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

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Oral; Adolescent; Adult; Benzoquinones; Body Weight; Double-Blind Method; Heptanoic Acids; Humans; Leukotriene B4; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Quinones; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

At birth, the intestine becomes the sole site for nutrient absorption requiring a dramatic increase in blood flow. The vascular changes accompanying this transition have been partly characterized in mammals. We investigated, using wire myography, the developmental changes in chick mesenteric artery (MA) reactivity. Rings of the MA from 15-day (E15) and 19-day (E19) chicken embryos (total incubation 21 days) as well as non-fed 0-3-h-old (NH3h) and first-fed 1-day-old (NH1d) newly hatched chicks contracted in response to KCl, norepinephrine (NE), U46619, and endothelin (ET)-1 and relaxed in response to acetylcholine (ACh), sodium nitroprusside (SNP), and forskolin indicating the presence of electro- and pharmaco-mechanical coupling as well as cGMP- and cAMP-mediated relaxation. In ovo development and transition to ex ovo life was accompanied by alterations in the response of the MAs, but a different developmental trajectory was observed for each reactivity pathway tested. Thus, the contractile efficacy of KCl underwent a linear increase (E15 < E19 < NH3h < NH1d). The efficacy of NE and U46619 increased in ovo, but not ex ovo (E15 < E19 = NH3h = NH1d) and the efficacy of ET-1 peaked at E19 (E15 < E19 > NH3h = NH1d). The relaxations elicited by ACh (endothelium-dependent), SNP, and forskolin did not undergo significant developmental changes. In conclusion, the ability of chick MAs to constrict in response to pharmacological stimuli increases during the embryonic period, but no dramatic changes are induced by hatching or the first feeding. Maturation of vasodilator mechanisms precedes that of vasoconstrictor mechanisms. Alterations of the delicate balance between vasoconstrictors and vasodilators may play an important role in perinatal intestinal diseases.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Animals, Newborn; Body Weight; Chick Embryo; Chickens; Colforsin; Embryonic Development; Endothelin-1; Enzyme Inhibitors; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Nitroprusside; Norepinephrine; Oxadiazoles; Potassium Chloride; Quinoxalines; Vasoconstriction; Vasodilation

Rho-kinase-dependent Ca2+ sensitization is an essential process for contraction of mammalian vascular smooth muscle but the information about its effects in non-mammalian vessels is scarce. We aimed to investigate, using the Rho-kinase inhibitor hydroxyfasudil, the potential role of the Rho-kinase pathway of Ca2+ sensitization in depolarization- and agonist-mediated contraction of chicken embryo (at day 19 of the 21 days of incubation) femoral arteries. Contraction elicited by KCl (125 mM) comprised two phases (phasic and tonic contraction), both of which were abolished in the absence of extracellular Ca2+. Hydroxyfasudil (10 microM) left the initial phasic component nearly intact but abolished the tonic component. Hydroxyfasudil also induced a marked impairment of the contractions elicited by phenylephrine (PE), the thromboxane A2 mimetic U46619, and endothelin-1. In contrast, inhibition of protein kinase C (PKC) by chelerythrine did not affect KCl- or PE-induced contractions, indicating lack of participation of PKC-mediated Ca2+ sensitization. Incubation under chronic hypoxia (15% O2 from day 0) impaired embryonic growth but did not significantly affect hydroxyfasudil-mediated relaxation. In summary, our findings are indicative of a role for Rho-kinase activity in depolarization- and agonist-induced force generation in chicken embryo femoral arteries.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzophenanthridines; Body Weight; Calcium; Chick Embryo; Egtazic Acid; Endothelin-1; Enzyme Inhibitors; Femoral Artery; Hypoxia; NG-Nitroarginine Methyl Ester; Oxadiazoles; Phenylephrine; Phorbol 12,13-Dibutyrate; Potassium Chloride; Protein Kinase C; Protein Kinase Inhibitors; Quinoxalines; rho-Associated Kinases; Vasoconstriction

