Cortical 5-HT(1A) receptor downregulation by antidepressants in rat brain

Total 5-HT binding sites and 5-HT_1A receptor density was measured in brain regions of rats treated with imipramine (5 mg/kg body wt), desipramine (10 mg/kg body wt) and clomipramine (10 mg/kg body wt), for 40 days, using [³H]5-HT and [³H]8-OH-DPAT, respectively. It was observed that chronic exposure to tricyclic antidepressants (TCAs) results in significant downregulation of total [³H]5-HT binding sites in cortex (42–76%) and hippocampus (35–67%). The 5-HT_1A receptor density was, however, decreased significantly (32–60%) only in cortex with all the three drugs. Interestingly, in hippocampus imipramine treatment increased the 5-HT_1A receptor density (14%). The affinity of [³H]8-OH-DPAT was increased only with imipramine treatment both in cortex and hippocampus. The affinity of [³H]5-HT to 5-HT binding sites in cortex was increased with imipramine treatment and decreased with desipramine and clomipramine treatment. 5-HT sensitive adenylyl cyclase (AC) activity was significantly increased in cortex with imipramine (72%) and clomipramine (17%) treatment, whereas in hippocampus only imipramine treatment significantly increased AC activity (50%). In conclusion, chronic treatment with TCAs results in downregulation of cortical 5-HT_1A receptors along with concomitant increase in 5-HT stimulated AC activity suggesting the involvement of cortical 5-HT_1A receptors in the mechanism of action of TCAs.     

Cortical alpha-adrenoceptor downregulation by tricyclic antidepressants in the rat brain

The aim of the present study was to examine the effect of chronic tricyclic antidepressants (TCAs) treatment on the density of -adrenoceptors in the rat brain. Density of ₁- and ₂-adrenoceptors was measured in cortex and hippocampus of rats treated with imipramine (IMI, 5 mg/kg body weight), desipramine (DMI, 10 mg/kg body weight), clomipramine (CMI, 10 mg/kg body weight) and amitriptyline (AMI, 10 mg/kg body weight), for 40 days, using [³H]prazosin and [³H]clonidine, respectively. The density of cortical ₁-adrenoceptors was significantly decreased with IMI (46%), DMI (21%), CMI (50%) and AMI (67%) treatment, without altering the affinity of the receptor. The density of cortical ₂-adrenoceptors was also significantly decreased with DMI (69%), CMI (81%) and AMI (80%) treatment, without affecting the affinity for [³H]clonidine. The density of hippocampal ₁-adrenoceptors was significantly decreased only with AMI treatment (47%), without affecting the affinity for [³H]prazosin. However, no change in hippocampal ₂-adrenoceptor density was observed with any of these TCAs. The results suggest that chronic antidepressant (AD) treatment downregulates the cortical, but not hippocampal, ₁- and ₂-adrenoceptors in rat brain. The region-specific downregulation of ₁- and ₂-adrenoceptors density, which occur after prolonged AD treatment, may underline the therapeutic mechanism of action.     

Cortical 5-HT1A receptor downregulation by antidepressants in rat brain

Total 5-HT binding sites and 5-HT_1A receptor density was measured in brain regions of rats treated with imipramine (5 mg/kg body wt), desipramine (10 mg/kg body wt) and clomipramine (10 mg/kg body wt), for 40 days, using [³H]5-HT and [³H]8-OH-DPAT, respectively. It was observed that chronic exposure to tricyclic antidepressants (TCAs) results in significant downregulation of total [³H]5-HT binding sites in cortex (42–76%) and hippocampus (35–67%). The 5-HT_1A receptor density was, however, decreased significantly (32–60%) only in cortex with all the three drugs. Interestingly, in hippocampus imipramine treatment increased the 5-HT_1A receptor density (14%). The affinity of [³H]8-OH-DPAT was increased only with imipramine treatment both in cortex and hippocampus. The affinity of [³H]5-HT to 5-HT binding sites in cortex was increased with imipramine treatment and decreased with desipramine and clomipramine treatment. 5-HT sensitive adenylyl cyclase (AC) activity was significantly increased in cortex with imipramine (72%) and clomipramine (17%) treatment, whereas in hippocampus only imipramine treatment significantly increased AC activity (50%). In conclusion, chronic treatment with TCAs results in downregulation of cortical 5-HT_1A receptors along with concomitant increase in 5-HT stimulated AC activity suggesting the involvement of cortical 5-HT_1A receptors in the mechanism of action of TCAs.     

