Effects of ß-adrenoceptor stimulation on delayed rectifier K(+) currents in canine ventricular cardiomyocytes.

BACKGROUND AND PURPOSE: While the slow delayed rectifier K(+) current (I(Ks)) is known to be enhanced by the stimulation of ß-adrenoceptors in several mammalian species, phosphorylation-dependent regulation of the rapid delayed rectifier K(+) current (I(Kr)) is controversial. EXPERIMENTAL APPROACH: In the present study, therefore, the effect of isoprenaline (ISO), activators and inhibitors of the protein kinase A (PKA) pathway on I(Kr) and I(Ks) was studied in canine ventricular myocytes using the whole cell patch clamp technique. KEY RESULTS: I (Kr) was significantly increased (by 30-50%) following superfusion with ISO, forskolin or intracellular application of PKA activator cAMP analogues (cAMP, 8-Br-cAMP, 6-Bnz-cAMP). Inhibition of PKA by Rp-8-Br-cAMP had no effect on baseline I(Kr). The stimulating effect of ISO on I(Kr) was completely inhibited by selective ß1-adrenoceptor antagonists (metoprolol and CGP-20712A), by the PKA inhibitor Rp-8-Br-cAMP and by the PKA activator cAMP analogues, but not by the EPAC activator 8-pCPT-2'-O-Me-cAMP. In comparison, I(Ks) was increased threefold by the activation of PKA (by ISO or 8-Br-cAMP), and strongly reduced by the PKA inhibitor Rp-8-Br-cAMP. The ISO-induced enhancement of I(Ks) was decreased by Rp-8-Br-cAMP and completely inhibited by 8-Br-cAMP. CONCLUSIONS AND IMPLICATIONS: The results indicate that the stimulation of ß1-adrenoceptors increases I(Kr), similar to I(Ks), via the activation of PKA in canine ventricular cells.

Action potential clamp fingerprints of K+ currents in canine cardiomyocytes: their role in ventricular repolarization.

AIM: The aim of the present study was to give a parametric description of the most important K(+) currents flowing during canine ventricular action potential. METHODS: Inward rectifier K(+) current (I(K1)), rapid delayed rectifier K(+) current (I(Kr)), and transient outward K(+) current (I(to)) were dissected under action potential clamp conditions using BaCl(2), E-4031, and 4-aminopyridine, respectively. RESULTS: The maximum amplitude of I(to) was 3.0 +/- 0.23 pA/pF and its integral was 29.7 +/- 2.5 fC/pF. The current peaked 4.4 +/- 0.7 ms after the action potential upstroke and rapidly decayed to zero with a time constant of 7.4 +/- 0.6 ms. I(Kr) gradually increased during the plateau, peaked 7 ms before the time of maximum rate of repolarization (V(max)(-)) at -54.2 +/- 1.7 mV, had peak amplitude of 0.62 +/- 0.08 pA/pF, and integral of 57.6 +/- 6.7 fC/pF. I(K1) began to rise from -22.4 +/- 0.8 mV, peaked 1 ms after the time of V(max)(-) at -58.3 +/- 0.6 mV, had peak amplitude of 1.8 +/- 0.1 pA/pF, and integral of 61.6 +/- 6.2 fC/pF. Good correlation was observed between peak I(K1) and V(max)(-) (r = 0.93) but none between I(Kr) and V(max)(-). Neither I(K1) nor I(Kr) was frequency-dependent between 0.2 and 1.66 Hz. Congruently, I(Kr) failed to accumulate in canine myocytes at fast driving rates. CONCLUSION: Terminal repolarization is dominated by I(K1), but action potential duration is influenced by several ion currents simultaneously. As I(to) was not active during the plateau, and neither I(K1) nor I(Kr) was frequency-dependent, other currents must be responsible for the frequency dependence of action potential duration at normal and slow heart rates in canine ventricular cells.

In vivo and in vitro acute cardiovascular effects of bimoclomol.

Effects of bimoclomol, the novel heat shock protein (HSP) coinducer, was studied in various mammalian cardiac and rabbit aortic preparations. Bimoclomol decreased the ST-segment elevation induced by coronary occlusion in anesthetized dogs (56% and 80% reduction with 1 and 5 mg/kg, respectively). In isolated working rat hearts, bimoclomol increased coronary flow (CF), decreased the reduction of cardiac output (CO) and left ventricular developed pressure (LVDP) developing after coronary occlusion, and prevented ventricular fibrillation (VF) during reperfusion. In rabbit aortic preparations, precontracted with phenylephrine, bimoclomol induced relaxation (EC(50)=214 microM). Bimoclomol produced partial relaxation against 20 mM KCl, however, bimoclomol failed to relax preparations precontracted with serotonin, PGF(2) or angiotensin II. All these effects were evident within a few minutes after application of bimoclomol. A rapid bimoclomol-induced compartmental translocation of the already preformed HSPs may explain the protective action of the compound.

Tumour necrosis factor-alpha and adenosine in endotoxin shockleading related cardiovascular symptoms.

We have observed uncontrollable cardiogenic shock as a cardiovascular manifestation of systemic inflammatory response syndrome (SIRS) leading to death in a 62-year-old woman. The diagnosis of SIRS was based on the demonstration of endotoxinaemia, and highly elevated plasma levels of tumour necrosis factor (TNF)-alpha, and interleukin (IL)-10. We suggest that these cytokines may contribute to the terminal SIRS-related arrythmias, impaired myocardial contractility, as well as increased vascular permeability. In addition, the increased production of adenosine, a counter-regulatory mediator of inflammation, may also play a role in cardiodepression. We suggest a relationship between the action of TNF-alpha , IL-10 and adenosine in the pathogenesis of circulatory symptoms described above.