Bradykinin (BK) and related kinins are autocoid peptides that play integral roles in many pathophysiological processes such as cough. In this study, the inhibitory effect of noscapine, the antitussive opioid alkaloid, on BK receptors, was tested in the guinea-pig ileum. Contractions of the isolated ileum of the guinea-pig in response to BK were inhibited by noscapine (10–1000 nM) in a concentration-dependent manner. Concentration-response curves (CRCs) to BK were slightly shifted to the right with a concomitant decrease in the maximum effect. A pA2value of 6.68 was calculated for noscapine. The slope of the Schild plot of the antagonism was found to be 0.56. Noscapine had no effect on contractions induced by KCl, acetylcholine, histamine,5-hydroxy tryptamine or angiotensin II. In conclusion, noscapine has a specific antagonistic effect on BK receptors and the mode of inhibition was found to be non-competitive.
Mebudipine and dibudipine are two new dihydropyridine (DHP) Ca2+ channel blockers that have been synthesized by Mahmoudian et al. (1997). In previous studies, they showed considerable relaxant effect on vascular and ileal smooth muscles. These two compounds also reduced the contraction force of rat left atrium (20, 22). In the present study, we attempted to compare the inhibitory actions of these new DHPs and nifedipine on the high threshold Ca2+ spikes of F1
Calcium channel blockers are clinically useful vasodilators, used widely in the treatment of hypertension. These agents are reported to preserve or improve renal function in patients with essential hypertensive renal disease or diabetic renal disease. Among the classes of calcium channel blockers, dihydropyridine derivatives are widely used because of their potent vasodilating activity and weak cardiodepressant action. Mebudipine and dibudipine are two new 1,4-dihydropyridine calcium channel blockers that recently have been synthesized. In previous research mebudipine and dibudipine showed considerable relaxant effects on vascular and ileal smooth muscle cells. In this study we investigated the effects of these new drugs on vascular flow of isolated kidney of diabetic rat and compare their potencies to amlodipine. It is concluded that mebudipine and dibudipine (1–10 μM) are at least as potent as amlodipine in inhibiting PE-induced perfusion pressure in isolated kidney of diabetic rats. These new dihydropyridines improve kidney perfusion of diabetic rat in the setting of PE infusion. Similarly, amlodipine.
The effects of an intraperitoneal (i.p.) injection of different doses of sildenafil, a cyclic guanosin monophosphate (cGMP) specific phosphodiesterase type 5 (PDE 5) inhibitor, on memory retention of young (2-month-old) and middle aged (12-month-old) male Wistar rats were investigated. Passive avoidance behaviour was studied in a one trial learning, step - through type, passive avoidance task utilizing the natural preference of rats for a dark environment. In each category (young or middle-aged) different groups of rats received vehicle or sildenafil (1, 3, 10, 20 mg*kg-1, i.p.) immediately after training and one group remained uninjected serwing as control. Retention latencies were measured 48 h later. To asses a possible non-specific proactive effect of sildenafil, the response latencies in a group of rats not receiving foot shock were also tested. The results showed that the post-training i.p. administration of sildenafil did not facilitate retention performance of a passive avoidance response in both young and middle aged rats compared to control or vehicle groups. Also, sildenafil did not affect response latencies in rats not having received the footshock on the training trial, indicating that sildenafil does not show a non-specific proactive affect on retention performance. The comparison of retention time between young and middle aged rats showed that the memory of the latter had been significantly reduced. In conclusion, this study suggests that sildenafil has no effects on memory retention in Wistar rats.
The inhibitory effects of calcium channel blockers; nifedipine and two new compounds, mebudipine and dibudipine, on contractions of isolated guinea-pig common bile duct were investigated. All the compounds tested induced a concentration-dependent reduction of the amplitude of contractile response to electrical stimulation and all the compounds displaced concentration-response curve of calcium chloride to the right in a concentration-dependent manner. The pIC50
Angiotensin Converting Enzyme Inhibitors (ACEI) like captopril and enalapril, can induce persistant cough in man. Noscapine, an antitussive alkaloid, can be used to suppress ACEI-induced cough. Some workers have suggested a role for bradykinin in precipitation of ACE-induced cough. Work carried out in our laboratory has shown noscapine to be a non-competitive inhibitor of bradykinin in guinea pig ileum. It is therefore possible that noscapine suppresses cough by blocking the effect of bradykinin receptor activation in the airways. Guinea pigs were placed in a cough-chamber connected to an air pump and a pressure transducer. Capsaicin was sprayed into the chamber and cough was recorded as a distinctive change in air pressure inside the cough-chamber. Animals treated with 1 mg/kg captopril and enalapril for 7 days, showed increased cough response. Ten µg/kg FR190997, a non-peptide agonist of the bradykinin B2 receptor, also increased the cough response. Noscapine at 0.5, 1 and 2 mg/kg was able to reverse the effects of ACEI and FR190997. Naloxone, a specific opioid receptor inhibitor, did not block the antitussive effects of noscapine in enalapril or FR190997 treated guinea pigs. This antitussive effect of noscapine is not mediated via the µ, κ or δ opioid receptors. It is therefore possible that noscapine exerts its antitussive action by interfering with the bradykinin cough mediation.
Mebudipine and dibudipine are two newly synthesized dihydropyridine (DHP) calcium channel blockers that have been shown to have considerable relaxant effects on vascular and atrial smooth muscle. The
half-lives of mebudipine and dibudipine are reported to be significantly longer than that of nifedipine. In this study, we investigated the effects of mebudipine and dibudipine on voltage-activated Ca
channels on differentiated PC12 cells and compared their potencies to amlodipine. Our results point to absence of voltage-activated Ca
currents in undifferentiated PC12 cells. It is also concluded that mebudipine and dibudipine, like amlodipine are L-type calcium channel blockers. When tested in a range of 10–100 μM, mebudipine is at least as potent as amlodipine in inhibition of peak Ba
currents in differentiated PC12 cells while dibudipine is significantly less potent compared to amlodipine and mebudipine.
Cytotoxic free radicals and release of several neurotransmitters such as bradykinin contribute to the pathogenesis of hypoxic-ischemic brain damage. We have studied the efficacy of noscapine, an opium alkaloid and a bradykinin antagonist, in reducing post-hypoxic-ischemic damage in developing brain of 7-d-old rat pups. Hypoxic-ischemic injury to the right cerebral hemisphere was produced by legation of the right common carotid artery followed by 3 h of hypoxia with 8% oxygen. Thirty to 45 min before hypoxia the rat pups received noscapine (dose = 0.5-2 mg/kg) or saline. Pups were scarified at 24 h post recovery for the assessment of cerebral damage by histological methods. Our results showed that noscapine was an effective agent in reducing the extent of brain injury after hypoxic-ischemic insult to neonatal rats. Therefore, it is concluded that noscapine may be a useful drug in the managements of patients after stroke.