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

The aim of this study was to evaluate the effects of an analogue of lacidipine, CZ454 in in vitro and in vivo. The isometric tension of Sprague-Dawley rat arterial ring segments was recorded by a myography system. Intracellular calcium of vascular smooth muscle was determined by the confocal laser microscopy. Blood pressure of spontaneously hypertensive rats was measured using a tail-cuff blood pressure system. The results showed that CZ454 (10 - 9-10 - 6 mol/L) relaxed the mesenteric artery contracted by high K + concentration-dependently, which was not affected by removal of the endothelium. CZ454 treatment shifted the concentration-contractile curves induced by phenylephrine, U46619, KCl and CaCl2 to the right with the decreased Emax. CZ454 was more potent in the coronary and basilar artery than in the mesenteric artery. CZ454 did not reduce phenylephrine-induced vasoconstriction; however, it did inhibit the contraction caused by addition of CaCl2 and did not change caffeine-induced contraction in the mesenteric artery in Ca2 + -free solution. CZ454 decreased the vasoconstriction induced by Bay K 8644 in the presence of 60 mmol/L K + . CZ454 1.0 mg/kg administered by gavage lowered the systolic pressure and diastolic pressure by 20% and 17%, respectively. It was concluded that CZ454 lowers blood pressure and relaxes arteries with higher potency in coronary and basilar artery and that the vasodilation may involve inhibition of calcium influx.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Antihypertensive Agents; Blood Pressure; Caffeine; Calcium; Calcium Chloride; Calcium Signaling; Dihydropyridines; Hypotension; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Phenylephrine; Potassium; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Vasoconstriction; Vasodilation; Vasodilator Agents

In the present study, we investigated the role of the central cholinergic system in mediating the pressor effect of intracerebroventricularly administrated U-46619, a thromboxane A2 (TxA2) analog, in hemorrhaged hypotensive rats. Hemorrhage was performed by withdrawing a total volume of 2.1 ml of blood per 100 g body weight over a period of 10 min. Intracerebroventricular (i.c.v.) injection of U-46619 (0.5, 1, 2 micro g) produced a dose- and time-dependent increase in arterial pressure and reversed the hypotension of this condition. Hemorrhage caused small increases in extracellular hypothalamic acetylcholine and choline levels. Intracerebroventricular administration of U-46619 (1 micro g) further increased the levels of extracellular acetylcholine and choline by 57% and 41%, respectively. Pretreatment with SQ-29548 (8 mug; i.c.v.), a selective TxA2 receptor antagonist, completely abrogated the effects of subsequent injection of U-46619 (1 mug; i.c.v.) on arterial pressure and extracellular acetylcholine and choline levels. Pretreatment with mecamylamine (50 micro g; i.c.v.), a cholinergic nonselective nicotinic receptor antagonist, attenuated the pressor effect of U-46619 (1 micro g, i.c.v.) in hemorrhaged rats whereas pretreatment with atropine (10 micro g; i.c.v.), a cholinergic nonselective muscarinic receptor antagonist, had no effect. Interestingly, pretreatment of rats with methyllycaconitine (10 micro g; i.c.v.) or alpha-bungarotoxin (10 micro g; i.c.v.), selective antagonists of alpha-7 subtype nicotinic acetylcholine receptors (alpha7nAChRs), partially abolished the pressor effect of U-46619 (1 micro g; i.c.v.) in the hypotensive condition. Pretreatment with a combination of mecamylamine plus methyllycaconitine or mecamylamine plus alpha-bungarotoxin attenuated the reversal effect of U-46619, but only to the same extent as pretreatment with either antagonist alone. In conclusion, i.c.v. administration of U-46619 restores arterial pressure and increases posterior hypothalamic acetylcholine and choline levels by activating central TxA2 receptors in hemorrhaged hypotensive rats. The activation of central nicotinic cholinergic receptors, predominantly alpha7nAChRs, partially acts as a mediator in the pressor responses to i.c.v. injection of U-46619 under these conditions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Cholinergic Fibers; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Fluid; Fatty Acids, Unsaturated; Hemorrhage; Hydrazines; Hypotension; Hypothalamus, Posterior; Injections, Intraventricular; Male; Neural Pathways; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Time Factors; Vasoconstrictor Agents

