Vascular Pressor Response Research Articles

Reduced capacitative calcium entry in the mesenteric vascular bed of bile duct-ligated rats

In this work, we analyzed the interaction of nitric oxide (NO) with some of the mechanisms known to regulate intracellular calcium levels in order to gain insight into the mechanisms responsible for the reduced vascular pressor response to vasoconstrictors observed in an experimental model of liver cirrhosis. Specifically, we hypothesized that the entry of calcium through capacitative channels is defective in this model. The experiments were performed with isolated, Krebs-perfused and de-endothelialized mesenteric arterial bed of rats with bile duct ligation (4 weeks) and their controls. Pretreatment with thapsigargin to inhibit calcium uptake into sarcoplasmic reticulum potentiated the pressor responses to methoxamine, but the response of the cirrhotic vessels was significantly lower than that of the controls. Under the same conditions, perfusion of the mesenteries with zero calcium-Krebs resulted in lower pressor responses to methoxamine, especially in the mesenteries of the bile duct-ligated rats. To specifically analyze the entry of calcium through store-operated calcium channels, the pressor response to the addition of calcium was studied in mesenteries perfused with zero calcium-Krebs and in the presence of thapsigargin. Again, the response of the cirrhotic mesenteric beds was significantly lower than that of the control vessels. Under all these experimental conditions, the differences between control and cirrhotic responses were abolished by pretreatment with the NO synthesis inhibitor N w-nitro- l-arginine (NNA). These results indicate that, in the mesenteric bed of bile duct-ligated rats, an excess of nitric oxide interferes with the release of calcium from thapsigargin-sensitive internal stores and also reduces the capacitative entry of calcium into vascular muscular cells induced by the depletion of calcium from internal stores. This mechanism may have an important role in the reduced pressor response observed in the mesenteric vascular bed in cirrhosis.

Mesenteric hyporesponsiveness in cirrhotic rats with ascites: role of cGMP and K+ channels

The mechanisms that mediate hyporesponsiveness to vasoconstrictors in liver cirrhosis are not completely established. In the present study we have explored the role of NO and potassium channels by studying the pressor response to methoxamine in rats with carbon tetrachloride-induced cirrhosis with ascites. Experiments were performed in the isolated and perfused mesenteric arterial bed of control rats and of cirrhotic rats with ascites. Pressor responses to methoxamine, an alpha-adrenergic agonist, were analysed under basal conditions, after inhibition of guanylate cyclase with Methylene Blue (MB; 10 microM), after inhibition of NO synthesis with N(G)-nitro-L-arginine (L-NNA; 100 microM) and after blockade of potassium channels with tetraethylammonium (TEA; 3 mM). Compared with those from controls, preparations from cirrhotic rats showed a lower pressor response to methoxamine (maximum: controls, 114.4+/-6.8 mmHg; cirrhotic rats, 74.7+/-7.3 mmHg). Pretreatment with MB or L-NNA increased the responses in both groups, but without correcting the lower than normal response of the cirrhotic rats. Pretreatment with TEA alone did not modify the responses as compared with the untreated groups. Pretreatment with TEA plus MB or TEA plus L-NNA also potentiated the responses, and the responses of the cirrhotic animals were greater than those of the groups treated with MB or L-NNA alone. However, no treatment completely normalized the lower response of the mesenteries from cirrhotic animals, suggesting that factors other than NO and potassium channels also participate, although to a lesser degree, in the lower pressor response of the mesenteric arterial bed of animals with cirrhosis. These results confirm that NO and potassium channels are important mediators of the lower vascular pressor response of the mesenteric bed of cirrhotic rats with ascites. This effect seems to be mediated by the NO-dependent formation of cGMP and by the NO-dependent and -independent activation of potassium channels.

Endotoxin priming of the cyclooxygenase-2-thromboxane axis in isolated rat lungs.

