Sites of pulmonary vasomotor reactivity in the dog during alveolar hypoxia and serotonin and histamine infusion

In order to evaluate separately changes in vascular tone occurring in arteries and veins, we measured pulmonary capillary red blood cell (RBC) concentration under zone II (waterfall) conditions in isolated dog lungs rapidly frozen with Freon 12. The lungs were frozen while being perfused from artery to vein and from vein to artery breathing normal and hypoxic gas mixtures and during infusions of serotonin and histamine. Changes in capillary RBC concentration which occurred during the experimental conditions indicated an alteration in vascular resistance upstream from the capillaries. Alveolar hypoxia caused a significant decrease in capillary RBC concentration during forward perfusion, but no change from the control values during reverse perfusion. Serotonin infusion caused a decrease in RBC concentration during forward perfusion comparable with that of hypoxia and a small but significant decrease during reverse perfusion. Histamine infusion caused no change in RBC concentration from control values during forward perfusion, but a large decrease during reverse perfusion. We conclude that vasoconstriction occurs (a) exclusively in arteries during alveolar hypoxia, (b) predominantly in arteries but to a lesser extent in veins during serotonin infusion, and (c) exclusively in veins during histamine infusion.     

Longitudinal distribution of vascular resistance in the pulmonary arteries, capillaries, and veins

A new method has been described for measuring the pressure and resistance to blood flow in the pulmonary arteries, capillaries, and veins. Studies were performed in dog isolated lung lobes perfused at constant flow with blood from a donor dog. Pulmonary artery and vein volume and total lobar blood volume were measured by the ether plethysmograph and dyedilution techniques. The longitudinal distribution of vascular resistance was determined by analyzing the decrease in perfusion pressure caused by a bolus of low viscosity liquid introduced into the vascular inflow of the lobe.The pulmonary arteries were responsible for 46% of total lobar vascular resistance, whereas the pulmonary capillaries and veins accounted for 34 and 20% of total lobar vascular resistance respectively. Vascular resistance was 322 dynes .sec.cm(-5)/ml of vessel in the lobar pulmonary arteries, 112 dynes.sec.cm(-5)/ml in the pulmonary capillaries, and 115 dynes.sec.cm(-5)/ml in the lobar pulmonary veins. Peak vascular resistivity (resistance per milliliter of volume) was in an area 2 ml proximal to the capillary bed, but resistivity was high throughout the pulmonary arterial tree. The pulmonary arteries accounted for approximately 50% of vascular resistance upstream from the sluice point when alveolar pressure exceeded venous pressure.The method described provides the first measurements of pulmonary capillary pressure. Mid-capillary pressure averaged 13.3 cm H(2)O, pulmonary artery pressure averaged 20.4 cm H(2)O, and pulmonary vein pressure averaged 9.2 cm H(2)O. These techniques also provide a way of analyzing arterial, capillary, and venous responses to various pharmacologic and physiologic stimuli.     

Endotoxemic pulmonary hypertension is largely mediated by endothelin-induced venous constriction

Objective To analyze the effect of endothelin-1 on pulmonary arterial and venous contractile force in vitro and on up- and downstream pulmonary vascular resistance in vivo under sham and endotoxemic conditions in pigs. Materials and methods In vitro: paired preparations of pulmonary arteries and veins were mounted in a myograph (n = 13) for measurements of contractile responses to increasing concentrations of phenylephrine, endothelin-1, and sarafotoxin (endothelin receptor type B agonist). In vivo: 20 pigs were anesthetized, mechanically ventilated, and subjected to phenylephrine (reference substance), endothelin-1, sarafotoxin, endotoxin, and tezosentan (dual endothelin receptor antagonist). Hemodynamic and gas-exchange variables were monitored. Pulmonary capillary pressure, used for calculation of upstream and downstream vascular resistance, was assessed by the pulmonary vascular occlusion technique. Measurements and results Pulmonary veins were more sensitive than arteries to endothelin-1 both in vitro and in vivo. This difference was more pronounced with sarafotoxin, where almost no arterial effects were noted. In vivo and in vitro exposure to phenylephrine resulted in selective arterial constriction. Endotoxin infusion resulted in pulmonary hypertension with a clear downstream dominance. The latter changes including the increase in capillary pressure were totally abolished by intervention with the dual endothelin receptor antagonist tezosentan. Conclusions The endothelin system is extensively involved in endotoxemic pulmonary venous hypertension, an effect possibly mediated by the endothelin B receptor. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. This study was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, and funds from the Karolinska Institute and Swedish Society of Medicine.     

