15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Myocardial-Ischemia

Myocardial ischemia is a complex process leading to the simultaneous release of a number of mediators, including thromboxane A(2) (TxA(2)) and bradykinin (BK), that activate cardiac spinal afferents. The present study tested the hypothesis that TxA(2) and BK reciprocally interact to excite ischemically sensitive cardiac afferents. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) of anesthetized cats. Fifty-two ischemically sensitive afferents (conduction velocity = 0.27-3.35 m/s, 7 Adelta-fibers and 45 C-fibers) were identified. Repeated injections (1 microg) of BK into the left atrium (LA) 4 min after the administration of U-46619 (5 microg into the LA), a TxA(2) mimetic, induced a significantly larger cardiac afferent response than the first response to BK (0.61 +/- 0.14 to 1.95 +/- 0.29 vs. 0.66 +/- 0.09 to 2.75 +/- 0.34 impulses/s, first injection vs. second injection, n = 8). Conversely, blockade of TxA(2) receptors with BM-13,177 (30 mg/kg iv) attenuated the responses of eight other afferents to BK (1 microg into the LA) by 45%. In contrast, repeated BK (1 microg into the LA) induced consistent discharge activity in six separate afferents. We then observed that the coadministration of U-46619 (5 microg) and BK (1 microg into the LA) together caused a total response that was significantly higher than the predicted response by the simple addition of the individual responses. BK (1 microg) facilitated eight cardiac afferent responses to U-46619 (5 microg into the LA) by 64%. In contrast, repeated U-46619 (5 microg into the LA) without intervening BK stimulation evoked consistent responses in seven other ischemically sensitive afferents. Finally, inhibition of cyclooxygenase with indomethacin (5 mg/kg iv) eliminated the potentiating effects of BK on the cardiac afferent response to U-46619 (5 microg into the LA) but did not alter the afferent response to U-46619. These data suggest that BK and TxA(2) reciprocally interact to stimulate ischemically sensitive cardiac afferent endings leading to synergistic afferent responses and that the BK sensitization effect is mediated by cyclooxygenase products.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bradykinin; Cats; Cyclooxygenase Inhibitors; Drug Synergism; Female; Heart; Indomethacin; Male; Myocardial Ischemia; Neurons, Afferent; Prostaglandin-Endoperoxide Synthases; Spinal Cord; Thromboxane A2; Vasoconstrictor Agents

Clinical and experimental evidence has shown that myocardial ischemia activates cardiac spinal afferents that mediate sympathoexcitatory reflex responses. During myocardial ischemia, thromboxane A2 (TxA2) is released in large quantities by activated platelets in the coronary circulation of patients with coronary artery disease. We hypothesized that endogenous TxA2 contributes to sympathoexcitatory reflexes during myocardial ischemia through stimulation of TxA2/prostaglandin endoperoxide (TP) receptors. Regional myocardial ischemia was induced by occlusion of a diagonal branch of left anterior descending coronary artery of anesthetized cats. Hemodynamic parameters and renal sympathetic nerve activity were recorded after sinoaortic denervation and bilateral vagotomy. Regional myocardial ischemia evoked significant increases in mean blood pressure (122+/-10 vs. 139+/-12 mmHg, before vs. ischemia), aortic flow (153+/-18 vs. 167+/-20 ml/min), first derivative of left ventricular pressure at 40-mmHg developed pressure (2,736+/-252 vs. 2,926+/-281 mmHg/s), systemic vascular resistance (0.6+/-0.1 vs. 0.9+/-0.12 peripheral resistance units), and renal sympathetic nerve activity (by 22%). The reflex nature of the excitatory responses was confirmed by observing its disappearance after blockade of cardiac nerve transmission with intrapericardial 2% procaine treatment. Moreover, application of U-46619 (2.5-10 microg), a TxA2 mimetic, on the heart caused graded increases in mean arterial pressure and renal nerve activity, responses that were abolished 3 min after local blockade of cardiac neural transmission with intrapericardial procaine. BM 13,177 (30 mg/kg iv), a selective TP receptor antagonist, eliminated the reflex responses to U-46619 and significantly attenuated the excitatory responses during brief (5 min) regional myocardial ischemia. The sympathoexcitatory reflex responses to U-46619 were unchanged by blockade of histamine H1 receptors with pyrilamine and serotonin 5-HT3 receptors with tropisetron, indicating specificity of this TP receptor agonist. These data indicate that endogenous TxA2 participates in myocardial ischemia-mediated sympathoexcitatory reflex responses through a TP receptor mechanism.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthetics, Local; Animals; Cats; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart; Hemodynamics; Histamine H1 Antagonists; Indoles; Kidney; Male; Myocardial Ischemia; Pressoreceptors; Procaine; Pyrilamine; Receptors, Thromboxane; Reflex; Serotonin Antagonists; Sulfonamides; Sympathetic Nervous System; Thromboxane A2; Tropisetron; Vagotomy

