Levosimendan alone and in combination with valsartan prevents stroke in Dahl salt-sensitive rats

Abstract

The effects of levosimendan on cerebrovascular lesions and mortality were investigated in models of primary and secondary stroke. We aimed to determine whether the effects of levosimendan are comparable to and/or cumulative with those of valsartan, and to investigate whether levosimendan-induced vasodilation has a role in its effects on stroke. In a primary stroke Dahl/Rapp rat model, mortality rates were 70% and 5% for vehicle and levosimendan, respectively. Both stroke incidence (85% vs. 10%, P<0.001) and stroke-associated behavioral deficits (7-point neuroscore: 4.59 vs. 5.96, P<0.001) were worse for vehicle compared to levosimendan. In a secondary stroke model in which levosimendan treatment was started after cerebrovascular incidences were already detected, mean survival times were 15 days with vehicle, 20 days with levosimendan (P=0.025, vs. vehicle), 22 days with valsartan (P=0.001, vs. vehicle), and 31 days with levosimendan plus valsartan (P<0.001, vs. vehicle). The respective survivals were 0%, 16%, 20% and 59%, and the respective incidences of severe lesions were 50%, 67%, 50% and 11%. In this rat model, levosimendan increased blood volume of the cerebral vessels, with significant effects in the microvessels of the cortex (∆R=3.5±0.15 vs. 2.7±0.17ml for vehicle; P=0.001) and hemisphere (∆R=3.2±0.23 vs. 2.6±0.14ml for vehicle; P=0.018). Overall, levosimendan significantly reduced stroke-induced mortality and morbidity, both alone and with valsartan, with apparent cumulative effects, an activity in which the vasodilatory effects of levosimendan have a role.

Levosimendan in intensive care and emergency medicine: literature update and expert recommendations for optimal efficacy and safety

“…Of further note in this context is recent work by Trinh-Duc et al [ 72 ] that elegantly supports the rationale of using levosimendan instead of dobutamine or phosphodiesterase-III inhibitors to treat TTS induced by a subarachnoid haemorrhage: saving the brain from disastrous vasospasms while protecting the heart from excessive catecholamines and promoting recovery of faster contractile function. This is a development of a concept introduced in previous publications [ 73 , 74 ] but is still at too early a stage of assessment to be commented on further in this review.…”

Levosimendan inhibits disulfide tau oligomerization and ameliorates tau pathology in TauP301L-BiFC mice

“…There is also evidence indicating that the neuroprotective effect of levosimendan is associated with its action as a vasodilator. In 2015, Levijoki et al reported that orally administered levosimendan increased the blood volume of the cerebral vessels, reducing mortality and morbidity in rat models of primary and secondary stroke 65 . In 2015, Matti Kivikko et al reported a pilot study showing that low-dose oral administration of levosimendan increased cerebral blood flow velocities in patients with an earlier ischemic cerebrovascular event, supporting the vasodilatory effect in the brain circulation 66 .…”

Levosimendan prevents tau pathology by inhibiting disulfide-linked tau oligomerization posing as a promising anti-tau therapeutics

“…There are also evidences indicating that the neurorotective effect of levosimendan is associated with its action as a vasodilator. In 2015, Levijoki et al reported that orally administered levosimendan increased blood volume of the cerebral vessels, reducing mortality and morbidity in rat models of primary and secondary stroke 53 . In 2015, Matti Kivikko et al reported a pilot study showing that low dose oral administration of levosimendan increased cerebral blood ow velocities in patients with an earlier ischemic cerebrovascular event, supporting the vasodilatory effect in the brain circulation 54 .…”