Endothelial dysfunction has been linked to a decrease in nitric oxide (NO) bioavailability and attenuated endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation. The small (SK(Ca)) and intermediate (IK(Ca)) calcium-activated potassium channels play a key role in endothelium-dependent relaxation. Because the repressor element 1-silencing transcription factor (REST) negatively regulates IK(Ca) expression, we hypothesized that augmented REST and decreased IK(Ca) expression contributes to impaired endothelium-dependent vasodilation associated with hypertension. Acetylcholine (ACh) responses were slightly decreased in small mesenteric arteries from male stroke-prone spontaneously hypertensive rats (SHRSPs) versus arteries from Wistar Kyoto (WKY) rats. Incubation with N-nitro-L-arginine methyl ester (L-NAME; 100mumol/L) and indomethacin (100mumol/L) greatly impaired ACh responses in vessels from SHRSP. Iberiotoxin (0.1mumol/L), which is a selective inhibitor of large-conductance K(Ca) (BK(Ca)) channels, did not modify EDHF-mediated vasodilation in SHRSP or WKY. UCL-1684 (0.1mumol/L), which is a selective inhibitor of SKCa channels, almost abolished EDHF-mediated vasodilation in WKY and decreased relaxation in SHRSP. 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34; 10mumol/L) and charybdotoxin (0.1mumol/L), which are both IKCa inhibitors, produced a small decrease of EDHF relaxation in WKY but completely abrogated EDHF vasodilation in SHRSP. EDHF-mediated relaxant responses were completely abolished in both groups by simultaneous treatment with UCL-1684 and TRAM-34 or charybdotoxin. Relaxation to SK(Ca)/IK(Ca) channels agonist NS-309 was decreased in SHRSP arteries. The expression of SK(Ca) was decreased, whereas IK(Ca) was increased in SHRSP mesenteric arteries. REST expression was reduced in arteries from SHRSP. Vessels incubated with TRAM-34 (10mumol/L) for 24h displayed reduced REST expression and demonstrated no differences in IK(Ca). In conclusion, IK(Ca) channel upregulation, via decreased REST, seems to compensate deficient activity of SK(Ca) channels in the vasculature of spontaneously hypertensive rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Blood Pressure; Body Weight; Charybdotoxin; Endothelium, Vascular; Indomethacin; Male; NG-Nitroarginine Methyl Ester; Potassium Channels, Calcium-Activated; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Up-Regulation; Vasodilation

We previously showed that testosterone, administered in vivo, increases the tone of cerebral arteries. A possible underlying mechanism is increased vasoconstriction through the thromboxane A2 (TxA2) pathway. Therefore, we investigated the effect of chronic testosterone treatment (4 wk) on TxA2 synthase levels and the contribution of TxA2 to vascular tone in rat middle cerebral arteries (MCAs). Using immunofluorescence and confocal microscopy, we demonstrated that TxA2 synthase is present in MCA segments in both smooth muscle and endothelial layers. Using Western blot analysis, we found that TxA2 synthase protein levels are higher in cerebral vessel homogenates from testosterone-treated orchiectomized (ORX + T) rats compared with orchiectomized (ORX) control animals. Functional consequences of changes in cerebrovascular TxA2 synthase were determined using cannulated, pressurized MCA segments in vitro. Constrictor responses to the TxA2 mimetic U-46619 were not different between the ORX + T and ORX groups. However, dilator responses to either the selective TxA2 synthase inhibitor furegrelate or the TxA2-endoperoxide receptor (TP) antagonist SQ-29548 were greater in the ORX + T compared with ORX group. In endothelium-denuded arteries, the dilation to furegrelate was attenuated in both the ORX and ORX + T groups, and the difference between the groups was abolished. These data suggest that chronic testosterone treatment enhances TxA2-mediated tone in rat cerebral arteries by increasing endothelial TxA2 synthesis without altering the TP receptors mediating constriction. The effect of in vivo testosterone on cerebrovascular TxA2 synthase, observed here after chronic hormone administration, may contribute to the risk of vasospasm and thrombosis related to cerebrovascular disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Androgens; Animals; Benzofurans; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Enzyme Inhibitors; Fatty Acids, Unsaturated; Hydrazines; Male; Middle Cerebral Artery; Orchiectomy; Rats; Rats, Inbred F344; Receptors, Thromboxane; Testosterone; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