Myocardial ischaemia activates blood platelets, which in turn stimulate cardiac sympathetic afferents, leading to chest pain and sympathoexcitatory reflex cardiovascular responses. Previous studies have shown that activated platelets stimulate ischaemically sensitive cardiac sympathetic afferents, and that thromboxane A(2) (TxA(2)) is one of the mediators released from activated platelets during myocardial ischaemia. The present study tested the hypothesis that endogenous TxA(2) stimulates cardiac afferents during ischaemia through direct activation of TxA(2) (TP) receptors coupled with the phospholipase C-protein kinase C (PLC-PKC) cellular pathway. Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) in anaesthetized cats. Single fields of 39 afferents (conduction velocity = 0.27-3.65 m s(-1)) were identified in the left or right ventricle initially with mechanical stimulation and confirmed with a stimulating electrode. Five minutes of myocardial ischaemia stimulated all 39 cardiac afferents (8 Adelta-, 31 C-fibres) and the responses of these 39 afferents to chemical stimuli were further studied in the following four protocols. In the first protocol, 2.5, 5 and 10 microg of the TxA(2) mimetic, U46619, injected into the left atrium (LA), stimulated seven ischaemically sensitive cardiac afferents in a dose-dependent manner. Second, BM13,177, a selective TxA(2) receptor antagonist, abolished the responses of six afferents to 5 microg of U46619 injected into the left atrium and attenuated the ischaemia-related increase in activity of seven other afferents by 44%. In contrast, cardiac afferents, in the absence of TP receptor blockade responded consistently to repeated administration of U46619 (n = 6) and to recurrent myocardial ischaemia (n = 7). In the fourth protocol, administration of PKC-(19-36), a selective PKC inhibitor, attenuated the responses of six other cardiac afferents to U46619 by 38%. Finally, using an immunohistochemical staining approach, we observed that TP receptors were expressed in cardiac sensory neurons in thoracic dorsal root ganglia. Taken together, these data indicate that endogenous TxA(2) contributes to the activation of cardiac afferents during myocardial ischaemia through direct stimulation of TP receptors probably located in the cardiac sensory nervous system and that the stimulating effect of TxA(2) on cardiac afferents is dependent, at least

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic Fibers; Afferent Pathways; Animals; Cats; Dose-Response Relationship, Drug; Female; Heart; Immunohistochemistry; Male; Myocardial Ischemia; Peptide Fragments; Protein Kinase C; Receptors, Thromboxane; Thromboxane A2

Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can restore endothelial function in coronary disease, in vitro and murine studies have shown their effects on myocardial angiogenesis to be biphasic and dose dependent. We investigated the functional and molecular effects of high-dose atorvastatin on the endogenous angiogenic response to chronic myocardial ischemia in hypercholesterolemic swine.. Yucatan pigs were fed either a normal (NORM group; n=7) or high-cholesterol diet, with (CHOL-ATR group; n=7) or without (CHOL group; n=6) atorvastatin (3 mg/kg per day) for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Seven weeks later, microvessel relaxation responses, myocardial perfusion, and myocardial protein expression were assessed. The CHOL group demonstrated impaired microvessel relaxation to adenosine diphosphate (29+/-3% versus 61+/-6%, CHOL versus NORM; P<0.05), which was normalized in the CHOL-ATR group (67+/-2%; P=NS versus NORM). Collateral-dependent myocardial perfusion, adjusted for baseline, was significantly reduced in the CHOL group (-0.27+/-0.07 mL/min per gram versus NORM; P<0.001) as well as the CHOL-ATR group (-0.35+/-0.07 mL/min per gram versus NORM; P<0.001). Atorvastatin treatment was associated with increased phosphorylation of Akt (5.7-fold increase versus NORM; P=0.001), decreased vascular endothelial growth factor expression (-68+/-8%; P<0.001 versus NORM), and increased expression of the antiangiogenic protein endostatin (210+/-48%; P=0.004 versus NORM).. Atorvastatin improves hypercholesterolemia-induced endothelial dysfunction without appreciable changes in collateral-dependent perfusion. Increased myocardial expression of endostatin, decreased expression of vascular endothelial growth factor, and chronic Akt activation associated with atorvastatin treatment may account for the diminished angiogenic response.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Angiostatins; Animals; Apoptosis; Apoptosis Inducing Factor; Arterioles; Atorvastatin; Caspase 3; Caspases; Cholesterol; Coronary Circulation; Coronary Vessels; Drug Evaluation, Preclinical; Endostatins; Endothelium, Vascular; Female; Fibroblast Growth Factor 2; Gene Expression Regulation; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Matrix Metalloproteinase 9; Myocardial Ischemia; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroprusside; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Receptor, TIE-2; Swine; Swine, Miniature; Vascular Endothelial Growth Factor A; Vasodilation

Urocortin is a vasodilator peptide related to corticotrophin-releasing factor, which may protect myocardium during coronary ischemia-reperfusion. To study whether urocortin also protects coronary endothelial function during ischemia-reperfusion, hearts from Sprague-Dawley rats were perfused at constant flow and then exposed to 15 mins ischemia followed by 15 mins reperfusion. In one series of experiments, we found that the coronary relaxation to urocortin (10(-11) to 10(-8) M) was reduced by ischemia-reperfusion (51 +/- 4% vs. 79 +/- 4% of the active tone, for the 10(-10) Mdose). In other series of experiments, we observed that ischemia-reperfusion reduced the coronary relaxation to a test dose of acetylcholine (10(-6) M) (25 +/- 2% vs. 54 +/- 9% of active tone), without modifying the relaxation to sodium nitroprusside (10(-6) M). Treatment with a low threshold concentration of urocortin (10(-11) M), administered before ischemia and during reperfusion, partly improved the coronary relaxation to acetylcholine (36 +/- 3% of active tone). These results suggest that ischemia-reperfusion impairs the coronary vasodilation to urocortin and produces endothelial dysfunction and that this endothelial dysfunction may be improved by urocortin.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Cardiotonic Agents; Coronary Vessels; Corticotropin-Releasing Hormone; Endothelium, Vascular; Male; Myocardial Ischemia; Myocardial Reperfusion; Nitroprusside; Rats; Rats, Sprague-Dawley; Urocortins

We hypothesized that exercise training preserves endothelium-dependent relaxation, lessens receptor-mediated constriction of coronary resistance arteries, and reduces myocardial contractile dysfunction in response to ischemia. After 10 wk of treadmill running or cage confinement, regional and global indexes of left ventricular contractile function were not different between trained and sedentary animals in response to three 15-min periods of ischemia (long-term; n = 17), one 5-min bout of ischemia (short-term; n = 18), or no ischemia (sham-operated; n = 24). Subsequently, coronary resistance vessels ( approximately 106 +/- 4 microm ID) were isolated and studied using wire myographs. Maximal ACh-evoked relaxation was approximately 25, 40, and 60% of KCl-induced preconstriction after the long-term, short-term, and sham-operated protocols, respectively, and was similar between groups. Maximal sodium nitroprusside-evoked relaxation also was similar between groups among all protocols, and vasoconstrictor responses to endothelin-1 and U-46619 were not different in trained and sedentary rats after short-term ischemia or sham operation. We did observe that, after long-term ischemia, maximal tension development in response to endothelin-1 and U-46619 was blunted (P < 0.05) in trained animals by approximately 70 and approximately 160%, respectively. These results support our hypothesis that exercise training lessens receptor-mediated vasoconstriction of coronary resistance vessels after ischemia and reperfusion. However, training did not preserve endothelial function of coronary resistance vessels, or myocardial contractile function, after ischemia and reperfusion.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Carbon Dioxide; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Hemodynamics; Hydrogen-Ion Concentration; Myocardial Contraction; Myocardial Ischemia; Nitroprusside; Oxygen; Partial Pressure; Physical Conditioning, Animal; Potassium Chloride; Rats; Time Factors; Vasoconstriction; Vasoconstrictor Agents

