The world would be a wonderful place if our natural resources (e.g., forests, fish, and wildlife) needed no management and conservation was not a concern. In a world with a global human population approaching 7 billion and where most developed nations overconsume these resources, however, conservation is a concern and management is necessary for sustainable use. Historically, natural resource management strategies were determined by the collection and interpretation of basic field data. Today, as challenges to the sustainability and conservation of our natural resources arise, managers often need data that cannot be acquired using conventional methods. For example, a natural resource manager might want to know the number of successful breeders in a population or if genetic variation was being depleted because of a management practice. Traditional field craft alone cannot directly address such questions, but the answers can be determined with some precision if the field work is coupled with modern molecular genetic techniques.
Molecules can enlighten us about biological attributes that are virtually impossible to observe in the field (Avise 2004). Parentage analysis is one such arena in which genetic data can inform management practices (DeWoody 2005), but there are a host of others. For example, molecular data have revealed deep evolutionary splits in stocks at one time thought to be homogeneous. This finding has concomitant management implications (Hoffman et al. 2006). Similarly, molecules can enlighten us about biologies that are virtually impossible to observe in the field, such as pollen flow (Hamrick, this volume) or the physiology of migration (Nichols et al. 2008).
Calcium sensitisers are a new class of positive inotropic drugs that are potentially useful in the treatment of acute decompensated heart failure. They have a unique mechanism of action that differs from other available intravenous agents such as dobutamine, a β-agonist, and milrinone, a phosphodiesterase inhibitor. Unlike dobutamine and milrinone, calcium sensitisers increase myocardial contractility without increasing cytosolic calcium release, reducing myocardial energy demand and the incidence of serious arrhythmias. Clinical trials have focused on demonstrating improved survival with levosimendan when compared to placebo and dobutamine. Levosimendan is the first intravenous calcium sensitiser to be approved in Europe for the treatment of acute decompensated heart failure.
Levosimendan is a pyridazinone-dinitrile derivative with the chemical name ((R) − (4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl)hydrazono)propanedinitrile. Levosimendan is the levo-isomer of the racemic compound simendan. It is moderately lipophilic with a small molecular weight (280.29) and is a weak acid (pKa 6.26).
β-adrenergic agonists and phosphodiesterase inhibitors produce positive inotropic effects by increasing intracellular concentrations of free calcium. This energy-dependent process involves increasing the intracellular concentration of cyclic adenosine monophosphate (cAMP). Levosimendan has a dual mechanism of action, acting as a positive inotrope and a vasodilator. The positive inotropic effect of levosimendan is achieved by calcium sensitisation rather than increasing intracellular free calcium concentration, therefore avoiding the energy-dependent process. Levosimendan binds to cardiac troponin C and stabilises the conformational changes of troponin C, facilitating actin-myosin cross-bridge formation. This binding occurs in a calcium concentration-dependent manner.
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