Effects of drugs on the negative (backflow) component of velocity patterns in the dog aorta.

Using an accurately calibrated flowmeter in the descending thoracic aorta of the dog, a study was made of alterations in aortic flow patterns following intravenous and intra-arterial injections of vasoactive drugs. When injected distal to the flowmeter, vasopressors caused marked backflow while vasodilators raised the level of the lowest portion of the pulsatile flow curve. When injected into the brachiocephalic artery, vasopressors prevented the development of a significant negative component whereas vasodilators caused the appearance of backflow, or augmented that which was already present. All acute elevations or decreases in peripheral resistance due to drugs were accompanied by increases in the negative or "backward" phase of flow in diastole. A significant negative flow component was noted only during these acute adjustments. A temporary differential in resistances of the upper and lower portions of the arterial circulation protected cerebral and coronary blood flow during acute haemodynamic adjustments.

Effects of halothane on the intramyocardial pressure of the canine left ventricle.

In the intact canine heart a gradient of systolic intramyocardial pressure from a minimum at the epicardial region to a maximum at the endocardial region is well established. No information is, however, available regarding the effects of various anaesthetic agents on this gradient. In the present study the effects of halothane on intramyocardial pressure recorded from subendocardial and subepicardial layers of the canine left ventricular free wall were assessed. Experiments were performed on seven anaesthetised mongrel dogs ventilated with 100% oxygen. Intramyocardial pressure was recorded simultaneously from the inner and outer regions of the myocardium using two Mikro-tip pressure transducers. Halothane concentration in the inspired gas varied from 0% to 2%. In the pentobarbital anaesthetised dog halothane does not significantly change the heart rate. With increasing concentrations of halothane in inspired gas systolic intramyocardial pressure at both endocardium and epicardium decreased significantly from control values. As the halothane concentration increased, the normal differential between systolic left ventricular pressure and endocardial intramyocardial pressure was abolished. The intramyocardial pressure gradient from endocardium to epicardium, however, persisted during systole. During diastole the pressure gradient was reversed, becoming maximum in the epicardial region and minimum in the endocardial region in both control and halothane treated animals. Over the range of 0-2% halothane concentration there was no significant effect on the diastolic intramyocardial pressure gradient. These results suggest that halothane affects the myocardial tissue pressure non-uniformly across the left ventricular free wall and therefore influence sth e transmural distribution of coronary blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelets and the vascular responses to arachidonic acid in dogs.

UNLABELLED: Platelets are rich in components of the prostaglandin synthetase system which converts arachidonic acid into vasoactive and platelet-active prostanoate and nonprostanoate compounds. Repeated injections of arachidonic acid in dogs cause hypotension of reproducible magnitude and lower circulating platelet counts with each injection. However, the circulatory response to injected arachidonic acid was unchanged when platelet-poor blood was exchanged in dogs. Moreover, in the hind limb preparation and the isolated lung lobe, the vasoactive responses to arachidonic acid were indistinguishable whether perfused with whole blood or an artificial perfusate. CONCLUSION: the vascular responses to arachidonic acid do not appear dependent on the presence of platelets.

Inhibition of myointimal proliferation of the rat carotid artery by the peptides, angiopeptin and BIM 23034.

Proliferation of vascular smooth muscle is an early and major event in the formation of an atherosclerotic lesion. Here we report for the first time the inhibitory effects on myointimal proliferation of the rat carotid artery by a synthetic peptide, angiopeptin, and its closely related congener, BIM 23034. Proliferation was initiated in the carotid artery of anesthetized rats by air-drying of the endothelium. After 15 days the rats were killed and the carotid artery was pressure-fixed and subjected to morphologic analysis for evaluation of the degree of myointimal thickening. Five synthetic somatostatin-like peptides were tested by pretreating rats (20 and 50 micrograms/kg/rat s.c. daily) for 2 days prior to and for 5 days after the endothelial injury. Angiopeptin and the closely related octapeptide (BIM 23034) significantly inhibited myointimal thickening. Angiopeptin was also effective when the pretreatment period was reduced from 2 days to 30 min. The inhibitory effect of angiopeptin was further confirmed in an additional experiment involving [3H]thymidine incorporation. In this experiment angiopeptin (100 micrograms/kg/day s.c.) was also administered for 2 days prior to and five days following the endothelial injury and it significantly inhibited thymidine uptake. All the peptides tested inhibit the release of growth hormone. However, only angiopeptin and BIM 23034 inhibited myointimal proliferation. Thus the effect of angiopeptin and its congener is unlikely to be mediated through growth hormone. Since angiopeptin inhibits myointimal proliferation it may have clinical utility in preventing restenosis following angioplasty and coronary artery by-pass procedures.

