Thromboxane receptor analog, U-46619, redistributes pulmonary microvascular perfusion in isolated rat lungs.

Effects of vasoconstriction on the distribution of perfusion among alveoli are not well understood. To address this, we used a new method we developed to determine how microvascular perfusion distribution was affected by a potent vasoconstrictor, the thromboxane receptor analog U-46619. Our method was to infuse 4-microm-diameter fluorescent latex microspheres into the circulation of isolated rat lungs vasoconstricted with U-46619. We used a confocal microscope to image trapping patterns of the particles in dried sections of the lungs and then used dispersion index analysis to quantify the particle patterns in the images, which encompassed approximately 2,000 alveoli. Dispersion indexes revealed significantly more particle clustering (inhomogeneous distribution) in vasoconstricted lungs than in normal flow controls or in controls in which flow was reduced by either lowering pulmonary arterial pressure or raising left atrial pressure. These results suggest that vasoconstriction occurred in the microvessels themselves, which are much smaller vessels than those previously thought to be capable of vasoconstriction.     

Effects of PKC isozyme inhibitors on constrictor responses in the feline pulmonary vascular bed

The effects of G?-6976, a Ca(2+)-dependent protein kinase C (PKC) isozyme inhibitor, and rottlerin, a PKC-delta isozyme/calmodulin (CaM)-dependent kinase III inhibitor, on responses to vasopressor agents were investigated in the feline pulmonary vascular bed. Injections of angiotensin II, norepinephrine (NE), serotonin, BAY K 8644, and U-46619 into the lobar arterial constant blood flow perfusion circuit caused increases in pressure. G?-6976 reduced responses to angiotensin II; however, it did not alter responses to serotonin, NE, or U-46619, whereas G?-6976 enhanced BAY K 8644 responses. Rottlerin reduced responses to angiotensin II and NE, did not alter responses to serotonin or U-46619, and enhanced responses to BAY K 8644. Immunohistochemistry of feline pulmonary arterial smooth muscle cells demonstrated localization of PKC-alpha and -delta isozymes in response to phorbol 12-myristate 13-acetate and angiotensin II. Localization of PKC-alpha and -delta isozymes decreased with administration of G?-6976 and rottlerin, respectively. These data suggest that activation of Ca(2+)-dependent PKC isozymes and Ca(2+)-independent PKC-delta isozyme/CaM-dependent kinase III mediate angiotensin II responses. These data further suggest that Ca(2+)-independent PKC-delta isozyme/CaM-dependent kinase III mediate responses to NE. A rottlerin- or G?-6976-sensitive mechanism is not involved in mediating responses to serotonin and U-46619, but these PKC isozyme inhibitors enhanced BAY K 8644 responses in the feline pulmonary vascular bed.     

Methylene blue selectively inhibits pulmonary vasodilator responses in cats

The effects of methylene blue on vascular tone and the responses to pressor and depressor substances were investigated in the constricted feline pulmonary vascular bed under conditions of controlled blood flow and constant left atrial pressure. When tone was elevated with U46619, intralobar injections of acetylcholine, bradykinin, nitroglycerin, isoproterenol, epinephrine, and 8-bromoguanosine-3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intralobar infusions of methylene blue elevated lobar arterial pressure without altering base-line left atrial or aortic pressure, heart rate, or cardiac output. When methylene blue was infused in concentrations that raised lobar arterial pressure to values similar to those attained during U46619 infusion, the pulmonary vasodilator responses to acetylcholine, bradykinin, and nitroglycerin were reduced significantly, whereas vasodilator responses to isoproterenol, epinephrine, and 8-bromo-cGMP were not altered. Moreover, the pressor responses to angiotensin II and BAY K 8644 during U46619 infusion and during methylene blue infusion were similar. The enhancing effects of methylene blue on vascular tone and inhibiting effects of this agent on responses to acetylcholine, bradykinin, and nitroglycerin were reversible. These responses returned to control value when tone was again increased with U46619, 30-45 min after the methylene blue infusion was terminated. The present data are consistent with the hypothesis that cGMP may play a role in the regulation of tone in the feline pulmonary vascular bed and in the mediation of vasodilator responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, and to nitrogen oxide-containing vasodilators such as nitroglycerin.     

