Equine coronary artery responds to 5-hydroxytryptamine with relaxation in vitro

Isolated equine coronary arteries responded to 5-hydroxytryptamine (5-HT) with relaxations in both endothelium-dependent and endothelium-independent mechanisms. Experiments were designed to characterize the 5-HT receptor sub type mediating these relaxations. Both 5-HT and alpha-methyl-5-HT (α-Me-5- HT; 5-HT₂ agonist) produced concentration-dependent relaxations in equine coronary arteries precontracted with a thromboxane A₂ derivative (0N011113). The degree of the maximal relaxation induced by α t-Me-5-HT was about one-half of that induced by 5-HT. In the coronary arteries without endothelium, α -Me-5-HT produced no relaxation, but 5-HT caused relaxation, which was inhibited by a 5-HT₁ antagonist (methysergide, mianserin and methiothepin), but was inhibited neither by ketanserin (5-HT₂ antagonist) nor by MDL72222 (5-HT₃ antagonist). In the coronary arteries with endothelium, however, the relaxation induced by α -Me-5-HT was inhibited by ketanserin, L-nitro-arginine (NO synthase inhibitor) and methylene blue (soluble guanylate cyclase inhibitor). These results suggest that the relaxation induced by 5-HT in equine coronary arteries depends mainly on the stimulation of both 5-HTi receptor subtype on smooth muscle cells directly, and 5-HT₂ receptor subtype on endothelial cells indirectly by liberating endothe-lium-derived NO.     

Characterization of bradykinin-induced endothelium-independent contraction in equine basilar artery

We investigated the effect of bradykinin (BK) on isolated equine basilar arterial rings with and without endothelium. BK induced concentration-dependent contraction of resting arterial rings and no relaxation when the rings were precontracted by prostaglandin F_2α. The maximal response and pD₂ value were 161.2 ± 28.1% (to 60 m m KCl-induced contraction) and 8.24 ± 0.25 respectively. The cumulative concentration–response curve for BK was not shifted to the right by des-Arg⁹-[Leu⁸]-BK (a B₁-receptor antagonist), HOE140 (a B₂-receptor antagonist) or NPC567 (another B₂-receptor antagonist). In four of six basilar arteries, NPC567 induced concentration-dependent contraction. Indomethacin (a cyclooxygenase inhibitor), nordihydroguaiaretic acid (a lipoxygenase inhibitor), quinacrine (a phospholipase A₂ inhibitor), tetrodotoxin (a selective blocker of Na⁺ channels), guanethidine (a nor-adrenergic neuron blocking drug), phentolamine (an α-adrenoceptor antagonist), Nω-nitro- l -arginine ( l -NNA, a nitric oxide (NO) synthase inhibitor) and endothelial denudation did not affect the BK-induced contraction. l -NNA and indomethacin induced contraction and relaxation under resting vascular tone respectively. These results suggest that endothelial cells are not involved in BK-induced contraction and that the contraction is not mediated via activation of known B₁ and B₂ receptors. Arachidonic acid metabolites and neurotransmitters like norepinephrine and NO might not play a role in BK-induced contraction in equine basilar artery.     

Reactivity of Equine Palmar Digital Arteries and Veins to Vasodilating Agents

Palmar digital arteries and veins removed surgically from healthy horses under general anesthesia were cut into 4 mm vascular rings, suspended in tissue baths, and attached to force displacement transducers for continuous measurement of vascular tension. In vitro vascular responses were determined for acetylcholine, acepromazine, isoxsuprine hydrochloride (isoxsuprine), prostaglandin E₂ (PGE₂), and prostaglandin I₂ (prostacyclin). After preconstriction with norepinephrine hydrochloride (norepinephrine), or prostaglandin F₂ alpha (PGF₂ alpha), the concentrations needed to produce 50% maximum relaxation (EC₅₀) and the maximum percentage of relaxation were determined for each drug.
Acetylcholine was the most potent arterial vasodilator (smallest EC₅₀ value) and PGE₂ was the least potent. Prostacyclin was the least potent venodilator (highest EC₅₀ value); there were no differences between acetylcholine, acepromazine, isoxsuprine, and PGE₂. Isoxsuprine produced greater arterial relaxation than all other agents. Isoxsuprine and acepromazine produced significantly greater venous relaxation than did acetylcholine and PGE₂. Prostacyclin produced minimal vasodilation of arteries or veins. Acepromazine and isoxsuprine relaxed the veins significantly more than the arteries. When PGF₂ alpha was used instead of norepinephrine to preconstrict the arteries and veins, the potency and effectiveness of acepromazine and isoxsuprine to produce vasodilation were significantly decreased. Results indicate that acepromazine and isoxsuprine can relax the equine digital vasculature but their effectiveness varies depending on the origin of the constriction.     