1. In the present study, we aimed to determine the involvement of brain thromboxane A2 (TXA2) in blood pressure decreases evoked by acute and/or graded haemorrhage in rats. 2. Sprague-Dawley rats were used throughout the study. Acute haemorrhage was achieved by withdrawing a total volume of 2.1 and 2.5 mL blood/100 g bodyweight over a period of 10 min. A microdialysis study was performed in a hypothalamic area to measure extracellular TXA2 levels. Graded haemorrhage was conducted successively by withdrawing carotid arterial blood (0.55 mL/100 g bodyweight) over a 10 s period four times (S1-S4) at 5 min intervals. Furegrelate (125, 250 and 500 microg), a TXA2 synthase inhibitor, was injected intracerebroventricularly (i.c.v.) 60 min before acute or graded haemorrhage was initiated. U-46619 (0.5, 1 and 2 microg, i.c.v.), a synthetic TXA2 analogue, was administered 5 min before acute haemorrhage (2.1 mL/100 g bodyweight). 3. Acute haemorrhage produced a severe and long-lasting decrease in blood pressure and had a tendency to increase heart rate. Both haemorrhage protocols (2.1 or 2.5 mL/100 g) generated similar approximate twofold increases in extracellular hypothalamic TXA2 levels. Intracerebroventricular furegrelate (250 microg) pretreatment completely blocked the TXA2 increases induced by acute haemorrhage. Furegrelate administration (100, 250 and 500 microg, i.c.v.) attenuated the fall in arterial pressure evoked by acute haemorrhage and caused significant increases in heart rate at all doses injected. 4. Graded haemorrhage progressively lowered arterial pressure and increased plasma vasopressin and adrenaline levels in the last period. Furegrelate-injected rats were greatly resistant to the hypotensive effect of haemorrhage for all degrees of blood removed. Plasma adrenaline and vasopressin levels were significantly elevated in furegrelate-pretreated rats compared with the saline-treated group during S2-S3 and S4, respectively. U-46619 administration caused small but statistically significant decreases in arterial pressure induced by haemorrhage. 4. The results show that acute hypotensive haemorrhage increases extracellular hypothalamic TXA2 levels. The increase in brain endogenous TXA2 levels involves a decrease in blood pressure evoked by haemorrhage because the blockade of TXA2 synthesis by furegrelate pretreatment attenuated the haemorrhagic hypotension. Increases in plasma adrenaline and vasopressin levels may mediate this effect.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzofurans; Blood Pressure; Disease Models, Animal; Epinephrine; Heart Rate; Hemorrhage; Hypotension; Hypothalamus; Injections, Intraventricular; Male; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane-A Synthase; Time Factors; Vasoconstrictor Agents; Vasopressins

In the present study, we investigated the cardiovascular effects of centrally injected U-46619, a thromboxane A(2) (TXA(2)) analog, and the central and peripheral mechanisms of these effects in hemorrhagic shock conditions. Hemorrhage was performed by withdrawing a total volume of 2.1 ml of blood/100 g body weight over a period of 10 min. Injections were made into the lateral cerebral ventricle (LCV), nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM) and paraventricular nucleus of hypothalamus (PVN). U-46619 (0.1, 1 and 2 microg) increased blood pressure and reversed hypotension in hemorrhagic shock. The pressor effect was dose- and time-dependent in all investigated brain areas. Heart rate changes were not significantly different in all groups. Pretreatment of rats with an injection of SQ-29548 (4 or 8 microg), a TXA(2) receptor antagonist, into the LCV, NTS, RVLM and PVN completely blocked the pressor effect of U-46619 (1 microg) injected into respective brain areas. Hemorrhage itself increased plasma adrenaline, noradrenaline, vasopressIN levels and renin activity. U-46619 (1 microg) injected into the LCV, PVN, RVLM and NTS produced additional increases in these hormone levels and in renin activity. Intravenous pretreatments of rats with prazosin (0.5 mg/kg), an alpha(1)-adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl(1), O-Me-Tyr(2),Arg(8)]- vasopressin (10 microg/kg), a vasopressin V(1)-receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, in hemorrhaged rats partially blocked the pressor response to U-46619 (1 microg) injected into the LCV, PVN, RVLM and NTS. Results show that centrally administered U-46619, a TXA(2) analog, increases blood pressure and reverses hypotension in hemorrhagic shock. Activation of central TXA(2) receptors mediates the pressor effect of the drug. Furthermore, the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity are involved in these effects.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic alpha-1 Receptor Antagonists; Angiotensin II Type 1 Receptor Blockers; Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Brain; Bridged Bicyclo Compounds, Heterocyclic; Catecholamines; Fatty Acids, Unsaturated; Heart Rate; Hemodynamics; Hemorrhage; Hydrazines; Hypotension; Injections; Injections, Intraventricular; Male; Medulla Oblongata; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Renin; Shock, Hemorrhagic; Solitary Nucleus; Thromboxane A2; Vasoconstrictor Agents; Vasopressins