Responses of saphenous and mesenteric veins to administration of dopamine

Others have observed that dopamine (3,4-dihydroxyphenylethylamine) constricts resistance vessels in skin, but dilates these vessels in the mesentery. We studied the effects of dopamine on cutaneous and mesenteric veins of dogs to see if this agent also produced qualitatively different effects on the tone of capacitance vessels (veins) in these vascular beds. The lateral saphenous or the left colic vein was perfused at constant flow with blood from a femoral artery. Pressures at the tip of the perfusion cannula and at the tip of a catheter 15 cm downstream were recorded continuously. Increases in the pressure gradient between these two points indicated venoconstriction; decreases indicated venodilatation. Dopamine and norepinephrine injected into the perfusion tubing caused constriction of both veins. The constriction was antagonized by blockade of alpha receptors. A dilator action of dopamine was not seen, even after alpha receptor blockade or in the presence of increased venous tone produced by serotonin, norepinephrine, or nerve stimulation. Reserpine and cocaine did not alter responses to dopamine in the saphenous vein; this suggests that the venoconstrictor action of dopamine results mainly from a direct effect on alpha receptors and that uptake into sympathetic nerve endings may not be important in regulating the amount of dopamine available to receptors in the saphenous vein.     

Peripheral vascular reactions in anaphylaxis of the mouse

Pronounced vascular changes occurring in the ears and claws of mice during anaphylactic shock are described. Practically at once after a foreign serum (pig, horse, or rabbit) enters the blood stream of sensitized animals both the arterial and venous vessels undergo marked, local or generalized constriction in the organs mentioned. Usually spasm of the vessel walls occurs simultaneously in the arteries and veins, but it may appear first in the arteries, or occasionally in the veins. When venous spasm precedes arterial spasm, the true capillaries become distended with cells; if the reverse order holds, the ears appear bloodless. There is no active constriction or dilatation of capillaries; the capillary behavior follows passively the changes in the large vessels. Peripheral vascular spasm occurs while the carotid blood pressure is high, but a few minutes later, while this still holds true, the ear vessels begin to relax and the circulation is resumed. Shortly afterwards the blood pressure falls to levels far below normal, but the vessels remain open. If the circulation of one ear is obstructed while anaphylactic shock is produced, no vascular spasm occurs in it. Release of the obstruction during the animal's recovery results in belated constriction of the blood vessels of this ear although by now the vessels in the other ear are dilated and the general systolic blood pressure is very low. The vascular reactions in the ears appear to be uninfluenced by the blood pressure in the large vessels, and they are not a response to nervous stimuli. They are local in origin. The vascular changes are often not clearly perceptible in the gross but are plainly to be seen under a low power of the microscope. They occur in some sensitized mice exhibiting no manifest signs of shock, differing only in degree from the changes taking place when shock is severe or fatal.     

Influence of prostaglandins E1 and F2alpha on pulmonary vascular resistance, isolated lobar vessels and cyclic nucleotide levels.