Plasma pharmacokinetics of ranitidine HCl in adult horses

Plasma pharmacokinetics of ranitidine HCl were investigated after intravenous (i.v.) and oral (p.o.) administration of 2.2 mg/kg drug to six healthy adult horses. Concentrations of ranitidine were determined using normal-phase, high-performance liquid chromatography. Plasma concentrations of ranitidine HCl declined from a mean of 5175 ng/mL at 5 min to 37 ng/mL at 720 min after i.v. administration. A three-exponent equation, C_p= A₁· e^–k1t+ A₂· e^–k2t+ A₃· e^–k3t, best described data for all horses. Mean values for model-independent values calculated from the last quantifiable time point were: apparent volume of distribution (Vd_ss) = 1.07 L/kg; area under the curve ( AUC ) = 231,000 ng · min/mL; area under the moment curve ( AUMC ) = 26,900,000 ng · min²/mL; mean residence time ( MRT ) = 113 min; and clearance (Cl) = 9.8 mL/min.kg. Following p.o. administration, a two-exponent equation, C_p= A₁· e^–k1t+ A₂· e^–k2t, best described the data for five horses; data for the remaining horse were best described by a three-exponent equation. Mean values of pharmacokinetic values from the p.o. study include: AUC = 59,900 ng · min/mL; AUMC = 10,600,000 ng · min²/mL; mean absorption time ( MAT ) = 58.9 min; T _max= 99.2 min; C _max= 237 ng/mL; and F = 27%.     

A pharmacodynamic and pharmacokinetic study with vedaprofen in an equine model of acute nonimmune inflammation

The pharmacodynamics and enantioselective pharmacokinetics of vedaprofen were studied in six ponies in a two period cross-over study, in which a mild acute inflammatory reaction was induced by carrageenan soaked sponges implanted subcutaneously in the neck. Vedaprofen, administered intravenously at a dosage of 1 mg/kg, produced significant and prolonged inhibition of ex vivo serum thromboxane B₂ (TXB₂) synthesis and short-lived inhibition of exudate prostaglandin E₂ (PGE₂) and TXB₂ synthesis. Vedaprofen also partially inhibited oedematous swelling and leucocyte infiltration into exudate. Vedaprofen dis-played enantioselective pharmacokinetics, plasma concentrations of the R(–) enantiomer exceeding those of S(+) vedaprofen. The plasma concentration ratio, R:S, increased from 69: 31 at 5 min to 96: 4 at 3 h and plasma mean AUC values were 7524 and 1639 ng.h/mL, respectively. Volume of distribution was greater for S(+) vedaprofen, whilst elimination half-life (t_½β) and mean residence time were greater for R(–) vedaprofen. The penetration of vedaprofen into inflammatory exudate was also enantioselective. For R(–) and S(+) veda-profen maximum concentration (C_max) values were 2950 and 1534 ng/mL, respectively, and corresponding AUC values were 9755 and 4400 ng.h/mL. Vedaprofen was highly protein bound (greater than 99%) in both plasma and exudate. The significance of these data for the therapeutic use of vedaprofen is discussed.     

