overexpression, which were reduced by pretreatment with Cap (100 mumol.L-1). Icatibant acetate (Hoe 140, a specific antagonist of bradykinin B2 receptor) 0.1-10 mumol.L-1 blocked the effects of Cap in a concentration-dependent manner. CONCLUSION: Endogenous kinins exhibited a negative modulatory effect on growth of cardiomyoctes via BK B2 receptor. (+info)
Inhibitory effects of S-nitrosocaptopril on vasomotor tone.
(27/1305)
AIM: To study effects of captopril (Cap) and S-nitrosocaptopril (CapNO) on vascular tension. METHODS: Tension of rabbit aortic rings and perfusion pressure of rat renal artery (PPr) were examined to evaluate the effects of CapNO. RESULTS: CapNO (3 nmol.L-1-10 mumol.L-1) produced concentration-dependent vasorelaxation response in the rings of rabbit thoracic aortas. Endothelium denudation did not alter the relaxations to CapNO. In contrast, Cap had no vasorelaxing effect on the rings precontracted with phenylephrine. CapNO (10 nmol.L-1) decreased rat PPr in vivo (P < 0.01), and the effect was concentration-dependent and reversible. Cap showed a reduction in rat PPr only at the concentration 1000 nmol.L-1 (P < 0.05). The relaxing potency of CapNO was 100 times higher than that of Cap in this respect. Pre-perfusion of rat renal arteries with NG-monomethyl-L-arginine monoacetate (L-NMMA, 0.03 nmol.L-1) or L-arginine (3 nmol.L-1) did not significantly blocked the relaxing effect induced by CapNO. CONCLUSION: CapNO had a direct vasodilatory effect. (+info)
How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure?
(28/1305)
OBJECTIVE: Angiotensin II (AII) and aldosterone are not always fully suppressed during chronic angiotensin converting enzyme (ACE) inhibitor treatment. In congestive heart failure (CHF) such failure of hormonal suppression is associated with increased mortality. This study examined how common AII and aldosterone increases are observed during routine clinical practice. PATIENTS AND METHODS: 91 patients with symptomatic (mean New York Heart Association class 2.7) CHF (mean (SD) left ventricular ejection fraction 29.9 (8)%, range 9-46%) were studied 4-6 hours after ACE inhibitor dosing. A representative range of ACE inhibitors (enalapril, lisinopril, captopril, perindopril, and fosinopril) was examined. RESULTS: Supine measurements showed a wide range of AII (10.5 (25.5) pg/ml), aldosterone (130.8 (136) pg/ml), and serum ACE (12.1 (13.3) EU/l; excludes captopril data) concentrations on diuretics. AII concentrations > 10 pg/ml were seen in 15% of patients, and aldosterone concentrations > 144 pg/ml were seen in 38% of patients. AII concentrations were significantly correlated (p < 0.001) with ACE but not with aldosterone concentrations. Aldosterone concentrations were not significantly correlated with ACE concentrations. CONCLUSIONS: AII "reactivation" occurred in 15% and failure of aldosterone suppression in 38% of routine CHF patients taking ACE inhibitor treatment. AII "reactivation" was associated with both low and high levels of ACE activity, which suggests that multiple different mechanisms are at play. In patients with high plasma ACE concentrations, non-compliance should be considered along with inadequate dose titration. In patients with low plasma ACE and high AII concentrations, non-ACE mediated production of AII may be operative. Raised aldosterone concentrations appear to be more common than AII "reactivation". It is important to establish the cause of detectable or increased AII concentrations in a heart failure patient treated with an ACE inhibitor. The measurement of serum ACE may help to identify the likely cause as poor compliance or inadequate dose. (+info)
Bradykinin down-regulates LPS-induced eosinophil accumulation in the pleural cavity of mice through type 2-kinin receptor activation: a role for prostaglandins.
(29/1305)
1. The role of both exogenously administered and endogenously generated bradykinin (BK) on LPS-induced eosinophil accumulation in the mice pleural cavity was investigated by means of treatment with BK selective receptor agonists/antagonists and captopril. 2. Intrathoracic (i.t.) injection of LPS (250 ng cavity(-1)) induced eosinophil influx at 24 h as previously described (Bozza et al., 1993). Pretreatment with the B1 receptor antagonist des-Arg9-[leu-8]BK (0.025 and 0.25 nmol cavity(-1)) showed no effect on this phenomenon, whereas pretreatment with the B2 receptor antagonists, NPC 17731 (0.025 and 0.25 nmol cavity(-1)) or HOE 140 (2.5 nmol cavity(-1)), increased LPS-induced eosinophil influx. Accordingly, pretreatment with captopril at 10 mg kg(-1) i.p., inhibited eosinophil infiltration induced by LPS in the pleural cavity, suggesting that endogenous BK is down-regulating LPS-induced eosinophil accumulation. 3. BK administered at 15 and 25 nmol cavity(-1), i.t. or i.p. also inhibited LPS-induced eosinophil accumulation. BK alone had no effect on the basal number of leucocytes in the pleural or peritoneal cavity in doses up to 25 nmol cavity(-1). Nevertheless, when injected at doses of 50 and 100 nmol cavity(-1) BK induced leucocyte influx characterized by neutrophil and eosinophil accumulation at 24 h. 4. Similarly to what was observed with BK, a specific B2 receptor agonist, Tyr8BK, administered at 0.25 nmol cavity(-1) i.p., significantly inhibited the eosinophil influx induced by LPS. 5. The mechanism by which B2 receptor agonists inhibit LPS-induced eosinophil accumulation was investigated by pretreating the animals with indomethacin or a selective cyclooxygenase-2 inhibitor, NS-398. Pretreatment with either indomethacin or NS-398 had no effect on eosinophil influx induced by LPS alone, but those drugs were able to restore the LPS-induced eosinophil influx in Tyr8BK (0.25 nmol cavity(-1)) injected mice. 6. In conclusion, endogenously generated bradykinin seems to modulate, through activation of B2 receptors, eosinphil accumulation induced by LPS via a mechanism dependent on prostanoid synthesis. (+info)
Effects of subfornical organ lesions on acutely induced thirst and salt appetite.