The effects of prostaglandins E1 (PGE1) and F2alpha) on the pulmonary vascular bed were studied in the intact dog under conditions of controlled pulmonary blood flow. PGF2alpha increased lobar arterial and venous pressure when injected or infused into the lobar, artery. The pressor response was dose-related and doses as low as 0.03 and 0.1 mug, which established concentrations of 0.1 to 0.3 ng/ml in lobar arterial blood, increased pulmonary vascular resistance. PGF2alpha also increased airway resistance in the left lower lobe. However, the effects of this substance on the vascular bed were not related to its effects on bronchomotor tone since similar pressor responses were observed in normal and nonrespiring lobes, PGE1 decreased pressure in the lobar artery and vein when infused into the lobar artery and the effects of PGE1 and PGF2alpha on the pulmonary vascular bed were similar when the lung was perfused with dextran or with blood. PGF2alpha increased isometric tension in isolated helical segments of lobar vein 3 to 5 mm in diameter but was without effect on arterial segments of the same diameter. The increase in isometric tension in the venous segments with PGF2alpha was associated with a significant increase in intracellular levels of guanosine 3',5'-monophosphate (cGMP) but no change in adenosine 3',5'-monophosphate (cAMP) levels. PGE1 decreased isometric tension in both arterial and venous segments and the decrease in tension was accompanied by a significant elevation in smooth muscle cAMP levels and a small but significant reduction in vein cGMP. Results of the present study indicate that PGF2alpha increases pulmonary resistance by constricting lobar veins and to a lesser extent vessels upstream in the precapillary bed whereas PGE1 dilates lobar veins and upstream vessels. These results suggest that PGE1-induced vasodilation may be mediated by an increase in cAMP levels while PGF2alpha-induced venoconstriction may be related to increased smooth muscle levels of cGMP.     

Influence of sympathetic stimulation and vasoactive substances on the canine pulmonary veins.

The contribution of the intrapulmonary lobar veins to the increase in pulmonary vascular resistance in response to sympathetic stimulation was studied under conditions of controlled blood flow in the anesthetized dog in which vascular pressures were measured simultaneously in the perfused lobar artery, an intrapulmonary lobar vein 2-3 mm in diameter and in the left atrium. Stimulation of the stellate ganglia at 3, 10, and 30 cycles/s increased pressure in the lobar artery and small vein in a stimulus-related manner but decreased pressure in the left atrium. Injection of norepinephrine into the perfused lobar artery also increased pressure in the lobar artery and small vein but decreased pressure in the left atrium. The increase in lobar arterial and venous pressure in response to either injected norepinephrine or to nerve stimulation was antagonized by an alpha receptor blocking agent. The rise in pressure in both labor artery and small vein with nerve stimulation but not administered norepinephrine was inhibited by an adrenergic nerve terminal blocking agent. The results suggest that under conditions of steady flow, sympathetic nerve stimulation increases the resistance to flow in the lung by constricting pulmonary veins and vessels upstream to the small veins, and that at each stimulus-frequency studied approximately 50% of the total increase in resistance may be due to venoconstriction. It is concluded that the increase in resistance to flow in the lung in response to nerve stimulation is thre result of activation of alpha adrenergic receptors by norephinephrine liberated from adrenergic nerve terminals in venous segments and in vessels upstream to samll veins, presumed to be small arteries.     