Prostaglandins potentiate U-46619-induced pulmonary microvascular dysfunction.

The induction of cyclooxygenase is an important event in the pathophysiology of acute lung injury. The purpose of this study was to examine the synergistic effects of various cyclooxygenase products (PGE(2), PGI(2), PGF(2alpha)) on thromboxane A(2) (TxA(2))-mediated pulmonary microvascular dysfunction. The lungs of Sprague-Dawley rats were perfused ex vivo with Krebs-Henseleit buffer containing indomethacin and PGE(2) (5 x 10(-8) to 1 x 10(-7) M), PGF(2alpha) (7 x 10(-9) to 5 x 10(-6) M), or PGI(2) (5 x 10(-8) to 2 x 10(-5) M). The TxA(2)-receptor agonist U-46619 (7 x 10(-8) M) was then added to the perfusate, and then the capillary filtration coefficient (K(f)), pulmonary arterial pressure (Ppa), and total pulmonary vascular resistance (RT) were determined. The K(f) of lungs perfused with U-46619 was twice that of lungs perfused with buffer alone (P = 0.05). The presence of PGE(2), PGF(2alpha), and PGI(2) within the perfusate of lungs exposed to U-46619 caused 118, 65, and 68% increases in K(f), respectively, over that of lungs perfused with U-46619 alone (P < 0.03). The RT of lungs perfused with PGE(2) + U-46619 was approximately 30% greater than that of lungs exposed to either U-46619 (P < 0.02) or PGE(2) (P < 0.01) alone. When paired measurements of RT taken before and then 15 min after the addition of U-46619 were compared, PGI(2) was found to attenuate U-46619-induced increases in RT (P < 0.01). These data suggest that PGE(2), PGI(2), and PGF(2alpha) potentiate the effects of TxA(2)-receptor activation on pulmonary microvascular permeability.     

Differential effects of losartan and candesartan on vasoconstrictor responses in the rat

Losartan has been reported to have inhibitory effects on thromboxane (TP) receptor-mediated responses. In the present study, the effects of 2 nonpeptide angiotensin II (AT1) receptor antagonists, losartan and candesartan, on responses to angiotensin II, the thromboxane A2 mimic, U46619, and norepinephrine were investigated and compared in the pulmonary and systemic vascular beds of the intact-chest rat. In this study, intravenous injections of angiotensin II, U46619, and norepinephrine produced dose-related increases in pulmonary and systemic arterial pressure. Losartan and candesartan, in the doses studied, decreased or abolished responses to angiotensin II. Losartan, but not candesartan, and only in a higher dose, produced small, but statistically significant, reductions in pressor responses to U46619 and to norepinephrine in the pulmonary and systemic vascular beds. Furthermore, losartan significantly reduced arachidonic acid-induced platelet aggregation, whereas candesartan had no effect. Pressor responses to angiotensin II were not changed by thromboxane and alpha-adrenergic receptor antagonists, or by cyclooxygenase and NO synthase inhibitors. These results show that losartan and candesartan are potent selective AT1 receptor antagonists in the pulmonary and systemic vascular beds and that losartan can attenuate thromboxane and alpha-adrenergic responses when administered at a high dose, whereas candesartan in the highest dose studied had no effect on responses to U46619 or to norepinephrine. The present data show that the effects of losartan and candesartan on vasoconstrictor responses are different and that pulmonary and systemic pressor responses to angiotensin II are not modulated or mediated by the release of cyclooxygenase products, activation of TP receptors, or the release of NO in the anesthetized rat.     

Effect of pulsatile flow on microvascular resistance in adult rabbit lungs.