Pharmacokinetics and pharmacodynamics of meloxicam in piglets

The pharmacokinetics and pharmacodynamics of meloxicam in piglets (16–23 days old) were studied using a stratified parallel group design. One group ( n  = 13) received 0.4 mg/kg meloxicam intravenously, while the other group ( n  = 12) received physiological saline solution. A carrageenan-sponge model of acute inflammation was used to evaluate the effects of meloxicam. The plasma clearance was low (0.061 L/kg/h), the volume of distribution was low (0.19 L/kg) and the elimination half-life was short (2.7 h). At most time points, the mean concentration of meloxicam in plasma exceeded the concentrations in exudate indicating a limited accumulation of the drug at the site of the inflammation. There were significant differences between the groups in the exudate prostaglandin E₂ (PGE₂) concentration, but the inhibition of PGE₂ in the meloxicam group was limited. The inhibition of thromboxane B₂ (TXB₂) production in serum in the meloxicam group was extensive, but of shorter duration than the PGE₂ inhibition in exudate.     

Characterization of vasodilatory adenosine receptors in equine digital veins

Isolated equine digital veins (EDVs) which had been denuded of their endothelium were used to study adenosine receptors causing vasodilation. When the blood vessel wall tension was raised with the thromboxanemimetic, U44069 (30 n m ), the order of vasodilator potency of adenosine receptor agonists was: 5'-N-ethylcarboxamidoadenosine (NECA) > 2- p -(2-carboxyethyl)phenyl amino-5'-N-ethylcarboxamido-adenosine (CGS 21680) > 5'-N-methylcarboxamido-adenosine (MECA) > > N⁶-cyclohexyladenosine (CHA) > N⁶-cyclopentyladenosine (CPA) > N⁶–2-(4-Aminophenyl)ethyladenosine (APNEA) > adenosine. Removal of the endothelium had no significant effect on the responses to NECA. The adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; A₁-selective) and xanthine amine cogener (XAC; non-selective antagonist) inhibited responses to NECA and CHA in a competitive manner and XAC proved to be 8–25 times more potent than DPCPX against both agonists. These data support the presence of A₂ adenosine receptors in EDVs, located on the vascular smooth muscle cells, which are most likely to be of the A_2A-adenosine receptor subtype. A direct comparison between the potency and efficacy of NECA and adenosine as vasodilators of EDV and equine digital arteries was made and both agonists proved to be significantly more potent and efficacious as vasodilators of EDVs. These data suggest that adenosine may be an important local mediator regulating blood flow through the digital circulation and that its generation under hypoxic conditions would lead to selective venodilation.     

Femtomolar bradykinin-induced relaxation of isolated bovine coronary arteries, mediated by endothelium-derived nitric oxide

We reported previously that bradykinin induces endothelium-dependent relaxation at nanomolar (n M ) concentrations in isolated bovine coronary arteries with an intact endothelium. Recently we have found that in the presence of 10 μ m indomethacin, femtomolar (f M ) concentrations of bradykinin induce endothelium-dependent relaxation in some bovine coronary arteries (≈ 10% of the coronary arteries examined). The present study was designed to characterize the relaxation induced by f M bradykinin. Relaxation was completely abolished by repeated application of f M bradykinin, by 100 μ m N^ω- nitro- l - arginine methyl ester and by 10 μ m methylene blue. Relaxation induced by n M bradykinin was partly affected by these treatments. Relaxation induced by both concentrations of bradykinin was inhibited by a B₂-kinin receptor antagonist, [Thi^5,8, D-Phe⁷]-bradykinin, in a concentration-dependent manner, but not by a B₁-kinin receptor antagonist, des-Arg⁹, [Leu⁸]-bradykinin. In the presence of 10 μ m captopril, an angiotensin-converting enzyme (ACE) inhibitor, all coronary arteries examined in this experiment showed endothelium-dependent relaxation to f M bradykinin. These results show that some bovine coronary arteries relax in response to f M bradykinin, and this response is mediated predominantly by the release of nitric oxide via stimulation of endothelial B₂-kinin receptors. The relaxation may be dependent on ACE activity.     

The effects of aspirin and paracetamol on the aggregation of equine blood platelets

The responses of equine blood platelets in citrated platelet-rich plasma to arachidonic acid, U44069 (prostaglandin endoperoxide analogue), adenosine 5'-diphosphate, platelet-activating factor or collagen were investigated by turbidimetric aggregometry. Pre-treatment of the platelets with aspirin (1 mmol/1) or Paracetamo1 d-3 mmol/1) abolished shape change and aggregation in response to arachidonic acid; decreased the rate of aggregation in response to collagen, with no separate effect on shape change; had no marked effect on aggregation caused by the other agonists; but in no case transformed irreversible aggregation to reversible aggregation. We conclude that thromboxane A₂ generation is of minor importance in the aggregation of equine platelets, and in particular that thromboxane A₂ is not a significant mediator of irreversible aggregation.     