Pulmonary Vasodilator Responses to Nitroprusside and Nitroglycerin in the Dog

The objective of this study was to determine the direct actions of nitroprusside and nitroglycerin on the pulmonary vascular bed in the intactchest dog. These widely used nitrogen oxide-containing vasodilator agents decreased pulmonary arterial pressure and increased cardiac output without altering left atrial pressure. Reductions in pulmonary arterial pressure and pulmonary vascular resistance were small under resting conditions, but were enhanced when pulmonary vascular tone was elevated by infusion of a stable prostaglandin analog that increases pulmonary vascular resistance by constricting intrapulmonary veins and upstream segments. In studies in which pulmonary blood flow to the left lower lobe was maintained constant, nitroprusside and nitroglycerin caused small but significant reductions in lobar arterial and small-vein pressures without significantly affecting left atrial pressure. With constant blood flow, lobar vascular pressures that were reduced in response to the vasodilators were more greatly reduced when lobar vascular resistance was increased by infusion of the prostaglandin analog or serotonin. However, when lobar vascular pressures were elevated by passive obstruction of lobar venous outflow, vasodilator responses to nitroprusside and nitroglycerin were not enhanced. These data suggest that nitroprusside and nitroglycerin decrease pulmonary vascular resistance by dilating intrapulmonary veins and upstream segments. These responses were minimal under control conditions but were enhanced when vascular tone was increased. This vasodilator action is independent of passive factors such as changes in pulmonary blood flow or left atrial pressure and is not secondary to an effect of these agents on the systemic circulation. Pulmonary vasodilator responses to nitroprusside and nitroglycerin were, however, found to be dependent on the existing level of vasomotor tone in the pulmonary vascular bed.     

Effects of prostaglandins B2 and B1 on the pulmonary circulation in the intact dog.

The effects of prostaglandins (PG) B2 and B1 on the pulmonary circulation were studied in the intact spontaneously breathing dog under conditions of controlled blood flow using right heart and transseptal catheterization techniques to isolate and perfuse the left lower lung lobe. Infusion of PGB2 and PGB1 into the left lower lung lobe increased lobar arterial and lobar venous pressure but had no significant effect on left atrial pressure. PGB2 and PGB1 increased pressure gradients between the lobar artery and lobar small vein and between the lobar small vein and the left atrium. PGB2 and PGB1 increased isometric tension in isolated helical segments of lobar vein (3-5 mm diameter) but had little or no effect on lobar arterial segments of the same size. These results indicate that in the intact dog prostaglandins of the B series increase pulmonary vascular resistance by constricting lobar veins and to a lesser extent vessels upstream to lobar small veins, presumably small lobar arteries. PGB2 and PGB1 both produced large increases in pulmonary vascular resistance in the dog with PGB2 being about 10 times as potent as PGB1. It is concluded that PGB2 is one of the most potent pressor substances in the canine pulmonary vascular bed.     

Effects of antihistamines on the lung vascular response to histamine in unanesthetized sheep. Diphenhydramine prevention of pulmonary edema and increased permeability.

To see whether antihistamines could prevent and reverse histamine-induced pulmonary edema and increased lung vascular permeability, we compared the effects of a 4-h intravenous infusion of 4 mug/kg per min histamine phosphate on pulmonary hemodynamics, lung lymph flow, lymph and plasma protein content, arterial blood gases, hematocrit, and lung water with the effects of an identical histamine infusion given during an infusion of diphenhydramine or metiamide on the same variables in unanesthetized sheep. Histamine caused lymph flow to increase from 6.0+/-0.5 to 27.0+/-5.5 (SEM) ml/h (P less than 0.05), lymph; plasma globulin concentration ratio to increase from 0.62+/-0.01 to 0.67+/-0.02 (P less than 0.05), left atrial pressure to fall from 1+/-1 to -3+/-1 cm H2O (P less than 0.05), and lung lymph clearance of eight protein fractions ranging from 36 to 96 A molecular radius to increase significantly. Histamine also caused increases in lung water, pulmonary vascular resistance, arterial PCO2, pH, and hematocrit, and decreases in cardiac output and arterial PO2. Diphenhydramine (3 mg/kg before histamine followed by 1.5 mg/kg per h intravenous infusion) completely prevented the histamine effect on hematocrit, lung lymph flow, lymph protein clearance, and lung water content, and reduced histamine effects on arterial blood gases and pH. 6 mg/kg diphenhydramine given at the peak histamine response caused lymph flow and lymph: plasma protein concentration ratios to fall. Metiamide (10 mg/kg per h) did not affect the histamine lymph response. We conclude that diphenhydramine can prevent histamine-induced pulmonary edema and can prevent and reverse increased lung vascular permeability caused by histamine, and that histamine effects on lung vascular permeability are H1 actions.     

