Lidocaine does not affect myocardial electrical heterogeneity: implications for low proarrhythmic actions.

An area of unidirectional conduction block is one requirement for reentrant arrhythmias to occur. Functional block caused by dispersion of repolarization and refractoriness is the most probable mechanism of drug-induced unidirectional conduction block. We assessed the effects of lidocaine on spatial dispersion of myocardial repolarization and refractoriness in the intact porcine heart. Monophasic action potential duration at 90% repolarization, effective refractory period (ERP), and ventricular fibrillation cycle length (VFCL) were measured at two endocardial and one epicardial sites at baseline and during a treatment phase with D5W (n=11) or lidocaine 10 mg/kg/hour (n=12). Dispersion was calculated as the difference between the maximum and minimum values of the three recording sites. Lidocaine produced significant changes in ERP, VFCL, paced QRS duration, and intraventricular conduction time. It did not change basal levels of dispersion in repolarization and refractoriness. Lidocaine produced changes in myocardial electrophysiology that are uniform across the myocardium and thus did not change myocardial electrical heterogeneity. This may be a mechanism of the agent's lower proarrhythmic effects compared with other sodium channel blockers that increase myocardial electrical heterogeneity.

Importance of nitric oxide in hepatic arterial blood flow and total hepatic blood volume regulation in pigs.

The importance of nitric oxide in regulating basal arterial blood flow has been examined in several different vascular beds by intra-arterial infusion of inhibitors of nitric oxide synthesis, but not in the arterial vascular bed of the liver. In the present study, N(G)-nitro-L-arginine (L-NNA), in a dose of 0.5 and 1.0 mumol mL-1 of hepatic arterial blood flow, was infused for 5 min into the hepatic artery in seven pigs anaesthetized with pentobarbital sodium. The haemodynamic effects observed by the first infusion were not further enhanced by the second infusion. Hepatic arterial resistance increased by 143 +/- 38% and hepatic arterial blood flow declined by 38 +/- 10%. A systemic effect due to 'spillover' was observed, as evidenced by an increase in mean aortic blood pressure of 24 +/- 4 mmHg. However, no significant increase in arterial mesenteric resistance was observed and total liver blood flow remained unchanged. Hepatic arterial vasodilation in response to occlusion of the portal vein, the arterial buffer response, remained intact after inhibition of nitric oxide synthesis. Liver lobe thickness, measured by an ultrasonic technique, was not found to change with inhibition of arterial nitric oxide synthesis, excluding a significant direct effect of arterial nitric oxide on liver capacitance. In conclusion, nitric oxide is an important regulator of hepatic arterial resistance, but does not mediate the hepatic arterial buffer response and was not found to play any significant role in total hepatic capacitance regulation.

Nitrovasodilators relax mesenteric microvessels by cGMP-induced stimulation of Ca-activated K channels.

Nitric oxide (NO) released from endothelial cells or exogenous nitrates is a potent dilator of arterial smooth muscle; however, the molecular mechanisms mediating relaxation to NO in the microcirculation have not been characterized. The present study investigated the relaxant effect of nitrovasodilators on microvessels obtained from the rat mesentery and also employed whole cell and single-channel patch-clamp techniques to identify the molecular target of NO action in myocytes from these vessels. Both sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) relaxed phenylephrine-induced contractions by approximately 80% but were significantly less effective in relaxing contractions induced by 40 mM KCl. Relaxation to SNP was also inhibited by the K(+)-channel blocker tetraethylammonium or by inhibition of the activity of the guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (PKG). These results suggest that SNP stimulated K+ efflux by opening K+ channels via PKG-mediated phosphorylation. Perforated-patch experiments revealed that both SNP and SNAP increased outward currents in microvascular myocytes, and single-channel studies identified the high-conductance Ca(2+)- and voltage-activated K+ (BKCa) channel as the target of nitrovasodilator action. The effects of nitrovasodilators on BKCa channels were mimicked by cGMP and inhibited by blocking the activity of PKG. We conclude that stimulation of BKCa-channel activity via cGMP-dependent phosphorylation contributes to the vasodilatory effect of NO on microvessels and that a direct effect of NO on BKCa channels does not play a major role in this process. We propose that this mechanism is important for the therapeutic effect of nitrovasodilators on peripheral resistance and arterial blood pressure.

Influence of hypertonic saline solution infusion on defibrillation efficacy.

Hypertonic saline solution may enhance cardiac conduction via the fast inward sodium channel and alter transmembrane Ca+2 conductance via the sodium-calcium exchanger. Evidence suggests that both Ca+2 conductance and myocardial conduction velocity may affect ventricular defibrillation. Since hypertonic saline solution solutions (ie, sodium bicarbonate) may be administered to patients who have conditions that often require ventricular defibrillation (ie, cardiac arrest or hypovolemic shock), we studied the effect of hypertonic saline solution on the defibrillation threshold (DFT) in 16 pentobarbital-anesthetized domestic farm swine (20 to 30 kg). Defibrillation was performed using two interfaced epicardial electrode patches. DFTs were determined at baseline and during treatment phase. Pigs were randomly assigned to treatment consisting of either hypertonic saline solution (6 mmol/kg load, 2.0 to 3.0 mmol/kg infusion) to maintain serum sodium concentrations 10 to 15 mmol/L above baseline or control (D5W given in equal volume). DFT values (joules) that predicted 50% success were modeled from a best-fit histogram. Hypertonic saline solution did not change DFT values from baseline values (10.2 +/- 4.3 vs 10.8 +/- 7.0, respectively). Likewise, placebo (D5W) did not change DFT values from baseline values (10.1 +/- 4.5 vs 11.3 +/- 4.3). During treatment phase, DFT values were 99 +/- 28% of baseline values in the hypertonic saline solution group and 116 +/- 23% of baseline values in the D5W groups (p = 0.21). The administration of hypertonic saline solution also did not affect ventricular conduction velocity, right ventricular action potential duration, or right ventricular effective refractory period. These data indicate that hypertonic saline solution does not appreciably affect defibrillation efficacy or electrical treatment of ventricular fibrillation.