Biomarkers of inflammation in cattle determining the effectiveness of anti-inflammatory drugs

Myers, M. J., Scott, M. L., Deaver, C. M., Farrell, D. E., Yancy, H. F. Biomarkers of inflammation in cattle determining the effectiveness of anti-inflammatory drugs. J. vet. Pharmacol. Therap. 33 , 1–8.
The impact of nonsteroidal anti-inflammatory drugs (NSAID) on prostaglandin E₂ (PGE₂) production and cyclooxygenase 2 (COX-2) mRNA expression in bovine whole blood (WB) cultures stimulated by lipopolysaccharide (LPS) was determined, using the blood from six Holstein dairy cattle in various stages of lactation. Peak production of PGE₂ occurred 24 h after LPS stimulation but did not result in detectable concentrations of thromboxane B₂ (TXB₂). The NSAID indomethacin, aspirin, flunixin meglumine, and 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzene sulfonamide (PTPBS; celecoxib analogue), along with dexamethasone, were all equally effective in reducing the concentration of PGE₂ in the bovine WB culture supernatants. Bradykinin exhibited peak supernatant concentrations 1 h after LPS stimulation. Dexamethasone and the NSAID used in this study were equally effective at inhibiting bradykinin production. Peak induction of COX-2 mRNA occurred 3 h post-LPS stimulation. However, neither dexamethasone nor any of the NSAID used in this study altered COX-2 mRNA concentrations. In contrast, aspirin, flunixin meglumine, and PTPBS reduced tumor necrosis factor-alpha (TNFα) mRNA concentration. These results demonstrate that bovine blood cells respond to NSAID therapy like other mammalian cells with respect to inhibition of PGE₂ production and suppression of TNF mRNA induction, but do not inhibit induction of COX-2 mRNA.     

A Simple Apparatus for Frequent Measurement of Gastrointestinal Intraluminal PCO2

The accuracy and precision of an end-tidal infrared CO₂ monitor and customized capnography tubing system designed to measure gastrointestinal intraluminal CO₂ partial pressure (P_iCO₂) were tested in vitro. Samples were taken from the customized capnography tubing placed in either 5% or 10% CO₂ gas at discrete intervals ranging from one minute to twelve minutes. For a given time interval, the tubing PCO₂ measurement was a constant fraction of the actual PCO₂ (all standard errors < 0.02). For increasing time intervals, the ratio of the tubing PCO₂ to actual PCO₂ increased logarithmically. In the 5% and 10% CO₂, the regression coefficients were 0.89 and 0.85 for 8 French tubing and 0.99 and 0.91 for 6 French tubing. Beacuase of its accuracy and precision, this system may provide automated gastrointestinal CO₂ partial pressure monitoring at short intervals (e.g. 5 minutes), facilitating testing of the role of gastrointestinal P_iCO₂ information in treatment algorithms. (Vet Emerg & Crit Care, 1998; 8: 109–116)     

Functional characterization of the muscarinic receptors involved in endothelium-dependent relaxation in isolated canine uterine artery