Injections of the thromboxane A(2) mimetic U-46619 (10 and 20 microg) into the left atrium of anesthetized rabbits evoked decreases in heart rate (HR) and arterial blood pressure (ABP) followed by an increase in ABP. Bilateral, cervical vagotomy abolished the U-46619-induced bradycardia and attenuated the hypotension. Injections of U-46619 into the ascending aorta did not evoke the bradycardia and hypotension but did cause arterial hypertension. To further define the origin of the vagal reflex, recordings of nerve impulses were made from 11 chemosensitive cardiac vagal afferent nerves. Impulse frequency increased in all 11 fibers in response to left atrial injections of phenylbiguanide (20-30 microg) and U-46619 (5-10 microg). Onset time of nerve activity induced by U-46619 correlated with the onset time of bradycardia. We conclude that U-46619 injections into the left heart elicit decreases in HR and ABP via a vagal reflex that originates from the heart similar to the coronary chemoreflex described for other agents.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthesia; Animals; Biguanides; Blood Pressure; Bradycardia; Chemoreceptor Cells; Female; Heart Atria; Heart Rate; Hypertension; Hypotension; Male; Neurons, Afferent; Rabbits; Reflex; Serotonin Receptor Agonists; Thromboxane A2; Vagotomy; Vagus Nerve; Vasoconstrictor Agents

1. This study attempts to investigate if endogenous nitric oxide (NO) can modulate the eicosanoid-releasing properties of intravenously administered endothelin-1 (ET-1) in the pulmonary and circulatory systems in the guinea-pig. 2. The nitric oxide synthase blocker N(omega)-nitro-L-arginine methyl ester (L-NAME; 300 microM; 30 min infusion) potentiated, in an L-arginine sensitive fashion, the release of thromboxane A2 (TxA2) stimulated by ET-1, the selective ET(B) receptor agonist IRL 1620 (Suc-[Glu9,Ala11,15]-ET-1(8-21)) or bradykinin (BK) (5, 50 and 50 nM, respectively, 3 min infusion) in guinea-pig isolated and perfused lungs. 3. In anaesthetized and ventilated guinea-pigs intravenous injection of ET-1 (0.1-1.0 nmol kg(-1)), IRL 1620 (0.2-1.6 nmol kg(-1)), BK (1.0-10.0 nmol kg(-1)) or U 46619 (0.2-5.7 nmol kg(-1)) each induced dose-dependent increases in pulmonary insufflation pressure (PIP). Pretreatment with L-NAME (5 mg kg(-1)) did not change basal PIP, but increased, in L-arginine sensitive manner, the magnitude of the PIP increases (in both amplitude and duration) triggered by each of the peptides (at 0.25, 0.4 and 1.0 nmol kg(-1), respectively), without modifying bronchoconstriction caused by U 46619 (0.57 nmol kg(-1)). 4. The increases in PIP induced by ET-1, IRL 1620 (0.25 and 0.4 nmol kg(-1), respectively) or U 46619 (0.57 nmol kg(-1)) were accompanied by rapid and transient increases of mean arterial blood pressure (MAP). Pretreatment with L-NAME (5 mg kg(-1); i.v. raised basal MAP persistently and, under this condition, subsequent administration of ET-1 or IRL 1620, but not of U-46619, induced hypotensive responses which were prevented by pretreatment with the cyclo-oxygenase inhibitor indomethacin. 5. Thus, endogenous NO appears to modulate ET-1-induced bronchoconstriction and pressor effects in the guinea-pig by limiting the peptide's ability to induce, possibly via ET(B) receptors, the release of TxA2 in the lungs and of vasodilatory prostanoids in the systemic circulation. Furthermore, it would seem that these eicosanoid-dependent actions of ET-1 in the pulmonary system and on systemic arterial resistance in this species are physiologically dissociated.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Bradykinin; Bronchoconstriction; Cyclooxygenase Inhibitors; Drug Synergism; Eicosanoids; Endothelin-1; Endothelins; Enzyme Inhibitors; Female; Guinea Pigs; Hypotension; In Vitro Techniques; Indomethacin; Lung; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oligopeptides; Peptide Fragments; Perfusion; Piperidines; Thromboxane A2; Vasoconstrictor Agents