We have determined the effect of pulsatile flow on segmental vascular resistance in lungs from 29 adult rabbits. In group I (n = 4), II (n = 8), and III (n = 8) lungs were isolated. In group IV (n = 9) rabbits were anesthetized, their chests were opened, and lungs were studied in vivo. Group I and II lungs had steady-flow perfusion: group I with intact vasotonus and group II with papaverine treatment. Group III lungs (papaverine treated) were perfused for two consecutive 45-min periods with steady and pulsatile flow. In all isolated lungs and in lungs of five anesthetized rabbits, we measured pressures in subpleural 20- to 50-microns-diam arterioles and venules by use of the micropipette servo-nulling method. Measurement of distribution of blood flow in lungs of four anesthetized rabbits by use of radiolabeled microspheres revealed no abnormality of blood flow to the micropunctured lobe. We found that total and segmental vascular resistances were similar in group I and II lungs, with microvessels representing 55% of total resistance. In group III lungs, total resistance was 30% lower during pulsatile flow than during steady flow because of a lower microvascular resistance. Lungs in vivo (group IV) had a significantly lower total vascular resistance than isolated lungs and had a low fractional resistance in microvessels (approximately 28%). We conclude that, in isolated perfused adult rabbit lungs, vascular resistance is very high, particularly in the microvascular segment, and that pulsatile flow decreases microvascular resistance.     

Inhibitory effects of DuP 753 and EXP3174 on responses to angiotensin II in pulmonary vascular bed of the cat.

The effects of the non-peptide antagonist DuP 753 and its metabolite EXP3174 on responses to angiotensin II were investigated in the pulmonary vascular bed of the intact-chest cat. Under conditions of controlled blood flow and constant left atrial pressure, injections of angiotensin II into the perfused lobar artery caused dose-related increases in lobar arterial pressure. Responses to angiotensin II were reproducible and were not changed by meclofenamate or prazosin, indicating that prostaglandin or norepinephrine release does not mediate or modulate pulmonary vascular responses to the peptide. DuP 753 (1-5 mg/kg iv) decreased responses to angiotensin II in a competitive manner, and the duration of the blockade was related to dose of the antagonist. DuP 753 had no significant effect on responses to U-46619, norepinephrine, serotonin, endothelin-1, vasopressin, or BAY K 8644. EXP3174 also decreased responses to angiotensin II without altering responses to agents that act by a variety of mechanisms. The inhibitory effect of EXP3174 (1 mg/kg iv) was not overcome by angiotensin II in the range of doses studied, and the shift to the right of the dose-response curve was nonparallel, suggesting that the blockade was noncompetitive. The blockade was long in duration, and, when the dose of EXP3174 was decreased to 0.1 mg/kg iv, the blockade was surmounted and the shift to the right of the dose-response relationship was parallel. DuP 753 and EXP3174 had little effect on mean baseline pressures in the cat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary microvascular endothelial cell contractility on silicone rubber substrate

Endothelial cell (EC) motility may contribute to the regulation of microvascular perfusion and/or paracellular permeability. The experiments reported herein demonstrate that bovine pulmonary microvessel EC can reversibly deform a silicone substrate in response to agents known to contract and relax smooth muscle cells. Contracting pulmonary microvessel EC exerted a tension that created wrinkles in the underlying deformable substrate. Relaxation and loss of tension were revealed by the disappearance of these wrinkles without loss of cell adhesion to the substratum. Angiotensin II (Ang II) and bradykinin stimulated pulmonary microvessel EC to contract within 3 to 8 min in a Ca2+-dependent fashion. The peak of contraction at 10 to 20 min was followed by relaxation. Forskolin and sodium nitroprusside (SNP) initiated relaxation of the microvessel EC within 3 to 10 min respectively. Relaxed EC contracted following the addition of Ang II, also within 3 min. Dibutyryl cAMP, dibutyryl cGMP, and the photoactivated internalized "caged" cAMP and cGMP promoted EC relaxation in a manner similar to forskolin and SNP. Increases in the intracellular concentration of inositol triphosphate (IP3) with the photoactivated IP3 complex promoted EC contraction in 2 min with a peak at 7 min. The contraction was followed by relaxation, which occurred at 20-25 min. Neither bovine pulmonary artery nor retinal microvessel EC, used as controls, contracted under these experimental conditions. One could speculate that this unique contractile property of pulmonary microvessel EC as observed in vitro may play a regulatory role in vivo, in local perfusion and/or in intercellular gap regulation.     

Comparative responses to alpha,beta-methylene-ATP in cat pulmonary, mesenteric, and hindquarter vascular beds.