Automated integer programming based separation of arteries and veins from thoracic CT images

Automated computer-aided analysis of lung vessels has shown to yield promising results for non-invasive diagnosis of lung diseases. To detect vascular changes which affect pulmonary arteries and veins differently, both compartments need to be identified. We present a novel, fully automatic method that separates arteries and veins in thoracic computed tomography images, by combining local as well as global properties of pulmonary vessels. We split the problem into two parts: the extraction of multiple distinct vessel subtrees, and their subsequent labeling into arteries and veins. Subtree extraction is performed with an integer program (IP), based on local vessel geometry. As naively solving this IP is time-consuming, we show how to drastically reduce computational effort by reformulating it as a Markov Random Field. Afterwards, each subtree is labeled as either arterial or venous by a second IP, using two anatomical properties of pulmonary vessels: the uniform distribution of arteries and veins, and the parallel configuration and close proximity of arteries and bronchi. We evaluate algorithm performance by comparing the results with 25 voxel-based manual reference segmentations. On this dataset, we show good performance of the subtree extraction, consisting of very few non-vascular structures (median value: 0.9%) and merged subtrees (median value: 0.6%). The resulting separation of arteries and veins achieves a median voxel-based overlap of 96.3% with the manual reference segmentations, outperforming a state-of-the-art interactive method. In conclusion, our novel approach provides an opportunity to become an integral part of computer aided pulmonary diagnosis, where artery/vein separation is important.     

Raloxifene relaxes rat pulmonary arteries and veins: roles of gender, endothelium, and antagonism of Ca2+ influx

Effects of raloxifene have been documented in the systemic circulation. However, its impact on the pulmonary circulation is unclear. The present study investigated the role of gender, endothelial modulation, and Ca(2+) channel in relaxations evoked by raloxifene in rat pulmonary arteries and veins. Vascular responses were studied on isolated pulmonary blood vessels mounted in a myograph and constricted by U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha)). Constrictions to CaCl(2) were studied in Ca(2+)-free, 60 mM K(+) solution. Changes in the intracellular calcium ion concentration ([Ca(2+)](i)) in vascular smooth muscle were measured using a calcium fluorescence imaging method. Raloxifene was more effective in relaxing U46619-constricted pulmonary arteries from male than female rats. Raloxifene-induced relaxation was unaffected by ICI 182,780 [7alpha-[9-[(4,4,5,5,5,-pentafluoropentyl)-sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol], inhibition of the nitric oxide (NO) pathway, or removal of the endothelium. In arteries without endothelium, raloxifene attenuated CaCl(2)-induced constriction and CaCl(2)-stimulated increase in [Ca(2+)](i) with similar potencies. Raloxifene caused endothelium-independent relaxations in pulmonary veins, albeit to a lesser degree than in pulmonary arteries. The venous responses showed a gender difference because raloxifene was more potent in male veins. In summary, raloxifene relaxed rat pulmonary arteries, and this effect did not involve the endothelium/NO or ICI 182,780-sensitive estrogen receptors. Raloxifene, like nifedipine, reduced constriction and [Ca(2+)](i) increase in response to CaCl(2) in high K(+) solution. Raloxifene also relaxed high K(+)-constricted pulmonary veins. Our data indicate that raloxifene acutely relaxes rat pulmonary blood vessels primarily via inhibition of Ca(2+) influx through voltage-sensitive Ca(2+) channels. Finally, raloxifene induced more relaxation in blood vessels isolated from male than female rats.     

