Heparin-Protamine Complexes Cause Pulmonary Hypertension in Goats

Horiguchi, Takashi; Enzan, K; Mitsuhata, H; Murata, Makoto; Suzuki, Masahiro

doi:10.1097/00000542-199510000-00018

Cited by 34 publications

(12 citation statements)

References 11 publications

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“…Morel et al (3) and Horiguchi et al (20) demonstrated that the heparinprotamine complex induced bronchoconstriction and pulmonary hypertension in vivo, respectively. These constrictive phenomena are thought to be induced by thromboxane A 2 generation after protamine reversal of heparin (3,20). Thus, the direct inhibitory effect of heparin-protamine complex on the carbachol-induced contraction of airway smooth muscle seen in this study is not incompatible with these data.…”

Section: Discussionsupporting

confidence: 58%

The Direct Effects of Heparin and Protamine on Canine Tracheal Smooth Muscle Tone

Yamakage

Matsuzaki

Tsujiguchi

et al. 1999

Anesthesia &Amp; Analgesia

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Heparin and protamine are used for cardiopulmonary bypass in cardiac surgery; however, the direct effects and mechanisms of these drugs on airway smooth muscle tone are still not fully known. We investigated the in vitro effects of these drugs on canine tracheal smooth muscle by measuring the muscle tension and intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and by measuring inward Ca 2ϩ currents (I Ca ) through voltage-dependent Ca 2ϩ channels.[Ca 2ϩ ] i was monitored by the 500-nm light emission ratio of preloaded Ca 2ϩ indicator fura-2. Isometric tension was measured simultaneously. Whole-cell patch clamp recording techniques were used to investigate the effects of the drugs on I Ca in freshly dispersed smooth muscle cells. Heparin (0.12-120 U/mL), protamine (0.15-150 U/mL), or heparin-protamine complex (4:5 U/U) was introduced into a bath solution. Protamine and heparinprotamine complex dose-dependently inhibited both carbachol-induced contraction of the muscle and increase in [Ca 2ϩ ] i . These drugs also decreased the I Ca of the muscle cells and shifted the inactivation curve to a more negative potential. Heparin itself had a slight enhancing effect on carbachol-induced muscle contraction without changing [Ca 2ϩ ] i . Protamine and heparin-protamine complex can decrease the agonist-induced increase in [Ca 2ϩ ] i by the inhibition of voltage-dependent Ca 2ϩ channels both in the activated and inactivated states. Implications: Protamine and heparin-protamine complex inhibited carbachol-induced canine tracheal smooth muscle contraction by inhibiting the increase in intracellular concentration of free Ca 2ϩ . These drugs can decrease the agonistinduced increase in intracellular Ca 2ϩ by the inhibition of voltage-dependent Ca 2ϩ channels in both the activated and inactivated states.

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Section: Discussionsupporting

confidence: 58%

The Direct Effects of Heparin and Protamine on Canine Tracheal Smooth Muscle Tone

Yamakage

Matsuzaki

Tsujiguchi

et al. 1999

Anesthesia &Amp; Analgesia

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“…Beyond the speculative aspects on human disease, our data and previous investigations (60) support the fact that different Nox in different species and models of PH can contribute to PH development. The mechanism described in the current article would be taken into account for PH development not only in humans, but also in animals such as cattle, horses, sheep, goats, and dogs (26,34,37).…”

mentioning

confidence: 99%

Function of NADPH Oxidase 1 in Pulmonary Arterial Smooth Muscle Cells After Monocrotaline-Induced Pulmonary Vascular Remodeling

Veit

Pak

Egemnazarov

et al. 2013

Antioxidants & Redox Signaling

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“…The changes seen were limited solely to RL, and not in either EL or the chest wall mechanical properties. This is not unexpected, given that protamine complexes can enhance the production of thromboxanes via the archidonic acid pathway, with resultant bronchoconstriction and pulmonary hypertension (14). Bronchoconstriction should I4I affect predominantly RL through narrowing of the mid-size (&dquo;resistance&dquo;) airways, and not necessarily EL, which is related to more distal, complex alveolar processes.…”

Section: Discussionmentioning

confidence: 98%

Protamine Reversal of Heparin After Cardiopulmonary Bypass Increases Lung Resistance, Not Elastance

Gilbert

Barnas

Miller

et al. 1999

J Cardiovasc Pharmacol Ther

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BACKGROUND: Protamine, an immunologically active, cationic amine, has been suspected of impairing lung mechanics when administered after cardiopulmonary bypass (CPB) to reverse heparin. Whether such adverse changes are an effect of protamine itself, the formation of heparin-protamine complexes, the extent of heparin anticoagulation, or its chemical reversal is not known. METHODS AND RESULTS: Using a computer-controlled, forced-ventilation method over a variety of physiological tidal volume (V(T)) and frequency (f) combinations, we prospectively studied 18 adult, elective patients before systemic heparinization and after protamine reversal to confirm and, possibly, elucidate an etiology for any adverse pulmonary effects. Protamine and heparin doses, their sum (Sigma-dose) and differential (Delta-dose) doses, and activated clotting times were tabulated. In all patients, lung resistance (R(L)) and, to a lesser extent, elastance (E(L)) increased after CPB, compared with pre-CPB values (P <.05). However, R(L) particularly increased after CPB with increases correlated to the Delta-dose, where R(LPRE-->POST) = -0.037 [Delta-dose] - 0.56f \_ 0.019V(T) + 36.1 (r =.652, P <.05). No other significant correlations were found among the remaining clinical parameters and changes in either R(L) or E(L), or any chest wall component (all P >.05). CONCLUSIONS: The changes seen in R(L) after CPB were greatest in those patients receiving the most nearly balanced doses of heparin and protamine, and were not related significantly to the total heparin or protamine doses, or their sum. These suggests that the extent of anticoagulation reversal or formation of heparin-protamine complexes, and not protamine itself, are more responsible for changes seen in lung mechanics. The changes seen were limited solely to R(L), and not in either E(L) nor the chest wall mechanical properties.

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Heparin-Protamine Complexes Cause Pulmonary Hypertension in Goats

Abstract: H-P complexes play a major role in pulmonary hypertension after protamine reversal of heparin, and thromboxane A2 is a main mediator of the pulmonary hypertensive response to H-P complexes in goats.

Cited by 34 publications

References 11 publications

The Direct Effects of Heparin and Protamine on Canine Tracheal Smooth Muscle Tone

The Direct Effects of Heparin and Protamine on Canine Tracheal Smooth Muscle Tone

Function of NADPH Oxidase 1 in Pulmonary Arterial Smooth Muscle Cells After Monocrotaline-Induced Pulmonary Vascular Remodeling

Protamine Reversal of Heparin After Cardiopulmonary Bypass Increases Lung Resistance, Not Elastance

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