Effect of verapamil on the pulmonary vasoconstrictor action of prostaglandin F2 alpha and a synthetic PGH2 analogue.

1 The vasopressor response to prostaglandin F2 alpha (PGF2 alpha) and to ((15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)-prosta-5Z, 13E-dienoic acid) (U-46619) in the canine isolated lung lobe was significantly attenuated following the administration of verapamil. 2 The pressor response to arachidonic acid (AA) was not affected by the presence of verapamil. 3 The pulmonary pressor effect of PGF2 alpha and U-46619 is dependent, at least in part, on Ca2+ influx into vascular smooth muscle cells. 4 The pulmonary pressor response to AA cannot be attributed to PGF2 alpha or to endoperoxide intermediates but to some other product dependent on intracellular calcium stores.

Tromboxane B2 inhibits the pulmonary inactivation of prostaglandin E2 in the dog.

1 The systemic vasodepressor response to intravenously administered prostaglandin E2 (PGE2, 0.3, 1.0 and 3.0 micrograms/kg) is potentiated during intravenous infusion of thromboxane B2 (TXB2, 1.0 micrograms kg-1 min-1) in the anaesthetized dog. 2 The augmented haemodynamic response returns toward control values following cessation of the TXB2 infusion. 3 The systemic haemodynamic responses to intra-arterially administered PGE2, PGF2 alpha and PGI2 as well as intravenously administered PGF2 alpha and PGI2 are not altered by TXB2 infusion. 4. This study suggests that TXB2 inhibits the pulmonary inactivation of PGE2. 5 Arachidonic acid metabolites may interact, producing haemodynamic responses differing from their individual effects.

Vasoconstrictor response to arachidonic acid in the isolated hind limb of the dog.

1 Arachidonic acid(AA) (25-200 mug/kg) produced a dose-related increase in perfusion pressure in dog isolated hind limbs perfused with either blood or a platelet-free perfusate. 2 Prostaglandin E2 produced vasodilation while prostaglandin F2 alpha produced no vascular change at these administered doses. 3 Phentolamine did not alter the arachidonic acid response, eliminating possible alpha-adrenoceptor mediation. 4 Aspirin and idomethacin blocked the vasoconstrictor response to AA. 5 This study indicates that a vasoactive intermediate in prostaglandin synthesis can be elaborated in the absence of platelets.

Circulatory effects of prostaglandin endoperoxide analogues studied in the dog during left ventricular bypass.

1. Intravenous administration of both the 9alpha,11alpha-(epoxymethano) and 11alpha,9alpha-(epoxymethano) analogues of prostaglandin H2 (0.25 microgram/kg) produced a prominent rise in pulmonary arterial pressure and a moderate increase in systemic arterial pressure. 2. Direct administration of the endoperoxide analogues (1.25 microgram/kg) into the bypass reservoir produced a greater rise in systemic arterial pressure and less prominent rise in pulmonary arterial pressure. 3. An intravenous dose of prostaglandin F2alpha that was 20 times larger was needed to produce a comparable rise in pulmonary arterial pressure. 4. The pulmonary and systemic pressor responses produced by the endoperoxide analogues were due to a direct increase in the vascular resistance.

Effect of TMB-8 on the pulmonary vasoconstrictor action of prostaglandin F2 alpha and the thromboxane mimic, U 46619.

1 TMB-8 (8-(N,N-diethylamino)octyl-3,4,5 trimethoxybenzoate HCl), an intracellular calcium antagonist, had no direct action on the pulmonary vasculature of the perfused canine lung lobe preparation. 2 The pulmonary pressor response to the thromboxane mimic, U46619, was not affected by TMB-8. 3 The vasopressor response to prostaglandin F2 alpha (PGF 2 alpha) was significantly attenuated but not completely blocked by TMB-8. 4 We conclude that the pulmonary pressor response to PGF 2 alpha is dependent on both intracellular and extracellular calcium pools for contraction and that U46619 facilitates either solely extracellular calcium influx or mobilizes an intracellular calcium pool not inhibited by TMB-8.