The effects of [Leu13]motilin were examined in vivo after its intravenous administration into anesthetized dogs and in vitro with isolated preparations of canine mesenteric artery. [Leu13]Motilin (0.1-10 nmol x kg(-1), i.v.) induced both strong and clustered phasic contractions in the gastric antrum and duodenum. At doses of over 1 nmol x kg(-1), [Leu13]motilin also produced transient decreases in arterial blood pressure, left ventricular pressure, maximum rate of rise of left ventricular pressure, and total peripheral resistance, and an increase in aortic blood flow and heart rate. A selective motilin antagonist, GM-109 (Phe-cyclo[Lys-Tyr(3-tBu)-betaAla] trifluoroacetate), completely abolished the gastric antrum and duodenal motor responses induced by [Leu13]motilin. In contrast, hypotension induced by [Leu13]motilin (1 nmol x kg(-1)) was unchanged in the presence of GM-109. In isolated mesenteric artery preparations precontracted with U-46619 (10(-7) M), [Leu13]motilin (10(-8)-10(-5) M) induced an endothelium-dependent relaxation, and this was inhibited by a pretreatment with N(omega)-nitro-L-arginine, a competitive inhibitor of NO synthase (10(-4) M). A high dose (10(-4) M) of GM-109 slightly decreased [Leu13]motilin-induced relaxation, and shifted the concentration-response curve of [Leu13]motilin to the right. However, the pA2 value (4.09) of GM-109 for [Leu13]motilin in the present study was conspicuously lower than that previously demonstrated in the rabbit duodenum (7.37). These results suggest that [Leu13]motilin induces hypotension via the endothelial NO-dependent relaxation mechanism and not through the receptor type that causes upper gastrointestinal contractions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Dogs; Gastrointestinal Agents; Gastrointestinal Motility; Hemodynamics; Hormone Antagonists; Hypotension; Male; Mesenteric Arteries; Motilin; Peptides, Cyclic; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Vasoconstrictor Agents

Because some patients with Streptococcus pneumoniae bacteremia may present with shock, we reasoned that this organism may produce substances that cause shock. To test this hypothesis, type III pneumococcus supernatant, suspended in 10 ml of sterile water, was infused over 1 min in 8 adult anesthetized sheep. Normal saline was used as a control and had no effect on any of the hemodynamic parameters. Infusion of supernatant resulted in a precipitous fall in cardiac output from a control value of 4.25 +/- 0.54 to 2.80 +/- 0.43 (SE) l/min, a fall in mean systemic arterial pressure from 70 +/- 4 to 49 +/- 8 mmHg, and an increase in the mean pulmonary arterial pressure from 13 +/- 2 to 23 +/- 4 mmHg within 1 min after the infusion was completed. The peak hemodynamic effects were observed at approximately 3 min and returned to normal within 10 min after the infusion was completed. The thromboxane B2 level increased from a control value of 10 +/- 5 to 156 +/- 43 pg/ml at 3 min after the infusion was completed and decreased to 63 +/- 34 pg/ml at 20 min. A second identical dose of pneumococcal supernatant, repeated within 2 h of the first dose, had no effect on hemodynamic variables. Pretreatment with indomethacin, 5 mg/kg body wt, completely blocked the hemodynamic effects of pneumococcal supernatant (n = 3 sheep). Thus, we conclude that S. pneumoniae supernatant contains substances that cause septic shock syndrome through the synthesis of arachidonic acid metabolites and that a sublethal dose of the supernatant causes rapid tachyphylaxis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Cardiac Output; Hypertension, Pulmonary; Hypotension; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Pneumococcal Infections; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Serotonin; Sheep; Shock, Septic; Streptococcus pneumoniae; Thromboxane A2; Thromboxane B2

Platelet-activating factor (PAF) is a phospholipid mediator that induces cardiovascular collapse and release of the secondary mediator thromboxane A2 (TxA2). To clarify mechanisms involved in this collapse and, specifically, the relative contribution of left ventricular and right ventricular dysfunction, we studied 12 open-chest pigs. PAF infusion (0.04-0.28 nmol.kg-1.min-1) induced a 5- to 120-fold increase in pulmonary vascular resistance, a 75-98% fall in cardiac output, and systemic arterial hypotension. Right ventricular failure was indicated by chamber enlargement, decreased shortening, and increased right atrial pressures. In contrast, left ventricular dysfunction was accompanied by decreases in chamber dimensions and filling pressures that were unresponsive to volume expansion. U 46619 (a stable TxA2 analogue) and mechanical pulmonary artery constriction induced changes similar to PAF. In 11 additional closed-chest pigs, TxA2 blockade with indomethacin attenuated the PAF-induced rise in pulmonary vascular resistance, right ventricular dysfunction, and systemic hypotension. A specific TxA2 synthase inhibitor, OKY-046, also diminished hemodynamic effects of PAF in six other pigs. Tachyphylaxis was not observed in five pigs repeatedly given PAF. We conclude that acute right ventricular failure as the result of severe increase in pulmonary vascular resistance is the primary mechanism early in the course of PAF-induced shock in the pig. PAF-induced release of TxA2 may contribute significantly to these events.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Female; Hypotension; Indomethacin; Male; Methacrylates; Platelet Activating Factor; Prostaglandin Endoperoxides, Synthetic; Swine; Thromboxane A2; Thromboxane-A Synthase