Pulmonary Depressor Research Articles

Characterization of the pulmonary arterial response to endothelin-1 and bosentan in neonatal pigs

Background. This study determined the pulmonary vascular responses to intravenous (IV) administration of endothelin-1 (ET-1) before and after an IV bolus of bosentan (Ro 47-0203), an endothelin receptor antagonist, in anesthetized open-chest 48-hour-old and 2-week-old Yorkshire pigs. Methods. Eighteen 48-hour-old and 25 2-week-old pigs were randomly allocated to receive either (1) 400 ng · kg−1 · min−1 of ET-1 or (2) 5 mg/kg or 10 mg/kg of Ro 47-0203 followed by 400 ng · kg−1 · min−1 of ET-1 over a 10-minute interval. Pulmonary vascular resistance (PVR, dyne sec/cm −5), elastic modulus (E Yo, dyne/cm 2), and characteristic impedance (Z o) were determined (± SEM). Results. In 48-hour-old pigs, ET-1 decreased pulmonary artery pressure (PAP, dyne/cm 2; 21,317 ± 1833 versus 17,757 ± 1823; p = 0.003). In 2-week-old pigs, ET-1 elevated PAP (19,009 ± 1834 versus 21,935 ± 2104; p = 0.003) and PVR (1624 ± 254 versus 2302 ± 416; p = 0.001), whereas bosentan abolished the ET-1 induced pulmonary and systemic vasoconstriction. Neither agent altered E Y or Z o. Conclusions. ET-1 caused a pulmonary depressor response in 48-hour-old pigs and a constrictor response in 2-week-old pigs, whereas bosentan inhibited the ET-1 induced pulmonary arteriolar vasoconstriction in 2-week-old pigs. The response to ET-1 changes from dilation in 48-hour-old pigs (neonates) to constriction in 2-week-old pigs (infants) suggests a maturational dependent alteration in ET receptors during the first 2 weeks of life. These data suggest that bosentan may have potential clinical application in the treatment of newborn pulmonary hypertensive episodes as it ablated ET-1 induced pulmonary vasoconstriction, while maintaining systemic pressure.

Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo. Effect on agonist-induced and flow-mediated vascular responses.

The effects of transfer of the endothelial nitric oxide synthase (eNOS) gene to the lung were studied in mice. After intratracheal administration of AdCMVbetagal, expression of the beta-galactosidase reporter gene was detected in pulmonary airway cells, in alveolar cells, and in small pulmonary arteries. Gene expression with AdCMVbetagal peaked 1 day after administration and decayed over a 7- to 14-day period, whereas gene expression after AdRSVbetagal transfection peaked on day 5 and was sustained over a 21- to 28-day period. One day after administration of AdCMVeNOS, eNOS protein levels were increased, and there was a small reduction in mean pulmonary arterial pressure and pulmonary vascular resistance. The pressure-flow relationship in the pulmonary vascular bed was shifted to the right in animals transfected with eNOS, and pulmonary vasodepressor responses to bradykinin and the type V cGMP-selective phosphodiesterase inhibitor zaprinast were enhanced, whereas systemic responses were not altered. Pulmonary vasopressor responses to endothelin-1 (ET-1), angiotensin II, and ventilatory hypoxia were reduced significantly in animals transfected with the eNOS gene, whereas pressor responses to norepinephrine and U46619 were not changed. Systemic pressor responses to ET-1 and angiotensin II were similar in eNOS-transfected mice and in control mice. Intratracheal administration of AdRSVeNOS attenuated the increase in pulmonary arterial pressure in mice exposed to the fibrogenic anticancer agent bleomycin. These data suggest that transfer of the eNOS gene in vivo can selectively reduce pulmonary vascular resistance and pulmonary pressor responses to ET-1, angiotensin II, and hypoxia; enhance pulmonary depressor responses; and attenuate pulmonary hypertension induced by bleomycin. Moreover, these data suggest that in vivo gene transfer may be a useful therapeutic intervention for the treatment of pulmonary hypertensive disorders.