Insulin attenuates alpha-adrenergic aortic contraction in normotensive but not borderline hypertensive rats.

Hyperinsulinemia can alter vasoconstrictor responses in normotensive and hypertensive rats, but the effects of insulin on vascular contraction have not been evaluated in borderline hypertension. This study determined the effects of insulin on alpha-adrenoceptor mediated aortic contraction in male and female borderline hypertensive rats (BHR) and normotensive Wistar Kyoto (WKY) rats. Dose-response curves to norepinephrine (NE) and phenylephrine (PE) were performed in thoracic aorta in the absence or presence of insulin (100 microU/ml) for 2 hrs. Contraction to NE and PE was reduced in aorta from female WKY rats incubated with insulin compared to control. In aorta from 6 of 13 male WKY rats (insulin responders), an attenuated response to NE and PE was observed in the presence of insulin. However, insulin did not alter responses to NE or PE in aorta from male or female BHR. These results indicate that insulin impairs alpha-adrenoceptor mediated contraction in the normotensive female WKY rat and in a group of responder male WKY rats, but not in BHR. This study supports the presence of a resistance to the vascular effects of insulin in BHR.

Reversal of the electrocardiographic effects of cocaine by lidocaine. Part 2. Concentration-effect relationships.

Ventricular arrhythmias due to cocaine may be related to its ability to slow ventricular conduction or prolong repolarization. We previously showed that lidocaine reversed QRS prolongation due to cocaine. The purposes of these experiments were to characterize cocaine's concentration-effect relationship on both ventricular conduction and repolarization, and to determine the effects of lidocaine on these relationships. The effects of lidocaine on cocaine-induced electrocardiographic changes were studied in 20 isolated, Tyrode-perfused guinea pig hearts. Variables at cocaine concentrations ranging from 3-195 microM were measured and repeated in the presence of a fixed concentration of lidocaine 30 microM. Using nonlinear regression analysis, the sigmoid Emax and simple Emax models were fit to cocaine concentration versus percentage change in QRS plots. Measures of best fit indicated that this relationship was best described by the sigmoid Emax model. Compared with cocaine alone, the curve for cocaine with lidocaine showed a greater EC50 (concentration at 50% of maximum effect) (59 vs 100 microM) but similar Emax (371 vs 367%), consistent with competition. Similar values were obtained from the linear transformation of the data. Cocaine concentration versus percentage change in the JTc interval showed a biphasic effect: concentrations below 65 microM prolonged JTc, but those above 65 microM had no effect or decreased JTc. In contrast to changes in QRS, addition of lidocaine increased the effects of cocaine on JTc: area under the concentration-effect curve for cocaine alone was 720 versus 859 microM% for cocaine with lidocaine. Lidocaine reverses cocaine-induced slowed ventricular conduction through competition for binding, but it appeared to increase cocaine-induced prolongation of repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of the electrocardiographic effects of cocaine by lidocaine. Part 1. Comparison with sodium bicarbonate and quinidine.

Based on modulated receptor concepts, an agent with fast on-off sodium channel binding properties (e.g., lidocaine) may reverse the effects of a drug with slow on-off kinetics (e.g., cocaine) through competition for a single receptor site on the sodium channel. We compared the effects of two drugs with different sodium channel-binding kinetics with those of sodium bicarbonate, a known antidote, on cocaine-induced slowing of ventricular conduction. Electrocardiographic (ECG) intervals were recorded before and after the addition of cocaine 30 microM in 26 isolated, Tyrode-perfused guinea pig hearts. The effects of the three potential antidotes were then analyzed: equimolar lidocaine (8 hearts), equimolar quinidine (6), and sodium bicarbonate (8). Cocaine significantly increased all ECG intervals. The addition of lidocaine to cocaine-containing perfusate decreased QRS duration from 42 +/- 3 to 29 +/- 3 msec (p < 0.01), a 60% reversal. Addition of sodium bicarbonate to increase the pH of the perfusate from 7.37 +/- 0.09 to 7.52 +/- 0.08 (p < 0.01) decreased the QRS duration from 38 +/- 4 to 30 +/- 6 msec (p < 0.01), a 47% reversal. Addition of quinidine 30 microM augmented the effects of cocaine: QRS increased from 40 +/- 6 msec to 54 +/- 9 msec (p < 0.01). Consistent with modulated receptor concepts, lidocaine reverses slowed ventricular conduction due to cocaine. The magnitude of this reversal is similar to that due to sodium bicarbonate. The potential of fast on-off agents to serve as antidotes for cocaine-induced arrhythmias requires further study.

Cocaine-related sudden cardiac death: a hypothesis correlating basic science and clinical observations.

Sudden, unexpected death due to cocaine in young otherwise healthy individuals occurs in an idiosyncratic manner and is commonly felt to be arrhythmogenic in nature, although the exact cause of death is rarely documented. In addition to indirect sympathomimetic actions, cocaine is a potent sodium channel blocking drug and, in this regard, most closely resembles agents such as flecainide. We suggest that sudden death due to cocaine is proarrhythmic in nature, occurring under similar circumstances as that due to specific antiarrhythmic drugs.