Enhanced prostanoid generation has been implicated in vascular abnormalities occurring during endotoxemia and sepsis, and the lung is particularly prone to such events. Prostanoids are generated from arachidonic acid (AA) via cyclooxygenase (COX)-1 or -2, both isoenzymes recently demonstrated to be expressed in different lung cell types. Upregulation of COX may underlie the phenomenon that endotoxin [lipopolysaccharide (LPS)]-exposed lungs show markedly enhanced vasoconstrictor responses to secondarily applied stimuli (priming). Isolated rat lungs were perfused with a physiological salt buffer solution in the absence and presence of 1.5% rat plasma and exposed to different concentrations of LPS (1,000 or 10,000 ng/ml) during a 2-h priming period. No change in physiological variables was noted during this period, although enhanced baseline liberation of both thromboxane (Tx) A(2) and PGI(2) as well as of tumor necrosis factor (TNF)-alpha was evident compared with that in control lungs in the absence of LPS. LPS priming caused a significant elevation in AA-induced pulmonary arterial pressure, ventilation pressure, and lung weight gain. Concomitant increased levels of TxA(2) were found in the buffer perfusate. All changes were largely suppressed by three selective, structurally unrelated COX-2 inhibitors (NS-398, DUP-697, and SC-236) in both buffer- and buffer-plasma-perfused lungs. Anti-TNF-alpha neutralizing antibodies were ineffective under conditions of buffer perfusion. In the presence of plasma components, manyfold augmented TNF-alpha generation was noted, and anti-TNF-alpha antibodies significantly suppressed the increase in ventilation pressure but not in the vascular pressor response and lung edema formation. We conclude that the propensity of LPS-primed lungs to respond with enhanced vasoconstriction, edema formation, and bronchoconstriction to a secondarily applied stimulus proceeds nearly exclusively via COX-2 and increased Tx formation, with TNF-alpha generation being involved in the change in bronchomotor reactivity in the presence of plasma constituents. In context with recent immunohistological investigations, LPS-induced upregulation of the COX-2-thromboxane synthase axis in vascular and bronchial smooth muscle cells is suggested to underlie these events.

The influence of nanomolar ouabain on vascular pressor responses is modulated by the endothelium.

Ouabain has been shown to be an endogenous hormone that is synthesized and released from the adrenal cortex and is present in nanomolar to subnanomolar concentrations in plasma. It has been proposed that endogenous ouabain can increase vascular resistance and induce hypertension. This substance inhibits the Na(+)-pump activity, which leads to intracellular Na+ accumulation and ultimately to increased vascular tone. It is also suggested that circulating ouabain influences the vascular smooth muscle response to vasopressor substances. However, the mechanisms by which low concentrations of ouabain influence the smooth muscle, directly or acting through the endothelium, have not been completely elucidated. We tested the hypothesis that the endothelium exerts a modulatory effect on the actions of ouabain. In these studies, isolated rat-tail vascular bed preparations obtained from normotensive animals were used. The effects of 10 nM ouabain on the reactivity of the vascular smooth muscle to phenylephrine were determined under conditions in which endothelial function was preserved or reduced by endothelial removal and treatment with N(omega)-nitroL-arginine methyl ester (L-NAME) or potassium channel blocker (tetraethylammonium; TEA). Results showed that ouabain enhanced the reactivity to phenylephrine. The enhancement of the reactivity to phenylephrine produced by ouabain was potentiated by deendothelialization and by using TEA, but it was reduced by treatment with L-NAME. The effect of 10 nM ouabain on the functional activity of the Na+,K(+)-adenosine triphosphatase (ATPase) also was evaluated. Na+,K(+)-ATPase activity was reduced after 1-h treatment with ouabain. These results suggested that low concentrations of ouabain reduced the functional activity of the Na+,K(+)-ATPase and stimulated the release of a potassium channel opener, suggesting that the effects of ouabain are partially modulated by the endothelium.