Coronary chemoreflex evoked by intrapericardial nicotine has a somatic component.

Stimulation of vagally innervated cardiac or pulmonary receptors reflexly evokes depressor responses called the coronary chemoreflex and pulmonary depressor reflex, respectively. The efferent arm of the pulmonary depressor reflex contains a somatic component wherein monosynaptic and polysynaptic muscle reflexes are attenuated. The purpose of the present investigation was to determine whether the efferent arm of the coronary chemoreflex also attenuates the monosynaptic knee-jerk reflex. Cardiac receptors were stimulated by injection of nicotine and bradykinin into the pericardial sac of 15 chloralose-anesthetized (50 mg/kg) cats. The knee-jerk reflex was elicited by tapping the patellar tendon intermittently. Intrapericardial nicotine attenuated the knee-jerk reflex by -26.2 +/- 6.5%. The attenuation was mediated by the vagus nerves, because vagotomy abolished the nicotine-induced attenuation. Stimulation of cardiac receptors evoked the attenuation, because blockade using intrapericardial procaine abolished the nicotine-induced attenuation. On the other hand, intrapericardial bradykinin augmented the knee-jerk reflex by 17.5 +/- 3.3%. The effect was not mediated by the vagus nerves; vagotomy did not abolish the bradykinin-induced augmentation. Changes in the knee-jerk reflex were not correlated with changes in blood pressure or heart rate evoked by intrapericardial nicotine or bradykinin. These findings demonstrate that reflex somatomotor responses accompany the reflex autonomic responses elicited by cardiac receptors. The somatic component of the vagally mediated coronary chemoreflex could contribute to the fainting reaction associated with exertional syncope of aortic stenosis and vasovagal syncope.

Capsaicin-induced bronchial vasodilation in dogs: central and peripheral neural mechanisms.

In 21 anesthetized dogs, we placed a flow probe around the right bronchial artery and examined changes in bronchial blood flow and bronchial vascular conductance when pulmonary C-fibers were stimulated by right atrial injection of capsaicin. When vagus nerves were intact, capsaicin evoked a pulmonary depressor chemoreflex and increased bronchial blood flow by 125% and bronchial vascular conductance by 175%; flow in an adjacent intercostal artery did not increase. Injection of color-coded microspheres revealed that blood flow to mucosa of lower trachea and to a peripheral bronchus doubled, whereas flow to posterior tracheal wall increased little. Cooling (to -1 degree C) or cutting cervical vagi (in 17 dogs) abolished the pulmonary chemoreflex and abolished all bronchial vascular effects in nine dogs but 33% of the vasodilation persisted in eight. In five of six dogs, this persisting vasodilation was potentiated by phosphoramidon (a neutral endopeptidase inhibitor that retards breakdown of neuropeptides released by C-fibers). Atropine reduced the capsaicin-induced bronchial vasodilation by approximately 30%. We conclude that the bronchial vasodilation was largely due to a centrally mediated vagal reflex and that a neuropeptide-dependent axon-reflex component was also present in about one-half the dogs.

Vasopressin Lowers Pulmonary Artery Pressure in Hypoxic Rats by Releasing Atrial Natriuretic Peptide