Repeated treatment with imipramine, fluvoxamine and tranylcypromine decreases the number of escape failures by activating dopaminergic systems in a rat learned helplessness test.

Chronic administration of antidepressants has been shown to reduce the number of escape failures in the rat learned helplessness test (LH). In the present study we investigated the role of D1, D2 and D3 receptors in mediating this effect. In our first series of experiments, we demonstrated that SKF38393, D1 receptor agonist, in a dose of 2.5 mg/kg (i.p.) and quinpirole, D2 receptor agonist in a dose of 0.5 mg/kg (i.p.), significantly decreased the number of escape failures in LH, and these were reversed by SCH23390 (0.015 mg/kg), D1 receptor antagonist, and by sulpiride (25 mg/kg), D2 receptor antagonist, respectively. In contrast, 7-OH-DPAT, a D3 receptor agonist, in a dose of 10 mg/kg (i.p.) did not affect the number of escape failures in LH. In a second series of experiments, we showed that eight days of repeated treatment with imipramine (10 mg/kg, p.o.), fluvoxamine (1.25 mg/kg, p.o.) and tranylcypromine (1.25 mg/kg, p.o.) significantly decreased the number of escape failures in LH. The decrease in escape failures seen with use of imipramine and tranylcypromine was reversed by sulpiride in LH, but not by SCH23390. On the other hand, the effect of fluvoxamine was reversed by both SCH23390 and sulpiride. These findings indicate that stimulation of D1 and D2 receptors decreased the number of escape failures in LH, respectively. Thus, D2 and/or D1 receptors are probably involved in the decreased number of escape failures in case of repeated treatment with antidepressants in LH.     

Antihypertensive substance in seeds of Areca catechu L

Among various tannins tested, Areca II-5-C, a fraction isolated from seeds of Areca catechu L., showed the most potent angiotensin-converting enzyme (ACE) inhibitory activity in vitro. Its antihypertensive activity was therefore investigated in normotensive and spontaneous hypertensive rats (SHR) after both oral and intravenous (i.v.) administration. The activity was compared with that of captopril (D-3-mercapto-2-methylpropanoyl-L-proline), a potent ACE inhibitor. Oral administration of Areca II-5-C to SHR produced a lasting, dose-related antihypertensive effect, and the responses obtained with doses of 100 and 200 mg/kg were comparable to those of captopril at doses of 30 and 100 mg/kg. Intravenous administration of Areca II-5-C to SHR produced a rapid and marked reduction in blood pressure at doses of 10 and 15 mg/kg. The maximum antihypertensive effect of Areca II-5-C in SHR, at an i.v. dose of 15 mg/kg, was about 5 times as large as that of captopril at the same dose. Although the vasopressor response to norepinephrine and vasodepressor responses to bradykinin and acetylcholine were not appreciably changed by i.v. treatment with Areca II-5-C at a dose of 5 mg/kg, it did produce dose-related inhibition of the pressor responses to angiotensin I and II. It is suggested that Areca II-5-C has favorable properties as a hypotensive drug through its ability to inhibit the pressor responses to both angiotensin I and II.     

Effect of dihydroxyphenylalanine, imipramine and coffeine on the light induced decrease in nocturnal serotonin N-acetyltransferase in the rat pineal gland.

The s.c. administration of 150mg L-dihydroxphyenylalaine/kg b.w. 15 min before the decapitation prevents the light induced decrease in nocturnal serotonin N-acetyltransferase activity in the rat pineal gland. The s.c. administration of 50mg imipramine/kg b.w., resp. 100mg/kg b.w., 15 min before the decapitation, slows down, or prevents the light induced fall in the activity. The maintenance of a sufficient level of active norepinephrine on beta-receptors, either by displacement of norepinephrine in the nerve endings by dopamine, or by the inhibition of norepinephrine reuptake by imipramine, thus slows down or prevents the decrease in serotonin N-acetyltransferase activity after exposure to light during the night. The i.p. administration of a phosphodiesterase inhibitor coffeine citrate in a dose 200mg/kg 90 min after switching off the light for the night stimulated serotonin N-acetyltransferase activity 270 min after the light and been switched off, but did not influence the abrupt decrease induced in nocturnal activity by exposure to light.     

Effects of 9-ene-tetrahydrocannabinol on uterine estrogenicity in the mouse.