Sensory CGRP depletion by capsaicin exacerbates hypoxia-induced pulmonary hypertension in rats

Pulmonary hypertension is a debilitating disease that occurs among infants and adults. One of many etiologies is airway hypoxia. We previously demonstrated a role of endogenous calcitonin gene-related peptide (CGRP), a potent vasodilator, in ameliorating the pulmonary vascular pressor response to chronic hypoxia and related changes in the lungs and heart. This study evaluates the role of endogenous sensory CGRP in hypoxic pulmonary hypertension and examines the intrinsic neural microcircuitry. Rats were pretreated with capsaicin i.p. to deplete pulmonary sensory C-fiber stores of CGRP and substance P and placed in hypobaric hypoxia (10% O 2, 16 days) or normoxia together with sham controls. Hypoxia increased pulmonary artery pressure, right-ventricular weight, arterial medial thickness, elasticized capillaries, endothelial cell density, lung water and hematocrit in control rats. Capsaicin augmented pulmonary artery pressure and right-ventricular hypertrophy in hypoxia, and medial thickness and endothelial cell density both in normoxia and hypoxia. Because of the limited effects on these parameters by substance P and other capsaicin-sensitive lung agents, our results suggest that sensory CGRP deficit severely exacerbates pathological signs of hypoxic pulmonary hypertension. A neural microcircuitry consistent with an axon reflex pathway is outlined histochemically. We conclude that endogenous CGRP modulates pulmonary vascular tone in hypoxic pulmonary hypertension which requires intact primary sensory fibers.

Segmental pulmonary vascular responses to ATP in rat lungs: role of nitric oxide.

ATP exhibits vascular pressor and depressor responses in a dose- and tone-dependent manner. The vascular site of ATP-induced contraction or dilation has not previously been characterized. Using the vascular occlusion technique, we investigated the effects of ATP in isolated rat lungs perfused with autologous blood (hematocrit = 20%) and described its action during resting and elevated tone in terms of changes in resistances of the small and large arteries and veins. During resting tone, ATP (10(-5) M) caused contraction primarily in the small arteries and, to some extent, in the small veins, suggesting that P2x purinoceptors are present in these small vessels. During hypoxia, ATP caused dilation primarily in the small arteries, suggesting that P2y purinoceptors are predominant in small arteries. During U-46619-induced contraction, which occurred evenly throughout the four segments, ATP caused dilation in the large arteries and veins but not in the small arteries and veins. After treatment with N omega-nitro-L-arginine to inhibit nitric oxide synthesis, ATP-induced contraction was potentiated, and its dilatory effects during hypoxia were attenuated. The action of ATP was independent of prostanoids, because its constrictor and dilatory responses were not affected significantly by indomethacin. In conclusion, the results indicate that the effects of ATP on the pulmonary vasculature are primarily due to P2x and P2y purinoceptors in the small arteries. Contribution of these purinoceptors in other vessels to changes in total vascular resistance in rat lung was minor.

Peripheral vasculature in essential hypertension.

1. Haemodynamic evidence shows that in essential hypertension minimum vascular resistance and vascular pressor response are increased and that the vascular reserve is decreased. 2. The haemodynamic changes are most easily explained in terms of a generalized narrowing of the vasculature and an increase in the ratio between the thickness of the tunica media and the lumen diameter (media: lumen ratio), with no change in the functional properties of the smooth muscle itself. 3. Histological and in vitro studies of resistance vessels confirm these predictions. Moreover, the evidence indicates that these changes are associated mainly with remodelling (rearrangement of the same amount of material) of the vessels, rather than growth. 4. Although the alteration in small artery structure is usually appropriate to the actual blood pressure, the structure appears not only to be a secondary adaptation, but is also dependent on other factors, including neurohumoral factors. 5. The available evidence shows that normalization of the resistance vessel structure (by increasing lumen diameter and decreasing the media:lumen ratio) should be achieved not by inhibition of growth but by (reverse) remodelling. Recent evidence from clinical investigations shows that this can be achieved in essential hypertensive patients treated with the angiotensin-converting enzyme inhibitor perindopril. 6. The role of the resistance vasculature as a primary determinant of blood pressure remains unclear. It is suggested that the requirement for normalization of resistance vascular structure is due to a need to increase the vascular reserve.