Simultaneous Doppler recording of the pulmonary artery and vein: a new technique for the evaluation of a fetal arrhythmia

We describe a new technique to evaluate cardiac rhythm using color and pulsed Doppler ultrasonography to identify and record pulmonary arterial and venous waveforms. Fifty fetuses were examined during the second and third trimesters of pregnancy. Simultaneous pulsed Doppler recording of the pulmonary artery and vein was obtained in 100% of fetuses between 15 and 40 weeks' gestation. Atrial systole was identified from the pulmonary vein and was manifested by an interruption of venous flow. Ventricular systole was manifested by a sharp peak that returned toward the baseline before it continued through the duration of systole as a lower-velocity waveform. This technique has the following advantages: (1) the lung parenchyma is easily accessible, irrespective of fetal position; (2) the pulmonary arteries and veins are adjacent to each other as they enter and exit the lung, thus making it easy to simultaneously obtain Doppler recordings of these vessels; (3) the pulsed Doppler waveform has an appearance similar to an electrocardiogram.     

Influence of losartan and nicardipine on the contractile responses of human subcutaneous arteries and veins to angiotensin II

In the human forearm vascular bed, the arterial constrictor effects of angiotensin II were found to be caused by an AT1-receptor mediated calcium influx, while the venous constrictor effects appeared to be independent of L-type calcium channels. In this study, we investigated the influences of the AT1-receptor antagonist losartan and the calcium channel blocker nicardipine on the angiotensin II-induced constriction of small isolated subcutaneous arteries and veins obtained from human mammary tissue. Subcutaneous arteries and veins were isolated from mammary tissue from 9 healthy women who underwent breast reduction surgery. Effects of angiotensin II (0.3 nM to 1 mM), losartan (0.1 mM) and nicardipine (0.1 mM) were investigated in a myograph set up. Identification of arteries and veins was confirmed histologically after the experiments. Drug effects were expressed relatively to the potassium-induced contraction. Angiotensin II concentration-dependently contracted arteries and veins by maximally 1.66 +/- 0.31 N/m and 0.43 +/- 0.08 N/m, respectively (P < 0.05). In arteries the angiotensin II were subject to a mild degree of tachyphylaxis: the Emax of the repetitive concentration-response curve (CRC) was reduced from 105 +/- 4% of the potassium-induced contraction to 84 +/- 6% (P < 0.05); the EC50 value was unchanged (P > 0.05). In veins no tachyphylaxis was observed. Losartan caused a rightward shift of the CRC of angiotensin II in arteries and veins (P < 0.05), and reduced the Emax in arteries from 105 +/- 4 to 85 +/- 9% (P < 0.05), but did not change the Emax in veins. Nicardipine significantly decreased the Emax in arteries and veins (to residual values of 10 +/- 2 and 20 +/- 4%, respectively, of the control values). In conclusion, the angiotensin II-induced constriction of human arteries and veins isolated from mammary tissue are AT1-receptor mediated and inhibited by losartan. The nearly complete inhibition by nicardipine indicates that the constrictor effects in both types of vessels are dependent on L-type calcium channels.     

Hypoxia Impairs Vasodilation in the Lung

Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation after angiotensin II, bradykinin, or serotonin pressor responses. Progressive slowing of vasodilation followed angiotensin II-induced constriction as the lung oxygen tension fell progressively below 60 Torr. KCl, which is not metabolized by the lung, caused vasoconstriction; the subsequent vasodilation time was delayed during hypoxia. However, catecholamine depletion in the lungs abolished this hypoxic vasodilation delay after KCl-induced vasoconstriction. In lungs from high altitude rats, the hypoxia-induced vasodilation impairment after an angiotensin II pressor response was markedly less than it was in lungs from low altitude rats. We conclude from these studies that (a) hypoxia impairs vasodilation of rat lung vessels following constriction induced by angiotensin II, serotonin, bradykinin, or KCl, (b) hypoxia slows vasodilation following KCl-induced vasoconstriction probably by altering lung handling of norepinephrine, (c) the effect of hypoxia on vasodilation is not dependent on its constricting effect on lung vessels, (d) high altitude acclimation moderates the effect of acute hypoxia on vasodilation, and (e) the hypoxic impairment of vasodilation is possibly the result of an altered rate of dissociation of agonists from their membrane receptors on the vascular smooth muscle.     

