15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Reperfusion-Injury

Diadenosine tetraphosphate (AP4A) is a vasoactive mediator that may be released from platelet granules and that may reach higher plasma concentrations during coronary ischemia-reperfusion. The objective of this study was to analyze its coronary effects in such conditions. To this, rat hearts were perfused in a Langendorff preparation and the coronary response to Ap4A (10(-7)-10(-5) M) was recorded. In control hearts, Ap4A produced concentration-dependent vasodilatation both at the basal coronary resting tone and after precontracting coronary vasculature with 11-dideoxy-1a,9a-epoxymethanoprostaglandin F2α (U46619), and this vasodilatation was reduced by reactive blue 2 (2×10(-6) M), glibenclamide (10(-5) M), H89 (10(-6) M), U73122 (5×10(-6) M) and endothelin-1 (10(-9) M), but not by L-NAME (10(-4) M), isatin (10(-4) M), GF109203x (5×10(-7) M), or wortmannin (5×10(-7) M). After ischemia-reperfusion, the vasodilatation to Ap4A diminished, both in hearts with basal or increased vascular tone, and in this case the relaxation to Ap4A was not modified by reactive blue 2, L-NAME, glibenclamide, isatin, H89, GF109203x or wortmannin, although it was reduced by U73122 and endothelin-1. UTP produced coronary relaxation that was also reduced after ischemia-reperfusion. These results suggest that the coronary relaxation to Ap4A is reduced after ischemia-reperfusion, and that this reduction may be due to impaired effects of KATP channels and to reduced response of purinergic P2Y receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Androstadienes; Animals; Coronary Vessels; Dinucleoside Phosphates; Endothelin-1; Estrenes; Glyburide; Heart; In Vitro Techniques; Indoles; Isatin; Isoquinolines; Male; Maleimides; NG-Nitroarginine Methyl Ester; Perfusion; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Rest; Sulfonamides; Triazines; Vasoconstriction; Wortmannin

Tacrolimus (FK506) is widely used as an immunosuppressive drug in small bowel transplantation. However, its precise effects on the vascular tone of the transplanted organ have not been studied. This study aimed to clarify the effects of FK506 on the porcine mesenteric artery.. The effects of FK506 on the changes in cytosolic Ca(2+) concentration ([Ca(2+)]i) and force using fura-2 fluorometry were investigated in mesenteric arterial strips of the porcine small intestine. The effects of FK506 on the activity of voltage-dependent Ca(2+) channels and receptor-operated Ca(2+) channels using high K(+) (118 mmol/L K(+)) depolarization and thromboxane A(2) analog (U46619) stimulation were also examined.. FK506 inhibited the force development induced by 118 mmol/L K(+) depolarization and 1 micromol/L U46619 stimulation in a concentration-dependent manner. The extent of inhibition of this contraction was greater than that of the K(+)-induced contraction, and its inhibitory potency was about 10-fold. FK506 (10 micromol/L) inhibited the increases in [Ca(2+)]i (24.9% +/- 7.4%) and the force development (52.0% +/- 5.6%) induced by 1 micromol/L U46619, respectively.. FK506 induces arterial relaxation by decreasing [Ca(2+)]i. Pretreatment of a graft with FK506 may reduce the risk of vasospasm, ischemia-reperfusion injury, and thrombosis in small bowel transplantation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arteries; Calcium; Calcium Channels; Cytosol; Dose-Response Relationship, Drug; Fluorometry; Fura-2; Immunosuppressive Agents; Intestine, Small; Mesenteric Arteries; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Reperfusion Injury; Swine; Tacrolimus; Vasoconstrictor Agents; Vasodilation