Haemodynamic Response to Fibreoptic Versus Laryngoscopic Nasotracheal Intubation Under Total Intravenous Anaesthesia

Comment: A simple study, obviously performed by skilled anesthetists, is presented. It is certainly likely that if there was a pressor response to intubation, it was transient in extent. With an intermittent blood pressure measuring technique, it could not be stated unequivocally that there was no response to the maneuvers. It might be questioned as to whether the intranasal cocaine could have attenuated any vascular pressor response. Unfortunately, we do not have any indiction of the amount of cocaine solution used (or its strength) and thus whether there might have been pharyngeal as well as nasal analgesia. Years ago, Stoelting established that laryngoscopy itself was a major contributor to the pressor response associated with intubation. The 1-min data does support the suggestion of a slightly greater rise in systolic blood pressure (from the first reading after induction of anesthesia) in the laryngoscoped group. The stability of the cardiovascular system in this healthy group of patients during intubation under total intravenous anesthesia is another mark of the acceptability of this technique. The changes in hypertensive patients would make an interesting further study.

Vascular angiotensin and the sympathetic nervous system: do they interact?

We tested the hypothesis that local vascular formation of angiotensin (ANG) II and the sympathetic nervous system potentiate each other. Isolated rat hindquarters were perfused with an artificial medium, and ANG I and II release was measured by high-performance liquid chromatography and radioimmunoassay. Electrical stimulation of the lumbar sympathetic chain (0.5, 2, and 8 Hz) did not affect vascular ANG release in Sprague-Dawley (SD) rats. Hypertensive, ren-2 transgenic (TG+) rat hindquarters released significantly more ANG I (110 +/- 19 vs. 65 +/- 21 fmol/30 min in SD rats) and ANG II (235 +/- 22 vs. 140 +/- 30 fmol/30 min); however, nerve stimulation did not alter ANG release in TG+ rats. Captopril inhibited vascular ANG II release by 90%, but neither captopril nor ANG II receptor blockade by losartan affected the pressor response to nerve stimulation in SD and TG+ rats. Isoproterenol failed to increase either vascular ANG release or pressor response to nerve stimulation in SD or spontaneously hypertensive rat hindquarters. Exogenous renin, which increased vascular ANG release approximately 100-fold, prolonged the pressor responses to nerve stimulation. We conclude that the vascular renin-ANG system does not interact with the sympathetic nervous system locally. However, high concentrations of ANG II, which can be induced by circulation-derived renin, may prolong the duration of sympathetic nerve-induced vasoconstriction.

Intravascular anti-IgE challenge in perfused lungs: mediator release and vascular pressor response

Intravascular application of goat anti-rabbit immunoglobulin E (IgE) was used to stimulate parenchymal mast cells in situ in perfused rabbit lungs. Sustained pulmonary arterial pressure rise was evoked in the absence of lung vascular permeability increase and lung edema formation. Early prostaglandin (PG) D2 and histamine release into the perfusate was documented, accompanied by more sustained liberation of cysteinyl leukotrienes (LT), LTB4, and PGI2. The quantities of these inflammatory mediators displayed the following order: histamine greater than cysteinyl-LT greater than PGI2 greater than LTB4 greater than PGD2. Pressor response and inflammatory mediator release revealed corresponding bell-shaped dose dependencies. Cyclooxygenase inhibition (acetylsalicylic acid) suppressed prostanoid generation, increased LT release, and did not substantially affect pressor response and histamine liberation. BW755 C, a cyclo- and lipoxygenase inhibitor, blocked the release of cysteinyl-LT and markedly reduced the liberation of the other inflammatory mediators as well as the pressor response. The H1-antagonist clemastine caused a moderate reduction of the anti-IgE-provoked pressure rise. We conclude that intravascular anti-IgE challenge in intact lungs provokes the release of an inflammatory mediator profile compatible with in situ lung parenchymal mast cell activation. Pulmonary hypertension represents the predominant vascular response, presumably mediated by cysteinyl-LT and, to a minor extent, histamine liberation.

