Negative cardiovascular side effects of PS have been described in human patients ( Conahan et al., 1981 Shapira et al., 1982) as well as in animals ( Goldman et al.,1969). However, increasing evidence from clinical and experimental data indicated a direct influence of PS on the myocardial tissue. Being a polycationic peptide, it reverses the anticoagulant effects of the highly negatively charged heparin by forming a complex with heparin ( Viaro et al., 2002).Īlthough studies on healthy volunteers who received PS intravenously showed rapid decrease in protamine blood concentration, no significant changes were found in heart rate, mean arterial blood pressure, or cardiac output ( Butterworth et al., 2002). Among these, protamine sulfate (PS) is commonly used as an antidote for heparin. We propose that this excessive increase in ROS concentrations results in mitochondrial dysfunction and thus might relate to the “protamine reaction,” contributing to the development of various cardiovascular adverse effects.ĭuring cardiovascular surgical procedures, a number of drugs are administered depending on the patients’ condition and the surgical procedure. This effect was associated with a strong consequent increase in the production of ROS, i.e., 85% and 88.6% compared with control respectively. Furthermore, the inhibition of mitochondrial respiration by PS was concentration dependent and accompanied by hyperpolarization of the mitochondrial membrane potential (Δ ψ m), i.e., 18% increase at 50 µg/ml and an additional 3.3% increase at 250 µg/ml PS compared with control. 38.0 ± 9.9 nmol O 2 ⋅min −1⋅ml −1, P < 0.001) and later stimulated by substrates of cytochrome oxidase (CytOx) i.e., ascorbate and tetramethyl phenylene diamine, suggesting that PS exerted its effect through inhibition of CytOx activity. The same effect was found when respiration was inhibited by antimycin A (101.0 ± 8.9 vs. PS inhibited intact rat heart mitochondrial respiration (stimulated by ADP) to 76% ( P < 0.001) from the baseline of 51.6 ± 6.9 to 12.4 ± 2.3 nmol O 2⋅min −1⋅ml −1.

Polarographic measurements were performed in parallel to membrane potential and ROS measurements by FACS analyzer using tetramethylrhodamine ethyl ester and MitoSOX fluorescent dyes, respectively. Here we show the effect of PS on mitochondrial bioenergetics profile resulting in mitochondrial reactive oxygen species (ROS) production. Protamine sulfate (PS) is widely used in heart surgery as an antidote for heparin, albeit its pharmacological effects are not fully understood and applications are often accompanied by unwanted side effects.

Protamine sulfate antidote