Several early (Phase I) and late (Phase II) estrogenic effects of 9-ene-tetrahydrocannabinol (THC) were examined in the adult mouse uterus. An injection of THC (2.5 or 10 mg/kg body wt) in ovariectomized mice neither stimulated uterine water imbibition or accumulation of [125I]bovine serum albumin (Phase I responses) at 6 h, nor antagonized these Phase I responses elicited by estradiol-17 beta (E2). With respect to Phase II responses, although single injections of THC (2.5, 5.0 and 10 mg/kg body wt) alone were ineffective in influencing uterine weight at 24 h or incorporation of [3H]thymidine at 18 h, this drug interfered with these responses elicited by E2 in a dose-dependent manner. In contrast, an injection of THC in progesterone (P4)-primed ovariectomized mice modestly enhanced (61%) uterine incorporation of [3H]thymidine. However, E2-stimulated uterine thymidine incorporation in P4-primed ovariectomized mice was antagonized by THC treatment. Effects of THC on blastocyst implantation were examined. Single or multiple injections of various doses of THC neither induced implantation in P4-primed delayed implanting mice, nor interfered with E2-induced implantation. Furthermore, daily injections of THC (10 mg/kg body wt) during the peri-implantation period had no apparent adverse effects on implantation, or on experimentally induced decidualization (deciduomata). The data suggest that THC is neither pro- nor antiestrogenic with respect to Phase I responses. However as regards Phase II responses, THC is modestly pro-estrogenic in the P4-treated uterus, but is anti-estrogenic in the presence of E2. These estrogen agonistic/antagonistic effects of THC on uterine Phase II responses do not adversely affect the process of implantation and decidualization.     

Tricyclic antidepressants prevent the differentiation of monocytes into macrophage-like cells in vitro

The investigation was designed to determine whether the two tricyclic antidepressant agents (TCAs) clomipramine and imipramine and the selective reuptake inhibitor citalopram affect differentiation of human monocytes to macrophage-like cells (MAC-LCs). We established primary adherent cultures of peripheral blood monocytes and monitored their morphology, capacity for phagocytosis and antigen expression during transformation to MAC-LCs. As expected, maturation of monocytes to MACs is accompanied by changes in morphology, elevated expression of the antigens CD16 and CD51 and an increase in the percentage of phagocytic cells. Treatment of cells with the TCAs clomipramine (40 μmol/L) or imipramine (100 μmol/L) and with citalopram (100 μmol/L), for 11 days resulted in the following observations: (1) monocytes treated with TCAs never developed the morphology characteristic of the MAC-LCs; (2) TCAs reduced the percentage of phagocytic cells; (3) TCAs had little influence on the expression of CD14, CD16, CD51, and HLA-DR. However, when added after monocyte differentiation into MAC-LCs, citalopram and clomipramine no longer reduced the percentage of phagocytic cells and these effects were not simply due to irreversible cytotoxicity. Thus clomipramine, imipramine, and citalopram inhibit differentiation of human monocytes into MAC-LCs in vitro, but in a reversible manner. This revised version was published online in July 2006 with corrections to the Cover Date.     

Exploration of the antidepressant potential of iprindole.

Iprindole, a tricyclic indole compound with an antidepressant activity was evaluated in an animal test model. In this test a potential antidepressant agent should potentiate the behavioral and cardiovascular effects of yohimbine, a naturally occurring indole alkaloid, in conscious dogs. For comparison, imipramine, a standard antidepressant drug was used. Iprindole was tested at a dose of 3, 9, and 15 mg per kg. It potentiated the behavioral and cardiovascular effects of yohimbine at a dose of 9 mg per kg. Iprindole failed to potentiate norepinephrine response in dogs; similar observations are reported in man. The results further confirm the validity of the present test for evaluation of potential antidepressant agents in conscious dog.     

Hemodynamic and cardiac actions of trazodone and imipramine in the anesthetized dog.

The relative cardiovascular effects of trazodone and imipramine were compared in two open-chest, anesthetized dog models. Trazodone lowered arterial blood pressure (0.3 mg/kg), slowed heart rate (3 mg/kg) and reduced myocardial contractile force (3–10 mg/kg) following i.v. administration. Low i.v. doses (0.05–0.15 mg/kg) of imipramine increased arterial blood pressure and heart rate, presumably as a consequence of its known anticholinergic properties and/or effects on neuronal catecholamine re-uptake mechanisms. Subsequent to administration of 1.5 and 5 mg/kg, however, the vascular and myocardial depressant effects of imipramine were evident. Trazodone (1–10 mg/kg, i.v.), unlike imipramine, effected a substantial level of $\text{alpha}$-adrenergic blockade $\text{vs.}$ a fixed challenge dose of norepinephrine, although less than that associated with phentolamine. Both trazodone and imipramine reduced aortic flow although $\text{via}$ different mechanisms. The reduction following administration of trazodone resulted from a decrease in heart rate whereas imipramine depressed aortic flow by lowering stroke volume.     

