Myocardial contractility impairment with racemic bupivacaine, non-racemic bupivacaine and ropivacaine. A comparative study

PURPOSE: To study racemic bupivacaine, non-racemic bupivacaine and ropivacaine on myocardial contractility. METHODS: Isolated Wistar papillary muscles were submitted to 50 and 100 mM racemic bupivacaine (B50 and B100), non-racemic bupivacaine (NR50 and NR100) and ropivacaine (R50 and R100) intoxication. Isometric contraction data were obtained in basal condition (0.2 Hz), after increasing the frequency of stimulation to 1.0 Hz and after 5, 10 and 15 min of local anesthetic intoxication. Data were analyzed as relative changes of variation. RESULTS: Developed tension was higher with R100 than B100 at D1 (4.3 ± 41.1 vs -57.9 ± 48.1). Resting tension was altered with B50 (-10.6 ± 23.8 vs -4.7 ± 5.0) and R50 (-14.0 ± 20.5 vs -0.5 ± 7.1) between D1 and D3. Maximum rate of tension development was lower with B100 (-56.6 ± 38.0) than R50 (-6.3 ± 37.9) and R100 (-1.9 ± 37.2) in D1. B50, B100 and NR100 modified the maximum rate of tension decline from D1 through D2. Time to peak tension was changed with NR50 between D1 and D2. CONCLUSIONS: Racemic bupivacaine depressed myocardial contractile force more than non-racemic bupivacaine and ropivacaine. Non-racemic and racemic bupivacaine caused myocardial relaxation impairment more than ropivacaine. .

Inibição da corrente de cálcio tipo l por tramadol e enantiômeros em miócitos cardíacos de ratos / Inhibition of L-type calcium current by tramadol and enantiomers in cardiac myocytes from rats

FUNDAMENTO: O tramadol é um analgésico de ação central cujo mecanismo de ação envolve a ativação de um receptor opioide. Anteriormente, mostramos que o tramadol e seus enantiômeros apresentavam um efeito inotrópico negativo sobre o músculo papilar no qual o (+)-enantiômero era mais potente que (-)- e (±)-tramadol. OBJETIVO: No presente trabalho, investigamos os efeitos do tramadol e seus enantiômeros na corrente de cálcio tipo L (I Ca-L). MÉTODOS: Os experimentos foram realizados em miócitos ventriculares isolados de ratos Wistar utilizando a técnica de patch-clamp com configuração de célula inteira. RESULTADOS: O tramadol (200 µM) reduziu a amplitude de pico do I Ca-L em potenciais de 0 a +50 mV. Em 0 mV, a I Ca-L foi reduzida em 33,7 ± 7,2 por cento. (+)- e (-)-tramadol (200 µM) produziram uma inibição semelhante da I Ca-L, na qual a amplitude do pico foi reduzida em 64,4 ± 2,8 por cento e 68,9 ± 5,8 por cento, respectivamente a 0 mV (P > 0,05). O tramadol, (+)- e (-)-tramadol mudaram a inativação de estado estacionário de I Ca-L para potenciais de membrana mais negativos. Além disso, tramadol e (+)-tramadol alteraram significativamente a curva de recuperação dependente de tempo da I Ca-L para a direita e reduziram a recuperação de I Ca-L da inativação. A constante de tempo foi aumentada de 175,6 ± 18,6 a 305,0 ± 32,9 ms (P < 0,01) para o tramadol e de 248,1 ± 28,1 ms para 359,0 ± 23,8 ms (P < 0,05) para o (+)-tramadol. O agonista do receptor µ-opioide (DAMGO) não tem nenhum efeito na I Ca-L. CONCLUSÃO: A inibição da I Ca-L induzida por tramadol e seus enantiômeros não teve relação com a ativação de receptores opioides e poderia explicar, pelo menos em parte, seu efeito inotrópico negativo cardíaco.

BACKGROUND: Tramadol is a centrally acting analgesic, whose mechanism of action involves opioid-receptor activation. Previously, we have shown that tramadol and its enantiomers had a negative inotropic effect on the papillary muscle in which the (+)-enantiomer is more potent than (-)- and (±)-tramadol. OBJECTIVE: In this study, we investigated the effects of tramadol and its enantiomers on L-type calcium current (I Ca-L). RESULTS: Tramadol (200 µM) reduced the peak amplitude of I Ca-L at potentials from 0 to +50 mV. At 0 mV, I Ca-L was reduced by 33.7 ± 7.2 percent. (+)- and (-)-tramadol (200 µM) produced a similar inhibition of I Ca-L, in which the peak amplitude was reduced by 64.4 ± 2.8 percent and 68.9 ± 5.8 percent, respectively at 0 mV (p > 0.05). Tramadol, (+)- and (-)-tramadol shifted the steady-state inactivation of I Ca-L to more negative membrane potentials. Also, tramadol and (+)-tramadol markedly shifted the time-dependent recovery curve of I Ca-L to the right and slowed down the recovery of I Ca-L from inactivation. The time constant was increased from 175.6 ± 18.6 to 305.0 ± 32.9 ms (p < 0.01) for tramadol and from 248.1 ± 28.1 ms to 359.0 ± 23.8 ms (p < 0.05) for (+)-tramadol. The agonist of µ-opioid receptor DAMGO had no effect on the I Ca-L. CONCLUSION: The inhibition of I Ca-L induced by tramadol and its enantiomers was unrelated to the activation of opioid receptors and could explain, at least in part, their negative cardiac inotropic effect.