The objectives of the study were to (1) characterize the dose-response relationship to the TXA2 analog, U46619 (0.01, 0.1, and 1 micromol/L) after global cerebral ischemia, (2) determine whether chronic 17beta-estradiol (E2) replacement alters this relationship, and (3) determine if E2's mechanisms are transduced through cognate estrogen receptors. Rats were assigned to five groups (n=6): placebo-implanted ovariectomized (OVX) females, OVX plus chronic E2 (CE), OVX plus acute E2 (AE), OVX plus chronic E2 plus the estrogen receptor inhibitor ICI 182,780 (CEI), and OVX plus acute E2 plus ICI 182,780 (AEI). Rats were anesthetized, intubated, cannulated (femoral artery and vein), fitted with a closed cranial window, and subjected to 15-min reversible forebrain ischemia (4-vessel occlusion, 4-VO) and 60 mins of reperfusion. Arterial blood gases, intrawindow pressure, and temperature were controlled. Vessel diameter was measured before and 5 mins after superfusion of each concentration of U46619. Compared with preischemic responses, contractile response to U46619 was depressed at all concentrations after ischemia in the OVX group. In the chronic E2 and acute E2 groups, contractile response to 1 micromol/L of U46619 was normalized to near baseline values. However, in the CEI and the AEI groups, postischemic vasoconstriction was similar to that observed in the OVX rats. We conclude that E2 targets the cerebral microvasculature to preserve postischemic pial artery reactivity and that the effect is receptor mediated. Restoration of normal constriction to vascular agonists may be an important mechanism by which E2 protects the vasculature and diminishes tissue damage after ischemia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Cerebral Arteries; Dose-Response Relationship, Drug; Estradiol; Female; Hemoglobins; Hydrogen-Ion Concentration; Ischemic Attack, Transient; Ovariectomy; Oxygen; Prosencephalon; Rats; Rats, Wistar; Receptors, Estrogen; Reperfusion Injury; Thromboxane A2; Vasoconstrictor Agents

Lipid mediators, thromboxane A2 (TxA2) and platelet-activating factor (PAF), are potent vasoconstrictors, and have been implicated as mediators of liver diseases, such as ischemic-reperfusion injury. We determined the effects of a TxA2 analogue (U-46619) and PAF on the vascular resistance distribution and liver weight (wt) in isolated guinea pig livers perfused with blood via the portal vein. The sinusoidal pressure was measured by the double occlusion pressure (P(do)), and was used to determine the pre- (R(pre)) and post-sinusoidal (R(post)) resistances. U-46619 and PAF concentration-dependently increased the hepatic total vascular resistance (R(t)). The minimum concentration at which significant vasoconstriction occurs was 0.001 microM for PAF and 0.1 microM for U-46619. Moreover, the concentration of U-46619 required to increase R(t) to the same magnitude is 100 times higher than PAF. Thus, the responsiveness to PAF was greater than that to U-46619. Both agents increased predominantly R(pre) over R(post). U-46619 caused a sustained liver weight loss. In contrast, PAF also caused liver weight loss at lower concentrations, but it produced liver weight gain at higher concentrations (2.5 +/- 0.3 per 10g liver weight at 1 microM PAF), which was caused by substantial post-sinusoidal constriction and increased P(do). In conclusion, both TxA2 and PAF contract predominantly the pre-sinusoidal veins. TxA2 causes liver weight loss, while PAF at high concentrations increases liver weight due to substantial post-sinusoidal constriction in isolated guinea pig livers.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bile; Capillary Permeability; Guinea Pigs; In Vitro Techniques; Infusion Pumps; Liver; Liver Circulation; Liver Diseases; Male; Organ Size; Platelet Activating Factor; Portal Vein; Reperfusion Injury; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents

This study further investigates the mechanisms responsible for the effects of acute and severe hypoxia, and subsequent reoxygenation, on the contractility of isolated rat mesenteric arteries. In noradrenaline (NA)-contracted arteries, hypoxia caused a relaxation to near baseline levels. Reoxygenation resulted in an immediate transient contraction before tension returned more slowly to prehypoxia levels. Similar responses to hypoxia were observed in tissues precontracted by addition of KCl (60 mM) or U46619 (10 microM); however, the transient contraction upon reoxygenation was absent (KCl) or reduced (U46619). Responses to hypoxia were independent of changes in intracellular calcium ([Ca2+]i), while those to reoxygenation were accompanied by corresponding changes in [Ca2+]i and were completely abolished by ryanodine. In NA-contracted tissues, all responses were unaffected by endothelial removal or by inhibitors of nitric oxide synthase and cyclooxygenase. The K+ channel blockers triethylamine (TEA), glibenclamide, and 4-aminopyridine (4-AP) had no effect on the responses to hypoxia. The transient contractile response to reoxygenation was, however, significantly reduced in the presence of 4-AP. The response to reoxygenation, but not that to hypoxia, was inhibited by the antioxidant dithiothreitol (DTT) and the NAD(P)H-oxidase inhibitor diphenyliodonium (DPI). These data suggest that hypoxic vasodilation occurs independently of reductions in [Ca2+]i. Alternatively, transient contractions on reoxygenation are dependent upon the generation of reactive oxygen species and the release of stored Ca2+.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 4-Aminopyridine; Adenosine Triphosphate; Animals; Anti-Arrhythmia Agents; Calcium; Endothelium, Vascular; Ethylamines; Glyburide; Hypoxia; Male; Mesenteric Arteries; Muscle Contraction; Norepinephrine; Oxygen; Potassium; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar; Reperfusion Injury; Ryanodine