1. The purpose of this study was to investigate whether a membrane-permeable superoxide dismutase mimetic, tempol, added either alone or in combination with the nitric oxide (NO) donor molsidomine, prevents the development of pulmonary hypertension (PH) in chronic hypoxic rats. 2. Chronic hypobaric hypoxia (10% oxygen) for 2 weeks increased the right ventricular systolic pressure (RVSP), right ventricle and lung wet weight. Relaxations evoked by acetylcholine (ACh) and the molsidomine metabolite SIN-1 were impaired in isolated proximal, but not distal pulmonary arteries, from chronic hypoxic rats. 3. Treatment with tempol (86 mg x kg(-1) day(-1) in drinking water) normalized RVSP and reduced right ventricular hypertrophy, while systemic blood pressure, lung and liver weights, and blunted ACh relaxation of pulmonary arteries were unchanged. 4. Treatment with molsidomine (15 mg x kg(-1) day(-1) in drinking water) had the same effects as tempol, except that liver weight was reduced, and potassium and U46619-evoked vasoconstrictions in pulmonary arteries were increased. Combining tempol and molsidomine did not have additional effects compared to tempol alone. ACh relaxation in pulmonary arteries was not normalized by these treatments. 5. The media to lumen diameter ratio of the pulmonary arteries was greater for the hypoxic rats compared to the normoxic rats, and was not reversed by treatment with tempol, molsidomine, or the combination of tempol and molsidomine. 6. We conclude that tempol, like molsidomine, is able to correct RVSP and reduce right ventricular weight in the rat hypoxic model. Functional and structural properties of pulmonary small arteries were little affected. The results support the possibility that superoxide dismutase mimetics may be a useful means for the treatment of PH.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Administration, Oral; Animals; Body Weight; Chronic Disease; Cyclic N-Oxides; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Endothelin-1; Free Radical Scavengers; Heart Rate; Hypertrophy, Right Ventricular; Hypoxia; Male; Molsidomine; Muscle, Smooth, Vascular; Organ Size; Pulmonary Artery; Rats; Rats, Wistar; Spin Labels; Superoxide Dismutase; Vasoconstriction; Vasodilation; Ventricular Pressure

To determine the role of Rho associated kinase (ROK) in contraction of rat femoral arteries after 14 d tail suspension.. Male Wistar rats were randomly divided into control group (CON) and 14 d -30 degrees tail suspension group (TS14d). Analysis was performed on the contractile responses of perfused femoral arterial rings from both TS14d and CON rats to KCl, phenylephrine (PE), and U-46619 in the presence of Y-27632.. Arterial rings from TS14d rats displayed a reduced contractile response to KCl and PE but not significantly to U-46619. In the response to KCl, Y-27632 caused a concentration-dependent relaxation and significantly larger decrease of contraction in tissues from TS14d rats. Y27632 nearly abolished the tonic component of KCl-induced contraction when its dose was increased from 10(-6)mol/L to 10(-5) mol/L. It had also an inhibitive effect on the PE and U-46619-induced contraction and caused significantly larger decrease in U-46619 but not in KCl or PE induced contraction in tissues from TS14d rats.. ROK activity may be enhanced and play a compensational role in rat femoral arteries after TS14d.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amides; Animals; Body Weight; Femoral Artery; Hindlimb Suspension; Intracellular Signaling Peptides and Proteins; Male; Phenylephrine; Potassium Chloride; Protein Serine-Threonine Kinases; Pyridines; Rats; Rats, Wistar; rho-Associated Kinases; Vasoconstriction; Vasoconstrictor Agents; Weightlessness Simulation