Chronic treatment with antidepressants prevents the inhibitory effect of small doses of apomorphine on dopamine synthesis and motor activity.

In control rats small doses of apomorphine (25 to 100 μg/kg) decreased motor activity and reduced DOPAC content in the caudate nucleus. A larger dose (500 μg/kg) increased motor activity and elicited stereotypy. Chronic treatment with imipramine, amitryptiline and mianserine (10, 10 and 2.5 mg/kg twice daily for 10 days respectively) counteracted or reversed the effect of small doses of apomorphine on motor activity, left DOPAC content unchanged and potentiated the central stimulant response to the larger dose of apomorphine. Changes in apomorphine responses were observed after ten but not after two days of imipramine treatment and persisted unaltered up to 4 days after imipramine withdrawal. It is suggested that chronic treatment with antidepressants induces persistent subsensitivity in presynaptic dopamine receptors. The relevance of the findings in the therapeutic effect of these drugs is discussed.     

Sensitization of anorexia and locomotion induced by chronic administration of ephedrine in rats.

Repeated daily administration of the sympathomimetic agent ephedrine (EPH) leads to an augmentation (sensitization) of locomotor activity in rats. The present experiments examined the impact of repeated administration of the (-)- and (+)-EPH enantiomers on feeding in rats to assess whether the anorexic activity of EPH exhibits tolerance or sensitization during chronic exposure and whether the time course of these effects follows that observed in studies of locomotion. Adult male rats were injected once daily for 12 days with either vehicle or 5, 10 or 20 mg/kg (-)-EPH or with 10 or 20 mg/kg (+)-EPH. Horizontal locomotion and diet consumption were assessed for 60 min in an activity chamber. Suppression of feeding and the induction of locomotion were augmented over the first four days of administration of either 10 mg/kg or 20 mg/kg of the (-)-EPH enantiomer. In contrast, repeated administration of 20 mg/kg (+)-EPH resulted in augmentation of appetite suppression but not locomotion. These results confirm and extend the phenomenon of locomotor and feeding sensitization for ephedrine, but suggest that these effects may differ for the two enantiomers of ephedrine.     

A comparative study on immunosuppressive effects of cyclosporin A and FK 506 on peripheral blood lymphocytes in dogs

Immunosuppressive effects of cyclosporin A (CsA) and FK 506 (FK) on peripheral blood lymphocytes were studied in dogs in respect to mixed lymphocyte reaction, proliferative responses to recombinant interleukin-2 (rIL-2), phytohemagglutinin (PHA) and concanavalin-A (Con-A); phenotypes of OKIa1, CD3, CD8 and surface IgM; cytotoxic activity against xenogeneic tumor cells. CsA (2.0 or 5.0 mg/kg, intravenously) or FK (0.16 mg/kg, intramuscularly) was given to mongrel dogs every morning for serial 21 days. The blood concentrations of CsA, measured as trough levels by fluorescence polarization method, ranged from 37 to 350 ng/ml in dogs administered at 2.0 mg/kg and from 170 to 894 ng/ml in dogs administered at 5.0 mg/kg during treatment, respectively. In dogs treated with FK at a dose of 0.16 mg/kg, the drug concentrations in the plasma during treatment ranged from 0.16 to 1.8 ng/ml. Mixed lymphocyte reaction and proliferative responses to rIL-2, PHA and Con-A, which were declined by CsA, were not affected by FK. In contrast, the proportion of OKIa1+ cells was not affected by CsA, whereas FK decreased the proportion of OKIa1+ cells progressively during the course of treatment. Cytotoxic activity was suppressed by both CsA and FK. These results possibly indicate that CsA and FK exert their immunosuppressive effects via different mechanisms.     

The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test

Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10 mg/kg), CORT 108297 (30 mg/kg and 60 mg/kg), imipramine (10 mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60 mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest that CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.     

Development of cardiovascular responses to sympathomimetic amines and autonomic blockage in the unanesthetized fetus

The cardiovascular effects of phenylephrine or ephedrine alone and after autonomic blockade was studied in the chronically cannulated fetal lamb (100-145 days), the newborn lamb, and adult sheep. As gestation advanced, phenylephrine and ephedrine produced an increasing pressor response before and after pretreatment with atropine (1 mg/kg). Compared with the fetus, the magnitudes of the pressor responses were somewhat greater in the newborn and much larger in the adult. Both drugs produced a reflex bradycardia in the unatropinized fetus which in the case of ephedrine was followed by a tachycardia. Pretreatment with atropine resulted in an immediate tachycardia after ephedrine but not after phenylephrine administration. Pretreatment with phentolamine (0.15 mg/kg) produced about a 55% inhibition of the phenylephrine pressor response in both the fetus and adult, suggesting a linear relationship between body weight and number of alpha-adrenergic receptors. Pretreatment with metoprolol blocked the tachycardia associated with ephedrine administration to unatropinized fetuses. In summary, the increase in the magnitude of the pressor response to phenylephrine suggested development of the receptor-effector system. The greater development of the response to ephedrine suggested that there was an increasing amount of noradrenaline being released with advancing gestation.     

Anesthesia alters pulmonary vasoregulation by angiotensin II and captopril.

We investigated the effects of an intravenous (pentobarbital sodium) and inhalational (halothane) general anesthetic on the pulmonary vascular responses to angiotensin II and angiotensin-converting enzyme inhibition (CEI). Multipoint pulmonary vascular pressure-flow (P/Q) plots were generated in conscious pentobarbital- (30 mg/kg iv) and halothane-anesthetized (approximately 1.2% end-tidal) dogs in the intact (no drug) condition, during angiotensin II administration (60 ng.kg-1.min-1 iv), and during CEI (captopril 1 mg/kg plus 1 mg.kg-1.h-1 iv). In conscious dogs, angiotensin II increased (P less than 0.001) the pulmonary vascular pressure gradient [pulmonary arterial pressure--pulmonary arterial wedge pressure (PAP-PAWP)] over the empirically measured range of Q; i.e., angiotensin II caused pulmonary vasoconstriction. Pulmonary vasoconstriction (P less than 0.01) in response to angiotensin II was also observed during pentobarbital sodium anesthesia. In contrast, angiotensin II had no effect on the P/Q relationship during halothane anesthesia. In conscious dogs, CEI decreased (P less than 0.001) PAP-PAWP over the empirically measured range of Q; i.e., CEI caused pulmonary vasodilation. However, CEI caused pulmonary vasoconstriction (P less than 0.02) during pentobarbital sodium and had no effect on the P/Q relationship during halothane. Thus, compared with the conscious state, the pulmonary vasoconstrictor response to angiotensin II is unchanged or abolished, and the pulmonary vasodilator response to CEI is reversed to vasoconstriction or abolished during pentobarbital sodium and halothane anesthesia, respectively.     

Pharmacological analysis of the mechanisms involved in the tachycardic and vasopressor responses to the antimigraine agent, isometheptene, in pithed rats

The present study set out to investigate the pharmacological profile of the cardiovascular responses induced by the antimigraine agent, isometheptene, in pithed rats. For this purpose, intravenous (i.v.) administration of blocking doses of the antagonists prazosin (alpha1; 100 microg/kg), rauwolscine (alpha2; 300 microg/kg), the combination of prazosin (100 microg/kg) plus rauwolscine (300 microg/kg), propranolol (beta; 1000 microg/kg), ritanserin (5-HT2; 100 microg/kg) or equivalent volumes of saline (1 ml/kg) were used. Isometheptene (0.03, 0.1, 0.3, 1 and 3 mg/kg, i.v.) produced dose-dependent increases in heart rate and diastolic blood pressure which were highly reproducible as they remained unaltered after saline. These tachycardic responses to isometheptene remained unaffected after prazosin, rauwolscine, ritanserin or the combination prazosin plus rauwolscine, but were abolished after propranolol. In contrast, the isometheptene-induced vasopressor responses were not significantly modified after the above doses of rauwolscine, ritanserin or propranolol, but were markedly blocked after prazosin or the combination of prazosin plus rauwolscine; the latter blockade did not significantly differ from that produced by prazosin alone. Interestingly, in rats pretreated intraperitoneally (i.p.) with reserpine (5 mg/kg; -24 h), isometheptene-induced tachycardic responses were abolished whereas the corresponding vasopressor responses were markedly attenuated and subsequently blocked by prazosin. It is concluded that isometheptene-induced tachycardic responses seem to involve only an indirect (tyramine-like action) mechanism mediated by beta-adrenoceptors, whilst the corresponding vasopressor responses are mediated by a predominantly indirect (tyramine-like action), as well as a minor direct (alpha1-adrenoceptors), sympathomimetic mechanism.     

麻黄碱复合利多卡因对顺式阿曲库铵肌松效应的影响

目的比较麻黄碱预处理、利多卡因预处理和麻黄碱复合利多卡因预处理对顺式阿曲库铵起效时间、插管条件及其血流动力学的影响。方法选择全麻下行择期手术的患者120例随机分为4组,Ⅰ组生理盐水0.5ml,Ⅱ组麻黄碱70μg/kg,Ⅲ组利多卡因1.5mg/kg,Ⅳ组麻黄碱复合利多卡因70μg/kg+1.5mg/kg,预处理3min后4组患者均静脉注射顺式阿曲库铵0.15mg/kg,在5s内注射完成。患者入睡后行肌松监测,使用4个成串刺激(TOF),待T1达最大抑制程度时行气管插管,记录肌松起效时间,评估气管插管条件,同时观察HR、BP的变化。结果Ⅱ、Ⅲ、Ⅳ组肌松起效时间明显短于Ⅰ组(P0.05),而且Ⅳ组起效时间较Ⅱ、Ⅲ组短(P0.05);Ⅱ、Ⅲ、Ⅳ组气管插管优良率高于Ⅰ组(P0.05),但Ⅱ、Ⅲ组气管插管优良率比较无统计学意义;各组麻醉诱导期间均无明显心血管不良反应。结论麻黄碱复合利多卡因70μg/kg+1.5mg/kg预处理为较好的选择。     

Blunted hypoxic vasoconstriction in oleic acid lung injury: effect of cyclooxygenase inhibitors.

Cyclooxygenase inhibitors have been reported to accentuate pulmonary hypertension and to improve gas exchange in oleic acid (OA) lung injury (Leeman et al. J. Appl. Physiol. 65: 662-668, 1988), suggesting inhibition of hypoxic pulmonary vasoconstriction by a vasodilating prostaglandin. To test this hypothesis, the hypoxic pulmonary vasoreactivity was examined at constant flow (Q; with an arteriovenous femoral bypass or a balloon catheter placed in the inferior vena cava) before and after OA in three groups of anesthetized and ventilated [inspired O2 fraction (FIO2) 0.4] dogs. Intrapulmonary shunt was measured using a SF6 infusion. A time control group (n = 7) had two consecutive hypoxic challenges after OA and received no drug. A treatment group (n = 6) received indomethacin (2 mg/kg iv) before the second hypoxic challenge after OA. A pretreatment group received indomethacin (2 mg/kg iv, n = 7) or aspirin (30 mg/kg iv, n = 6) before OA. In control and treated dogs, the hypoxic pulmonary vasopressor response was attenuated after OA. It was restored after indomethacin but also during the second hypoxic stimulus in the control dogs. After OA, gas exchange at FIO2 0.4 improved with indomethacin but not in controls. In pretreated dogs the hypoxic vasopressor response to hypoxia was preserved after OA, and gas exchange at FIO2 0.4 was less deteriorated compared with nonpretreated dogs (arterial O2 pressure 139 +/- 7 vs. 76 +/- 6 Torr, P less than 0.01, and intrapulmonary shunt 14 +/- 2 vs. 41 +/- 5%, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic actions of endothelin in conscious and anesthetized dogs

The newly described endogenous peptide, endothelin, was administered to five chronically instrumented conditioned dogs. Endothelin produced significant and simultaneous increases in both heart rate (HR) and mean arterial pressure (MAP) in conscious dogs. Endothelin also produced significant increases in MAP in anesthetized animals. Ganglionic suppression induced by hexamethonium (10 mg/kg) and atropine (0.1 mg/kg) blocked HR responses and markedly inhibited the pressor responses to endothelin in conscious animals. These results suggest that endothelin in part acts to elevate blood pressure and heart rate through modification of autonomic nervous system tone. When endothelin and angiotensin II were administered in mole equivalent doses, angiotensin II produced a pressor response of greater magnitude than did endothelin in conscious animals.