Meclofenamate blocks the pulmonary arterial vasopressor effects of leukotriene B4 in awake sheep

This study examined the hemodynamic effects of leukotriene B4 (LTB4) in chronically instrumented awake sheep, and the role of cyclooxygenase products in the sheep's response to LTB4. LTB4 (25 micrograms) was given as a bolus into the pulmonary artery. Six sheep were studied with LTB4, both before and after pretreatment with meclofenamate (5 mg/kg load, 3 mg/kg/hr maintenance infusion). LTB4 alone caused a rapid rise in pulmonary arterial pressure from 15 +/- 1 to 42 +/- 11 cm H2O. LTB4 had no effect on pulmonary arterial pressure following pretreatment with meclofenamate. LTB4 alone caused an increase in serum thromboxane B2 (TxB2) from 130 +/- 35 to 320 +/- 17 pg/ml 3 minutes after dosing but did not increase TxB2 following pre-treatment with meclofenamate. LTB4 caused a slight decrease in mean systemic arterial pressure and a transient fall in circulating white blood cells, both of which were unaffected by meclofenamate pre-treatment. The vasoactive effects of LTB4 in the pulmonary circulation appear to be mediated indirectly through the production of cyclooxygenase metabolites of arachidonic acid.     

Coronary effects of endothelin-1 and vasopressin during acute hypotension in anesthetized goats

Coronary effects of endothelin-1 and vasopressin during acute hypotension, and the role of NO and prostanoids in these effects were examined in anesthetized goats. Left circumflex coronary artery flow was measured electromagnetically, and hypotension was induced by constriction of the caudal vena cava in animals non-treated (7 goats) or treated with the inhibitor of NO synthesis N(w)-nitro-L-arginine methyl esther (L-NAME, 5 goats), the cyclooxygenase inhibitor meclofenamate (5 goats) or both drugs (5 goats). Under normotension (22 goats), mean arterial pressure averaged 93 +/- 3 mm Hg and coronary vascular conductance (CVC) 0.37 +/- 0.025 ml/min/mm Hg. Endothelin-1 (0.01-0.3 nmol) and vasopressin (0.03-1 nmol), intracoronarily injected, dose-dependently decreased CVC by up to 56% for endothelin-1 and 40% for vasopressin. During hypotension in every condition tested, mean arterial pressure decreased to approximately 60 mm Hg, and CVC only decreased during hypotension pretreated with L-NAME (23%) or L-NAME + meclofenamate (34%). Under non-treated hypotension, the decreases in CVC by endothelin-1 were augmented approximately 1.5 fold, and those by vasopressin were not modified. This increase in CVR by endothelin-1 was not affected by L-NAME and was reversed by meclofenamate or L-NAME + meclofenamate. The coronary effects of vasopressin were not modified by any of these treatments. Therefore, acute hypotension increases the coronary vasoconstriction in response to endothelin-1 but not to vasopressin. This increased response to endothelin-1 may be related to both inhibition of NO release and release of vasoconstrictor prostanoids.     

Systemic and renal hemodynamic responses to vascular blockade of vasopressin in conscious dogs with ascites

A role for arginine vasopressin has been implicated in the compensatory control of arterial blood pressure in several animal models with reported increases in plasma levels of arginine vasopressin. A threefold elevation in plasma vasopressin has been reported in conscious dogs following constriction of the inferior vena cava. In the present study, infusion of the arginine vasopressin antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine] Arg8-vasopressin into conscious dogs with chronic caval constriction did not decrease mean arterial blood pressure. However, the dose of infused antagonist completely blocked the pressor response to 2 micrograms of exogenous vasopressin. Also the antagonist produced no effect on heart rate, plasma renin activity, or urinary volume and electrolyte excretions. A slight, transient increase (P less than or equal to 0.05) was observed in creatinine clearance and in PAH clearance following antagonist infusion, suggesting a possible decrease in renal vascular resistance. These data suggest that the direct vasoconstrictor actions of vasopressin contribute minimally, if at all, to blood pressure maintenance following chronic caval constriction. Alternatively, blockade of endogenous vasopressin receptors at the level of peripheral arterioles may have resulted in no depressor response due to a masking of this response by other compensatory hormonal and neural pressor systems.     

