vapiprost and phosphoramidon

E2-isoprostanes are recently discovered compounds that are produced in vivo from free radical-catalysed peroxidation of arachidonic acid. One such compound whose formation is favoured by this mechanism is isoprostaglandin E2 type III (iPE2-III, also named 8-iso-prostaglandin E2 or 15-E2t-isoprostaglandin). The aim of this study was to evaluate the vasomotor properties of iPE2-III in isolated human internal mammary artery. In organ bath, iPE2-III was approximately 10 times more potent than isoprostaglandin F2alpha-III and 27 times more potent than prostaglandin E2, whereas both isoprostaglandin F3alpha-III and 15-epi-isoprostaglandin F2alpha-II induced weak contractions. The responses to iPE2-III were inhibited in a concentration-dependent manner by the thromboxane A2 receptor antagonist GR 32191 (3.10(-9) to 3.10(-7) M). Indomethacin, a cyclooxygenase inhibitor and phosphoramidon, an endothelin converting enzyme inhibitor, did not affect iPE2-III response. These data shows that iPE2-III is a more potent vasoconstrictor of human internal mammary arteries than isoprostaglandin F2alpha-III. These effects are mediated by TP receptors, but involve neither cyclooxygenase products nor endothelins. iPE2-III production may induce more pronounced vasomotor effects than isoprostaglandin F2alpha-III in situations of oxidative stress, and in particular may modulate internal mammary artery tone following coronary bypass surgery.

Topics: Aged; Biphenyl Compounds; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; F2-Isoprostanes; Female; Glycopeptides; Heptanoic Acids; Humans; Indomethacin; Isoprostanes; Male; Mammary Arteries; Middle Aged; Muscle Contraction; Muscle, Smooth, Vascular; Organ Culture Techniques; Vasoconstrictor Agents

Following the use of deep hypothermic circulatory arrest in cardiac surgery, cerebral blood flow and cerebral oxygen metabolism are impaired. These may result from abnormal cerebral vasospasm. Powerful vasoconstrictors including endothelins and thromboxane A2 could mediate these processes. We investigated possible involvement of these two factors by assessing the effects of (a) phosphoramidon-an inhibitor of endothelin converting enzyme, and (b) vapiprost (GR32191B)-a specific thromboxane A2-receptor antagonist, on the recovery of cerebral blood flow and cerebral oxygen metabolism following deep hypothermic circulatory arrest.. A total of 18 1-week-old piglets were randomised into three groups (n = 6 per group). At induction, the control group received saline; group PHOS received phosphoramidon 30 mg kg-1 intravenously. Group VAP received vapiprost 2 mg kg-1 at induction and at 30 min intervals thereafter. All groups underwent cardiopulmonary bypass cooling to 18 degrees C, exposed to 60 min of deep hypothermic circulatory arrest, rewarmed and reperfused for 1 h. Cerebral blood flow was measured with radio-labeled microspheres: cerebral oxygen metabolism was calculated at baseline before deep hypothermic circulatory arrest and at 1 h of reperfusion and rewarming.. In the control group, cerebral blood flow decreased to 40.2 +/- 2.0% of baseline after deep hypothermic circulatory arrest and cerebral oxygen metabolism decreased to 50.0 +/- 5.5% (P < 0.0005). The responses in group PHOS were similar. In group VAP, cerebral blood flow and cerebral oxygen metabolism were 64.3 +/- 10.6 and 80.1 +/- 9.8% of baseline, respectively, after deep hypothermic circulatory arrest. Thus, treatment with vapiprost significantly improved recovery of cerebral blood flow (P = 0.046) and cerebral oxygen metabolism (P = 0.020) following deep hypothermic circulatory arrest. No such improvement was seen after treatment with phosphoramidon.. Thromboxane A2 mediates impairments in cerebral perfusion and metabolism following deep hypothermic circulatory arrest. These changes were attenuated by blockade of thromboxane A2-receptors using vapiprost. Endothelins are not shown to be involved. Better knowledge of injury mechanisms will enable development of more effective cerebral protection strategies and allow safer application of deep hypothermic circulatory arrest.

Topics: Animals; Animals, Newborn; Biphenyl Compounds; Brain; Cardiopulmonary Bypass; Cerebrovascular Circulation; Confidence Intervals; Disease Models, Animal; Endothelins; Glycopeptides; Heart Arrest, Induced; Heptanoic Acids; Hypothermia, Induced; Metalloendopeptidases; Oxygen; Random Allocation; Receptors, Thromboxane; Reference Values; Swine; Vascular Resistance

Bradykinin (BK) induces bronchoconstriction in asthmatic but not in normal individuals. Studies in vivo in the human suggest that BK causes cholinergic nerve activation, release of prostanoids, and local axon reflexes with release of tachykinins in the airways. To determine the mechanisms of BK-induced airway narrowing, we investigated the effects of epithelium removal, inhibition of the enzymes neutral endopeptidase (NEP) and cyclooxygenase, and blockade of neural conductance with tetrodotoxin (TTX) on BK-induced responses of human isolated peripheral airways. Responses to BK were recorded from airways with spontaneous intrinsic tone and from airways precontracted with methacholine. Furthermore, we measured the BK-induced release of the prostanoids PGE2, PGI2, and TXA2 from airways with and without epithelium in the absence and presence of indomethacin by radioimmunoassay. Finally, we examined the effect of the bradykinin beta 2 receptor antagonist Hoe 140 and the thromboxane prostanoid (TP) receptor blocking drug GR32191 on BK-induced responses. BK contracted intact and epithelium-denuded airways with spontaneous intrinsic tone, whereas precontracted airways either relaxed or contracted to BK. Removal of the epithelium increased the sensitivity to BK sevenfold without changing the direction of the response. The NEP inhibitor phosphoramidon tended to increase the sensitivity to BK (NS) and did not change the direction of the response. Both contractile and relaxation responses to BK and the release of the prostanoids PGE2, PGI2, and TXA2 by the airway tissues were largely inhibited by indomethacin, whereas TTX had no effect. PGE2, PGI2, and TXA2 were released by both intact and epithelium-denuded airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Bronchi; Bronchoconstriction; Dose-Response Relationship, Drug; Drug Interactions; Epithelium; Female; Glycopeptides; Heptanoic Acids; Humans; In Vitro Techniques; Indomethacin; Male; Methacholine Chloride; Middle Aged; Protease Inhibitors; Receptors, Bradykinin; Receptors, Thromboxane