It was examined to what extent congestive heart failure (CHF) in rats, induced by ligation of the left coronary artery, affects the vascular responses to the vasodilatory substances acetylcholine (ACh), calcitonin gene-related peptide (CGRP), and substance P (SP). After induction of CHF status, the basilar, mesenteric and renal arteries and the iliac vein were studied in vitro. Dilatory responses were determined in relation to pre-contraction by the thromboxane mimetic U46619. Sham-operated animals (Sham) served as controls. U46619 induced stronger contraction in CHF basilar and renal arteries compared with the corresponding segments in Sham. ACh induced concentration-dependent dilations in all vessels examined with no difference of maximum relaxation or potency between CHF and Sham. SP induced weak dilations in all arteries examined while the response was markedly attenuated in CHF iliac veins compared with Sham (Emax% 12.2 +/- 3.4 vs. 32.3 +/- 4.8, P = 0.01). The CGRP induced dilation in the CHF basilar artery was weaker (Emax% 18.6 +/- 6.5 vs. 66.9 +/- 5.0, P < 0.001) and less potent (pEC50: 8.2 +/- 0.2 vs. 9.0 +/- 0.2, P = 0.01) compared with Sham. Further, CGRP was less potent in the renal artery of CHF rats compared with Sham (pEC50: 8.1 +/- 0.2 vs. 9.5 +/- 0.3, P < 0.01). In the CHF iliac vein, CGRP was more potent compared with Sham (pEC50: 9.7 +/- 0.4 vs. 8.3 +/- 0.4, P < 0.05). It can be concluded CHF is accompanied by alterations in the vascular response to the dilatory substances studied. The changes differ between vascular beds and between the different substances.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Calcitonin Gene-Related Peptide; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Failure; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Ischemia; Potassium; Rats; Rats, Sprague-Dawley; Substance P; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

1. The aim of this study was to assess whether the protective effect of ischaemic preconditioning on endothelial function in coronary arteries of the rat involves kinins. 2. Isolated hearts of the rat were exposed to a 30-min low-flow ischaemia (flow rate of 1 ml min[-1]) followed by 20-min reperfusion, after which coronaries were precontracted with 0.1 microM U-46619, and the response to the endothelium-dependent vasodilator, 5-hydroxytryptamine (5-HT, 10 microM), compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). 3. In untreated hearts, ischaemia-reperfusion diminished selectively 5-HT-induced vasodilatation, compared with time-matched sham hearts. The vasodilatation to SNP was unaffected after ischaemia-reperfusion. Preconditioning (5 min of zero-flow ischaemia followed by 10 min reperfusion) in untreated hearts preserved the vasodilatation produced by 5-HT. 4. Blockade of B1 and B2 receptors with either 3 nM [Lys[0], Leu8, des-Arg9]-bradykinin (LLDBK) or 10 nM Hoe 140 (icatibant), respectively, (started 15 min before ischaemic preconditioning or a corresponding sham period and stopped just before the 20-min reperfusion period) had no effect on the vasodilatation produced by either 5-HT or SNP in sham hearts. Pretreatment with Hoe 140 did not block the protective effect of ischaemic preconditioning on the 5-HT vasodilatation. In contrast, LLDBK halved the protective effect of ischaemic preconditioning on endothelium-dependent vasodilatation. 5. Perfusion with either bradykinin or des-Arg9-bradykinin (1 nM) 30 min before and lasting throughout the ischaemia protected the endothelium. 6. In conclusion, ischaemic preconditioning affords protection to the endothelial function in coronary resistance arteries of the rat partly by activation of B1 receptors. Although exogenous BK perfusion can protect the endothelium, B2 receptors do not play an important role in this protection in the rat isolated heart.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bradykinin; Bradykinin Receptor Antagonists; Endothelium, Vascular; Heart; Ischemic Preconditioning; Kinins; Male; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Vascular Resistance

