Interdependence Between Cardiac Function, Oxygen Demand, and Supply
Samuel Sideman, Rafael Beyar in Analysis and Simulation of the Cardiac System — Ischemia, 2020
A similar response in efficiency was observed when a combination of positive inotropic agents, having different mechanisms of action, was administered to patients with documented idiopathic dilated cardiomyopathy.8 The combined effects of a beta adrenergic receptor agonist, dobutamine (15 |xg/kg/min), and a phosphodiesterase inhibitor, amrinone (1 mg/kg), on minute work were found to be additive without an adverse elevation in (MV̇O2) or the appearance of myocardial lactate production. Therefore, the clinical experience to date with positive inotropic agents indicates that, in the nonischemic, enlarged, and failing heart, cardiac performance is not restricted by a limitation in its O2 availability and myocardial efficiency is increased.
Heart failure with reduced ejection fraction in older adults
Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich in Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
The long-term use of oral phosphodiesterase inhibitors, such as amrinone, milrinone, and vesnarinone, is associated with increased mortality (104,143); thus, these drugs and are not approved for clinical use. Intravenous milrinone is also not associated with significant mortality benefit (144,145). The calcium-sensitizing phosphodiesterase inhibitor levosimendan has been shown to improve hemodynamic function and symptoms in younger patients with decompensated HF (146), but it does not have a mortality benefit compared with dobutamine (147,148). Synthetic catecholamines such as dobutamine or dopamine may also be used intravenously to treat refractory HF symptoms although older HFrEF patients may derive smaller hemodynamic benefits (149).
Receptors and Signal Transduction Pathways Involved in Autonomic Responses
Kenneth J. Broadley in Autonomic Pharmacology, 2017
Selective PDE III inhibitors have been developed for the treatment of congestive heart failure, their cardiotonic activity providing inotropic support to the heart and vasodilatation reducing pre- and after-load. Amrinone was the lead compound of this class and was the first to be approved in the USA for short-term intravenous administration in patients with severe heart failure refractory to other measures. Other agents of this type include milrinone (PrimacorR), enoximone (PerfanR), imazodan, siguazodan, SK&F 94120 and potent derivatives, cilostamide and lixazinone (Table 13.4). In clinical trials these compounds have shown short-term haemodynamic improvement in patients with heart failure; however, long-term therapy with PDE III inhibitors has generally resulted in increased mortality and evidence of modification of the underlying disease process is lacking. As a result these agents are restricted to acute use in severe cardiac failure. They may also have the disadvantage of having an arrhythmic potential. Agents that combine PDE inhibitory activity with the ability to sensitize the contractile myofibrils to Ca2+ and anti-arrhythmic activity may prove more useful than those with PDE III inhibitory activity alone (eg Org 30029). Combination with β-adrenoceptor blocking activity, in the compound GI104313, may also have the advantage of preventing the undesirable cardiac arrythmias. The positive inotropy of PDE III inhibition would also offset the negative inotropy of the β-blockade (Shaffer et al. 1993). Although only 2% of the total cardiac cAMP hydrolytic activity resides in the SR fraction, it appears that PDE III inhibitors act at the level of the SR-PDE III (Nicholson et al. 1991, Thompson 1991).
Proteomics based drug repositioning applied to improve in vitro fertilization implantation: an artificial intelligence model
Published in Systems Biology in Reproductive Medicine, 2021
Roberto Matorras, Raquel Valls, Mikel Azkargorta, Jorge Burgos, Aintzane Rabanal, Felix Elortza, Jose Manuel Mas, Teresa Sardon
Amrinone is a phosphodiesterase inhibitor that prevents the degradation of cAMP. Since high intracellular cAMP levels are required for the initiation of decidualization, the drug may support this biological process. Amrinone also inhibits the production of TNFα, which plays a role in implantation, as discussed above. Amrinone is an excellent candidate that may promote decidualization while averting implantation failure induced by excessive TNF.
Treatment for beta-blocker poisoning: a systematic review
Published in Clinical Toxicology, 2020
Joe-Anthony Rotella, Shaun L. Greene, Zeff Koutsogiannis, Andis Graudins, Yit Hung Leang, Kelvin Kuan, Helen Baxter, Elyssia Bourke, Anselm Wong
Three animal studies have examined the effect of glucagon and a phosphodiesterase inhibitor (milrinone or amrinone) in treating propranolol toxicity induced in mongrel dogs [29,30,53]. Amrinone temporarily increased cardiac output, but had no effect on heart rate [30]. Milrinone increased cardiac output in mongrel dogs compared to controls but had no effect on heart rate [29,53]. Measures of survival between groups were not reported.
Effects of inhibition of phosphodiesterase 3B in pancreatic islets on insulin secretion: a potential link with some stimulatory pathways
Published in Archives of Physiology and Biochemistry, 2021
Agnieszka Kilanowska, Tomasz Szkudelski
Based on the literature data, it can be concluded that bipyridine derivatives, including amrinone, are one of the most effective inhibitors of PDE3B isoform in pancreas (Parker et al.1995). We have previously shown that inhibition of this enzyme by amrinone increases insulin secretion induced by 6.7 mM glucose in pancreatic islets of non-diabetic rats (Zywert et al.2014). In the current study, incubation of isolated pancreatic islets was performed for 15, 30 and 90 min to determine the time-dependent effects of amrinone on glucose-induced insulin secretion. It was demonstrated that in each of those intervals, there was a significant increase in insulin release in response to amrinone. These results provide a basis for a conclusion that the used inhibitor penetrates into β cells in a relatively short time, enhancing hormone secretion. This is in line with the outcomes of our preliminary study using pancreas perfusion in situ in non-diabetic rats (Zywert et al.2014). The obtained results also prove the effectiveness of amrinone in rat islets. The potentiation of insulin secretion, observed in the presence of amrinone, is associated with the increase of intracellular cAMP concentration, which is to a certain degree, a reflection of glucose metabolism in β cells. However, the intracellular pool of cAMP depends not only on the rate of its synthesis, but also the rate of degradation. Therefore, its concentration is also largely dependent on the activity of PDE, mostly PDE3B. It is estimated that out of all isoforms of phosphodiesterases, PDE3B is responsible for the hydrolysis of approximately 70% of cAMP in endocrine pancreas (Tengholm 2012). However, increased insulin secretion from isolated pancreatic islets depends on the concentration of glucose in the incubation buffer. In our studies, we did not observe changes in insulin secretion after exposure to glucose at 2.8 mM and with amrinone incubated with glucose at the same concentration (Figure 7).
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