Cyclooxygenase inhibition attenuates sympathetic responses to muscle stretch in humans

Passive muscle stretch performed during a period of post-exercise muscle ischemia (PEMI) increases muscle sympathetic nerve activity (MSNA), and this suggests that the muscle metabolites may sensitize mechanoreceptors in healthy humans. However, the responsible substance(s) has not been studied thoroughly in humans. Human and animal studies suggest that cyclooxygenase products sensitize muscle mechanoreceptors. Thus we hypothesized that local cyclooxygenase inhibition in exercising muscles could attenuate MSNA responses to passive muscle stretch during PEMI. Blood pressure (Finapres), heart rate, and MSNA (microneurography) responses to passive muscle stretch were assessed in 13 young healthy subjects during PEMI before and after cyclooxygenase inhibition, which was accomplished by a local infusion of 6 mg ketorolac tromethamine in saline via Bier block. In the second experiment, the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased prostaglandin synthesis to approximately 34% of the baseline. Before ketorolac Bier block, passive muscle stretch evoked significant increases in MSNA (P < 0.005) and mean arterial blood pressure (P < 0.02). After ketorolac Bier block, passive muscle stretch did not evoke significant responses in MSNA (P = 0.11) or mean arterial blood pressure (P = 0.83). Saline Bier block had no effect on the MSNA or blood pressure response to ischemic stretch. These observations indicate that cyclooxygenase inhibition attenuates MSNA responses seen during PEMI and suggest that cyclooxygenase products sensitize the muscle mechanoreceptors.     

Influence of tone on responses to acetylcholine in the rabbit pulmonary vascular bed

Pulmonary vascular responses to acetylcholine were compared under resting and high tone conditions of the intact-chest rabbit. Under resting tone conditions, intralobar injections of acetylcholine increased lobar arterial pressure in a dose-related manner. The pressor responses to acetylcholine under resting conditions were blocked by meclofenamate, indomethacin, atropine, and pirenzepine. When lobar vascular resistance was raised to a high steady level, low doses of acetylcholine decreased lobar arterial pressure, whereas higher doses elicited a biphasic response with the pressor component predominating at the highest dose studied. Under high tone conditions, only the pressor component of the response was blocked by meclofenamate or indomethacin, whereas pressor and depressor responses were blocked by atropine or the 600-micrograms/kg iv dose of pirenzepine. Pressor responses to acetylcholine under resting and high tone conditions were blocked by pirenzepine (50 micrograms/kg iv), whereas gallamine had no effect on responses to acetylcholine. The 50-micrograms/kg iv dose of pirenzepine had no effect on depressor responses or the depressor component of the response to acetylcholine. The present data support the concept that acetylcholine has significant cyclooxygenase-dependent pressor activity in the rabbit pulmonary vascular bed and suggest that this response is mediated by a muscarinic M1-type receptor. These data also show that, under high tone conditions, a vasodilator response or a vasodilator component of a biphasic response is unmasked. This response is not dependent on the release of cyclooxygenase products and is mediated by a muscarinic receptor that is neither of the M1- nor the M2-type.     

Hemodynamic effects of hypertonic saline in the conscious rat

The present study examines the role of vasopressin and the sympathetic nervous system on the hemodynamic effects of an infusion of hypertonic saline (NaCl 1.5 M) in conscious rats. The cardiovascular response to hypertonic saline was similar in both untreated and hexamethonium-pretreated rats. Mean arterial pressure increased by 15 mmHg as a consequence of the elevation of total peripheral resistance, while cardiac index was decreased. The administration of an antagonist to the pressor activity of vasopressin in rats with intact reflexes, partially decreased mean arterial pressure and total peripheral resistance and increased cardiac index toward basal values. In contrast, the hemodynamic response to hypertonic saline was totally reverted when the vasopressin antagonist was injected in the hexamethonium-pretreated rats. The results of the present study indicate that the hypertensive response induced by hypertonic saline in conscious rats is due to the vasoconstrictor effects of both vasopressin and the sympathetic nervous system.     