Ischemia and reperfusion stun the myocardium and the coronary vasculature. We have previously shown that a short period (15 min) of global ischemia in the isolated rat heart causes impaired coronary constriction in response to a thromboxane analog U46619 during reperfusion. Sepsis has also been shown to affect myocardial and vascular function. In the present study, we determined whether Escherichia coli-induced sepsis would exacerbate the effects of ischemia on the coronary circulation. Sepsis prolonged the impairment in the coronary constriction response to U46619 following short term ischemia. We hypothesized that sepsis-induced increases in nitric oxide (NO) production caused the delay in the recovery of the contractile response to U46619. Perfusion with NO synthase inhibitors however indicated that the impaired response was not due to NO. However, NO did appear to have a significant role in the development of myocardial ischemic contracture and on the recovery of diastolic function after ischemia. Inhibitors of NO synthase also caused a significant increase in basal coronary perfusion pressure as well as in the maximum coronary pressure generated in response to U46619, suggesting a role of NO in regulating basal coronary vascular resistance in the isolated rat heart. Some of these effects were more pronounced in septic rat hearts than in the sham surgical rat hearts, consistent with altered nitric oxide production in the septic rat hearts.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Disease Models, Animal; Escherichia coli Infections; Male; Myocardial Contraction; Myocardial Ischemia; Nitric Oxide; Rats; Rats, Sprague-Dawley; Sepsis; Time Factors; Vascular Resistance

Oestrogen-replacement therapy is associated with a reduced incidence of cardiovascular disease. The acute administration of oestrogen improves myocardial ischemia in women with coronary heart disease. In this study we investigated the relaxing effect of oestradiol-17 beta on human coronary arteries in vitro and determined the role of endothelial modulation in this relaxation by using isolated human coronary arteries.. Atherosclerosis-free epicardial arteries from men and women were removed from patients undergoing heart or combined heart and lung transplantation. The arteries were cut into ring segments and placed into organ baths containing Tyrode's solution. Changes in isometric tension were measured. The relaxing response to oestradiol-17 beta (10(-10) - 10(-5) mol/l) was investigated and the effects of endothelium, NGmonomethyl-L-arginine and indomethacin on the response of oestradiol-17 beta were assessed.. Oestradiol-17 beta (10(-10) - 10(-5) mol/l) induced significant relaxation in coronary arteries pre-contracted with the thromboxane A2 analog (U46619; 3 x 10(-8) mol/l). Relaxation was significantly greater in coronary arteries from female patients. No significant differences were observed between arteries with or without endothelium nor after nitric oxide synthase or cyclo-oxygenase inhibition. These results indicate that oestradiol-17 beta induces human coronary artery relaxation via an endothelium-independent mechanism in vitro. The sex of the patients significantly affects sensitivity of the coronary arterial rings to oestrogen.. Oestradiol-17 beta-induced coronary relaxation may play an important role in regulation of coronary tone, and may partly explain why oestrogen improves myocardial ischemia in women and why it protects postmenopausal women from the risk of developing coronary heart disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Arginine; Child; Child, Preschool; Coronary Vessels; Endothelium, Vascular; Enzyme Inhibitors; Estradiol; Estrogen Replacement Therapy; Female; Humans; In Vitro Techniques; Indomethacin; Infant; Male; Middle Aged; Myocardial Ischemia; omega-N-Methylarginine; Prostaglandin Endoperoxides, Synthetic; Sex Factors; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Reperfusion of the ischemic myocardium is a cornerstone of current therapy for acute coronary syndromes. Experiments show that reperfusion is associated with injury to the coronary artery. Such injury may manifest as augmented vasospasm or impaired vasodilation, and in this study we assessed whether such coronary responses to serotonin do occur.. Left anterior descending arteries (LAD) were occluded in 12 open-chested dogs for 1 h, then reperfused for 1 h. Vasoreactivity to serotonin was measured in isolated rings from the LAD and circumflex arteries (Cx), both at basal resting tension and after preconstriction with U-46619. Endothelium was removed in half of the rings.. In the basal state, LAD rings displayed increased initial constriction and decreased dilation in response to serotonin (maximum dilation: LAD, -4.5 +/- 1.7% versus Cx, -7.6 +/- 1.4%, P < 0.05). With endothelium removed, peak constrictions of the LAD and Cx were significantly augmented, and LAD dilations remained slightly impaired compared with the Cx. After U-46619, dilation in response to serotonin was impaired in the LAD compared with Cx rings (maximum dilation: LAD, -18.3 +/- 11.4% versus Cx, -44.0 +/- 8.4 LAD, P < 0.05). Endothelium removal diminished, but did not abolish, this relationship. De-endothelialized Cx, but not LAD, rings displayed slightly impaired dilations in response to serotonin compared with their respective controls.. After ischemia-reperfusion, coronary arteries respond to serotonin with enhanced constriction and impaired dilation. Changes in both the endothelium and the smooth muscle may determine these responses to serotonin.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Coronary Vasospasm; Coronary Vessels; Dogs; Endothelium, Vascular; Male; Muscle, Smooth, Vascular; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Serotonin; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

