Drugs online research references
Naunyn Schmiedebergs Arch Pharmacol. 1993 Jun;347(6):658-63.
Positive inotropic action of angiotensin II in the pithed rat.
Zhang J, Pfaffendorf M, van Zwieten PA.
Department of Pharmacotherapy, Faculty of Medicine, University of Amsterdam, The Netherlands.
The cardiovascular effects of angiotensin II were examined in aortic blood pressure-controlled and -uncontrolled pithed rats. Angiotensin II induced a dose-dependent increase in diastolic blood pressure, left ventricular pressure (LVP), dP/dt (the first derivative of LVP) and heart rate in pithed rats. The maximal responses for these parameters were similar to those to noradrenaline, except for the rise in diastolic blood pressure, where noradrenaline caused a greater increase than angiotensin II. After treatment with propranolol, the positive chronotropic effect of angiotensin II was abolished. Angiotensin II produced a dose-dependent increase in diastolic blood pressure, which was similar to that of vasopressin, and an increase in dP/dtmax, which proved much greater than that of vasopressin. When aortic blood pressure was controlled and the beta-receptors were blocked by propranolol, angiotensin II caused a dose-dependent increase in dP/dtmax without affecting the left ventricular enddiastolic pressure. The same results were obtained after both beta- and alpha-adrenoceptors were blocked by propranolol and phentolamine. Losartan but not PD123177 caused parallel rightward shifts of the dose-response curve of angiotensin II for dP/dtmax in the aortic blood pressure controlled pithed rat without altering the maximal response. It is concluded that in the pithed rat angiotensin II produced an increase in myocardial contractile force which is not mediated by beta- or alpha-adrenoceptors. The inotropic effect appears to be mediated by angiotensin receptors, of the AT1-subtype.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8103195&dopt=Abstract
J Hypertens Suppl. 1993 Jun;11(4):S41-8.
Myocardial protection by the novel vasodilating beta-blocker, carvedilol: potential relevance of anti-oxidant activity.
Feuerstein GZ, Yue TL, Cheng HY, Ruffolo RR Jr.
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0930.
AIM: Carvedilol is a multiple action antihypertensive drug with potential use in angina and congestive heart failure. The pharmacological profile of carvedilol includes both beta-adrenoceptor blockade and vasodilation, the latter primarily a result of alpha 1-adrenoceptor blockade. Since many beta-blockers have cardioprotective properties, the present study was designed to determine whether carvedilol is also cardioprotective. Because oxygen radicals are believed to influence ischemic tissue injuries, a secondary study was designed to determine whether carvedilol has anti-oxidant actions which could contribute to cardioprotective properties of carvedilol. METHODS: Four different models of acute myocardial infarction in were examined in three animal species, and the effects of carvedilol were compared to those of propranolol. First, in rats subjected to 30 min of cardiac ischemia followed by 24 h of reperfusion, carvedilol was administered both pre- and post-ischemia (1 mg/kg, intravenously). Second, minipigs were subjected to 45 min of cardiac ischemia followed by 4 h of reperfusion, with carvedilol pretreatment (0.3 or 1 mg/kg intravenously). Third, dogs were subjected to 1 h of cardiac ischemia followed by 24 h of reperfusion with carvedilol pretreatment (1 mg/kg, intravenously) or to permanent coronary occlusion (6 h) with carvedilol pretreatment (0.3 or 1 mg/kg, intravenously). Finally, to examine the anti-oxidant activity of carvedilol, pig myocardial membranes were exposed to oxidizing systems that elicit lipid peroxide products assessed as thiobarbituric acid-reactive substances (TBARS). RESULTS: In the rats, carvedilol reduced the infarct size by 47% (P < 0.01), in contrast to propranolol, which is inactive in this model. In the minipigs the infarct size was reduced by 46 and 89% (P < 0.01) with carvedilol at 0.3 and 1 mg/kg, respectively; at comparable beta-adrenoceptor blocking doses, carvedilol produced a significantly greater reduction in the infarct size than propranolol (89 versus 48%). In dogs, carvedilol reduced the infarct size by 78% (P < 0.05) compared to the 64% reduction produced by propranolol. In dogs with permanent coronary occlusion, carvedilol produced dose-dependent reductions in the infarct size of 46 and 63% for 0.3 and 1 mg/kg, respectively (P < 0.05), compared to propranolol which did not reduce the infarct size in this model. Carvedilol inhibited lipid peroxidation in a dose-dependent manner with a 50% inhibitory concentration (IC50) of 5 mumol/l. Moreover, superoxide generation by activated human neutrophils in vitro was also inhibited by carvedilol with an IC50 of 28 mumol/l. Finally, carvedilol was shown to scavenge oxygen free radicals in a cell-free system with an IC50 of 25 mumol/l. CONCLUSIONS: Taken together, these data indicate that carvedilol is a potent cardioprotective drug, which presumably acts by multiple mechanisms, possibly including a novel anti-oxidant effect that is not shared by other beta-blockers.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8104241&dopt=Abstract
Br J Pharmacol. 1993 Aug;109(4):1157-63.
Ligand binding properties of putative beta 3-adrenoceptors compared in brown adipose tissue and in skeletal muscle membranes.
Sillence MN, Moore NG, Pegg GG, Lindsay DB.
CSIRO Division of Tropical Animal Production, University of Central Queensland, Rockhampton, Australia.
1. The beta-adrenoceptor population was characterized in membrane preparations from rat brown adipose tissue (BAT) and from soleus muscle by use of the radioligand [125I]-iodocyanopindolol ([125I]-ICYP). In addition, atypical binding sites for [125I]-ICYP found in both tissues were examined, and the relationship between these sites and the putative rat beta 3-adrenoceptor is discussed. 2. It was established that BAT membranes host a mixed population of beta 1- and beta 2-adrenoceptors. Of these two sites, 55% showed a high affinity for the beta 1-selective ligand CGP 20712A (pK 8.5), and 45% showed a high affinity for the beta 2-selective antagonist ICI 118551 (pK 8.6). Soleus muscle membranes were found to host a population of beta 2-adrenoceptors, characterized by a high affinity for ICI 118551 (pK 9.1), but beta 1-adrenoceptors could not be detected in this preparation. 5-Hydroxytryptamine receptors were not detected in either preparation. 3. In addition to beta 1- and beta 2-adrenoceptors, atypical binding sites were identified in both tissues using high concentrations of radioligand (0.5-0.6 nM) and in the presence of 1 microM (-)-propranolol. The atypical sites were abundant, representing 80 and 81% of the total [125I]-ICYP binding sites in BAT and soleus muscle respectively. When the pK values for 11 ligands were compared, the correlation coefficient for atypical sites in BAT and soleus muscle was 0.94.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8104645&dopt=Abstract
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