iloprost and Arrhythmias--Cardiac

Nitric oxide and prostacyclin are endothelial-derived vasodilators which inhibit platelet aggregation in a synergistic manner. Experiments were designed to examine whether 3-morpholino-sydnonimine (SIN-1) and iloprost have synergistic cardioprotective actions and whether their effects on infarct size are related to inhibition of platelet aggregation. Anaesthetized rabbits (n = 9-10 per group) were subject to 40 min myocardial ischaemia followed by 3 h reperfusion. Infarct size (percentage of area at risk) was not altered significantly by 3 microg kg(-1) min(-1) SIN-1 (29.7 +/- 1.9%), but was reduced by 0.03 microg kg(-1) min(-1) iloprost (24.6 +/- 1.6%) and to a greater extent by the combination of SIN-1 and iloprost (18.8 +/- 1.7%), compared to controls (33.6 +/- 4.7%). In control rabbits, there were reductions in the ex vivo aggregation of platelets in response to ADP or collagen after ischaemia and reperfusion. SIN-1 and iloprost caused some alterations in platelet responses, but combined administration of both drugs did not produce greater effects. Although the reduction in myocardial infarct size was greatest with both drugs, this did not appear to be a synergistic interaction and was not dependent on the effects of the drugs on haemodynamics or platelet aggregation.

Topics: Animals; Arrhythmias, Cardiac; Creatine Kinase; Drug Synergism; Electrocardiography; Hemodynamics; Iloprost; Male; Molsidomine; Myocardial Infarction; Platelet Aggregation; Rabbits

The effects of iloprost infusion (100 ng/kg/min for 75 min) alone and in combination with aspirin (3 mg/kg IV bolus) were compared in a canine model of myocardial reperfusion injury. Regional ischemia of 40 min was produced by temporary occlusion of the left anterior descending coronary artery, after which the myocardium was reperfused for a period of 3 hours. Mean arterial pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), positive (+) LVdP/dtmax and negative (-) LVdP/dtmax were monitored. Rate pressure product and (-) dP/dt/Pmax were also derived from the above. Myocardial tissue levels of adenosine triphosphate (ATP), creatine phosphate (CP), glycogen and lactate were estimated. Following reperfusion in the saline treated group, there was a significant fall in (i) MAP, (ii) (+) LVdP/dtmax and (iii) (-) LVdP/dtmax. LVEDP was corrected about 2 hours after reperfusion. Despite correction of lactate accumulation, ATP and glycogen were not restored although the CP store was replenished. The hemodynamic profiles in both iloprost and in combination treated groups were similar; (i) depressed MAP (particularly during iloprost infusion) without any significant change in HR (ii) no significant depression in (+) LVdP/dtmax (iii) depression in (-) LVdP/dtmax but not when corrected for lower Pmax and (iv) a significant reduction in the incidence of reperfusion arrhythmias. Similarly, in both the drug/s treated groups, ATP, CP and lactate were normalised although glycogen store was not restored. The results of this study indicate (i) cardioprotective effect of iloprost even when administered prior to reperfusion and (ii) no additional protective effect of combining iloprost and aspirin.

Topics: Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Dogs; Drug Synergism; Drug Therapy, Combination; Glycogen; Heart Rate; Iloprost; Lactic Acid; Myocardial Reperfusion Injury; Myocardium; Phosphocreatine; Ventricular Pressure