Phenylpropanolamine constricts mouse and human blood vessels by preferentially activating alpha2-adrenoceptors

Phenylpropanolamine (dl-norephedrine) was one of the most widely used therapeutic agents to act on the sympathetic nervous system. Because of concerns regarding incidents of stroke, its use as a nasal decongestant was discontinued. Although considered an alpha1-adrenergic agonist, the vascular adrenergic pharmacology of phenylpropanolamine was not fully characterized. Unlike most other circulations, the vasculature of the nasal mucosa is highly enriched with constrictor alpha2-adrenoceptors. Therefore, experiments were performed to determine whether phenylpropanolamine activates vascular alpha2-adrenoceptors. Mouse tail and mesenteric small arteries and human small dermal veins were isolated and analyzed in a perfusion myograph. The selective alpha1-adrenergic agonist phenylephrine caused constriction of tail and mesenteric arteries and human veins. The selective alpha2-adrenergic agonist UK14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine] caused constriction in tail arteries and in human veins, but not mesenteric arteries. The lack of constriction to UK14,304 was also observed in endothelium-denuded mesenteric arteries. Phenylpropanolamine constricted both types of artery but was 62-fold more potent in tail arteries. In mesenteric arteries, constriction to phenylpropanolamine was not affected by the selective alpha2-adrenergic antagonist, rauwolscine (10(-7) M) but was abolished by the selective alpha1-adrenergic antagonist, prazosin (3 x 10(-7) M). In contrast, constriction to phenylpropanolamine in tail arteries and in human veins was inhibited by rauwolscine but not prazosin. Therefore, phenylpropanolamine is a preferential alpha2-adrenergic agonist. At low concentrations, it constricts blood vessels that express functional alpha2-adrenoceptors, whereas at much higher concentrations, phenylpropanolamine also activates vascular alpha1-adrenoceptors. This action likely contributed to phenylpropanolamine's therapeutic activity, namely constriction of the nasal vasculature.     

Acute alveolar hypoxia increases bronchopulmonary shunt flow in the dog.

To study the effects of alveolar hypoxia on canine bronchopulmonary shunt flow, a biventricular bypass preparation was employed. The preparation allowed a constant and sensitive measure of changes in pulmonary venous blood flow. In 16 of 18 dogs with intact bronchial arteries, alveolar hypoxia caused an increase in pulmonary venous return both under conditions of constant pulmonary arterial inflow and under conditions of no pulmonary arterial inflow, suggesting bronchopulmonary shunting. This effect was accompanied by systemic vasodilation despite vagotomy and ganglionic blockade, and was abolished by division of all bronchial vessels. Ibuprofen, 3 mg/kg, and indomethacin, 15 mg/kg, in dogs with intact bronchial vessels, abolished both the increase in pulmonary venous return and the systemic vasodilatation caused by hypoxia. Thus, alveolar hypoxia directly augments bronchopulmonary flow, most likely through release of one or more vasodilating prostaglandins.     

Pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease has recently been recognized as a distinct pathological entity and a cause of pulmonary arterial hypertension. Twenty previously reported cases and a new patient are here reviewed. The majority presented with breathlessness and in the early stages of the disease, when the abnormal signs were not striking, some patients were wrongly diagnosed as suffering from an anxiety state. The condition usually has an insidious onset but is remorselessly progressive and since no effective treatment is available at present, invariably fatal and the majority of patients have died within two years. The fully developed clinical picture is dominated by symptoms and signs of pulmonary arterial hypertension, similar to those found with other diseases causing a raised pulmonary arterial blood pressure. However, some patients with pulmonary veno-occlusive disease show, in addition, signs of pulmonary venous and capillary hypertension, which can lead to its clinical recognition when associated with a normal left atrial blood pressure. In this condition the pulmonary wedge pressure would appear to be unreliable as a record of the left atrial blood pressure. Pulmonary angiography and lung scanning will differentiate pulmonary veno-occlusive disease from massive thromboembolic pulmonary arterial hypertension but not from primary pulmonary arterial hypertension or micro thromboembolism. Although in some patients it should now be possible to recognise pulmonary veno-occlusive disease in life, there will be others where, even after full investigation, it will still be impossible to differentiate the condition from primary pulmonary arterial hypertension or micro thromboembolism and in these the diagnosis will only be made when the distinctive histological pattern of the disease is demonstrated. In pulmonary veno-occlusive disease there is a widespread occlusion of the pulmonary veins and venules by a loose intimal fibrosis which is often basophilic. Recanalization of the occluded veins is common and in some cases may be very striking. These occlusive lesions in the pulmonary veins lead to an elevation of pulmonary arterial pressure with associated disease of these vessels, and are also responsible for chronic oedema of the elveolar walls with subsequent development of interstitial pulmonary fibrosis. In the present case organised thrombi were present in the pulmonary arteries in addition to the pulmonary venous lesions.     

Influence of TMB-8 and thapsigargin on vasoconstrictor responses in the pulmonary vascular bed of the cat

The effects of 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8), a protein kinase C (PKC) inhibitor, and thapsigargin, a CaATPase inhibitor, on pressor responses were studied in the pulmonary vascular bed of the intact-chest anesthetized cat. Under conditions of constant lobar blood flow in the cat, injections of the angiotensin peptides (ANG II), norepinephrine (NE), serotonin (5-HT), Bay K 8644, and the thromboxane A2 mimic U46619 into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure and responses were reproducible with respect to time. Intravenous infusion of TMB-8 at 1.0 mug . kg reduced the pressor response to the ANG II and to NE. However, TMB-8 did not alter pressor responses to 5-HT, U46619, or Bay K 8644. In a separate series of experiments, the effects of thapsigargin were investigated and intravenous infusion of the CaATPase inhibitor at 1.0 mug . kg also reduced pressor responses to the ANG II and to NE but did not alter pressor responses to 5-HT, U46619, and Bay K 8644. The data provide support for the hypothesis that vasoconstrictor responses to ANG II and NE in the pulmonary vascular bed are mediated in part by the activation of protein kinase C (PKC) and sarcoplasmic reticulum CaATPase-sensitive mechanisms in the cat. The present data suggest that pulmonary pressor responses to U46619, 5-HT, and Bay K 8644 are not mediated by PKC or CaATPase activation in the pulmonary vascular bed of the cat.     

Metaraminol and dobutamine for the treatment of hypotension associated with epidural block

In 14 patients undergoing major abdominal surgery, epidural analgesia was performed and cardiovascular changes were examined by insertion of Swan-Ganz catheters. To counteract the hypotensive episodes associated with epidural block, Dobutamine (1-3 micrograms/kg body wt min-1) and Metaraminol (0.5-1.5 micrograms/kg body wt min-1) in various doses were infused and the effects of these vasoactive agents were examined. Epidural analgesia decreased arterial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure and central venous pressure associated with marked decrease in cardiac index, stroke volume index, left ventricular and right ventricular stroke work without changes in systematic vascular resistance, pulmonary vascular resistance or heart rate. The infusion of Metaraminol caused a marked increase in arterial pressure, pulmonary arterial pressure, wedge pressure and central venous pressure. Calculated variables of stroke volume, systemic vascular resistance, left and right stroke work and cardiac work increased significantly. The infusion of Dobutamine caused a marked increase in arterial and pulmonary arterial pressure, wedge pressure, central venous pressure and cardiac index associated with those calculated changes of left and right stroke work and cardiac work, which were increased markedly. On the other hand, heart rate, stroke volume and pulmonary vascular resistance did not show any remarkable changes. Our study indicates that the fall in arterial blood pressure associated with epidural block may be due to marked decrease in cardiac output, and the infusion of Dobutamine is one of the desirable methods to counteract the hypotensive episode.