Blood pressure and sympathetic activity in spontaneously hypertensive rats during food restriction

Young (7 weeks) spontaneously hypertensive rats (SHR) were kept on food-restriction (33%) during 4 weeks with (0.3% saline as drinking water) or without sodium supplementation. Body weight and indirect systolic blood pressure (tail plethysmography) were followed each weak. During the last week of the intervention period 24 hour excretions of sodium, dopamine and noradrenaline were measured. Vascular pressor responses to noradrenaline were evaluated in pithed rats and the sympathetic nerve activity was assessed from the disappearance of endogenous noradrenaline in the heart after synthesis inhibition. Despite a clear retardation of the growth rate in food-restricted rats the development of hypertension was not influenced. Food-restriction was associated with a moderate suppression of sympathetic activity. Furthermore, the vascular pressor responses to noradrenaline were decreased but this was reversed following sodium supplementation. It is concluded that despite evidence of sympathetic suppression weight reduction does not reduce the blood pressure in SHR once the blood pressure has started to rise.

Doppler Assessment of Pulmonary Hypertension Induced by Hypoxic Breathing in Subjects Susceptible to High Altitude Pulmonary Edema

To verify the abnormal pulmonary vascular response implicated in the pathogenesis of high altitude pulmonary edema (HAPE), we examined the hemodynamic responses to hypoxia in HAPE-susceptible subjects (HAPE-S) by means of both right heart catheterization and pulsed Doppler echocardiography. The HAPE-S were seven men and one woman with a history of HAPE. Six healthy volunteers who had repeated experiences of mountain climbing without any history of altitude-related problems served as control subjects. The HAPE-S showed much greater increase in pulmonary vascular resistance (PVR) than did the control subjects, resulting in a much higher level of pulmonary arterial pressure (Ppa) under acute hypoxia both of 15% O2 and 10% O2. We then evaluated the usefulness of pulsed Doppler echocardiography in the prediction of pulmonary hypertension. Acceleration time (AcT) and right ventricular ejection time (RVET) were measured from the flow velocity pattern in the right ventricular outflow tract. The ratio of AcT to RVET was correlated to invasively determined mean Ppa (Ppa) and PVR. The results were as follows: (1) AcT/RVET = 0.52 to 0.0047 (Ppa), r = -0.93, SEE = 0.017, p less than 0.001 (HAPE-S); (2) AcT/RVET = 0.55 to 0.0055 (Ppa), r = -0.70, SEE = 0.030, p less than 0.001 (HAPE-S); (4) AcT/RVET = 0.52 to 0.00077 (PVR), r = -0.91, SEE = 0.016, p less than 0.001 (control subjects). We conclude that HAPE-S have a constitutional abnormality in the pulmonary vascular response to hypoxia, which is a possible causative factor of HAPE, and that pulsed Doppler echocardiography may be supportive to assess the pulmonary vascular pressor response in the HAPE-S.

Vascular Pressor Responses in Treated and Untreated Essential Hypertension

Thirty-seven essential hypertensives received placebo for 3 weeks followed by nifedipine retard (n = 14) or enalapril (n = 13) or doxazosin (n = 10) as monotherapy for 6 weeks and attended study days to evaluate the effects of placebo, first dose, and chronic (1-6 weeks) treatment. On each study day, pressor responses to i.v. infusions of phenylephrine (PE) and angiotensin II (AII) were measured 1.5-3 h after drug administration and the derived PD20 values (dose required to increase mean blood pressure by 20 mm Hg) compared. Each treatment produced comparable reductions in BP. Nifedipine significantly attenuated the pressor responses to AII and PE: for AII, the mean PD20 (ng/kg/min) increased from 8.2 (placebo) to 9.9 (first dose), 13.9 (1 week), and 17.4 (6 weeks). Pressor responsiveness to both AII and PE was unchanged following enalapril: for PE, the mean PD20 (micrograms/kg/min) was 2.1 (placebo), 1.5 (first dose), and 1.5 (6 weeks). Doxazosin produced rightward shifts of the PE pressor dose-response curves but had no effect on responses to AII. The relationship between the simultaneous BP and HR changes during the infusion of PE was used as an index of cardiac baroreflex activity. In contrast to enalapril and doxazosin, which had no effect, nifedipine reduced the slope of the HR/BP relationship from -0.62 (placebo) to -0.38 (first dose) and -0.31 beats/min/mm Hg (6 weeks). For comparable reductions in BP, doxazosin only affects adrenergic mechanisms whereas nifedipine affects both adrenergic and non-adrenergically mediated vasoconstriction. The ACE inhibitor enalapril had no effect on pressor responses to AII and PE.