To analyze the effects of diabetes mellitus on the vascular responsiveness to nitric oxide and thromboxane receptor stimulation, 2 mm long segments of basilar, coronary, renal and tail arteries from male and female, control (normoglycemic) and streptozotocin-induced diabetic rats, were prepared for isometric tension recording. In the segments at basal resting tension, the thromboxane analog U46619 (10(-9)-10(-5) M) produced concentration-dependent contraction, which was similar in arteries from male and female rats, and was reduced by diabetes in coronary arteries from male and in tail arteries from female rats. In the vascular segments precontracted with endothelin-1 (10(-9) M), acetylcholine (10(-9)-3 x 10(-5) M) produced concentration-dependent relaxation which was similar in all arteries from normoglycemic male and female rats, and was increased by diabetes in tail arteries from female, but not in those from male rats. In precontracted segments the nitric oxide donor sodium nitroprusside (10(-10)-10(-5) M) also produced concentration-dependent relaxation, which was higher in basilar arteries from normoglycemic females compared with males, and was increased by diabetes in tail arteries from female but not from male rats. These results suggest that diabetes may increase the relaxation to nitric oxide in tail arteries, and may reduce the contraction to thromboxane receptor activation in coronary and tail arteries in a gender-dependent way. These changes in vascular reactivity may be adaptative to the vascular alterations produced by diabetes.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Basilar Artery; Blood Glucose; Body Weight; Coronary Vessels; Diabetes Mellitus, Experimental; Female; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Prostaglandins; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Renal Artery; Sex Characteristics; Tail; Vasoconstrictor Agents; Vasodilator Agents

We have previously shown that estrogen treatment increases cerebrovascular cyclooxygenase-1, prostacyclin synthase, and production of prostacyclin. Therefore, vascular tone and prostanoid production were measured to investigate functional consequences of estrogen exposure. Middle cerebral arteries were isolated from ovariectomized female Fischer-344 rats with or without chronic in vivo 17beta-estradiol treatment. In vivo 17beta-estradiol treatment increased cerebral artery diameter; functional endothelium was required for expression of these differences. The nonspecific cyclooxygenase inhibitor indomethacin constricted, whereas arachidonic acid dilated, cerebral arteries from estrogen-treated animals. Estrogen exposure increased production of prostacyclin by cerebral arteries. Conversely, in estrogen-deficient animals, indomethacin dilated and arachidonic acid constricted cerebral blood vessels. This correlated with vasorelaxation following inhibition of the thromboxane-endoperoxide receptor with SQ-29548 but not after selective blockade of thromboxane synthase with furegrelate, suggesting prostaglandin endoperoxide (i.e., PGH2) activity. Removal of the endothelium or selective blockade of cyclooxygenase-1 with SC-560 abolished estrogen-mediated differences in the effects of arachidonate on vessel diameter and on prostacyclin production by cerebral arteries. These data suggest 17beta-estradiol decreases cerebrovascular tone by shifting the primary end product of the endothelial cyclooxygenase-1 pathway from the constrictor prostaglandin PGH2 to the vasodilator prostacyclin. These effects of estrogen may contribute to the heightened thromboresistance and enhanced cerebral blood flow documented in pre-versus postmenopausal women.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arachidonic Acid; Body Weight; Cerebral Arteries; Cyclooxygenase 1; Cytochrome P-450 Enzyme System; Estradiol; Female; Intramolecular Oxidoreductases; Isoenzymes; Membrane Proteins; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Organ Size; Pressure; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Inbred F344; Uterus; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Atherosclerosis involves a complex array of factors, including leukocyte adhesion and platelet vasoactive factors. Aspirin, which is used to prevent secondary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A(2). The actions of TxA(2) as well as of other arachidonic acid products, such as prostaglandin (PG) H(2), PGF(2alpha), hydroxyeicosatetraenoic acids, and isoprostanes, can be effectively antagonized by blocking thromboxane (TP) receptors. The purpose of this study was to determine the role of platelet-derived TxA(2) in atherosclerotic lesion development by comparing the effects of aspirin and the TP receptor antagonist S18886. The effect of 11 weeks of treatment with aspirin (30 mg. kg(-1). d(-1)) or S18886 (5 mg. kg(-1). d(-1)) on aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA(2) metabolite TxB(2) was determined in apolipoprotein E-deficient mice at 21 weeks of age. Both treatments did not affect body or heart weight or serum cholesterol levels. Aspirin, to a greater extent than S18886, significantly decreased serum TxB(2) levels, indicating the greater efficacy of aspirin in preventing platelet synthesis of TxA(2). S18886, but not aspirin, significantly decreased aortic root lesions as well as serum ICAM-1 levels. S18886 also prevented the increased expression of ICAM-1 in cultured human endothelial cells stimulated by the TP receptor agonist U46619. These results indicate that inhibition of platelet TxA(2) synthesis with aspirin has no significant effect on atherogenesis or adhesion molecule levels. The effects of S18886 suggest that blockade of TP receptors inhibits atherosclerosis by a mechanism independent of platelet-derived TxA(2), perhaps by preventing the expression of adhesion molecules whose expression is stimulated by eicosanoids other than TxA(2).

