Disease relevance of TA 064

• Denopamine, a beta1-adrenergic agonist, prolongs survival in a murine model of congestive heart failure induced by viral myocarditis: suppression of tumor necrosis factor-alpha production in the heart [1].
• OBJECTIVES: This study was designed to examine the effects of denopamine, a selective beta1-adrenergic agonist, in a murine model of congestive heart failure (CHF) due to viral myocarditis [1].
• Patients with mild-to-moderate heart failure with sinus rhythm, but not those with atrial fibrillation because of its frequent induction of tachycardia, may be good candidates for denopamine therapy [2].
• Thus, TA-064 is unique among the beta-adrenergic and other cardiotonic agents in that it produces sustained hypoglycemia while it has no lactacidemic effect [3].
• In order to treat postprandial hypotension (PPH), we orally administered a combination of denopamine (10 mg, a selective beta 1-adrenergic agonist) and midodrine-HCl (4 mg, a selective alpha 1-adrenergic agonist) to eight patients with autonomic failure (AF) prior to and after eating [4].

High impact information on TA 064

• Isoproterenol (1 mumol/L) and denopamine (10 mumol/L) mimicked the effects of NE, but phenylephrine did not, indicating that NE-induced microtubular disassembly is mediated by beta 1-adrenergic receptor stimulation [5].
• In nonfailing myocardium, beta 1 responses predominated, as the selective beta 1 agonist denopamine produced a response that was 66% of the total contractile response of isoproterenol [6].
• METHODS: In vitro: The effects of denopamine on lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) production was studied in murine spleen cells [1].
• These in vitro and in vivo effects of denopamine were significantly inhibited by metoprolol [1].
• Dose responses were determined using isoproterenol (a nonselective beta-AR agonist), denopamine (beta 1-AR agonist), procaterol (beta 2-AR agonist), and CGP12177A (beta 1- and beta 2-AR antagonist, beta 3-AR agonist) [7].

Chemical compound and disease context of TA 064

• Since this hypoglycemic action of TA-064 was always preceded by a rise in plasma IRI and abolished in streptozotocin-diabetic rats, we conclude that increased secretion of pancreatic insulin and the lack of hyperglycemic action are responsible for the hypoglycemia by high doses of TA-064 [3].
• In conclusion, TA-064 has a hemodynamic effect similar to that of dobutamine and may be useful as an oral substitute for dobutamine in patients with congestive heart failure after temporary management with dobutamine [8].

Biological context of TA 064

• Denopamine increased heart rate in patients with atrial fibrillation but had little effect on heart rate in patients with sinus rhythm [2].
• Isoproterenol, denopamine, and procaterol stimulated lipolysis with EC50 values of 4,500, and 83 nmol/L, respectively [7].
• There was a significant increase in peak VO2 (p < 0.05) and anaerobic threshold (p < 0.01) with denopamine, whereas no significant change was observed in peak work rate or exercise time [2].
• Effects of (-)-(R)-1-(p-hydroxyphenyl)-2-[3,4-dimethoxyphenethyl)amino]ethanol (TA-064), a new cardiotonic agent, on circulating parameters of carbohydrate and lipid metabolism in the rat [3].
• A 24-hr pretreatment with denopamine produced a time-dependent reduction in the number of beta-1 AR with a rate of down-regulation slower than that produced by isoproterenol [9].

Anatomical context of TA 064

• Incubation with denopamine did not cause substantial elevation of c-AMP levels in rat reticulocytes and diaphragm [10].
• 2. The intrinsic activities of the positive inotropic actions of T-0509, denopamine and xamoterol compared with isoprenaline (= 100%) in the papillary muscle were 99%, 83% and 28%, respectively, while their relative potencies (EC50 agonist EC50 isoprenaline) were 0.23, 33 and 1.4, respectively [11].
• Denopamine at concentrations above 10(-6) M stimulated lipolysis in vitro, and, above 10(-5) M, elevated the c-AMP level in isolated rat fat cells [10].
• Species differences in denopamine glucuronidation were investigated with liver microsomes obtained from humans and experimental animals [12].
• The K(m) value of denopamine glucuronidation in recombinant UGT2B7 microsomes was close to those in human liver and jejunum microsomes [12].

Associations of TA 064 with other chemical compounds

• Prenalterol (beta 1-agonist), denopamine (beta 1-agonist), and zinterol (beta 2-agonist) were partial agonists of adenylate cyclase (AC) stimulation in human ventricular myocardium obtained from nonfailing chambers whose beta 1/beta 2 receptor subtype ratio was approximately 80/20 [13].
• Characterization of the beta adrenoceptor subtype(s) mediating the positive inotropic effects of epinine, dopamine, dobutamine, denopamine and xamoterol in isolated human right atrium [14].
• The denopamine glucuronidation activities in seven human liver microsomes were significantly correlated with diclofenac glucuronidation activities (r(2) = 0.685, p < 0.05) [12].
• On minimum cyclic AMP formation rates associated with positive inotropic effects mediated through beta 1-adrenoceptors in kitten myocardium. Beta 1-specific and non-adrenergic stimulant effects of denopamine [15].
• The maximum response of ICa was only a quarter of that induced by isoprenaline (ISO), while 10 microM denopamine elicited 70-75% of the maximum inotropic response in the papillary muscle preparations [16].

Gene context of TA 064

• In contrast, denopamine was a partial selective beta-1 adrenoceptor agonist (Emax = 0.75-0.85) [14].
• 3. Denopamine-induced dilations were significantly inhibited by 1 nmol betaxolol (a selective beta1-adrenoceptor antagonist), but it was not influenced by 1 nmol ICI 118,551 (a selective beta2-adrenoceptor antagonist) [17].
• In failing ventricular chambers with a beta 1/beta 2 receptor subtype ratio reduced from 82/19 (nonfailing) to 64/36 (p less than 0.001) and a beta 1-receptor density reduced by 61% (p less than 0.001), maximal denopamine stimulation was reduced by 49% (p less than 0.001) [13].
• Regioselective glucuronidation of denopamine: marked species differences and identification of human udp-glucuronosyltransferase isoform [12].
• In 9 patients with dilated cardiomyopathy, the effects of beta 1-agonist were tested at the beginning of therapy (30 mg/day denopamine) and 6 months later [18].

Analytical, diagnostic and therapeutic context of TA 064

• Symptom-limited exercise testing (ramp protocol) on a bicycle ergometer with gas exchange analysis was conducted 1 hour after oral administration of either 20 mg denopamine or placebo [2].
• Short-term effects of denopamine on anaerobic threshold and related parameters in patients with chronic heart failure: a double-blind crossover study [2].
• Enantiomer separation of denopamine by capillary electrophoresis with charged and uncharged cyclodextrins [19].
• Determination of denopamine in human and dog plasma by high-performance liquid chromatography with electrochemical detection [20].
• Long-term denopamine therapy for hemodialysis patients with chronic heart failure [21].

References