Responses to the P2X-purinoceptor agonist alpha,beta-methylene-ATP (alpha,beta-MeATP) were investigated in the pulmonary, hindquarter, and mesenteric vascular beds in the cat. Under constant-flow conditions, injections of alpha,beta-MeATP caused dose-related increases in perfusion pressure in the pulmonary and hindquarter beds and a biphasic response in the mesenteric circulation. In the pulmonary vascular bed, the order of potency was alpha,beta-MeATP > U-46619 > angiotensin II, whereas, in the hindquarters, the order of potency was angiotensin II > U-46619 > alpha,beta-MeATP. The order of potency was similar in the hindquarter and mesenteric beds when the pressor component of the response to alpha,beta-MeATP was compared with responses to angiotensin II and U-46619. The P2X-receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid attenuated the pressor response to alpha,beta-MeATP in the hindquarter circulation and the pressor component in the mesenteric vascular bed. Pressor responses to alpha,beta-MeATP were not altered by cyclooxygenase, alpha-adrenergic, or angiotensin AT(1) antagonists. These data show that alpha,beta-MeATP has potent pressor activity in the pulmonary circulation, where it was 100-fold more potent than angiotensin II. In contrast, alpha,beta-MeATP had modest pressor activity in the systemic bed, where it was 1,000-fold less potent than angiotensin II. These data suggest that responses to alpha,beta-MeATP are dependent on the vascular bed studied and may be dependent on the density of P2X receptors in the vascular bed.     

Leu-enkephalin provokes naloxone-insensitive pulmonary vasoconstriction

Leu-enkephalin evoked dose-dependent pulmonary vasoconstriction in isolated perfused rat lungs. The pressor responses were not attenuated by either naloxone or naltrexone nor were they mimicked by morphine. Blockade of histamine receptors with pyrilamine or blockade of serotonin receptors with methysergide also failed to antagonize leu-enkephalin-induced pulmonary vasoconstrictor responses. These result suggest that neither opiate, histamine, nor serotonin receptors are involved with the pressor effects of leu-enkephalin on the pulmonary circulation. We propose that leu-enkephalin may have direct vasoconstrictor effects on the pulmonary circulation of isolated perfused rat lungs that may not be mediated by conventional opiate receptors.     

Erythrocyte deformability and lung segmental vascular resistance: effect of hematocrit

We have investigated the role of erythrocyte (RBC) deformability and perfusate viscosity on lung segmental vascular resistance in 12 isolated perfused lungs of 3- to 5-wk-old rabbits. Each lung was perfused alternately with control and formaldehyde-fixed rabbit RBCs at a flow rate of 80 ml.kg-1.min-1, left atrial and airway pressures being 8 and 6 cmH2O, respectively (zone 3). Perfusate RBC concentration was kept constant at 3.2 x 10(6)/mm3 for group I lungs (n = 6) and 7.2 x 10(6)/mm3 for group II lungs (n = 6). In all lungs, we measured pressures in the pulmonary artery and in 20- to 50-microns-diam arterioles and venules with the micropipette servo-null method during both perfusion periods. Compared with control, fixed cells had a 60% decrease in deformability index (i.e., the volume of a dilute solution of RBCs filtered through a 5-microns Nuclepore filter in 1 min). In groups I and II, perfusate viscosity of fixed cells was 15 and 55% greater, respectively, than that of control cells. We found that perfusion with fixed cells in group I lungs did not alter total or segmental vascular pressure drops. However, in group II lungs, perfusion with fixed cells at twice the cell concentration resulted in an increase in total vascular pressure drop, mainly due to an increase in pressure drop in veins (50% of total) and arteries (33%). The relatively small (17%) increase in pressure drop in microvessels was probably due to distension and/or recruitment of capillaries resulting from increased venular pressures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary vascular reactivity in Fischer rats

