Levosimendan has inotropic and lusitropic actions in failing human myocardium. Comparison with the phosphodiesterase inhibitor milrinone indicates that in case of pronounced inotropic stimulation, the modes of action of the two agents may be similar (phosphodiesterase inhibition), whereas small inotropic effects of levosimendan may result predominantly from calcium sensitization.

Vascular reactivity to nitric oxide (NO) is mediated by NO-sensitive soluble guanylyl cyclase (sGC). Since a diminished activity of vascular sGC has been reported in an animal model of type 2 diabetes, the sGC activity was assayed in vitro in internal mammary artery specimens obtained during bypass surgery from patients with and without type 2 diabetes. The sensitivity of sGC to NO, which is dependent on Fe 2؉ -containing heme, was measured in vitro using stimulation with diethylamine NONOate (DEA/NO). In addition, the novel cyclic guanosine monophosphate-elevating compound HMR-1766 was used to test the stimulation of the oxidized heme-Fe 3؉ -containing form of sGC. Basal activity of sGC and its sensitivity to stimulation by DEA/NO and HMR-1766 were not different between control and type 2 diabetic patients: maximum stimulation by DEA/NO amounted to 475 ؎ 67 and 418 ؎ 59 pmol ⅐ mg ؊1 ⅐ min ؊1 in control and type 2 diabetic patients, respectively. The maximum effects of HMR-1766 were 95 ؎ 18 (control subjects) and 83 ؎ 11 pmol ⅐ mg ؊1 ⅐ min ؊1 (type 2 diabetic patients). Hypertension, hyperlipidemia, drug treatment with statins, ACE inhibitors, or nitrates had no effect on sGC activity. In conclusion, the present findings do not support the hypothesis that desensitization of sGC contributes to the pathogenesis of diabetic vascular dysfunction in humans. Diabetes 53

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This study confirms previous reports of impaired cardiac function after high catecholamine exposure. High catecholamine exposure is associated with a desensitization of contractile proteins for calcium. Acute T3 administration increased contractility in untreated myocytes, but further depressed myocyte shortening in epinephrine-treated cells. Our results show that T3 is ineffective at restoring myocardial contractility after excessive catecholamine stimulation.

The data show, that severe impairment of contractile function ('negative staircase phenomenon', reduced force, elevated diastolic calcium) is present in MVI classified as NYHA (III)-(IV) that may explain the poor long-term results. Most interestingly the data argue for a significant impairment of myocardial function even in NYHA (II) MVI. The results suggest an early surgical treatment of mitral valve incompetence as long as the myocardial function is normal (NYHA (I)) as (1) a reduced perioperative risk, (2) improved long-term results, and (3) a higher probability for mitral valve repair (instead of replacement) may be expected in these early stages of mitral valve disease.