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Aspirin; Body Weight; Cell Adhesion; Cholesterol; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Naphthalenes; Platelet Aggregation Inhibitors; Propionates; Receptors, Thromboxane; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; U937 Cells; Umbilical Veins; Vasoconstrictor Agents

The purpose of the study was to test the hypothesis that the increased media thickness: lumen diameter (M:L) ratio of spontaneously hypertensive rat (SHR) resistance arteries effects enhanced arterial contractile responses compared with those of Wistar-Kyoto (WKY) rat normotensive controls under pressurized conditions in vitro.. Contractile responses to the vasoconstrictor agonists noradrenaline and the thromboxane A2 analogue U46619 were assessed in femoral and mesenteric resistance arteries (internal diameters approximately 150 microm) after the development of spontaneous myogenic tone at 100 mmHg and at estimated in vivo pressures.. Arterial contractile responses and structure were assessed in an arteriograph. Relaxed arterial structure was determined by light microscopy. Mean arterial pressure was determined subsequent to femoral artery cannulation.. Under relaxed conditions M:L ratios were significantly greater in SHR arteries at 100 mmHg (P < 0.01) and at in vivo pressures (P<0.01). Myogenic responses were not significantly different between SHR and WKY. Under both pressure conditions the contractile responses of SHR femoral arteries were not significantly different to those of WKY in response to either agonist SHR mesenteric arteries achieved smaller diameters in response to noradrenaline (P<0.05) and U46619 (P<0.05) at 100 mmHg. At in vivo pressures, concentration-response relationships of SHR mesenteric arteries for both agonists were not significantly different compared with those of WKY; however, the maximum percentage reduction of lumen diameter in SHR mesenteric arteries in the presence of noradrenaline was greater than in WKY (P<0.05).. The increased M:L ratio of SHR femoral resistance arteries does not impart an exaggerated contractile function in myogenically active resistance arteries in vitro. For mesenteric arteries the relationship is less clear because increased M:L ratio is associated with increased contractile responses under some, but not all, circumstances.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Body Weight; Femoral Artery; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Tonus; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tunica Media; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents

We performed micropuncture studies to determine the role of thromboxane A2 in the exaggerated tubuloglomerular feedback (TGF) activity in young spontaneously hypertensive rats (SHR). Glomerular function was assessed by changes in proximal tubular stop-flow pressure (SFP) produced by different rates of orthograde perfusion through Henle's loop. Seven-week-old SHR exhibited an exaggerated TGF activity compared with Wistar-Kyoto rats (WKY) during euvolemia, confirming earlier studies. During control periods, the feedback-induced maximal SFP response (DeltaSFP) was greater in SHR (18-19 vs. 12-13 mmHg in WKY), whereas basal SFP and proximal tubular free-flow pressure were similar in both strains. In one series, the thromboxane A2 agonist U-46619 was added to the tubular perfusate for a final concentration of 10(-6) M. In WKY, DeltaSFP was increased by 100% to 26 mmHg. In contrast, DeltaSFP in young SHR was unaffected by the thromboxane A2 agonist. In other animals, the thromboxane synthase inhibitor pirmagrel (50 mg/kg) was injected intravenously to inhibit thromboxane production. In SHR, pirmagrel decreased DeltaSFP by 8.5 mmHg and reduced reactivity. Less attenuation was observed in WKY; DeltaSFP was reduced by 3 mmHg, whereas reactivity was unchanged. In other studies, tubular perfusion with the thromboxane receptor inhibitor SQ-29548 (10(-6) M) reduced DeltaSFP more in SHR (7 vs. 3 mmHg in WKY) and also decreased reactivity more in SHR (2.3 vs. 0.5 mmHg. nl-1. min-1). Coperfusion of SQ-29548 and U-46619 resulted in an 85% block of the effect of U-46619 on DeltaSFP. Tubular perfusion with the agonist U-46619 during thromboxane synthase inhibition markedly enhanced DeltaSFP in both strains, with a greater effect in WKY. These results suggest that elevated levels of thromboxane A2 in young SHR contribute to the exaggerated TGF control of glomerular function in SHR during the developmental phase of hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Age Factors; Animals; Blood Pressure; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Capillaries; Enzyme Inhibitors; Fatty Acids, Unsaturated; Feedback; Hematocrit; Hydrazines; Imidazoles; Juxtaglomerular Apparatus; Kidney Tubules, Proximal; Loop of Henle; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Thromboxane A2; Vasoconstrictor Agents