Lesion of the perinuclear zone attenuates cardiac sensitivity of vasopressinergic supraoptic neurons

Discrete stretch of the caval-atrial junction decreases the activity of vasopressin-secreting neurons in the supraoptic nucleus (SON). The perinuclear zone (PNZ) of the SON is necessary for inhibition of vasopressin neurons following an increase in blood pressure. To determine whether the PNZ is necessary for cardiopulmonary regulation of vasopressin neurons, male rats received three unilateral injections of the excitotoxin ibotenic acid (n = 9) or phosphate-buffered saline vehicle (n = 10) into the PNZ. Extracellular activity of antidromically identified phasic vasopressin neurons in the ipsilateral SON was recorded. Of the 26 neurons recorded from vehicle-injected rats 26 were inhibited by an increase in blood pressure and 22 of those neurons were sensitive to caval-atrial distension. Of the neurons recorded from PNZ-lesion rats, only 12 of 29 were inhibited by an increase in blood pressure (P < 0.05), and only 11 neurons were sensitive to caval-atrial stretch (P < 0.05). Functional lesion of the PNZ significantly attenuates both arterial and cardiopulmonary baroreceptor-mediated inhibition of supraoptic vasopressin neurons, suggesting that the PNZ is a necessary component of both pathways.     

Effect of cyclooxygenase inhibition on ethchlorvynol-induced acute lung injury in dogs

In anesthetized dogs ethchlorvynol (ECV, 9 mg/kg) was selectively administered into the right pulmonary circulation to produce unilateral acute lung injury (ALI) characterized by nonhydrostatic pulmonary edema and systemic hypoxemia. To investigate the hypothesis that products of cyclooxygenase activity are mediators of the arterial hypoxemia, but not the edema formation in this injury, animals were pretreated with one of two chemically dissimilar cyclooxygenase inhibitors, indomethacin (5 mg/kg), or ibuprofen (12.5 mg/kg), or vehicle (0.1 M sodium carbonate) prior to the administration of ECV. Pretreatment with either inhibitor prevented the ECV-induced systemic hypoxemia observed in animals pretreated with vehicle (P less than 0.01). Despite this protection of systemic oxygenation, there was no redistribution of blood flow to the uninjured lung following unilateral ECV administration. Cyclooxygenase inhibition prior to ALI did not attenuate the accumulation of lung water. In the ibuprofen group, left atrial pressure increased significantly following ECV administration. We conclude that a product(s) of cyclooxygenase-mediated arachidonic acid metabolism is responsible for the altered vascular reactivity and consequent systemic hypoxemia in this model, but that the edema formation following ECV is not related to cyclooxygenase activity. In addition, ibuprofen, administered prior to the induction of ALI, exhibits properties not shared by indomethacin but is not different in its capacity to attenuate hypoxemia or in its failure to limit edema formation.     

Effects of cyclooxygenase inhibition on pulmonary vascular responses to serotonin

The vasopressor response to graded bolus doses (50-500 micrograms) of serotonin (5-hydroxytryptamine; 5-HT) was examined in the isolated canine lower left lung lobe (LLL) perfused at constant flow with autogenous blood before and after cyclooxygenase inhibition (COI). Lobar vascular resistance (LVR) was partitioned into pre- (Ra) and postcapillary (Rv) segments by venous occlusion with lobar blood volume changes monitored gravimetrically. Before COI, 5-HT produced transient, dose-dependent increases in pulmonary arterial pressure (Ppa) of 43.8 +/- 4.8-123.0 +/- 8.5% (n = 22) and simultaneous decreases in lobar blood volume (5.5 +/- 0.5-8.2 +/- 0.6 g/100 g LLL) with nearly proportionate increases in Ra and Rv at each 5-HT dose. After the initial challenge to 5-HT, LLL's were treated either with saline (n = 7) or one of three chemically distinct cyclooxygenase inhibitors. COI with 40 microM indomethacin (n = 6) or 45 microM meclofenamate (n = 6) increased resting LVR by 36.0 +/- 8.3% (P less than 0.01; n = 12) and decreased the Ra/Rv from 1.9 +/- 0.3 to 1.1 +/- 0.2 (P less than 0.01), whereas 1 mM aspirin (n = 3) caused a fourfold increase in resting LVR without affecting Ra/Rv. After indomethacin or meclofenamate treatment, the vasopressor response to graded doses of 5-HT was markedly potentiated as Ppa increased by 71.6 +/- 7.6-207.0 +/- 24.6%. COI did not potentiate the lobar vasopressor response to graded doses (10-100 micrograms) of norepinephrine (NE, n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of thromboxane synthase and cyclooxygenase inhibition on PAF-induced changes in lung function and arachidonic acid metabolism.

