AIMTo investigate the role and mechanism of the bradykinin(BK) B1 receptor in the antiproliferative effects of the angiotensin-converting enzyme inhibitor (ACEI) captopril on rat cardiac fibroblasts (CFs) treated with angiotensin II (Ang II).

METHODSNeonatal rat cardiac fibroblasts were randomly treated with Ang II, captopril, B2 receptor antagonist (icatibant) or B1 receptor antagonist (des-Arg10, Leu9-kallidin). Thiazolyl blue (MTT) and flow cytometry (FCM) were used to evaluate cell number and cell cycle, respectively. Nitric oxide (NO) and intracellular cGMP level were measured by colorimetry and radioimmunoassay.

RESULTSAfter incubating the fibroblasts with 10(-7) mol/L Ang II for 48 hours, the percentage of CFs in the S stage and the value of MTT A490 nm were significantly increased (P < 0.01 vs control), and this increase was inhibited by 10(-5) mol/L captopril; however, NO and cGMP level were significantly higher than with Ang II alone (P < 0.01). 10(-5) mol/L icatibant attenuated the effects of captopril, which were blunted further by dual blockade of both B1 and B12.

CONCLUSIONActing via the B2 receptor, BK contributes to the antiproliferative effects of ACEI on CFs. In the absence of the B2 receptor, the B1 receptor may assume some of the functions of the B2 receptor and contribute to inhibition of CFs proliferation by ACEI.

Animals ; Bradykinin B1 Receptor Antagonists ; pharmacology ; Captopril ; pharmacology ; Cell Proliferation ; drug effects ; Heart Ventricles ; Myocytes, Cardiac ; cytology ; Rats ; Rats, Sprague-Dawley ; Receptor, Bradykinin B1 ; metabolism

Animals ; Apoptosis ; Bradykinin ; metabolism ; Bradykinin Receptor Antagonists ; Ischemia ; metabolism ; Ischemic Preconditioning ; Muscle, Skeletal ; blood supply ; metabolism ; pathology ; Myocardial Infarction ; metabolism ; Myocardium ; pathology ; Swine ; Swine, Miniature

Pharmacotherapy for the treatment of heart failure has advanced considerably in recent years, and clinical trials have demonstrated the favorable long-term effects of angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers on the morbidity and mortality. Although the current guidelines recommend ACEI and beta-blockers as standard therapy for heart failure, as they have demonstrated benefits in terms of mortality, only one third of patients with heart failure are receiving both classes of drug due to concern over their adverse effects. The benefit of ACEI has been attributed largely to blockade of angiotensin II production, but also to the accumulation of bradykinin. The accumulation of bradykinin however, has been implicated as contributing to adverse effects, such as a dry cough, associated with ACEI treatment, and has also been suggested to result in prejunctional norepinephine release. Recently, many clinical trials have shown that angiotensin receptor blockers (ARBs) had similar effect on the mortality and morbidity of patients with heart failure. The side effects, notably the cough, are significantly less than with ACE inhibitors. ARBs could also be recommended for patients who can not tolerate ACE inhibitors for symptomatic treatment. In combination with ACEI, ARBs may improve the symptoms of heart failure, and reduce hospitalizations due to heart failure deterioration. Whether concomitant beta-blockade negatively affects the effect of ARB will require further evaluation. In this paper, recent large clinical trials of ARBs therapy in heart failure, and the ongoing clinical trials, were reviewed for the recommendation of the optimal conditions for ARBs treatment in heart failures.
Angiotensin II* ; Angiotensin Receptor Antagonists* ; Angiotensin-Converting Enzyme Inhibitors ; Angiotensins* ; Bradykinin ; Cough ; Drug Therapy ; Estrogens, Conjugated (USP)* ; Heart ; Heart Failure* ; Hospitalization ; Humans ; Mortality ; Receptors, Angiotensin*

The present study aimed at evaluation of prophylactic efficacy and possible mechanisms of asiaticoside (AS) based standardized extract of Centella asiatica (L.) Urban leaves (INDCA) in animal models of migraine. The effects of oral and intranasal (i.n.) pretreatment of INDCA (acute and 7-days subacute) were evaluated against nitroglycerine (NTG, 10 mg·kg(-1), i.p.) and bradykinin (BK, 10 μg, intra-arterial) induced hyperalgesia in rats. Tail flick latencies (from 0 to 240 min) post-NTG treatment and the number of vocalizations post-BK treatment were recorded as a measure of hyperalgesia. Separate groups of rats for negative (Normal) and positive (sumatriptan, 42 mg·kg(-1), s.c.) controls were included. The interaction of INDCA with selective 5-HT1A, 5-HT1B, and 5-HT1D receptor antagonists (NAN-190, Isamoltane hemifumarate, and BRL-15572 respectively) against NTG-induced hyperalgesia was also evaluated. Acute and sub-acute pre-treatment of INDCA [10 and 30 mg·kg(-1) (oral) and 100 μg/rat (i.n.) showed significant anti-nociception activity, and reversal of the NTG-induced hyperalgesia and brain 5-HT concentration decline. Oral pre-treatment with INDCA (30 mg·kg(-1), 7 d) showed significant reduction in the number of vocalization. The anti-nociceptive effects of INDCA were blocked by 5-HT1A and 5-HT1B but not 5-HT1D receptor antagonists. In conclusion, INDCA demonstrated promising anti-nociceptive effects in animal models of migraine, probably through 5-HT1A/1B medicated action.
Administration, Intranasal ; Administration, Oral ; Animals ; Bradykinin ; Female ; Hyperalgesia ; chemically induced ; prevention & control ; Male ; Migraine Disorders ; chemically induced ; prevention & control ; Models, Animal ; Nitroglycerin ; Nociception ; drug effects ; Plant Leaves ; chemistry ; Pre-Exposure Prophylaxis ; Rats ; Rats, Wistar ; Reaction Time ; Receptors, Serotonin, 5-HT1 ; drug effects ; Serotonin 5-HT1 Receptor Antagonists ; metabolism ; Tail ; physiology ; Triterpenes ; administration & dosage ; pharmacology