Thromboxane A2 (TXA2) is a potent constrictor of both airway and vascular smooth muscle. In addition, plasma exudation is induced in the airways by a thromboxane mimetic (U-46619). Because plasma exudation is associated with a local vasodilatation and increased local blood flow, we hypothesized that the general vasoconstrictor effect of U-46619 would be weaker in the airways than in other vascular beds, perhaps resulting in increased local airway blood flow. We studied the effects of i.v. U-46619 on blood pressure, lung resistance as well as blood flow, plasma exudation in airways and leg skeletal muscle in guinea pigs. We found (1) i.v. U-46619 increases the systemic blood pressure, blood flow in tracheal mucosa but decreases blood flow in leg skeletal muscle; (2) i.v. U-46619 induces plasma exudation in the airways, but not in the leg skeletal muscle; (3) a positive relationship between blood pressure and tracheal blood flow as well as airway plasma exudation, a negative relationship between blood pressure and blood flow in leg skeletal muscle; (4) i.v. U-46619 significantly increases lung resistance. We conclude that i.v. U-46619 induces plasma exudation in airways but not in skeletal muscle, and that this plasma exudation is associated with the increased local blood flow, which in turn is caused by increased inflow pressure and redistribution of the total body blood flow to the airways.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Blood Circulation; Blood Pressure; Body Weight; Exudates and Transudates; Guinea Pigs; Muscle, Skeletal; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Thromboxanes; Vasoconstrictor Agents

We investigated endothelium-dependent responses of thoracic aorta isolated from age-matched male and female spontaneously hypertensive rats (SHR) to explore gender differences in endothelial dysfunction that may contribute to the sexual dimorphism observed in the development of hypertension in this strain. Endothelium-dependent relaxation in response to acetylcholine (10(-9) to 10(-4) mol/L) was significantly greater in female rats than in male rats, although impaired responses were seen in both sexes compared with normotensive controls. Inhibition of cyclooxygenase by indomethacin (10(-5) mol/L) improved endothelium-dependent relaxation, but it did not abolish the gender difference. Relaxations in response to sodium nitroprusside were identical in denuded aortic rings from male and female SHR. Acetylcholine at higher concentrations (10(-6) to 10(-4) mol/L) induced endothelium-dependent contraction in intact, quiescent aortic rings from male SHR but not in those from female SHR. After incubation with NG-nitro-L-arginine (10(-4) mol/L), contraction in response to acetylcholine became apparent in rings from female SHR, but it was still significantly less pronounced than in similarly treated rings from male SHR. Endothelium-dependent contraction was prevented by indomethacin in both sexes, suggesting that a cyclooxygenase product such as endoperoxide may be mediating this effect. Because responses evoked by the thromboxane/endoperoxide receptor agonist U46619 (10(-10) to 10(-6) mol/L) were not greater in rings from male SHR than those from female SHR, increased smooth muscle responsiveness or higher thromboxane/endoperoxide receptor density in the males could not account for the differences in endothelium-dependent contraction. These results suggest that sex steroid hormones may control endothelium-dependent vascular reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Aorta; Body Weight; Endothelium, Vascular; Female; Hypertension; Male; Nitric Oxide; Nitroprusside; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred SHR; Rats, Wistar; Sex Characteristics; Species Specificity; Thromboxane A2; Vasoconstrictor Agents