(30/1305)
We examined the role of the subfornical organ (SFO) in stimulating thirst and salt appetite using two procedures that initiate water and sodium ingestion within 1-2 h of extracellular fluid depletion. The first procedure used injections of a diuretic (furosemide, 10 mg/kg sc) and a vasodilator (minoxidil, 1-3 mg/kg ia) to produce hypotension concurrently with hypovolemia. The resulting water and sodium intakes were inhibited by intravenous administration of ANG II receptor antagonist (sarthran, 8 micrograms . kg(-1). min(-1)) or angiotensin-converting enzyme inhibitor (captopril, 2.5 mg/h). The second procedure used injections of furosemide (10 mg/kg sc) and a low dose of captopril (5 mg/kg sc) to initiate water and sodium ingestion upon formation of ANG II in the brain. Electrolytic lesions of the SFO greatly reduced the water intakes, and nearly abolished the sodium intakes, produced by these relatively acute treatments. These results contrast with earlier findings showing little effect of SFO lesions on sodium ingestion after longer-term extracellular fluid depletion. (+info)
ACE inhibition and glucose transport in insulinresistant muscle: roles of bradykinin and nitric oxide.
(31/1305)
Acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril enhances insulin-stimulated glucose transport activity in skeletal muscle of the insulin-resistant obese Zucker rat. The present study was designed to assess whether this effect is mediated by an increase in the nonapeptide bradykinin (BK), by a decrease in action of ANG II, or both. Obese Zucker rats (8-9 wk old) were treated for 2 h with either captopril (50 mg/kg orally), bradykinin (200 micrograms/kg ip), or the ANG II receptor (AT(1) subtype) antagonist eprosartan (20 mg/kg orally). Captopril treatment enhanced in vitro insulin-stimulated (2 mU/ml) 2-deoxyglucose uptake in the epitrochlearis muscle by 22% (251 +/- 7 vs. 205 +/- 9 pmol. mg(-1). 20 min(-1); P < 0.05), whereas BK treatment enhanced this variable by 18% (249 +/- 15 vs. 215 +/- 7 pmol. mg(-1). 20 min(-1); P < 0.05). Eprosartan did not significantly modify insulin action. The BK-mediated increase in insulin action was completely abolished by pretreatment with either the specific BK-B(2) receptor antagonist HOE 140 (200 micrograms/kg ip) or the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (50 mg/kg ip). Collectively, these results indicate that the modulation of insulin action by BK likely underlies the metabolic effects of ACE inhibitors in the insulin-resistant obese Zucker rat. Moreover, this modulation of insulin action by BK is likely mediated through B(2) receptors and by an increase in nitric oxide production and/or action in skeletal muscle tissue. (+info)
Captopril administration reduces thrombus formation and surface expression of platelet glycoprotein IIb/IIa in early postmyocardial infarction stage.
(32/1305)
Long-term administration of the angiotensin-converting enzyme inhibitor captopril in survivors of myocardial infarction (MI) reduces the risk of cardiovascular death, recurrence of MI, and unstable angina, suggesting that captopril may possess antithrombotic properties that have not been clearly elucidated. We assessed the short-term antithrombotic effects of captopril on platelet aggregation, platelet-subendothelium interaction, and the expression of major glycoproteins on platelet surface. A double-blind study was carried out in 25 patients with MI. Blood samples were taken before (baseline) and 12 days after treatment in both the control and captopril groups. Platelet aggregation was tested by conventional aggregometry using common activating agents. Platelet interaction with deeply damaged subendothelial surface was evaluated in a perfusion model, with blood maintained under flow conditions. Deposition of platelets was quantified by using computer-assisted morphometric techniques on histological sections, and it was expressed as a percentage of total vessel surface covered by platelets (CS) and as a ratio between large aggregates (T) and surface covered by platelets (100XT/CS). Glycoprotein expression was measured using flow cytometric techniques. Aggregometric responses showed no significant variations; however, in the captopril group, 100XT/CS decreased after 12 days of treatment (100XT/CS: 36+/-12.1% captopril versus 64+/-8.0% baseline; P=0.005). This parameter was also significantly decreased from that found in control group patients (100XT/CS:67=/-4.5%, P=0.008). Flow cytometry showed a 30% reduction in glycoprotein IIb/IIIa expression (P=0.02). Captopril reduced the formation of large aggregates in a perfusion system, which might be related to a down-regulation of glycoprotein IIb/IIIa complex on the platelet surface. These results suggest that captopril exerts an antiplatelet effect that may contribute to its beneficial action in MI. (+info)