We previously reported that Fischer (F) rat lungs developed more extensive injury when challenged with oxidants than age-matched Sprague-Dawley (SD) rat lungs. We now describe a reduced pulmonary vascular response to alveolar hypoxia and angiotensin II (ANG II) in F compared with SD rats. The comparative studies were performed with isolated lungs perfused with salt solution or blood, catheter-implanted awake rats, and isolated main pulmonary arterial rings. Isolated lungs from F rats perfused with either blood or salt solution had reduced vasoconstriction in comparison with lungs from SD rats when exposed to alveolar hypoxia or challenged with ANG II. Instrumented awake F rats had a smaller mean increase in total pulmonary vascular resistance (PVR) than SD rats (35 vs. 94 mmHg.min.l-1, P less than 0.05) when challenged with 8% oxygen. The contractile response of isolated pulmonary artery but not thoracic aortic rings to KCl and ANG II was reduced in F compared with SD rats. In addition, F rats exposed to 4 wk of hypobaric hypoxia developed less pulmonary hypertension and right ventricular hypertrophy (when corrected for the hematocrit) than SD rats. We conclude that the oxidant stress-sensitive inbred F rat strain is characterized by a lung vascular bed that is relatively unresponsive to vasoconstricting stimuli. The mechanism underlying this genetic difference in lung vascular control remains to be defined.     

Effect of flow and surface area on angiotensin-converting enzyme activity in rabbit lungs

Pulmonary angtiotensin-converting enzyme (ACE) is located on the luminal surface of pulmonary microvasculature. Multiple indicator-dilution techniques have been used to measure pulmonary ACE activity in vivo and in isolated lungs. These studies suggest that ACE activity is depressed in several forms of acute lung injury. Depression of ACE activity may reflect impaired substrate delivery to enzyme sites because of flow-related reduction of perfused surface area. To assess the role of altered microvascular flow and surface area in the measurement of ACE activity, we utilized similar techniques to estimate the apparent Km and Vmax of pulmonary ACE in isolated, Krebs-perfused rabbit lungs. Km is an estimate of the affinity of a synthetic ACE substrate, [3H]benzoyl-phenyl-alanyl-alanyl-proline ([3H]BPAP), for ACE and should not be influenced by the rate of substrate delivery to luminal enzyme sites. Conversely, Vmax is an index of the number of ACE sites and should be influenced by perfusion changes that alter the number of perfused sites (recruitment or derecruitment). When isolated lungs were subjected to physiological maneuvers designed to increase or decrease perfused surface area, apparent Vmax increased or decreased respectively. Apparent Km was not altered by these maneuvers. Km and Vmax were independent of changes in perfusion rate when surface area was held constant. Thus these parameters should be useful in evaluating perfusion changes in normal and injured lungs.     

Angiotensin is not required for hypoxic constriction in salt solution-perfused rat lungs

It has been reported that angiotensin II is specifically required for hypoxic vasoconstriction in rat lungs perfused with physiological salt solution. However, studies with other preparations indicate that angiotensin II does not play a necessary role in the mechanism of hypoxic vasoconstriction. In an attempt to resolve this disagreement I investigated in salt solution-perfused rat lungs whether vasoactive agents other than angiotensin II would induce hypoxic vasoconstriction, and, if so, whether the effect was due to selective action on the hypoxic mechanism or to a nonspecific increase in vascular reactivity. The results showed the development of hypoxic pressor responses after addition to perfusate of plasma, angiotensin II, KCl, vanadate, 4-aminopyridine, or norepinephrine plus propranolol. In contrast, addition of saline (control), ouabain, or tetraethylammonium chloride did not induce hypoxic vasoconstriction. Saralasin inhibited the effect of angiotensin II, but not that of plasma. Induction of responsiveness to hypoxia was associated with an increase in normoxic perfusion pressure and with potentiation of pressor responses to KCl. These results suggest that angiotensin II does not play a unique, integral role in the hypoxic mechanism, but instead is only one of many substances that will induce hypoxic pressor reactivity by reversing the vascular hyporeactivity of salt solution-perfused rat lungs.     

Use of microcarriers to isolate and culture pulmonary microvascular endothelium

Microcarriers of known diameter can be used to collect endothelial cells from microvessels of the same or slightly smaller internal diameter. The procedure is illustrated by collection of endothelial cells from rabbit pulmonary pre-capillary vessels. The lungs are perfused free of blood with physiological saline and then cold (4 °C) saline (containing EDTA, 0.02 %, and microcarriers 600/ml; 40–60 μm diameter) is perfused via the pulmonary artery. The direction of flow is reversed periodically to collect the bead-cell harvest from the arterial side. Cold shock and EDTA cause the endothelial cells to detach from the vessels under conditions such that the cells remain attached to the microcarriers. The selective attachment to microcarriers is apparently aided by the tight fit of the beads within vessels of the same diameter. Beads do not emerge on the venous side, all being trapped at the pre-capillary level. Electron microscopic examination of lungs fixed during the perfusion shows that the beads lodge in terminal arterioles and pre-capillary vessels (approximately 40–60 μm in diameter, with one, sometimes incomplete, muscle layer). Endothelial cells recovered on microcarriers can be allowed to migrate on to flasks and back on to beads. The resultant cultures have an endothelial morphology and possess high levels of angiotensin coverting enzyme and carboxypeptidase N activity.     