Eucalyptol, an essential oil, reduces contractile activity in rat cardiac muscle

Eucalyptol is an essential oil that relaxes bronchial and vascular smooth muscle although its direct actions on isolated myocardium have not been reported. We investigated a putative negative inotropic effect of the oil on left ventricular papillary muscles from male Wistar rats weighing 250 to 300 g, as well as its effects on isometric force, rate of force development, time parameters, post-rest potentiation, positive inotropic interventions produced by Ca2+ and isoproterenol, and on tetanic tension. The effects of 0.3 mM eucalyptol on myosin ATPase activity were also investigated. Eucalyptol (0.003 to 0.3 mM) reduced isometric tension, the rate of force development and time parameters. The oil reduced the force developed by steady-state contractions (50 percent at 0.3 mM) but did not alter sarcoplasmic reticulum function or post-rest contractions and produced a progressive increase in relative potentiation. Increased extracellular Ca2+ concentration (0.62 to 5 mM) and isoproterenol (20 nM) administration counteracted the negative inotropic effects of the oil. The activity of the contractile machinery evaluated by tetanic force development was reduced by 30 to 50 percent but myosin ATPase activity was not affected by eucalyptol (0.3 mM), supporting the idea of a reduction of sarcolemmal Ca2+ influx. The present results suggest that eucalyptol depresses force development, probably acting as a calcium channel blocker.

Action potential duration and contraction after rest at room temperature in guinea pig papillary muscle

Simultaneous recordings of action potential and isometric tension of right papillary muscles were performed. After regular stimulation at 1 Hz, pauses of 10 min were allowed. In the first beat after rest, we measured action potential duration at the 90 percent of the repolarization (APD90), maximal twitch tension (T), time to peak of contraction (TTP), and rate of development of tension (+dT/dt) and relaxation (-dT/dt). Values were normalized against pre-rest ones. No significative changes were observed after rest at 35 degrees Celsius. After rest at 25 degrees Celsius APD90 and TTP were prolonged but T was reduced. Post-rest+dT/dt were shower, dT/dt did not shown significative changes. Nifedipine 10 muM prevented post-rest APD90 tengthening, and produced a further reduction of mechanical response. Substitution of external Na+ by Li+ shortened APD90, increased T of either regular or post-rest beats and led to calcium overload signs. When pause were allowed during Na+ substitution, calcium overload signs were attenuated. We conclude that the combination of rest and room temperature diminished [Ca++]i mainly by Na+/Ca++ mechanism. The reduction of [Ca++]i in turn could delay the inactivation of iCa. As a consequence, longer APs were obtained, accompanied by weaker and slower mechanical responses. Changes in TTP and +dT/dt could suggest that post-rest contractions in room temperature, are dependent of extracellular Ca++ rather than a deplected RS.

Effects of mercury on the contractility of isolated rat cardiac muscle

The effects of increasing concentrations of mercury (Hg2+) chloride (1, 2.5, 5 and 10 microM) were studied on isometrically contracting papillary muscles from female rats (Wistar, EPM strain) weighing 150 to 180 g. Hg2+ promoted an increase of 12.7 +/- 2.2% in the developed force at 1 microM. At 2.5 microM, force values were similar to control, decreasing progressively as Hg2+ concentration increased to 5 (-13 +/- 6.4%) and 10 microM (-37 +/- 12.3%). Potentiated post-rest contractions (PRC) were also determined after 15-, 30- and 60-s pauses. There was a progressive reduction of the potentiated PRCs relative to their respective steady-state control contractions with increasing concentrations of HgCl2. Since in several tissues including myocardium Hg2+ inhibits the activity of Ca2+ and Na(+)-K(+)-ATPases the results described here suggest that Hg2+, at lower concentrations, could increase force by inhibiting Na(+)-K(+)-ATPase, while at higher concentrations Hg2+ would decrease relative PRC potentiation by inhibiting sarcoplasmic reticulum Ca(2+)-ATPase

Control of rest potentiation in ventricular myocardium by the Na-Ca exchange mechanism

To reinvestigate the possible regulating activity of the Na-Ca exchange mechanism on the rest potentiation phenomenon post rest contraction force development was studied in isometrically contracting rat papillary muscles, stimulated at a rate of 30/min and submitted to pauses varying from 5 to 60 seconds. The Na-Ca exchange activity was analysed using the relationship between the amplitude of the first post rest contractions and the steady state control contractions (relative potentiation) and by the changes of internal Na that are known to affect the Na-Ca exchange activity. Maneuvers that increased the internal Na concentration as high rate of stimulation and high external Na produced an increase of the relative potentiation. This was seen when stimulation rate was changed from 30/min to 60/min, even in low extracellular. Na concentration. On the other hand, the blockade of the fast Na channel by propafenone and the reduction of the external Na concentration, that are known to reduce internal Na, diminished the relative potentiation. These results suggest that the activity of the Na/Ca exchange mechanism might control the rest potentiation effects in cardiac muscle

Effects of Vanadate on Cellular Ca2+ Movements in Guinea Pig Papillary Muscles

The effects of vanadate on cellular Ca2+ movements across the sarcolemma of cardiac muscle cells were investigated by measuring the intracellular and extracellular Ca2+ activities of guinea pig papillary muscle with Ca2+-selective electrodes. During the rest period following a steady-state of 2 contractions per second the extracellular Ca2+ concentration was increased over the basal level within a minute. During the rest period Ca2+ was transported across the sarcolemma into the extracellular space. Vanadate decreased the change in extracellular Ca2+ concentration during the rest period implying that the Ca2+ efflux across the sarcolemma was decreased by vanadate. Vanadate increased intracellular Ca2+ activities significantly (from 1.9 X 10(-7) M to 10(-6)M) resulting in an increase in resting tension. These results suggest that vanadate decreases Ca2+ efflux from the cells into the extracellular space by blocking Ca2+ transport across the sarcolemma, possibly blocking the Na+-Ca2+ exchange transport.