Acetylcholine interacts with endothelial muscarinic receptors releasing nitric oxide and causing vasodilatation. To identify the receptor subtype responsible for acetylcholine-induced relaxation in canine uterine artery, the usual organ bath method for in vitro investigation on isolated blood vessels was applied. Using a range of muscarinic receptor antagonists such as atropine (nonselective), pirenzepine (M₁-selective), methoctramine (M₂-selective) and p -fluoro-hexahydro-sila-difenidol ( p -FHHSiD) (M₁/M₃) and determining pA2 value of those antagonists through Shild analysis, we aimed at establishing a precise receptor mechanism underlying acetylcholine-induced relaxation in isolated canine uterine artery. The relaxation of uterine arterial rings in response to acetylcholine in the presence or absence of selective muscarinic receptors antagonists was calculated using concentration response curves. Acetylcholine induced concentration-dependent and endothelium-dependent relaxation of arterial rings precontracted with phenylephrine (pEC₅₀ = 6.90 ± 0.02). Muscarinic receptors antagonists atropine, pirenzepine, methoctramine and p -FHHSiD competitively antagonized the response to acetylcholine and obtained pA₂ values were 9.91 ± 0.06, 6.60 ± 0.04, 6.21 ± 0.08 and 8.05 ± 0.1, respectively. This study showed that acetylcholine induced endothelium-dependent relaxation of canine uterine artery by stimulation of muscarinic receptors localized on the endothelial cells. On the basis of differential antagonist affinity, we suggest that the muscarinic receptors involved in the acetylcholine-induced relaxation of canine uterine artery are predominantly of M₃ subtype.     

Pharmacological evaluation of sheep lung strip

Isolated sheep lung parenchymal strips responded to histamine > carbachol > PGF_2a > 5-HT with contractions, and to isoproterenol (Isop), and to large doses of epinephrine (E), norepinephrine (NE) and phenylephrine (PE) with relaxations. PGF_2a-contracted lung strip responded to PGE₁ and PGE₂ with relaxation. The strips which were partially contracted to histamine, PGF_2a, 5-HT and carbachol also responded to isop, E and NE with relaxations. Histamine responses were not modified by metiamide (an H₂-receptor antagonist). Mepyramine and atropine selectively antagonized contractions to histamine and carbachol, respectively. After β-blockade with propranolol, lung strips responded to NE > E > PE > isop with contractions, which were inhibited or reversed by phentolamine and dibenzyline. It is concluded that H₁ receptors are present in sheep peripheral airway smooth muscles, and that a- and β-adrenoceptors mediate contraction and relaxation, respectively, in sheep lung strips.     

Specific binding of dl-cloprostenol and d-cloprostenol to PG F2α receptors in bovine corpus luteum and myometrial cell membranes

Prostaglandin F_2α receptors (PGF_2α Rs) were measured in bovine corpus luteum and myometrial cell membranes using a radiometric method. The inhibition of labelled PGF_2α binding exerted by d-cloprostenol, dl-cloprostenol, PGF_2α and PGE₁ (l0–¹¹ M to 10^–4 M) was evaluated in vitro. Results strongly suggest that cloprostenol binding to PGF_2αRs is stereospecific. d-Cloprostenol and PGF_2α were equipotent, about 150 times more potent than d-cloprostenol (P < 0.05) and approximately 280 times more potent than PGE, (P < 0.05) in inhibiting [3H]PGF_2α binding to corpus luteum cell membranes. Such differences were less evident in myometrial cell membranes, where d-cloprostenol and PGF_2α were about 10 times more potent than d-cloprostenol (P < 0.05) and approximately 95 times more potent than PGE_l (P < 0.05).     

Alpha-adrenoceptors in equine digital veins: Evidence for the presence of both alpha1 and alpha2-receptors mediating vasoconstriction

Rings of equine digital vein examined under conditions of isometric tension recording constricted to alpha-adrenoceptor agonists with an order of potency of 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline bitartrate (UK 14304) = noradrenaline > 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d) azepine (BHT-920) > phenylephrine > dopamine > methoxamine. The maximum force generated was greatest for the non-selective agonist noradrenaline and lowest for the alpha₂-selective agonist BHT-920 with the other agonists between these two extremes. Selective inactivation of alpha₁-adrenoceptors (achieved by treating yohimbine-protected tissues with phenoxybenzamine) reduced the maximum responses of all agonists, the EC₅₀ values of UK 14304, BHT-920 and noradrenaline and increased the EC₅₀ values of phenylephrine and methoxamine. Prazosin (30 n M ) had no inhibitory effect on responses to low concentrations of BHT-920 and UK 14304 and caused competitive inhibition of responses to phenylephrine and noradrenaline giving pK_b values of 8.49 ± 0.18 and 8.23 ± 0.14, respectively. Yohimbine (0.1 μ M ) caused significant competitive inhibition of responses to BHT-920 and noradrenaline with calculated pK_b values of 8.43 ± 0.11 for BHT-920 and 7.43 ± 0.31 for noradrenaline and non-competitive inhibition of responses to UK 14304. 2-[2-methoxy-1,4-benzodioxan-2-yl]-2-imidazoline (RX 821002; 10 n M ) caused competitive inhibition of responses to BHT-920 (pK_b 9.04 ± 0.27) and dopamine (pK_b 8.2 ± 0.2). These data indicate that equine digital veins possess both post-synaptic alpha₁ and alpha₂-adrenoceptors.     

