Drugs online research references
Ann N Y Acad Sci. 1995 Jul 12;763:112-24.
[3H]cirazoline as a tool for the characterization of imidazoline sites.
Angel I, Le Rouzic M, Pimoule C, Graham D, Arbilla S.
Synthelabo Recherche, Rueil-Malmaison, France.
Recent studies have shown that cirazoline, an alpha 1-adrenoceptor agonist, has greater affinity than do other imidazoline or guanidinium compounds at imidazoline recognition sites. In this report we used [3H]cirazoline as a probe to characterize imidazoline recognition sites present in membrane homogenates of rat brain and kidney as well as pancreatic beta HIT T15 cells. Specific binding of [3H]cirazoline to these various homogenates was saturable and reversible and was resolved into two classes of high affinity binding sites. Competition inhibition studies of [3H]cirazoline binding to these different membrane preparations were performed with alkaloid, phenylethylamine, imidazoline, and guanidinium compounds. Catecholamines and non-imidazoline adrenoceptor ligands such as epinephrine, benextramine, prazosin, propranolol, rauwolscine, or adrenoceptor ligands such as epinephrine, benextramine, prazosin, propranolol, rauwolscine, or yohimbine did not compete with [3H]cirazoline (Ki > 10 microM). Under our experimental conditions, only guanidinium and imidazoline derivatives had high affinities for [3H]cirazoline binding sites. Unlabeled cirazoline, clonidine, bromoxidine, idazoxan, and amiloride had the highest affinities with this respective rank order. These results suggest that [3H]cirazoline is a novel high affinity radioligand that specifically labels nonadrenergic imidazoline-guanidinium sites in the brain, kidney, and beta cells. Furthermore, the obtained rank order of inhibition suggests that [3H]cirazoline binding does not distinguish between I1 and I2 sites. In addition, we compared the specific binding of [3H]cirazoline with that of the alpha 2-adrenoceptor antagonist [3H]rauwolscine in chinese hamster ovary (CHO) cell lines stably expressing human alpha 2C2-, alpha 2C4-, and alpha 2C10-adrenoceptor subtypes. Using [3H]rauwolscine as a probe, each of these transfected cell lines expressed high levels for the three different alpha 2-adrenoceptor subtypes (Bmax values were between 2 and 7 pmol.mg-1 protein). In contrast, none of these cell lines displayed measurable imidazoline recognition sites. In summary, [3H]cirazoline is a novel high affinity radioligand that specifically labels imidazoline recognition sites without significant alpha- or beta-adrenoceptor binding. Furthermore, our results using alpha 2-adrenoceptor transfected cells confirm that the imidazoline recognition sites and each of the cloned alpha 2-adrenoceptor subtypes represent distinct macromolecular entities.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7677320&dopt=Abstract
Ann N Y Acad Sci. 1995 Jul 12;763:620-33.
Antiarrhythmic effect of the selective I1-imidazoline receptor modulator moxonidine on ouabain-induced cardiac arrhythmia in guinea pigs.
Mest HJ, Thomsen P, Raap A.
Department of Pharmacology, Beiersdorf-Lilly GmbH, Hamburg, Germany.
Moxonidine is a centrally acting antihypertensive agent with potent action on I1-imidazoline receptors. Moxonidine as an SIR modulator elicits a persistent reduction in circulating levels of epinephrine, demonstrating a reduction in sympathetic tone. In the first experiment the threshold dose of ouabain needed to induce ventricular arrhythmia and asystole was determined in guinea pigs, and the influence of moxonidine was tested. In a dose range of 0.1-0.4 mg/kg body weight i.v., moxonidine increased the threshold dose needed to induce ventricular tachycardia, premature ventricular beats, ventricular flutter, ventricular fibrillation, and asystole. The effect was dose-dependent and statistically significant. Clonidine, in a dose range of 0.2-0.8 mg/kg body weight i.v., also increased the threshold dose of ouabain necessary to induce different cardiac rhythm disturbances. Moxonidine was more effective than clonidine. Pretreatment with the alpha 2-receptor and I1-receptor-influencing substances efaroxan, idazoxan, and SKF 86466 attenuated the effect of moxonidine and clonidine. Efaroxan, idazoxan, or SKF 86466 alone reduced the threshold dose of ouabain necessary to induce cardiac arrhythmia as a sign for arrhythmogenic effects. The alpha 1-receptor antagonist prazosin had no influence on ouabain-induced arrhythmia. Pretreatment with prazosin reduced the moxonidine but not the clonidine effect. In the second experiment the influence of moxonidine on aconitine-induced extrasystoles (ES) in the spontaneously beating guinea pig auricle was investigated. Moxonidine in a dose of 10(-7)-10(-8) M reduced the number of ES. A 10-fold higher dose had no influence on ES number. The beta-blocking agent propranolol showed antiarrhythmic effects in both methods. The ouabain-induced cardiac arrhythmia is associated with increased sympathetic tone on central stimulation. The reduced sympathetic tone by centrally acting moxonidine via imidazoline receptors seems responsible for the antiarrhythmic effect of this drug. Clonidine also reduced the sympathetic tone via imidazoline receptor. The selectivity of clonidine to imidazoline receptors is less pronounced than is that of moxonidine. The interaction of moxonidine with imidazoline receptors is not clear. The possible interaction between imidazoline and alpha-adrenoceptors in relation to the antiarrhythmic effect of moxonidine or clonidine is also unknown. Modulation of imidazoline receptors by moxonidine could be an agonistic effect or an antagonism to an endogenous agonistic or antagonistic substance and vice versa.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7677382&dopt=Abstract
J Cardiovasc Pharmacol. 1993 Feb;21(2):221-7.
Carvedilol inhibits vascular smooth muscle cell proliferation.
Sung CP, Arleth AJ, Ohlstein EH.
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
The antiproliferative properties of carvedilol, a newly developed multiple-action antihypertensive agent, were evaluated in early passage cultured rat aortic vascular smooth muscle cells. Carvedilol (10(-7)-10(-5) M) produced concentration-dependent decreases in basal and endothelin-1-stimulated mitogenesis of rat aortic vascular smooth muscle cells. The IC50 for inhibition of [3H]thymidine incorporation by carvedilol in both basal and endothelin-1-stimulated rat aortic vascular smooth muscle cells was approximately 1 microM. Carvedilol (10 microM) inhibited basal mitogenesis by approximately 65%, and endothelin-1-stimulated mitogenesis by approximately 95%. Carvedilol (1-10 microM) also produced significant concentration-dependent inhibition of the mitogenic response mediated by thrombin (0.5 U/ml), epidermal growth factor (1 nM), platelet-derived growth factor (1 nM), and angiotensin II (5 nM). Endothelin-1- or PDGF A/B-induced increases in cell number were also significantly inhibited by carvedilol (10 microM). The antimitogenic effect of carvedilol on cell growth was reversible. The inhibitory effect of carvedilol was not shared by other beta-adrenoceptor antagonists such as labetalol (10 microM), celiprolol (10 microM), or sotalol (10 microM), which did not significantly affect [3H]thymidine incorporation in rat vascular smooth muscle cells. Propranolol (10 microM) was the only beta-adrenoceptor antagonist tested that inhibited [3H]thymidine incorporation, with effects of approximately 50 and 75% on basal and endothelin-1-mediated stimulation, respectively. In contrast, celiprolol (10 microM) produced significant stimulation of DNA synthesis (125% over basal). The calcium channel antagonist nifedipine (10 microM) inhibited basal and endothelin-1-mediated mitogenesis by 58 and 72%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7679155&dopt=Abstract
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