The anti-anginal effect of nitroglycerin and prostacyclin was examined using, as an index, the ischaemic electrocardiogram (ECG) change (ST elevation) induced by intracoronary arterial injection of 9,11-dideoxy-11 alpha,9 alpha-epoxymethano-PGF2 alpha (U-46619), a stable thromboxane A2 agonist, in anaesthetized rats. The ST elevation induced by U-46619 (5-20 micrograms kg-1, i.c.a.) was dose-dependent and reproducible. U-46619-induced ST elevation was markedly prevented by the pretreatment of intravenous administration of prostacyclin (0.01 micrograms kg-1), and to a lesser extent by nitroglycerin (0.3 mg kg-1). Simultaneously, platelet count decreased significantly in the coronary arterial blood which indicated that platelet aggregation was enhanced by U-46619. The decrease of platelet count in coronary arterial blood at the time of ST elevation was significantly suppressed by prostacyclin (0.1 microgram kg-1, i.v.), but not by nitroglycerin (0.3 mg kg-1, i.v.). These results suggest that the ST elevation induced by intracoronary arterial injection of U-46619 may be derived from spasm of coronary artery and platelet aggregation in the intracoronary artery in rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Blood Platelets; Blood Pressure; Coronary Vessels; Disease Models, Animal; Electrocardiography; Epoprostenol; Heart Rate; Injections, Intra-Arterial; Injections, Intravenous; Male; Myocardial Ischemia; Nitroglycerin; Platelet Aggregation; Platelet Count; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstrictor Agents

Antianginal effects of monatepil ([(+-)-N-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-(4-fluor ophenyl)-1-piperazinebutanamide]monomaleate, AJ-2615, CAS 10337-41-9), a new calcium antagonist, were evaluated in experimentally induced myocardial ischemia in anesthetized rats and compared with those of diltiazem. Ischemic electrocardiogram change (ST elevation) and reduction of myocardial tissue oxygen tension were induced by intracoronary arterial administration of U-46619 ((5Z,9a,11a,13E,15(S))-9,11-(methano-epoxy)prosta-5,13-di en-1-oic acid) (10 micrograms/kg), a stable thromboxane A2 agonist. The ST elevation induced by U-46619 was significantly prevented by monatepil pretreatment (0.1 mg/kg i.v.), and to a lesser extent by diltiazem (0.3 mg/kg i.v.). Moreover, the decrease in myocardial tissue oxygen tension at the time of ST elevation after U-46619 was inhibited by monatepil pretreatment (0.3 mg/kg i.v.). These results indicate that monatepil exerts a more potent preventive effect against U-46619-induced myocardial ischemic changes than diltiazem and suggest that monatepil has potential for treating vasospastic angina.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Calcium Channel Blockers; Dibenzothiepins; Diltiazem; Electrocardiography; Heart Rate; Male; Myocardial Ischemia; Myocardium; Oxygen Consumption; Piperazines; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstrictor Agents