The authors previously demonstrated that arginine vasopressin (AVP) lowers pulmonary artery pressure in rats with hypoxic pulmonary hypertension by activation of the V1 receptor. The pulmonary depressor effect of AVP in hypoxia-adapted rats is not due to its effect on cardiac output. The current study tested two alternative hypotheses: that AVP lowers pulmonary artery pressure in the hypoxia-adapted lung by (1) dilating pulmonary vasculature directly, or (2) releasing atrial natriuretic peptide (ANP) from the heart. The first hypothesis was tested by injecting AVP into the pulmonary arteries of isolated, buffer perfused lungs and monitoring pulmonary artery pressure, and by exposing preconstricted pulmonary artery rings to graded doses of AVP and monitoring the tension generated. AVP caused minimal vasodilation in perfused lungs and only a small vasodilator effect in pulmonary artery rings. The second hypothesis was tested by injecting AVP (160 ng/kg) or vehicle intravenously in conscious hypoxia-adapted (4 weeks) or air control rats and measuring ANP in arterial blood and atria, and by testing pretreatment with the V1 receptor antagonist d(CH2)5 Tyr(Me)AVP (130 micrograms/kg) on the AVP-induced increase in plasma ANP. AVP produced a 7-fold increase in plasma ANP (209 +/- 33 to 1346 +/- 233 pg/ml; p less than 0.05) in hypoxia-adapted rats and a 5-fold increase in ANP (122 +/- 22 to 573 +/- 174 pg/ml; p less than 0.05) in air controls. ANP release was abolished by pretreatment of both groups with d(CH2)5 Tyr(Me)AVP. The AVP-induced ANP release came mainly from left atrium. These data strongly suggest that the pulmonary depressor effects of AVP in hypoxia-adapted rats is due to augmented V1 receptor-induced release of ANP from left atrium.

Pulmonary depressor reflex elicited by capsaicin in conscious intact and lung-denervated dogs.

A pulmonary depressor reflex has been shown to be elicited in anesthetized cats, dogs, and rats by intravenous injection of capsaicin. The effects observed include apnea, hypotension, and bradycardia with some investigators reporting tachypnea following the apneic period. We investigated the response to a bolus injection of capsaicin (20 micrograms/kg) into the cephalic vein in 11 conscious beagle dogs. Five control dogs underwent sham thoracotomies, and six dogs underwent selective denervation of the lungs. A low dead-space latex rubber mask was used to monitor ventilation, and arterial blood pressure was obtained by catheterizing an exteriorized carotid artery. In four of the five control dogs the observed response was apnea concomitant with hypotension and bradycardia, followed by tachypnea. In five of the six lung-denervated dogs there was a slight tachypnea along with hypertension. It is concluded that the pulmonary depressor reflex can be elicited in conscious dogs by intravenous injection of capsaicin but is absent in lung-denervated dogs.

Direct and indirect effects of leukotriene D4 on the pulmonary and systemic circulations.

We investigated direct (vascular leukotriene receptor stimulation) and indirect (generation of cyclooxygenase metabolites) hemodynamic effects of leukotriene D4 (LTD4) in 6 conscious sheep. Pulmonary artery, pulmonary arterial wedge and systemic arterial pressures, and cardiac output were measured. From these parameters, pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) were calculated before and immediately after a rapid injection of LTD4 into the pulmonary artery. Injection of 0.1 micrograms/kg of LTD4 increased mean PVR to 421% of baseline (p less than 0.001). It produced a biphasic effect on SVR that, after an initial decrease of 18% (p less than 0.05), increased to 143% of baseline (p less than 0.05). Both PVR and SVR returned to baseline within 10 min. The same results were obtained when the dose of LTD4 was increased to 0.5 micrograms/kg. Dose-response curves with increasing doses of LTD4 )0.025 micrograms/kg to 0.5 micrograms/kg) revealed that the optimal dosage for maximal effect was 0.1 micrograms/kg. The effects of LTD4 (0.1 micrograms/kg) on the pulmonary circulation were completely blocked by the SRS-A antagonist, FPL-57231, as well as by indomethacin. In the systemic circulation, FPL-57231 blocked the biphasic effects of LTD4 on SVR, whereas indomethacin prevented the initial decrease without attenuating the subsequent increase in mean SVR (135% of baseline, p less than 0.05). We conclude that there are direct and indirect hemodynamic effects of LTD4: the systemic vasoconstrictor response is directly related to vascular leukotriene receptor stimulation, whereas activation of cyclooxygenase pathway products is responsible for the pulmonary vasoconstrictor and systemic depressor responses.

The role of cardiac sympathetic discharges during the pulmonary depressor reflex.