PAF was administered as an intravenous bolus (0.1 micrograms/kg) to eight chronically instrumented awake sheep. The effects of pretreatment with an inhibitor of cyclooxygenase (meclofenamate) on PAF-induced changes in lung function were compared to those observed with a specific inhibitor of thromboxane synthase (DP1904). Each animal was studied four times in varied order: PAF alone, PAF + DP1904, PAF + meclofenamate, and DP1904 alone. Saline alone (control), DP1904 alone, and meclofenamate alone did not cause changes in any of the measured variables. DP1904 and meclofenamate significantly attenuated the PAF-induced fall in lung compliance, elevation in peak pulmonary artery pressure, and increased lung lymph flow. Both drugs abolished the PAF-induced increases in lung lymph thromboxane B2 concentrations. Meclofenamate, but not DP1904, blocked the rise in lymph 6-keto-PGF1 alpha. Although meclofenamate blocked the rise in lymph PGE2, DP1904 resulted in levels 2.7 times higher than PAF alone. We conclude that: (1) inhibition of thromboxane synthase is as effective as inhibition of cyclooxygenase in attenuating PAF-induced changes in lung function, and (2) thromboxane synthase inhibition results in augmented production of PGE2 following PAF administration in vivo.     

Postexercise hypotension is not explained by a prostaglandin-dependent peripheral vasodilation.

In normally active individuals, postexercise hypotension after a single bout of aerobic exercise occurs due to an unexplained peripheral vasodilation. Prostaglandin production has been suggested to contribute to the increases in blood flow during and after exercise; however, its potential contribution to postexercise hypotension has not been assessed. The purpose of this study was to determine the potential contribution of a prostaglandin-dependent vasodilation to changes in systemic vascular conductance underlying postexercise hypotension; this was done by inhibiting production of prostaglandins with the cyclooxygenase inhibitor ibuprofen. We studied 11 healthy normotensive men (aged 23.7 +/- 4.2 yr) before and during the 90 min after a 60-min bout of cycling at 60% peak O(2) uptake on a control and a cyclooxygenase inhibition day (randomized). Subjects received 10 mg/kg of oral ibuprofen on the cyclooxygenase inhibition day. On both study days, arterial blood pressure (automated auscultation) and cardiac output (acetylene uptake) were measured, and systemic vascular conductance was calculated. Inhibition of cyclooxygenase had no effect on baseline values of mean arterial pressure or systemic vascular conductance (P > 0.2). After exercise on both days, mean arterial pressure was reduced (-2.2 +/- 1.0 mmHg change with the control condition and -3.8 +/- 1.5 mmHg change with the ibuprofen condition, both P < 0.05 vs. preexercise) and systemic vascular conductance was increased (5.2 +/- 5.0% change with the control condition and 8.7 +/- 4.1% change with the ibuprofen condition, both P < 0.05 vs. preexercise). There were no differences between study days (P > 0.6). These data suggest that prostaglandin-dependent vasodilation does not contribute to the increased systemic vascular conductance underlying postexercise hypotension.     

Cyclooxygenase mediated airway response to leukotriene D4 in the cat

The effects of leukotriene D4 (LTD4) on pulmonary mechanics were investigated in anesthetized, paralyzed cats under conditions of controlled ventilation. Intravenous injections of LTD4 in doses of 3, 10, and 30 micrograms caused significant increases in transpulmonary pressure (PTP) and lung resistance (RL) while decreasing dynamic compliance (Cdyn). LTD4 also increased systemic arterial pressure (PAo). The changes in PTP, RL, and Cdyn in response to LTD4 were blocked by sodium meclofenamate, a cyclooxygenase inhibitor. However, there was no significant change in the increase in PAo following cyclooxygenase blockade. U 46619, a thromboxane mimic, was 30 to 100 times more potent than LTD4 in increasing PTP, RL and decreasing Cdyn in the cat. These data show that LTD4 has significant smooth muscle constrictor activity in central airways as well as peripheral portions of the feline lung. In addition, these data suggest that in the cat the actions of intravenously administered LTD4 on lung mechanics are mediated by release of cyclooxygenase products while the systemic pressor effects are not dependent upon the integrity of the cyclooxygenase pathway.     

Atriopeptin alters the vasopressin and renin responses elicited by hemorrhage

This study was designed to investigate whether an infusion of atrial peptide is capable of modulating the hormonal and hemodynamic responses elicited by acute hemorrhage. Conscious dogs were bled at a rate of 0.8 ml.kg-1.min-1 until 20 ml of blood/kg body wt had been removed. Two experiments were performed on each dog; in one experiment the animal was given alpha-human atrial natriuretic peptide (alpha-hANP) (50 ng.kg-1.min-1) dissolved in saline; in the other only the saline vehicle was given. Right and left atrial pressures decreased during hemorrhage in all experiments; the absolute decreases were greater when the animals received atriopeptin, but the differences between treatments were statistically significant only for right atrial pressure. Cardiac output decreased (P less than 0.05) and total peripheral resistance increased (P less than 0.05) during hemorrhage when atriopeptin was infused; although these variables showed similar trends when vehicle alone was infused during hemorrhage, no significant changes occurred. Infusion of atrial peptide did not affect the decrease in arterial blood pressure that occurred during hemorrhage. The increase in plasma vasopressin induced by hemorrhage was potentiated, but the increase in plasma renin activity was attenuated when alpha-hANP was infused. Hemorrhage increased circulating aldosterone levels in each experiment, but the response was less pronounced when alpha-hANP was given during the experiment. Intravenous administration of alpha-hANP modulates the hemodynamic responses elicited by hemorrhage, potentiates the rise in plasma vasopressin, and attenuates the rise in plasma renin activity induced by acute blood loss in conscious dogs.     

Systemic and mesenteric O2 metabolism in endotoxic pigs: effect of ibuprofen and meclofenamate

The effect of two chemically dissimilar cyclooxygenase inhibitors was studied in pentobarbital-anesthetized endotoxic pigs. Animals in groups II-IV were infused with Escherichia coli lipopolysaccharide (LPS, 150 micrograms/kg) and resuscitated with normal saline (1.2 ml.kg-1.min-1). Animals in group I (n = 4) were resuscitated as above but were not infused with LPS. Animals in group II (n = 7) served as endotoxic controls. Pigs in groups III (n = 6) and IV (n = 5) were pre- and posttreated with ibuprofen (10 mg/kg bolus then 10 mg.kg-1.h-1 and meclofenamate (5 mg/kg then 5 mg.kg-1.h-1, respectively. Ileal intramucosal hydrogen ion concentration [( H+]) was estimated tonometrically. In group I, cardiac index (CI), mean arterial pressure (MAP), superior mesenteric arterial perfusion (QSMA), and mesenteric O2 delivery (DO2) increased significantly, but other variables were unchanged. After infusion of LPS in group II, MAP and systemic vascular resistance index were markedly diminished but CI was well preserved. In this group, QSMA, systemic DO2, and mesenteric DO2 decreased, whereas systemic O2 uptake (VO2) and gut [H+] increased; mesenteric VO2 was unchanged. Compared with pigs in group II, pigs treated with ibuprofen or meclofenamate manifested improved systemic and mesenteric DO2. In groups III and IV, QSMA remained normal, increased systemic VO2 was not observed, and gut intramucosal acidosis was ameliorated. Increased intramucosal [H+] in group II suggests that QSMA was inadequate. The salutary effects of ibuprofen and meclofenamate suggest that inadequate mesenteric perfusion was mediated, at least in part, by cyclooxygenase-derived metabolites or arachidonic acid.     

Aminergic control of vasopressin secretion in the conscious rat.

The influence of aminergic pathways on basal and stimulated vasopressin (AVP) release was studied in conscious rats, the stimulus for hormone release being an intracerebroventricular (ICV) injection of 5 microliters 0.85M sodium chloride. The animals were treated with either phenoxybenzamine, propranolol or haloperidol prior to administration of the central hypertonic stimulus. Phenoxybenzamine elevated basal plasma vasopressin concentrations, while propranolol and haloperidol had no effect. The secretion of AVP in response to the hypertonic stimulus was potentiated by phenoxybenzamine and haloperidol, but the effect of propranolol was equivocal. The antagonists had no effect on basal arterial pressure at the time of hypertonic saline administration or the pressor response to ICV sodium chloride.     

Pressor responses in rats following intravenous dynorphin A(1-13) administration are blocked by AVP-V1 receptor antagonism

Hemodynamic (blood pressure and heart rate) experiments were conducted in conscious and/or anesthetized male Sprague-Dawley (S.D.), heterozygous and homozygous Brattleboro rats given intravenous (iv) dynorphin A(1-13), arginine vasopressin (AVP), norepinephrine (HCl, (NE) or sterile saline before and 10 min after an iv bolus injection of a specific receptor antagonist. These receptor blockers (kappa receptor antagonist Mr2266, alpha adrenoceptor antagonist phentolamine HCl or the AVP-V1 receptor antagonist d(CH2)5Tyr-(Me)AVP were given in equimolar concentrations (15 nmol/kg iv). In all conscious S.D. groups, iv injection of AVP (60 pmol/kg), NE (12.5 nmol/kg) and dynorphin A(1-13) (60 nmol/kg) evoked significant increases in mean arterial pressure (MAP) associated with concomitant bradycardia. The hemodynamic responses to 'both' AVP and dynorphin A(1-13) were blocked if given subsequent to AVP-V1 administration but not following phentolamine or Mr2266 pretreatment. The pressor and bradycardic responses of conscious heterozygous and homozygous Brattleboro rats after iv AVP or dynorphin again were only blocked by the AVP-V1 receptor antagonist. Anesthetized heterozygous and homozygous Brattleboro rats again showed pressor responses following iv AVP, NE or dynorphin A(1-13) but with slight or no associated bradycardia. The rise in blood pressure with AVP 'and' dynorphin A(1-13) in these groups also was only blocked by the d(CH2)5Tyr(Me)AVP antagonist. The results indicate that the pressor responses of rats given intravenous dynorphin A(1-13) involve the interaction of AVP-V1 receptors and suggest a functional interaction of these two neuropeptides in the modulation of vascular tone.     

Pulmonary vascular reactivity and permeability to alveolar hypoxia in the dog

Hemodynamics and vascular permeability were studied during acute alveolar hypoxia in isolated canine lung lobes perfused at constant flow with autogenous blood. Hypoxia was induced in the presence (COI + Hypox, n = 6) or absence (Hypox, n = 6) of cyclooxygenase inhibition (COI) with indomethacin or meclofenamate. Hypoxic ventilation reduced blood PO2 from 143 to 25-29 Torr without a change in PCO2. During hypoxia a capillary filtration coefficient (Kf) was obtained gravimetrically as an index of vascular permeability to water. In COI + Hypox, pulmonary arterial pressure (Pa) increased from 11.5 +/- 0.7, post-COI normoxia, to a peak of 22.1 +/- 2.3 during hypoxia (P less than 0.01) without a change in capillary pressure (Pc). In contrast, hypoxia changed neither Pa nor Pc in Hypox relative to an untreated normoxic control group (Normox, n = 6, P greater than 0.05). Kfs (means +/- SE in ml.min-1.Torr-1.100 g-1) for Normox (0.070 +/- 0.014), Hypox (0.082 +/- 0.024), and COI + Hypox (0.057 +/- 0.017) did not differ from one another (P greater than 0.05). Although COI markedly enhanced the pressor response to acute alveolar hypoxia, hypoxia increased neither Pc nor vascular permeability regardless of COI.     

Opiate and alpha receptor antagonists block the pressor responses of conscious rats given intravenous dynorphin

Conscious, unrestrained rats were used to determine the hemodynamic (blood pressure and heart rate) responses following intravenous (IV) injection of dynorphin A(1-13) and the possible receptor mechanisms mediating those changes. Male Sprague-Dawley rats (300 g) were given IV bolus injections (via femoral venous catheter) of 6.0 to 600 nmoles/kg of dynorphin A(1-13), 8.0 nmoles/kg of norepinephrine HCl (NE), 14.3 pmoles/kg of angiotensin II or a vehicle control solution. Blood pressure (BP) and heart rate (HR) were monitored via femoral arterial catheter (into abdominal aorta) over 90 sec postpeptide or -amine administration before and 10 min after IV injection of 4.2 mumoles/kg of naloxone HCl (opiate antagonist), yohimbine HCl (alpha 2 receptor antagonist) or prazosin HCl (alpha 1 receptor antagonist). Dynorphin A(1-13) caused a transient but dose-related rise in mean arterial pressure (MAP) whereas mean pulse pressures (MPP) and mean heart rates (MHR) concomitantly fell, from preinjection control values in a dose-dependent fashion. Pretreatment with naloxone blocked the pressor response of only a subsequent injection with 20 nmoles/kg but not 60 nmoles/kg of dynorphin A or NE (8.0 nmoles/kg). Pretreatment with yohimbine suppressed the marked pressor responses of subsequent NE or Dyn A (60 nmoles/kg) administration whereas prazosin antagonized the rise in MAP of only the lower doses of dynorphin as well as NE. The suppression of the pressor responses of dynorphin by opiate or alpha receptor antagonists were not caused by tachyphylaxis for repeated injections of 6.0 or 60 nmoles/kg of dynorphin caused the same rise in MAP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostanoid inhibition potentiates vasoconstrictor response to acetylcholine in dog lung

We determined whether cyclooxygenase or phosphodiesterase inhibition would alter the vasomotor response to acetylcholine in the dog lung. Lower left lobes were removed and then cannulated, ventilated, and pump perfused with autogenous blood at constant flow [6.0 +/- 0.1 ml X min-1 X g-1 lower left lobe (LLL)]. LLLs were challenged with graded doses of acetylcholine (ACh) (100-1,000 nmol) into the arterial cannula before and after administration of either 40 microM indomethacin (n = 5), 1 mM aspirin (n = 4), or 1 mM theophylline (n = 5). ACh produced a dose-dependent increase in pulmonary arterial pressure (Pa) and a decrease in the upstream-to-down-stream resistance ratio (Rus/Rds). Pretreatment with either indomethacin or aspirin potentiated the Pa response to ACh while eliminating the ACh-associated decrease in Rus/Rds. Pretreatment with the phosphodiesterase inhibitor theophylline significantly antagonized the ACh pressor response and decrease in the Rus/Rds. The present study suggests that the pulmonary pressor response to ACh is enhanced with cyclooxygenase inhibition. Our results indicate that ACh stimulates pulmonary vascular muscarinic cholinoceptors to cause vasoconstriction. Additionally or as sequelae to this response, predominantly vasodilatory prostanoids appear to be released.     

Pulmonary hemodynamics at birth: effect of acute cyclooxygenase inhibition in lambs

The effect of acute cyclooxygenase (CYO) inhibition on the cardiopulmonary adjustments at birth was examined in chronically instrumented, unanesthetized, term lambs before, during, and after cesarean section (spontaneous respiration). One of three infusions was started 20 min before birth: saline control (C, n = 6), indomethacin (I, n = 6), or meclofenamate (M, n = 3). The stable metabolite of prostacyclin, plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha, aorta), was measured by radioimmunoassay as an index of CYO activity. Indomethacin blocked the rise of 6-keto-PGF1 alpha observed in control lambs after birth and indomethacin-treated lambs exhibited an attenuation of the postnatal decrease in mean pulmonary arterial pressure. Pulmonary arterial pressure (Ppa) was 53 +/- 2 and 47 +/- 2 Torr (mean +/- SE) at 15 min and 40 +/- 3 and 34 +/- 2 Torr at 120 min in I and C groups, respectively. There were no serial or group differences in cardiac output and cardiac right to left shunt (indicator dilution) from 15 to 120 min after birth. Arterial PO2 (PaO2) was not different between groups: 37 +/- 4 Torr at 15 min and 47 +/- 5 min at 120 min after birth (control lambs). The results for I and M were similar for all measurements.(ABSTRACT TRUNCATED AT 250 WORDS)