We studied the effect of ischaemia and reperfusion on vasoconstrictor and vasodilator mechanisms. Anaesthetized rabbits were subjected to 4-h abdominal aortic occlusion and 1-h reperfusion in vivo. Segments of the abdominal (ischaemic-reperfused) and thoracic (control) aorta were then removed for in vitro studies. Ischaemia/reperfusion had no significant effect on relaxant responses to either acetylcholine (ACh:endothelium-dependent) or sodium nitroprusside (SNP:endothelium-independent). The sensitivity of the aorta to contraction by phenylephrine was significantly increased in aortic rings with or without endothelium (by 2.2- and 3.7-fold, respectively), but was not different after 4-h ischaemia without reperfusion. In contrast, responses to methoxamine, serotonin, and U46619 were not affected by ischaemia/reperfusion. Moreover, the relative increase in aortic sensitivity to phenylephrine was prevented by treatment of control and ischaemic-reperfused aortic rings with the neuronal uptake inhibitor cocaine (10(-5) M). These results suggest that after 4-h ischaemia, reperfusion damages sympathetic neuronal uptake mechanisms in rabbit aorta. As a result, phenylephrine, an agonist normally susceptible to neuronal uptake, may exert more potent contractile effects. Endothelium-dependent and endothelium-independent relaxant mechanisms in the aorta appear to be resistant to acute ischaemia and reperfusion.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Aorta; Endothelium, Vascular; Female; In Vitro Techniques; Male; Methoxamine; Neurons; Phenylephrine; Prostaglandin Endoperoxides, Synthetic; Rabbits; Reperfusion Injury; Serotonin; Sympathetic Nervous System; Thromboxane A2; Vasoconstriction

The purpose of this investigation was to provide a detailed analysis of the effects of the thromboxane antagonist L655,240 (0.3 mg/kg i.v.) on early ischemia- and reperfusion-induced arrhythmias in a canine model of coronary artery occlusion. In a dose that abolished the pulmonary response to U46619, L655,240 attenuated markedly the severity of those arrhythmias that resulted from reperfusion of the myocardium; survival from the combined occlusion-reperfusion insult was increased from 10% in control animals to 70% in dogs administered L655,240. Drug intervention did not significantly alter the total number of arrhythmias during the period of ischemia, but a detailed analysis of the different types of arrhythmia that occurred during this period showed that L655,240 significantly reduced those arrhythmias in phase 1a (0-10 min of occlusion) without affecting the later phase 1b arrhythmias. This was particularly shown in the marked reduction in the number of salvos (couplets and triplets) during this period. Neither those arrhythmias occurring later in the ischaemia period (phase 1b) nor the total number of single ectopics and salvos or the incidence and duration of ventricular tachycardia was modified by L655,240. These results reveal that thromboxane antagonism protects especially against reperfusion-induced ventricular fibrillation and against early (phase 1a) ischemia-induced arrhythmias, possibly implicating a role for thromboxane in the genesis of these cardiac rhythm disturbances.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthesia; Animals; Arrhythmias, Cardiac; Blood Gas Analysis; Coronary Circulation; Dogs; Hemodynamics; In Vitro Techniques; Indoles; Myocardial Reperfusion; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Reperfusion Injury; Thromboxanes