Reduced erythrocyte deformability alters pulmonary hemodynamics

Isolated rat lungs were perfused with suspensions containing normal and stiffened erythrocytes (RBCs) to assess the effect of altered RBC deformability on pulmonary hemodynamics. RBC suspensions were prepared using cells previously incubated in isosmolar phosphate-buffered saline with or without 0.0125 or 0.01875% glutaraldehyde. Washed RBCs were resuspended in isosmolar 4% albumin saline solution. Isolated rat lungs were perfused with control and stiffened cells by the use of a perfusion system that allowed rapid switching between suspensions. Pressure-flow (P/Q) curves were constructed by measuring pulmonary arterial pressure (Ppa) over a range of flow rates. In a second set of experiments, P/Q curves were generated for perfusion with control and stiffened cells (0.0125% glutaraldehyde) before and after vasoconstriction with a synthetic prostaglandin analogue (U 46619). RBC deformability was quantified in all experiments by determination of filtration time of a dilute cell suspension through a 4.7 microns Nuclepore filter. Incubation with 0.0125 or 0.01875% glutaraldehyde produced a 6 or 21% decrease in RBC deformability, respectively. These decreases in deformability were associated with significant increases in Ppa at each flow rate. The increases in Ppa correlated significantly with the degree of RBC stiffening. With 0.0125% glutaraldehyde, the P/Q curve was shifted upward without a change in slope, whereas incubation with 0.01875% glutaraldehyde resulted in a significant increase in slope. Vasoconstriction and perfusion with stiffened RBCs had additive effects on Ppa. These findings suggest that decreases in RBC deformability cause physiologically significant elevations in hemodynamic resistance in the pulmonary circuit independent of vasoactivity.     

N omega-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.     

Functional comparison of the human isolated femoral artery, internal mammary artery, gastroepiploic artery, and saphenous vein

Human femoral, internal mammary, and gastroepiploic arteries and saphenous veins are used as bypass grafts for coronary surgery or for reconstruction in arterial occlusive disease. We have characterized the contractile responses of these vessels to various agents that are liberated during cardiac or vascular surgery. In organ baths, U46619 (a stable thromboxane A2 mimetic), norepinephrine, endothelin-1, angiotensin II, and KCl caused concentration-dependent contractions in all vessels tested. Leukotriene C4 did not induce any contraction in the arteries, whereas a contraction was obtained in the saphenous vein rings. U46619 induced the most powerful contraction in all vessels tested. The pD2 values for each agent did not differ among the different vessels. When responses were expressed as a percentage of KCl-induced contraction, the contraction of endothelin-1 (151+/-5%) and leukotriene C4 (43+/-5%) was more significant on saphenous veins than on arteries. In conclusion, thromboxane A2 appears to be the most potent endogenous constricting agent on different human vascular beds. Our second finding is that saphenous veins are more sensitive to contract to leukotriene C4 and endothelin-1 than arteries. These properties may influence early and (or) long-term vein graft patency.     

SQ 14,225 attenuates the vascular response to norepinephrine in the rat mesenteric arteries.

SQ 14, 225, a new angiotensin-converting enzyme inhibitor, attenuated the vascular contraction induced by norepinephrine in the perfused rat mesenteric vascular bed, while SQ 20, 881, an another converting enzyme inhibitor, did not have any effect on the vascular reactivity. Furthermore, this effect of SQ 14, 225 was not altered in the presence of bradykinin or angiotensin II in the perfusate. These results suggest that SQ 14, 225 may have a direct antihypertensive effect which is not mediated by the inhibition of angiotensin-converting enzyme.