We investigated the possible protective effects of benidipine (Coniel), a calcium antagonist, on mechanical dysfunction, metabolic damage and changes in vascular reactivity during ischemia and reperfusion in the Langendorff-perfused rat heart. The responses of perfusion pressure to U-46619, a vasoconstrictor, and acetylcholine, an endothelial-dependent vasodilator, were also determined as indices of the vascular function. Thirty min of reperfusion following 30 min of global ischemia produced contractile failure and the marked release of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK). Additionally, the ischemia and reperfusion augmented the vasoconstrictor response to U-46619, and depressed the endothelium-dependent vasodilator response to acetylcholine. These hearts were treated with 1 or 10 nM benidipine from 20 min before ischemia to the beginning of ischemia. While benidipine at 10 nM had a modest negative inotropic action, 1 nM of this drug had minimal depressant effects on the preischemic function. The depressed contractile function after the ischemia was improved, and the increased releases of LDH and CPK were significantly ameliorated by benidipine. Also, benidipine restored the augmented contractile response to U-46619 and preserved the vasodilator response to acetylcholine. These results demonstrate that pretreatment with benidipine prevents myocardial injury following ischemia and reperfusion. The cardioprotective effects of benidipine may in part be due to the protection of vascular reactivity by this drug.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Wistar; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents

We examined whether subtotal coronary artery occlusion and reperfusion alter coronary flow reserve and regional myocardial function.. Total coronary artery occlusion followed by reperfusion results in decreased coronary flow reserve and regional myocardial dysfunction.. Thirteen anesthetized dogs were subjected to subtotal occlusion of the left anterior descending coronary artery for 1 h, followed by reperfusion for 1 h. During subtotal left anterior descending occlusion, heart rate was increased by atrial pacing. After reperfusion, coronary flow reserve, indicated by reactive hyperemia, as well as coronary flow responses to acetylcholine and nitroglycerin, regional myocardial function and myocardial leukocyte accumulation were measured.. After reperfusion, coronary flow reserve was decreased in the ischemic left anterior descending but not the nonischemic circumflex coronary artery region. Myocardial function was also depressed in the left anterior descending coronary region and did not improve on reperfusion. Histologic study showed no leukocyte infiltration in the ischemic left anterior descending coronary region. Myeloperoxidase, an index of myocardial leukocyte accumulation, was similar in the left anterior descending and circumflex coronary regions. Sensitivity of epicardial left anterior descending coronary artery rings to the thromboxane A2 analog U46,619 was enhanced, and relaxation of these rings in response to endothelium-dependent relaxants was decreased.. Coronary flow reserve is reduced and regional myocardial function depressed after subtotal coronary artery occlusion and increased heart rate. A decreased synthesis or increased breakdown of endothelium-derived relaxing factor may be related to a decrease in coronary flow reserve. However, the reduction in coronary flow reserve appears to be unrelated to leukocyte accumulation in the reperfused region.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Cardiac Pacing, Artificial; Constriction; Coronary Circulation; Coronary Vessels; Dogs; Female; Heart; Heart Rate; Leukocytes; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Nitric Oxide; Nitroglycerin; Oxygen; Peroxidase; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

The thromboxane A2 receptor agonist, U-46619 ((5Z, 9 alpha, 11 alpha, 13E, 15(S))-9,11-(methanoepoxy)prosta-5,13-dien-1-oic acid) (10 micrograms/kg), induced a typical ischemic change (ST elevation) in the electrocardiogram on intracoronary arterial administration in the rat. The elevation of the ST segment induced by U-46619 was significantly reduced by pretreatment with anti-endothelin-1 rabbit serum. The plasma concentration of endothelin-1 dose dependently increased at the time of ST segment elevation after U-46619. These results indicate that endogenous endothelin-1 partly contributes to coronary spasmodic angina induced by thromboxane A2 in rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angina Pectoris; Animals; Electrocardiography; Endothelins; Injections, Intra-Arterial; Male; Myocardial Ischemia; Prostaglandin Endoperoxides, Synthetic; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstrictor Agents