GI PiCO2: Tissue Specific Monitoring For Improving Patient Outcomes

Improvements in human patient monitoring despite their development in animals, do not always find their way into veterinary clinical use due to financial constraints. Gastrointestinal intraluminal CO₂ partial pressure (Gip₁CO₂) monitoring, however, is not only proving very beneficial in human trauma and critical patient care but is also very likely to become relatively inexpensive. By providing information on the perfusion adequacy of a high risk, critically important tissue, the GI mucosa, GI P₁CO₂ monitoring offers an easily accesible indicator of the efficacy and adequacy of resuscitative interventions. The potential for decreasing morbidity and mortality is enormous. Therefore, the practicing veterinarian should become familiar with GI P₁CO₂ monitoring theory and technology so he or she can be better prepared to incorporate it into practice when in becomes available.     

Correlation between the pharmacokinetics of oxindanac and inhibition of serum thromboxane B2 in calves

The pharmacokinetics and pharmacodynamics of the non-steroidal antiinflammatory drug, oxindanac, were assessed simultaneously in calves after intravenous (i.v.) administration at dose rates of 0.5, 1, 2, 4 and 8 mg/kg. Plasma pharmacokinetic data were fitted to either two or three compartment open models. The elimination t ¹/₂ was constant in the dose range 0.5 to 4 mg/kg (20.2–22.8 h) and shorter at 8 mg/kg (14.7 h). The pharmacodynamics of oxindanac were assessed by its inhibition of serum TxB₂, an index of platelet cyclo-oxygenase activity. Plots of total plasma oxindanac concentration vs. inhibition of serum TxB₂ fitted in all cases a sigmoidal E_max equation. There were no significant differences in the estimates for ED ₅₀ (1.6-1.9 μg/ml), Hill constant (1.3-2.7) or Emax between the doses used in the in vivo studies or when blood was spiked with oxindanac in vitro. Plots of inhibition of serum TxB₂ vs. time were prepared from the pharmacokinetic model equations in each calf in combination with a single sigmoidal E_max plot generated in vitro. These data were not significantly different from the results produced in vivo. It is concluded that oxindanac causes reversible inhibition of platelet cyclo-oxygenase in calves. Its inhibition of serum TxB₂ can be predicted from total plasma drug concentration, as described by a multicompartmental model, and sigmoidal E_max enzyme kinetics. It was not necessary to take into account factors such as drug equilibration between plasma and its target site, free vs. total drug concentration or chirality. This simple model may be useful for predicting the pharmacodynamics of oxindanac in other species.     

Cardiopulmonary Effects of Using Carbon Dioxide for Laparoscopic Surgery in Dogs

Cardiopulmonary effects of laparoscopic surgery were investigated in five crossbred dogs (21 ± 1.9 kg). Premedicated dogs were anesthetized with thiopental and maintained with halothane at 1.5 times minimum alveolar concentration in oxygen. Controlled ventilation maintained partial pressure of end-tidal co₂ at 40 ± 2 mm Hg. Vecuronium was used for skeletal muscle relaxation. After instrumentation and stabilization, baseline measurements were made of cardiac output (thermodilution technique), mean systemic, mean pulmonary arterial and pulmonary wedge pressures, heart rate, saphenous vein and central venous pressures, and minute ventilation. Baseline arterial and mixed venous blood samples were drawn for analysis of pH, Pao₂, Paco₂, Pvo₂, Pvco₂, and bicarbonate concentrations. Systemic and pulmonary vascular resistances, oxygen delivery and consumption, shunt fraction, and dead space ventilation were calculated using standard formulas. Abdominal insufflation using co₂ to a pressure of 15 mm Hg for 180 minutes resulted in significant ( P <.05) increases in heart rate (15 to 180 minutes), minute ventilation (75 to 135 minutes), and saphenous vein pressure (15 to 180 minutes), and decreases in pH (60 to 180 minutes) and Pao₂ (60 to 180 minutes). For 30 minutes after desufflation, there was a significant decrease in Pao₂, and increases in cardiac output, o₂ delivery, and heart rate, compared with baseline. There was a significant increase in shunt fraction and decrease in pH at 15 minutes after desufflation only. The changes were within physiologically acceptable limits in these healthy, ventilated dogs.     

The actions of medetomidine may not be mediated exclusively by α2-adrenoceptors in the equine saphenous vein

Spirals of endothelially denuded equine saphenous vein were used to study the pre- and post-junctional effects of medetomidine in vitro . The pD₂ values were calculated for noradrenaline (6.7 /pm 0.1), phenylephrine (5.6 /pm 0.1), BHT 920 (6.2 /pm 0.2) and UK 14304 (5.7 /pm 0.2). Medetomidine produced a biphasic response, with a pD₂1 of 8.2 /pm 0.1 and a pD₂2 of 5.7 /pm 0.1 in the equine saphenous vein ( n = 6 ). Prazosin (10⁻⁷ m) significantly shifted the second phase of the medetomidine concentration-response curve to the right (pD₂1 was 8.1 /pm 0.2 and pD₂2 was 5.0 /pm 0.2, P < 0.05). Rings of equine saphenous vein were electrically stimulated to investigate the pre-junctional effects of medetomidine. Increasing concentrations of the α₂-adrenoceptor agonist BHT 920 reduced the response to electrical stimulation in a concentration dependent manner to a maximum of 40 /pm 5%. whereas medetomidine (0.1-100 nm) caused a concentration dependent enhancement to a maximum of 490 /pm 150%. These results suggest α₁- and α₂-adrenoceptors are functional in the equine saphenous vein, but that medetomidine is not acting exclusively as an α₂-adrenoceptor agonist.     

Effects of age and indomethacin on response and sensitivity of pulmonary artery to phenylephrine and to histamine in pigs

The vasoconstrictor effects of phenylephrine and histamine were investigated in isolated strips of pulmonary arteries in pigs during ageing. Interactions between phenylephrine-induced responses and arachidonic acid derivatives were also studied by incubating the blood-vessels with indomethacin. Potency (pD2 values) and maximal effects (E_maxx) recorded in 5-week-old piglets (group I, n = 5) with phenylephrine [5.71 ± 0.17 and 0.76 ± 0.22 g/mg of dry tissue respectively (mean ± SEM)] were similar to values found in 12-week-old animals (group 2, n = 5) (5.49 ± 0.30 and 1.06 ± 0.27 g/mg of dry tissue respectively). The sensitivity and responsiveness of tissues to this agonist were significantly reduced in 26-week-old mature pigs (group 3, n = 6) as indicated by the decrease in pD2 (3.91 ± 0.23; P < 0.01) and E_max (0.27 ± 0.13 g/mg of dry tissue; P < 0.05) values observed in this group. Histamine (10^_3M)-induced maximal responses (E_max) were significantly higher in group 2 (2.23 ± 0.49 g/mg) than in group 1 (0.85 ± 0.11 g/mg; P < 0.05) and in group 3 (0.48 ± 0.10 g/mg; P < 0.01). In 5-week-old animals, indomethacin (3.10˜⁵M) significantly ( P < 0.05) shifted the concentration-response curve to phenylephrine to the right (0.28 log. units) and depressed contractions to this drug as shown by the significant decrease of 39.5% ( P < 0.05) in E_max. This cyclo-oxygenase inhibitor had no effect in other groups. These data indicate that phenylephrine is a potent and effective vasoconstrictor agent for the main pulmonary arteries in 5-week-old piglets and that alpha-1-adrenergic-induced contractions are enhanced by cyclo-oxygenase products. These findings can be related with the high reactivity of pulmonary vascular smooth muscles in these animals.