The effects of iloprost, prazosin and propranolol were tested on ouabain-induced arrhythmia in guinea-pigs. Each drug used alone showed an antiarrhythmic effect. In a second step, iloprost was given in combination with drugs blocking alpha- and beta-adrenergic receptors. Propranolol and iloprost caused a statistically significant and comparable increase of the threshold dose of ouabain for the onset of arrhythmia (OA), the occurrence of premature ventricular beats (PVB), ventricular flutter (VF) and ventricular fibrillation (FIB). The effect of a combination of iloprost and propranolol was comparable to the effect of each drug administered alone. Prazosin enhanced the threshold dose of ouabain for OA and PVB in a statistically significant manner. The effect of a combination of iloprost and prazosin was nearly the same for OA and PVB compared to the single effect of these drugs. The threshold dose of ouabain was decreased for VF and FIB when a combination of iloprost and prazosin was given, compared to iloprost used alone. These results support the assumption that the adrenergic nervous system is involved in the antiarrhythmic effect of iloprost.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Arrhythmias, Cardiac; Drug Interactions; Drug Synergism; Guinea Pigs; Iloprost; Ouabain; Prazosin; Propranolol; Ventricular Fibrillation

Isolated hearts excised from normotensive (NT) and spontaneously hypertensive (SH) rats subjected to transient normothermic global ischemia were used to study the effect of chronic treatment with iloprost on reperfusion-induced arrhythmias and myocardial ion shifts. After 30 min of ischemia, iloprost given s.c. in doses of 10, 50, 100 and 200 micrograms/kg per day for 14 days reduced the incidence of reperfusion-induced ventricular fibrillation (VF) in isolated hearts from the control value of 91 to 83, 75, 50 (P less than 0.05) and 25% (P less than 0.01) respectively, in NT rats. In the SH groups, the incidence of VF was also reduced from 100 to 75, 58, 33 (P less than 0.01) and 17% (P less than 0.001), respectively, with 10, 50, 100 and 200 micrograms/kg per day of iloprost. A similar reduction was observed in the incidence of reperfusion-induced ventricular tachycardia (VT). Ischemia and reperfusion caused significant changes in myocardial ion contents, i.e. an increase in Na+ and Ca2+ and a decrease in K+ and Mg2+ concentrations. The myocardial water content was also increased in parallel to the Na+ gain. The effect of iloprost given s.c. in doses of 50 and 200 micrograms/kg per day for 14 days was also measured on myocardial ion contents after 15- or 30-min ischemia and 30-min ischemia plus 10-min reperfusion. The higher iloprost dose significantly reduced the myocardial Na+, Ca2+ and water gains and the loss of K+ induced by ischemia and reperfusion in the NT and SH groups, while the decrease in Mg2+ content was alleviated only in SH rats. The results suggest that long-term iloprost treatment reduces the incidence of reperfusion-induced VF and VT by preventing Na+, Ca2+ and water accumulation as well as K+ and Mg2+ loss from myocardial tissue.

Topics: Animals; Arrhythmias, Cardiac; Cations; Coronary Disease; Iloprost; In Vitro Techniques; Male; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tachycardia; Ventricular Fibrillation

Substances shifting the balance between thromboxane (TX) and prostacyclin (PGI2) in favour of PGI2 could be of therapeutic value for arrhythmia treatment. This seems to be independent of the pathogenetic mechanism. The TX receptor antagonist BM 13177, the lipoxygenase inhibitor esculetin were effective in ouabain and aconitine induced arrhythmias while the PGI2 formation stimulating substance nafazatrom was only effective in aconitine induced arrhythmia. BM 13177 and esculetin could also counteract the arrhythmogenic effect of PAF. TX synthetase inhibition by HOE 944 was ineffective or partially effective, resp..

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Anti-Arrhythmia Agents; Arachidonic Acids; Arrhythmias, Cardiac; Epoprostenol; Guinea Pigs; Heart; Iloprost; Ouabain; Prostaglandin Endoperoxides, Synthetic; Reference Values; Sulfonamides