Enhanced Neuroinhibitory Effect of Diltiazem in Blood Vessels of Spontaneously Hypertensive Rats

This study investigated the effects of diltiazem (a Ca2(+)-entry blocker) on neuromuscular junctions of blood vessels in hypertension. In isolated perfused mesenteric vasculatures prepared from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY), the effects of diltiazem on norepinephrine release from vascular adrenergic neurons and pressor responses were examined. The influences of extracellular Ca2(+)-reduction on these responses were also studied. Stimulation evoked pressor responses and norepinephrine release were significantly greater in the mesenteric vasculatures of SHR than in those of WKY. Diltiazem inhibited both pressor responses and norepinephrine release during electrical nerve stimulation in a dose-dependent manner. The suppression of these responses was more pronounced in SHR than in WKY. Reduction of extracellular Ca2(+)-concentration also decreased the responses in SHR and WKY, and the inhibitory degree was significantly greater in SHR than in WKY. These results demonstrate that diltiazem affected the presynaptic site of the mesenteric vasculatures and decreased the stimulation-evoked norepinephrine release from vascular adrenergic neurons with a concomitant reduction of pressor responses of the preparation. Furthermore, the marked inhibition of pressor responses and norepinephrine release by diltiazem or Ca2(+)-depletion in SHR may suggest the increased Ca2(+)-dependency in vascular neurotransmission in this model of hypertension.

Oxygen radicals and antioxidant enzymes alter pulmonary vascular reactivity in the rat lung.

It has been postulated that changes in the availability of partially reduced O2 species, such as O2 radicals, could serve as a link between PO2 in the alveolus and pulmonary vascular tone (Herz 11: 127-141, 1986). To assess this hypothesis, the hemodynamic effects of acute changes in the balance between the production of O2 radicals and availability of antioxidant enzymes were studied in the isolated perfused rat lung. Intravascular generation of O2 radicals, by administration of xanthine-xanthine oxidase, decreased the pulmonary vascular pressor response to alveolar hypoxia (-55 +/- 5%) and angiotensin II (-58 +/- 10%, P less than 0.01 for each) in isolated perfused rat lungs without increasing the lung wet-to-dry weight ratio. Decreases in pulmonary vascular reactivity were inhibited by pretreatment of the lung with desferrioxamine or a mixture of catalase and superoxide dismutase. Catalase and superoxide dismutase preserved the hypoxic pressor response whether given in liposomes or in dissolved form. Superoxide dismutase administered free in solution, or combined with catalase in liposomes, increased the normoxic pulmonary arterial pressure and enhanced vascular reactivity to angiotensin II and hypoxia. Lungs treated with antioxidant enzymes in liposomes had 50% higher lung catalase levels than control lungs (P less than 0.05). These findings demonstrate that exogenous partially reduced O2 species can decrease pulmonary vascular reactivity and suggest that endogenous radicals, superoxide radical in particular, might be important in modulating pulmonary vascular tone.

24 Vascular pressor responses in treated and untreated essential hypertension

24 Vascular pressor responses in treated and untreated essential hypertension

Staphylococcal alpha-toxin elicits hypertension in isolated rabbit lungs. Evidence for thromboxane formation and the role of extracellular calcium.