The role played by the cardiac sympathetic fibers in the pulmonary depressor reflex was analyzed in twenty dogs. The selective perfusion with homologous blood of the inferior lobar vessels of the left lung with pressures of 40 to 60 mmHg decreased the spontaneous background discharges recorded from the left superior or inferior cardiac sympathetic nerves. This decrease was maximal at perfusion pressure of 80-100 mmHg. Following the decrease in the sympathetic discharges, the systolic and diastolic systemic arterial blood pressure decrease about 10 per cent. The changes were reversible when the perfusion pressure was returned to the control. The intravenous injection of atropine sulphate did not change either the systemic hypotension or the responses of the sympathetic efferent discharges induced by elevation of the pressure in the vascular bed of the lung lobe. Thus, it is believed that the systemic arterial blood pressure during this reflex may have fallen due to a diminution of the vascular tone caused by a decrease in the sympathetic efferent discharges. After transection of the vagus nerve ipsilateral to the tested lobe, the reduction of the sympathetic discharges as well as the decrease of the systemic arterial blood pressure were no longer observed. Our results further substantiate the concept that the vagus nerve is the afferent pathway for the pulmonary depressor reflex, and it may be concluded that during this reflex the sympathetic efferent activities are inhibited.

Pulmonary depressor reflex, with special reference to mechano-receptor distribution in the small pulmonary vasculature

The response, systemic hypotension and bradycardia, provoked by elevating Intravascular pressure (IVP) in the lung lobe, whose perfusion was separated from the circulation in situ, was described as pulmonary depressor by Schwiegk, 1935. Although mechanism of the reflex has not been entirely disclosed yet, it Is generally approved that the vagus is the main pathway, both afferent and efferent, connected to the center. Regarding location of mechanoreceptor in the vascular tree, however, it is still controversial whether the receptor lies in the artery or in the vein system. Moreover, there has been few description in regard to receptors in the small vessels including capillary bed, until present time. Recently, Salisbury et al. and Daly. M. et al. discussed that inflation of the lung lobe also showed the similar systemic hypotension and bradycardia. Nowadays, a quotion has been raised whether the mechano-receptors in the vascular tree, which must be affected by deformation of the lung, could be considered to be comparable to the stretch receptors in the lung parenchyma. Following experiments were designed in the hope to throw a light on the above mentioned enigmatical mechano-receptors. Methods Twenty-eight adult mongrel dogs were anesthetized with pentobarbital soda (25mg/kg, i.v.) and thoracotomy was carried out in the fourth intercostal space under positive pressure ventilation. Both the artery (PA) and vein (PV) of the left lower lobe (LLL) were ligated and cannulated immediately distal to the ligation, for the purpose of rapid infusion with autologus heparinized blood and measurement of IVP. Ventilation of LLL was also separated from the other lung lobes by means of a small specially devised cuffed tube passed through the main tracheal tube. LLL was inflated with the gas mixture consisting of 5.6% CO2, 14% O2, and N2, as required in the course of the experiment. A free margin of LLL was stretched or corn-pressed slightly by using the finger tips with special care in order not to pull the hilus. The same procedures were carried out also in the ipsilaterally or bilaterally vagotomized dogs. After PA or PV embolization with Lycopodiurn spores, infusion with a high pressure of the embolized lobar vessel initially, then the similar infusion of the non-embolized one was performed.

Further observation on the mechanism of the reflex apnea caused by nicotine. The influences of several blocking agents administered intrapericardially on the nicotine apnea.