This article reviews the evidence we found in our study that the local generation of thromboxane and prostacyclin is one important factor involved in determining the severity of the ventricular arrhythmias that result from acute myocardial ischaemia and subsequent reperfusion. The hypothesis examined is that thromboxane release, presumably from platelets, is harmful in the early stages of ischaemia (perhaps because this induces further platelet aggregation and/or a reduction in blood flow as a result of both active vasoconstriction and of mechanical obstruction) and that prostacyclin generation (presumably mainly from endothelial cells) is beneficial at this time. The evidence is that in anaesthetised greyhound dogs, blockade of the thromboxane receptor (AH 23848) or inhibition of thromboxane synthesis (with a variety of "specific" inhibitors of thromboxane synthetase such as dazoxiben, dazmegrel, and "low-dose" aspirin) slightly reduces the severity of ischaemia-induced arrhythmias and markedly increases survival after myocardial reperfusion by reducing reperfusion-induced ventricular fibrillation (e.g., from 80% in control dogs to less than 20% in treated dogs). The evidence that prostacyclin generation is helpful in this situation comes from studies with locally infused prostacyclin or iloprost and with nafazatrom, a drug that increases the amount of prostacyclin released into local coronary venous blood soon after the onset of myocardial ischaemia; these procedures also reduce the number of ventricular extrasystoles occurring during ischaemia and the incidence of reperfusion-induced ventricular fibrillation. These findings do not imply that arachidonic acid derivatives are the only, or even the main, biochemical factor involved in the generation of these arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arrhythmias, Cardiac; Coronary Disease; Dogs; Epoprostenol; Iloprost; Norepinephrine; Perfusion; Pyrazoles; Pyrazolones; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxanes

Iloprost (ILO) and ZK 96 480 (96 480) are stable prostacyclin (PGI2) analogues with platelet aggregation-inhibiting and hypotensive activities equal or superior to PGI2 which in contrast to PGI2 show longlasting pharmacological effects also after oral application. PGI2 as well as ILO and 96 480 with i.v. infusion at equihypotensive doses in rats after coronary artery ligation reduce ventricular ectopic beats, markedly reduce or abolish the periods of ventricular tachycardia and entirely prevent ventricular fibrilloflutter. Even nonhypotensive doses of the prostanoids attenuate postligation arrhythmias. Catecholamine depletion by reserpine pretreatment also markedly reduced the incidence of arrhythmias. As PGI2 and ILO have previously been shown by others to preserve noradrenaline content of sympathetic nerve terminals in ischemic myocardium, prevention of excessive catecholamine loss from hypoxically compromised sympathetic nerve terminals might be involved in the antiarrhythmic action of PGI2, ILO and 96 480.

Topics: Adenosine Diphosphate; Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiovascular Agents; Epoprostenol; Iloprost; Lidocaine; Platelet Aggregation; Rats; Rats, Inbred SHR; Reserpine

Prostacyclin (PGI2) can protect the heart against ischemia, i.e. it can reduce myocardial damage [9, 10]. PGI2 protects the myocardium in vivo by preventing platelets from clumping and by dispersing preformed platelet aggregates [1,14]. However, also in the absence of platelets, PGI2 was shown to protect the myocardium against ischemia at concentrations that did not affect smooth muscle tone in the vessel wall [2]. This protective effect of PGI2 in vitro might be related to a stabilization of cell membranes in adrenergic nerve endings and hence to the prevention of ischemia-induced catecholamine release [13]. The instability of PGI2, both in vitro and in vivo, limits its application during long ischemic periods. Recently, a stable prostacyclin analogue, ZK 36 374, was demonstrated to have several prostacyclin-mimetic activities, both in vitro and in vivo [11,12]. In this communication we report upon the beneficial effect of this stable prostacyclin analogue at a low concentration (4 nM) on the extent of ischemic damage, on the recovery of myocardial function and on the occurrence of arrhythmias in the isolated rat heart after 24 h hypothermic cardiac arrest.

Topics: Animals; Arrhythmias, Cardiac; Cardiovascular Agents; Coronary Circulation; Coronary Disease; Electrophysiology; Epoprostenol; Heart; Heart Arrest; Hypothermia, Induced; Iloprost; Male; Rats; Rats, Inbred Strains