Staphylococcal alpha-toxin is known to damage mammalian cell membranes. Studies of erythrocytes indicate that the native toxin generates a discrete transmembrane channel with an effective diameter of 2-3 nm. (Füssle, R., S. Bhakdi, A. Szeigoleit, J. Tranum-Jensen, T. Kranz, and H.J. Wellensiek. 1981. J. Cell Biol. 91:83-94.) In isolated rabbit lungs, perfused with recirculating blood- and plasma-free perfusion fluid, the mediation of a toxin-provoked vascular pressor response by the triggering of the arachidonic acid cascade and its dependence on extracellular calcium were investigated. Dose-dependent pulmonary artery pressor responses were elicited by the injection of 0.5-5 micrograms staphylococcal alpha-toxin into the pulmonary artery. The pressor responses were completely abolished by preincubation of the toxin with neutralizing antibodies or by preformation of alpha-toxin hexamers in vitro. They were accompanied by the release of the arachidonic acid metabolites thromboxane B2 and 6-keto-prostaglandin F1 alpha (stable metabolites of thromboxane A2 and prostaglandin I2, respectively) into the perfusion fluid. They were blocked by inhibitors of thromboxane synthetase, cyclooxygenase, and phospholipase, as well as by substances that interfere with calcium-calmodulin function. alpha-Toxin induced selective release of potassium, but not lactatedehydrogenase into the medium. Calcium depletion of the intravascular space did not suppress the toxin-dependent potassium release but did abrogate the pressor response and the release of the arachidonic acid metabolites. When calcium was reintroduced into the circulation without the application of a second toxin stimulus, marked pressor responses paralleled by the release of arachidonic acid metabolites occurred. The conclusion drawn from these studies is that staphylococcal alpha-toxin provokes pulmonary vascular hypertension which is apparently mediated by thromboxane A2 formation, which surpasses the biological effect of the simultaneously formed prostaglandin I2. The triggering of the arachidonic acid cascade is strictly dependent on extracellular calcium and may be mediated by a nonphysiological calcium bypass through transmembrane toxin channels with subsequent stimulation of phospholipase activity.

Zymosan activation of plasma reduces hypoxic pulmonary vasoconstriction

Small doses of endotoxin (15 μg/kg IV) inhibit the pulmonary vascular pressor response to alveolar hypoxia in the anesthetized dog. One of the actions of endotoxin is to initiate the alternate pathway of complement activation. Incubation of human plasma with zymosan (ZAP) will activate this pathway. We wished to see if ZAP would mimic the effect of endotoxin. Prior to ZAP, hypoxia (F i O 2 12%) in 5 anesthetized dogs increased pulmonary vascular resistance (PVR: mm Hg/L/min) from 3.7±0.8 to 7.1±1.5. After 50 ml ZAP IV the PVR change with hypoxia was only from 3.6±0.6 to 3.9±0.8.Plasma heated to destroy complement prior to ZAP incubation in one experiment did not reduce the pressor response. In a further 5 dogs pretreated with meclofenamate (2 mg/kg IV) the PVR increased from 3.7±0.4 to 7.5±0.4 with hypoxia prior to IV ZAP and from 4.4±0.5 to 6.5±0.6 after ZAP. The effect of ZAP indicates that endotoxin may work through the activation of complement. The protection of the hypoxic pressor response by meclofenamate suggests that the ZAP inhibition (like endotoxin inhibition) may involve dilator prostaglandin-like substances.

Cigarette smoke ventilation decreases prostaglandin inactivation in rat and hamster lungs

The effects of cigarette smoke on the metabolism of exogenous PGE 2 and PGF 2α were investigated in isolated rat and hamster lungs. When isolated lungs from animals were ventilated with cigarette smoke during pulmonary infusion of 100 nmol of PGE 2 or PGF 2α, the amounts of the 15-keto-metabolites in the perfusion effluent were decreased. Pre-exposure of animals to cigarette smoke daily for 3 weeks did not change the metabolism of PGE 2 when the lungs were ventilated with air. Cigarette smoke ventilation of lungs from pre-exposed animals caused, however, a similar decrease in the metabolism of PGE 2 as in animals not previously exposed to smoke. After pulmonary injection of 10 nmol of 14C-PGE 2 the radioactivity appeared more rapidly in the effluent during cigarette smoke ventilation suggesting inhibition of the PGE 2 uptake mechanism. In rat lungs pulmonary vascular pressor responses to PGE 2 and PGF 2α were inhibited by smoke ventilation.

The metabolism of arachidonic acid in isolated rat lungs is not changed during cigarette smoke ventilation

Cigarette smoke ventilation of isolated perfused rat lungs partially inhibited the pulmonary vascular pressor response to arachidonic acid. The amounts of metabolites of exogenous arachidonic acid in the perfusion effluent remained unchanged during smoke ventilation. The antiaggregatory effect of the effluent during pulmonary infusion of AA was not decreased by smoke ventilation. The cause of the previously reported increased platelet aggregation after smoking remains unclear.