The previous experiments of Takasaki (1956), Takasaki et al. (1957, 1959b) have been shown that the mechanism of the reflex apnea caused by nicotine or diphenhydramine may be due to “pulmonary respiratory chemoreflex” as described by Dawes G. S. et al. (1954). Additionaly, the reflex systemic hypotension of veratrum alkaloids (Dawes, 1947, Aviado et al., 1951, Rose et al., 1957) is produced by a reflex from the lungs; it was called “pulmonary depressor chemoreflex” (Dawes et al., 1954). This was confirmed with nicotine by Takasaki (1962) . The localization of receptors responsible for this reflex may be in the lung andthis afferent path ascends in the vagi. On the other hand, it has been shown that the reflex circulatory depressor responses and the impulses from heart receptors were intercepted by intrapericardial administration of procaine or local anesthetics (Kurotubo, 1942, Hukuda, 1951, Kido, 1953). In the former experiment (Takasaki et al., 1959b), it was confirmed that the receptor in the heart is not responsible to the respiratory reflex caused by nicotine . It was also reported that the reflex apnea caused by nicotine was blocked by intravenous injection of tetraethylammonium bromide and hexamethonium bromide but not by atropine (Nakano et al., 1957, Takasaki et al., 1959a). In this report, it was done attempting that the separation of the receptors in the heart and lungs using several blocking agents administered intrapericardially and the absorption of the drugs into the systemic circulation was investigated.

Arterial pressure changes by drugs injected into isolated pulmonary circulation in dogs.

In open-chested, anesthetized dogs the pulmonary venous outflow of the left lung was diverted into an external bypass so that the flow rate could be measured and blood prevented from returning immediately to the general circulation. Pulmonary arterial pressure was recorded in the left pulmonary artery; systemic arterial pressure and heart rate were also recorded. Injection of nicotine, veratrine, or Veriloid into this limited lung circulation produced a systemic depressor response and bradycardia. Both effects were abolished by vagotomy. It is concluded that these systemic cardiovascular effects are mediated through vagal chemoreceptors. There is no reason to implicate a mechanical pulmonary depressor reflex since these drugs produce no change in the pulmonary arterial pressure.

THE CARDIOVASCULAR REFLEX CAUSED BY PHENYL DIGUANIDE

Phenyl diguanide has been described to cause, on intravenous injection, a reflex fall of blood pressure, bradycardia and apnoea by an action on sensory receptor in heart and lungs of cats. Dawes and Comroe (1954) proposed to describe these reflex effects as the coronary chemoreflex (Bezold-Jarisch effect), the pulmonary depressor chemoreflex and the pulmonary respiratory chemoreflex. Among these reflexes, the coronary chemoreflex has been extensively studied since the brilliant contribution by Bezold and Hirt (1867). There are, however, only a few reports on the pulmonary depressor or pulmonary respiratory chemoreflexes except those by Dawes et al.. In our laboratory, Takasaki (1956) clarified previously that the apnoea caused by intravenous injection of nicotine was due to the pulmonary respiratory chemoreflex, and furthermore the effects of several blocking agents on the reflex apnoea were reported in the other paper (Nakano et al., 1957). In the present experiments, the cardiovascular effects of phenyl diguanide have been reexamined and it comes to a somewhat different conclusion from those of Dawes and his coworkers, and the blocking actions of several drugs on the effects have been also studied.

Pulmonary depressor chemoreflex in the rat.

ArticlePulmonary Depressor Chemoreflex in the RatF. R. Blood, M. E. Kosman, and F. E. D'amourF. R. BloodFrom the Biologic Research Laboratories, University of Denver, Denver, Colorado, M. E. KosmanFrom the Biologic Research Laboratories, University of Denver, Denver, Colorado, and F. E. D'amourFrom the Biologic Research Laboratories, University of Denver, Denver, ColoradoPublished Online:01 Jul 1955https://doi.org/10.1152/ajplegacy.1955.182.1.180MoreSectionsPDF (475 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByREFLEXES ARISING FROM THE PULMONARY CIRCULATION AND NEIGHBORING STRUCTURESRENAL EFFECTS OF VERATRIDINE19 July 2012 | British Journal of Pharmacology and Chemotherapy, Vol. 14, No. 1 More from this issue > Volume 182Issue 1July 1955Pages 180-182 Copyright & PermissionsCopyright © 1955 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1955.182.1.180PubMed13248963History Received 26 December 1954 Published online 1 July 1955 Published in print 1 July 1955 Metrics