The myocardial salvage efficacy of a thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist has not been previously determined in a ferret model of ischemia and reperfusion. Assessments of the reproducibility of infarct size resulting from a 90 min period of occlusion followed by 5 hr of reperfusion of the left anterior descending coronary artery in saline-treated control ferrets revealed a consistent mean level of tissue damage representing 23.1 +/- 1.4% of the left ventricle. In subsequent studies, ferrets were given the thromboxane receptor antagonist SQ 30,741 (1 mg/kg bolus and 1 mg/kg/hr infusion, i.v.) or vehicle. At this dose, SQ 30,741 significantly reduced infarct size from that measured in control ferrets by 44%. Concurrently, the drug produced a 97% inhibition of platelet TP receptors as measured by inhibition of the ex vivo platelet shape change response to U-46,619. Drug administration was not associated with measurable alterations in mean blood pressure, heart rate or the rate-pressure-product. The importance of this finding to clinical utility and the mechanism of the observed cardioprotective action, however, remain unclear. These data indicate that the ferret represents a useful model for the assessment of the myocardial salvage efficacy of TP receptor antagonists and are consistent with attenuation of ischemic myocardial damage by doses of these agents which produce > 96% TP receptor blockade.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Blood Platelets; Blood Pressure; Ferrets; Heart; Heart Rate; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Orchiectomy; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Reperfusion; Thromboxane A2; Vasoconstrictor Agents

The coronary circulation has been shown to remain responsive to vasodilator and vasoconstrictor stimuli during myocardial ischaemia. The aim of this study was to investigate whether endogenous adenosine attenuates coronary vasoconstriction caused by the thromboxane A2 analogue, U46619.. Nine chronically instrumented dogs were studied during treadmill exercise in the presence of a coronary stenosis which resulted in distal left circumflex coronary artery hypoperfusion. Myocardial blood flow was assessed with radioactive microspheres during exercise prior to and during intracoronary infusion of U46619 (0.01 microgram.kg-1 x min-1), in the absence and the presence of adenosine receptor blockade with intravenous 8-phenyltheophylline (5 mg.kg-1) and intracoronary adenosine deaminase (50 units.kg-1). Distal coronary pressure was maintained constant during the control stenosis and the three interventions, at 49(SEM 3), 50(3), 50(3), and 50(3) mm Hg.. During control exercise mean myocardial blood flow was 0.91(0.09) ml.min-1 x g-1 in the stenosis region and 2.54(0.28) in the normal region. With no change in distal coronary pressure, U46619 decreased mean myocardial blood flow to 0.70(0.10) ml.min-1 x g-1 (p < 0.05). Adenosine blockade alone decreased myocardial blood flow in the stenosis region to 0.60(0.07) ml.min-1 x g-1 (p < 0.05 v control stenosis), indicating that endogenous adenosine contributed to coronary vasodilatation in the ischaemic region. However, adenosine blockade did not augment the vasoconstriction in response to U46619 [mean myocardial blood flow 0.49(0.05) ml.min-1 x g-1], indicating that endogenous adenosine did not attenuate the vasoconstriction caused by U46619.. Endogenous adenosine contributed to dilatation of resistance vessels in hypoperfused myocardium of exercising dogs in the absence as well as in the presence of U46619. However, endogenous adenosine did not attenuate the magnitude of the vasoconstrictor response to U46619. These findings are best explained by observations that thromboxane A2 and adenosine act on coronary vascular segments of different size.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine; Animals; Coronary Vessels; Dogs; Myocardial Contraction; Myocardial Ischemia; Physical Exertion; Prostaglandin Endoperoxides, Synthetic; Regional Blood Flow; Theophylline; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents