Search PubMed⌕ Search

Biomedical subjects

J D Catravas

Publications and source records attributed to J D Catravas.

At least 19 recordsLinked to original sources
PubMed1992

Effects of indomethacin on PMA-induced pulmonary endothelial enzyme dysfunction in vivo.

We investigated the effects of phorbol myristate acetate (PMA) on metabolic pulmonary endothelial ectoenzyme dysfunction. Anesthetized rabbits were placed on total heart bypass, and the single-pass transpulmonary metabolism of [3H]benzoyl-Phe-Ala-Pro (BPAP) by endothelial-bound angiotensin-converting enzyme (ACE) and [14C]adenosine 5'-monophosphate (AMP) by 5'-nucleotidase (NCT) was calculated before and after PMA (10 micrograms/kg iv), a dose that does not produce histologically evident endothelial damage. Under conditions of partial microvascular recruitment (blood flow = 400 ml/min through the entire lung), PMA, but not the vehicle, significantly reduced substrate utilization of both BPAP and adenosine 5'-monophosphate (AMP) and increased the apparent Michaelis constant (Km) values of ACE for BPAP, indicative of metabolic dysfunction. These changes were completely prevented by pretreatment with indomethacin. Under conditions of near full microvascular recruitment (blood flow = 640 ml/min through the left lung only), PMA similarly reduced substrate utilization and increased the apparent Km of ACE for BPAP. In this case, however, indomethacin failed to prevent the observed PMA-induced metabolic dysfunction. We conclude that PMA alters endothelial ectoenzyme substrate metabolism independently from changes in pulmonary blood flow; indomethacin appears to antagonize the effects of PMA under conditions of partial microvascular recruitment only, perhaps by diverting flow to previously unperfused, unexposed to PMA, and hence metabolically healthy vessels.

5'-Nucleotidase↗
PubMed1992

Endothelial cGMP does not regulate basal release of endothelium-derived relaxing factor in culture.

Guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in single and cocultures of calf pulmonary arterial endothelial (CPAE) and rabbit pulmonary arterial smooth muscle cells (RPASM) was investigated to discover whether endothelial cGMP is involved in the feedback regulation of basally released endothelium-derived relaxing factor (EDRF). Endothelial cell-induced increases in smooth muscle cGMP levels were inhibited by competitive inhibitors of endothelial nitric oxide synthesis, NG-monomethyl-L-arginine and N omega-nitro-L-arginine, in both long-term cocultures and short-term bioassay. Such treatment had no effect on endothelial content of cGMP. Coculture cGMP accumulation was stimulated (twofold increases) by endothelium-dependent vasodilators, bradykinin and acetylcholine. Bradykinin and acetylcholine did not elicit cGMP accumulation in single cultures of either smooth muscle or endothelial cells. To investigate the underlying mechanism(s) of dissociation in cGMP accumulation between cocultures and single endothelial cell cultures, the distribution profile of guanylate cyclase isoforms was determined by stimulating CPAE and RPASM cells with vasodilators activating selectively the soluble or particulate isoenzymes. Both nitrovasodilators, sodium nitroprusside and a putative EDRF, S-nitroso-L-cysteine, produced a 20-fold increase in cGMP content of RPASM cells only, having no effect on endothelial cells. Conversely, atriopeptin II caused 80-fold increases in endothelial cells. Exposure of the short-term bioassay system to 100 nM atriopeptin II, which caused 60-fold increases in CPAE cGMP levels, did not affect basal EDRF-induced smooth muscle cell cGMP accumulation, suggesting that a cGMP-mediated negative feedback mechanism does not appear to be involved in the regulation of basally released EDRF in culture.

1-Methyl-3-isobutylxanthine↗
PubMed1992

PMA-activated neutrophils decrease pulmonary endothelial ectoenzyme activities in perfused rabbit lungs.

We have studied the effects of phorbol 12-myristate 13-acetate (PMA, 15 micrograms) on pulmonary endothelial ectoenzyme [angiotensin-converting enzyme (ACE) and 5'-nucleotidase (NCT)] function in isolated rabbit lungs perfused in situ with platelet-poor (PPP) or platelet-rich (PRP) plasma in the presence or absence of neutrophils. Enzyme activities were estimated from the hydrolysis of the substrates [3H]benzoyl-Phe-Ala-Pro ([3H]BPAP) by ACE and 14C-labeled AMP by NCT during a single transpulmonary passage, using indicator-dilution techniques. In all treatment groups PMA produced a delayed increase in pulmonary vascular resistance to about three times the control value. PMA alone [in lungs perfused with PPP (n = 5 animals) or PRP (n = 6)] or neutrophils alone (in PPP-perfused lungs, n = 5) had no effect on enzyme activity. However, PMA-activated neutrophils (n = 5) decreased percent metabolism (%M) of [3H]BPAP from 87 +/- 3 to 77 +/- 4% (30 min after PMA), and the apparent first-order parameter [ratio of maximum activity to Michaelis constant (Amax/Km)] for ACE from 821 +/- 114 to 613 +/- 61 ml/min (30 min after PMA). At the same time, Km values of BPAP for ACE and AMP for NCT were elevated from 9.2 +/- 2.2 to 19.3 +/- 3 microM and 6.7 +/- 1.2 to 15.1 +/- 3.6 microM, respectively, whereas Amax (product of enzyme mass and rate of product formation, thus an index of perfused microvascular surface area) did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

5'-Nucleotidase↗
PubMed1992

PMA-activated neutrophils decrease ectoenzyme activities in rabbit aortic endothelial cells in culture.

We have studied the effects of phorbol 12-myristate 13-acetate (PMA)-activated neutrophils [polymorphonuclear leukocytes (PMN)] on endothelial ectoenzyme [angiotensin-converting enzyme (ACE) and 5'-nucleotidase (NCT)] activities in cultured rabbit aortic endothelial cells (EC) with the use of [3H]benzoyl-Phe-Ala-Pro and 14C-labeled AMP as substrates, respectively, under first-order reaction conditions. PMA (1-1,000 ng/ml) or PMN alone had no effect on ACE activity. When PMA was incubated together with PMN (PMN/EC = 1.25:1 or 2.5 x 10(5) neutrophils/ml) for 4 h in Earle's salts, a PMA dose-dependent decrease in ACE activity was observed. Threshold PMA concentration was 2 ng/ml. At 8 ng PMA/ml, ACE activity was totally abolished, without any evidence of cytotoxicity, as inferred from release of 51Cr from prelabeled EC. The decrease in ACE activity was also dependent on PMN concentration and was detectable at PMN/EC values as low as 1.25:10 (0.25 x 10(5) PMN/ml). Inhibition of ACE occurred as early as 1 h after incubation (PMA 10 ng/ml, PMN/EC = 1.25:1). PMA alone caused a small but significant increase in NCT activity, whereas PMA coincubation with PMN produced a significant decrease in NCT activity (20-29%), which was PMA and PMN concentration independent. PMA increased PMN adherence to endothelial monolayers in a concentration-dependent manner. Pretreating PMN with monoclonal antibody 60.3 (raised against the adhesion glycoprotein CD18) or placing a 2-microns filter between PMN and EC, protected the decrease in ACE activity.(ABSTRACT TRUNCATED AT 250 WORDS)

5'-Nucleotidase↗
PubMed1992

Muscarinic binding sites on bovine pulmonary arterial endothelial cells in culture.

We have investigated the presence and nature of muscarinic binding sites on membranes from cultured bovine pulmonary arterial endothelial cells (BPAE). BPAE were harvested and subcultured nonenzymatically; experiments were performed 3-5 days postconfluence and between 10 and 25 passage numbers. Utilizing radioligand binding techniques with the muscarinic receptor antagonists [3H]3-quinuclidinyl benzilate ([3H]QNB) and [3H]N-methylscopolamine ([3H]MS) as probes, we identified a small population of atropine-sensitive muscarinic sites (1,800-2,000 sites/cell or 7-8 fmol/mg protein). Muscarinic binding sites on BPAE membranes resembled classical muscarinic receptors in that (a) the binding of 2 nM [3H]QNB was inhibited by muscarinic agonists and antagonists, (b) [3H]QNB binding was 30 times more sensitive to R(-)- than to S(+)-QNB, (c) binding of the muscarinic receptor agonist carbamylcholine involved high and low affinity components, (d) the stable GTP analog, Gpp(NH)p (100 microM) shifted agonist binding curves to the right by a factor of three, and (e) the high affinity binding of the agonist [3H]oxotremorine-M to muscarinic receptors was depressed by Gpp(NH)p. On the other hand, gallamine, which allosterically regulates muscarinic receptor binding in other tissues, did not affect the rates of dissociation of [3H]QNB, [3H]MS or [3H]oxotremorine-M from BPAE binding sites. We concluded that BPAE in culture exhibit muscarinic binding sites which possess many but not all of the properties associated with classical muscarinic receptors.

Allosteric Site↗
PubMed1992

Effects of oxidant stress on endothelium-derived relaxing factor-induced and nitrovasodilator-induced cGMP accumulation in vascular cells in culture.

The effects of hydrogen peroxide (H2O2) on the action of basally produced endothelium-derived relaxing factor (EDRF) were investigated by measuring cGMP accumulation in single and cocultures of calf pulmonary artery endothelial cells (CPAEs) and rabbit pulmonary artery smooth muscle cells (RPASMs) as a model for determining the contribution of EDRF dysfunction to altered vascular tone and reactivity frequently associated with oxidant-induced vascular injury. Higher cGMP levels in long-term cocultures (20.4 +/- 1.8 pmol/mg protein/15 min) than in single-cell cultures (CPAE, 9.6 +/- 0.9 pmol/mg protein/15 min; RPASM, 3.7 +/- 0.2 pmol/mg protein/15 min), and CPAE-induced increases (fivefold) in intracellular RPASM cGMP content in short-term cocultures suggest basal release of EDRF. Basal generation and release of an L-arginine-derived endothelial labile factor accounted for the increases in cGMP, since the response was completely blocked by pretreatment of CPAEs with NG-monomethyl L-arginine. Pretreatment of long-term cocultures with H2O2 for 30 minutes resulted in a dose-dependent (0.5-2 mM) decrease in cGMP formation (49-79%). To determine the effects of H2O2 on EDRF synthesis, transport, and RPASM responsiveness, CPAEs or RPASMs were selectively pretreated with H2O2 before establishment of short-term cocultures. In cocultures of H2O2-pretreated CPAEs with untreated RPASMs, RPASM cGMP levels were reduced, suggesting a decrease in EDRF production rather than deterioration of EDRF during transport, because cGMP levels were unaffected by posttreatment with oxygen radical scavengers during coculture. Pretreatment of RPASMs with H2O2 attenuated the untreated CPAE-induced, the putative EDRF S-nitroso-L-cysteine-induced, or the nitroprusside-induced increases in RPASM cGMP levels. This attenuation was prevented by pretreatment with either dimethylthiourea, deferoxamine, or dithiothreitol, suggesting a mechanism of H2O2 action involving iron-catalyzed formation of intracellular hydroxyl radicals and their attack on cellular thiols. H2O2 diminution of cGMP accumulation was not associated with lytic cell injury in the experimental time frame, because morphology and 51Cr release from prelabeled RPASMs and CPAEs were unchanged.

Animals↗
PubMed1992

Influence of vascular smooth muscle heterogeneity on angiotensin converting enzyme activity in chicken embryonic aorta and in endothelial cells in culture.

The smooth muscle of the abdominal region of the chicken aorta derives from locally recruited mesenchyme (mesenchymal smooth muscle), whereas that of the thoracic region derives from the neural crest (ectomesenchymal smooth muscle). We hypothesized that this smooth muscle heterogeneity might affect important enzymatic functions of the vessel wall. Therefore, we measured angiotensin converting enzyme (ACE) activity in homogenates of chicken thoracic and abdominal aorta at different embryonic stages (days 10, 14, and 18 of gestation). ACE activity increased in both regions over the time of gestation (p less than 0.001 in both cases); the increase was steeper and ACE activity was higher in thoracic than in abdominal segments (p less than 0.001). Km values were similar (approximately 7 microM) at all times and between the two segments, whereas changes in Vmax values closely paralleled those in enzyme activity, indicating gestation-dependent increases in the amount of enzyme. Neural crest ablation at an early developmental stage resulted in an increase of ACE activity in thoracic homogenates (p less than 0.001), predictably leaving that in abdominal homogenates unaffected. Bovine pulmonary artery endothelial cell monolayers exposed to media conditioned with cultured mesenchymal or ectomesenchymal smooth muscle cells exhibited elevated ACE activity (46% and 83%, respectively, relative to control medium, with p less than 0.01 in both cases; p less than 0.05 between the two media). Increases in endothelial cell ACE activity corresponded to proportional increases in ACE protein determined by enzyme-linked immunosorbent assay (r = 0.99) and were interpreted as indicative of enhanced enzyme synthesis subsequent to exposure of endothelial cells to smooth muscle-conditioned media.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Methylene blue inhibits nitrovasodilator- and endothelium-derived relaxing factor-induced cyclic GMP accumulation in cultured pulmonary arterial smooth muscle cells via generation of superoxide anion.

The mechanism of modulation of cyclic guanosine monophosphate (cGMP) accumulation by methylene blue (MB), a putative inhibitor of soluble guanylate cyclase, was investigated in cultured rabbit pulmonary arterial smooth muscle cells (RPASM). Control or MB-pretreated RPASM were stimulated with sodium nitroprusside (SNP), nitrosothiols or endothelium-derived relaxing factor (EDRF) released basally from bovine pulmonary arterial endothelial cells, in short-term co-cultures. The putative EDRF, S-nitroso-L-cysteine (CYSNO), a stable deaminated analog of CYSNO, S-nitroso-3-mercaptoproprionic acid (MPANO) and SNP produced concentration-dependent (1-100 microM) increase (1.5- to 12-fold) in RPASM cGMP levels. MB pretreatment inhibited CYSNO and SNP-induced cGMP accumulation by 51% to 100%, but MPANO-mediated responses were not altered by MB. The inhibition profile of MB on nitrovasodilator-induced cGMP accumulation was quantitatively reproduced by extracellular generation of superoxide anion with xanthine (100 microM) and xanthine oxidase (5 mU). Similarly to MB pretreatment, superoxide anion generation had no effects on base-line cGMP levels or cGMP responses elicited by MPANO. Furthermore, MB induced a dose- and time-dependent generation of superoxide anion from RPASM, as evidenced from spectrophotometric determination of cytochrome c reduction. Inhibition of cGMP accumulation in response to CYSNO and SNP by MB was completely prevented by superoxide dismutase but not catalase. Selective pretreatment of endothelial cells with MB before co-culture with untreated RPASM produced a reduction in RPASM cGMP levels of a magnitude comparable with that seen in co-cultures of MB-pretreated RPASM with untreated endothelial cells, and which was partially prevented by superoxide dismutase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The nature of muscarinic receptor subtypes mediating pulmonary vasoconstriction in the rabbit.

The interaction of muscarinic receptor subtype-selective antagonists with ACh was studied in the pulmonary vasculature of rabbits. In anesthetized rabbits, ACh (5-20 nmol/kg, i.v.) increased pulmonary vascular resistance (PVR) and decreased systemic arterial pressure (SAP). After 2.85 nmol/kg i.v. pirenzepine (PNZ), the ACh-induced increase in PVR was attenuated by 67% while the decrease in SAP was not altered. After 2.85 mumol/kg i.v. pirenzepine, the ACh-induced increase in PVR was totally blocked, while the SAP response was only partially inhibited (43%). Similar results were obtained with trihexyphenidyl. Atropine or secoverine (SEC) inhibited equally the PVR and SAP responses to ACh. In isolated rabbit lungs perfused in situ at 140 ml/min, ACh (1 microM) increased PVR by 210%, perfusate levels of TXB2 by 1000% and 6-keto-PGF1 alpha by 21% of baseline values. PNZ (50 nM) inhibited the effects of ACh on PVR, TXB2 and 6-keto-PGF1 alpha levels. SEC (50 nM) did not alter the effects of ACh on PVR, or the TXB2 to 6-keto-PGF1 alpha ratio. At 100 nM, both PNZ and SEC reduced all effects of ACh. These results suggest that the rabbit pulmonary vascular muscarinic receptors mediating vasoconstriction and thromboxane release are sensitive to pirenzepine and thus behave more like M1 receptors.

Acetylcholine↗
PubMed1991

Multiple muscarinic receptor subtypes in the canine pulmonary circulation.

The vascular response to the muscarinic receptor agonist acetylcholine (ACh) in the presence of selected antagonists was examined in the isolated blood-perfused canine left lower lung lobe under conditions of normal (resting) and elevated vascular tone. At normal vascular tone, ACh (1-5 mumol) produced a dose-dependent increase in pulmonary arterial pressure (Ppa), total pulmonary vascular resistance (PVR), and downstream resistance (Rds) without altering upstream resistance (Rus). Pirenzepine (50 and 100 nM), the prototype M1-selective antagonist, and gallamine, an M2-selective antagonist, as well as atropine (50 nM) and secoverine (100 nM), nonselective antagonists, attenuated (P less than 0.05) the ACh-induced increase in Ppa and Rds. With elevated vascular tone induced by serotonin infusion, ACh produced a dose-dependent increase in Ppa in 19 of 25 lobes, although Rus decreased while Rds increased in all lobes. At high vascular tone, pirenzepine or gallamine attenuated the ACh-induced increase in Rds, whereas Rus was not affected. Secoverine and atropine antagonized ACh-induced increases in both Rds and Rus. The pA2 values (i.e., the negative log antagonist concentration requiring a doubling of ACh dose for an equivalent increase in Rds) for gallamine, pirenzepine, secoverine, and atropine were 6.1 +/- 0.1, 7.4 +/- 0.1, 8.3 +/- 0.2, and 10.2 +/- 0.3, respectively. These results suggest that 1) ACh increases PVR in the dog by constricting the venous segments (downstream) of the pulmonary circulation via activation of pulmonary vascular muscarinic receptors under conditions of both normal and elevated vascular tone, 2) both M1- and non-M1-muscarinic receptor subtypes appear to participate in mediating the ACh-induced increase in Rds, and 3) ACh moderately relaxes the upstream (arterial) vessels, especially under conditions of elevated tone.

Acetylcholine↗
PubMed1991

Effects of blood flow on lung ACE kinetics: evidence for microvascular recruitment.

The parameter Amax/Km (product of reactant enzyme mass in perfused microvessels and the constant kcat/Km), calculated from in vivo assays of pulmonary endothelial ectoenzymes (e.g., angiotensin-converting enzyme, ACE), can provide estimates of the perfused pulmonary microvascular surface area (PMSA) in the absence of enzyme dysfunction. We examined the relationship between PMSA and pulmonary blood flow (Qb) in anesthetized rabbits placed on total heart bypass, using [3H]benzoyl-Phe-Ala-Pro (BPAP) as the ACE substrate. When Qb was increased from 250 to 1,100 ml/min, at zone 3 conditions, pulmonary arterial pressure increased, pulmonary vascular resistance (PVR) decreased, and Amax/Km increased linearly, reflecting increasing PMSA. When only the left lung was perfused, increasing Qb from 250 to 636 +/- 17 ml/min (the last value representing fully recruited and/or distended vascular bed), PVR decreased, while Amax/Km increased. When Qb was further increased to 791 +/- 44 ml/min, both PVR and Amax/Km remained unchanged, confirming the lack of additional changes in PMSA. We conclude that Amax/Km provides a sensitive indication of PMSA, because it 1) increases with increasing Qb and decreasing PVR, 2) reaches a maximum at Qb values that correspond to the minimal values in PVR, and 3) like PVR, did not change with further increases in Qb. Compared with predicted changes in PMSA produced by either microvascular recruitment alone or distension alone, our data indicate that recruitment is a larger contributor to the observed increase in PMSA.

Amino Acid Sequence↗
PubMed1991

Species variation in pulmonary endothelial aminopeptidase P activity.

Pulmonary endothelial aminopeptidase P (AmP) may be an important contributor to the inactivation of circulating bradykinin in certain species. To examine this possibility, we measured AMP activity in vivo and in vitro using Arg-Pro-Pro-[3H]benzylamide (3H-APPB) as substrate under conditions of first order enzyme kinetics. Utilizing multiple indicator dilution techniques, metabolism of 3H-APPB to Arg and Pro-Pro-[3H]benzylamide by AmP was not detectable during a single transpulmonary passage in anesthetized rabbits (n = 4), cats (n = 3) and pigs (n = 4). However, percent metabolism of 3H-APPB ranged from 54 to 63% in anesthetized rats (n = 6). In all experiments, the substrate remained within the vascular space and was thus accessible to endothelial and blood AmP only. At the same time, single-pass transpulmonary percent metabolism of [14C]benzoyl-Ala-Gly-Pro by endothelial-bound angiotensin converting enzyme was remarkably similar among rabbits, cats, rats and pigs (60-65%). In culture, Vmax/Km of AmP was 3 to 10 x 10(-4) min-1 for human basal arterial and rabbit and bovine pulmonary arterial endothelial cell monolayers (2 x 10(5) cells). AmP activity in the supernatant of lung and kidney tissue (homogenized in saline containing 1-o-n-octyl-beta-glucopyranoside) from rabbit, cat, pig and rat expressed as Vmax/Km(min-1) per (g wet tissue/ml) was 0.74, 2.25, 3.91 and 185.8 (lung), and 1.0, 3.7, 8.4 and 438.3 (kidney), respectively. Similarly, Vmax/Km values of AmP in plasmas of cat, dog, rabbit, pig, calf (serum), human and rat were 0, 0.016, 0.025, 0.068, 0.191, 0.237 and 3.53 min-1. These results suggest that 1) there are large interspecies variations in AmP activities of plasma, lung and kidney; 2) of the species studied, the rat contains the largest activities of AmP; and 3) AmP appears to be located on the luminal surface of the rat pulmonary endothelium.

Aminopeptidases↗
PubMed1990

Inhibition of endothelial-bound angiotensin converting enzyme, in vivo.

1. We determined apparent Ki constants of two inhibitors, captopril and CL242,817, for pulmonary endothelial-bound angiotensin converting enzyme (ACE) in anaesthetized rabbits. [3H]-benzoyl-Phe-Ala-Pro was used as the substrate. The apparent kinetic parameters Km and Amax (product of Vmax and microvascular plasma volume) were measured, as was the ratio (Amax/Km) (measured under first order reaction conditions) before and 30s after the i.v. administration of captopril 10 nmol kg-1 or CL242,817, 35 nmol kg-1. 2. Under mixed order reaction conditions, ([S] greater than or equal to Km), apparent Km values increased from 12.2 +/- 1.9 microM to 32.9 +/- 3.3 microM (P less than 0.05) in the captopril-treated rabbits and from 9.3 +/- 2.3 microM to 45.8 +/- 9.8 microM (P less than 0.05) in the CL242,817-treated rabbits, indicative of competitive inhibition. However, apparent Amax values decreased from 10.3 +/- 2.1 to 4.5 +/- 0.8 mumol min-1 (P less than 0.05) and 8.9 +/- 1.7 to 4.8 +/- 0.5 mumol min-1 (P less than 0.05), respectively. 3. Under first order reaction conditions ([S] much less than Km), the Amax/Km ratio decreased from 763 +/- 100 to 125 +/- 38 ml min-1 (P less than 0.05) and 1009 +/- 149 to 126 +/- 44 ml min-1 (P less than 0.05) in the captopril- and CL242,817-treated groups respectively. 4. When the single pass transpulmonary binding of 80pmol [3H]-RAC-X-65 (an ACE inhibitor) was measured in additional rabbits, a significant (P < 0.05) decrease in RAC-X-65 binding was observed 30s after captopril (80% decrease) or CL242,817 (85% decrease), a result expected for a loss of catalytically active enzyme mass due to tightly bound captopril or CL242,817. 5. These results indicate that, in vivo, both captopril and CL242,817 are competitive, tight binding inhibitors of lung ACE. Furthermore, they suggest means for evaluating the interaction of other potential ACE inhibitors with the pulmonary endothelial membrane-bound enzyme, in vivo, possibly in phase I clinical trials.

5'-Nucleotidase↗
PubMed1990

Effects of arachidonic acid in the rabbit pulmonary and systemic vascular beds in vivo.

We studied the effects of arachidonic acid (AA) in the pulmonary and systemic circulations of rabbit under constant blood flow conditions in vivo, using a total heart bypass model. AA (100-150 micrograms/kg) injected into the pulmonary artery produced a dose-dependent increase in pulmonary arterial pressure (Ppa), without altering systemic arterial pressure (Psa). Conversely, injection of AA into the aorta reduced Psa in a dose-dependent fashion, but did not significantly alter Ppa. FPL55712, a leukotriene receptor antagonist, did not affect any of these responses to AA. Indomethacin, a cyclo-oxygenase inhibitor, totally prevented the pulmonary pressor response to intravenously administered AA and reduced the systemic depressor response to intra-arterially administered AA. The thromboxane A2 synthetase inhibitor, 7-(1-imidazolyl)heptanoic acid, totally abolished the increase in Ppa in response to intravenously administered AA, but did not alter the dose-dependent decrease in Psa in response to intra-arterially administered AA. These results suggest that in rabbits (1) AA produces pulmonary vasoconstriction and systemic vasodilation, (2) blood metabolites of AA mediate these effects and are then rapidly deactivated, and (3) AA-induced pulmonary vasoconstriction appears to be largely dependent on thromboxane A2.

Animals↗
PubMed1978

Effect of 1-alpha-acetylmethadol (LAAM) on various physiological parameters in the conscious dog.

LAAM was administered intravenously to conscious dogs at doses of either 0.1, 0.3 or 1.0 mg/kg. Cardiopulmonary responses were measured prior to drug administration, 0.5 hr post-drug and hourly thereafter. All doses produced a sleep-like state which was dose-related in duration (3-14 hr). Cardiac output, heart rate, respiratory rate and minute volume were decreased below mean pre-drug control values after drug administration in the two higher dosage groups; cardiac output in both groups failed to return to pre-drug control levels. Additionally, total peripheral resistance was elevated in these dosage groups although mean arterial pressure remained stable. Arterial pCO2 increased and arterial pH decreased as respiratory rate and minute volume decreased. Depression of rectal temperature occurred only in response to the highest dose.

Animals↗
PubMed1978

Acute cocaine intoxication in the conscious dog: pathophysiologic profile of acute lethality.

Cocaine HCl was infused intravenously to conscious mongrel dogs until death (0.5 mg/kg/min; 0.82 ml/min). All animals convulsed (mean convulsive dose: 12 +/- 1 mg/kg) and died approximately 42 min after the beginning of cocaine infusion (mean lethal dose: 21 +/- 2 mg/kg). All animals exhibited significant increases in arterial systolic and diastolic pressures, left ventricular pressure, cardiac output, heart rate, respiratory rate, minute volume, tidal volume, oxygen uptake, plasma glucose, blood lactate and body temperature. Statistically significant reductions from pre-drug control levels were observed in total peripheral resistance, arterial pH, and arterial pO2.

Alanine Transaminase↗