The role of N omega-nitro-L-arginine in modulation of pulmonary vascular tone in the maturing newborn pig.

Current therapeutic modalities for treatment of newborn pulmonary hypertensive crisis include but are not limited to the administration of nitric oxide (endothelium-derived relaxing factor). However, few data are available on the role of endogenously produced endothelium-derived relaxing factor in the modulation of pulmonary vascular tone in the neonate. In the current study, we investigated the acute effects of N omega-nitro-L-arginine (a potent competitive inhibitor of endothelium-derived relaxing factor synthase) on the pulmonary vasculature of anesthesized open-chest 48-hour-old (n = 8) and 2-week-old (n = 7) Yorkshire pigs. After baseline data were acquired, all animals received a 10 mg/kg per minute infusion of N omega-nitro-L-arginine for 10 minutes. To discern distal and proximal pulmonary arterial vessel changes, input mean and characteristic impedance were respectively determined. Pulmonary vascular resistance was also calculated (units determined in dyne.sec.cm-5 plus or minus the standard error of the mean). Results showed N omega-nitro-L-arginine infusion did not significantly alter baseline pulmonary arterial pressure (22,370 +/- 1473 dyne/cm2), pulmonary vascular resistance (5171 +/- 805 dyne.sec.cm-5), input impedance (6343 +/- 806 dyne.sec.cm-5), or characteristic impedance (2073 +/- 418 dyne.sec.cm-5) in 48-hour-old pigs. In 2-week-old pigs, infusion of N omega-nitro-L-arginine elevated pulmonary arterial pressure (18,162 +/- 1415 dyne/cm2 versus 23,838 +/- 1810 dyne/cm2, p = 0.015), pulmonary vascular resistance (810 +/- 137 dyne.sec.cm-5 versus 1519 dyne.sec.cm-5, p = 0.030), and input impedance (2302 +/- 251 dyne.sec.cm-5 versus 2900 +/- 255 dyne.sec.cm-5, p = 0.018). Characteristic impedance was not altered in 2-week-old pigs. These data indicate that N omega-nitro-L-arginine infusion resulted in pulmonary arteriolar vasoconstriction in 2-week-old pigs, but not in 48-hour-old pigs. This finding suggests that endothelium-derived relaxing factor does not modulate basal pulmonary arteriolar tone during the early newborn period, but does play a significant role in 2-week-old pigs. These data also suggest that the functional role for endothelium-derived relaxing factor is confined to the distal arteriolar pulmonary bed and does not extend to the larger proximal arterial vessels.

Reactivity of rat abdominal aorta to U46619 following whole-body gamma irradiation.

Rats exposed to 20 Gy whole-body irradiation demonstrated a depressed aortic responsiveness to the thromboxane mimic, U46619, 48 h postirradiation. The mechanism for this observed response was investigated. Shielding the abdominal aorta attenuated this altered vascular reactivity. Since this suggests that radiation exposure induces local changes in the aorta, vascular smooth muscle function was assessed with cumulative concentrations of KCl. Radiation-induced smooth muscle damage was insufficient to account for the decreased reactivity to U46619. Next, calcium availability for vascular smooth muscle function was evaluated and found not to be responsible for the radiation-induced depression in aortic responsiveness. Finally, the role that cyclooxygenase products play in the depressed contractile response was investigated. Indomethacin treatment prior to and for 48 h after irradiation attenuated the altered vascular reactivity to U46619. These data suggest that a radiation-induced increase in cyclooxygenase products may play a role in the decreased aortic reactivity to the thromboxane mimic.

WR2721 ameliorates the radiation-induced depression in reactivity of rat abdominal aorta to U46619.

Previous studies showed that 20 Gy whole-body gamma irradiation results in a decreased response of the abdominal aorta to the stable thromboxane A2 (TXA2) mimic, U46619. The present study evaluated the effect of WR2721 on this radiation-induced decrease in vascular responsiveness. Rats receiving WR2721 (200 mg/kg, i.p.) 20 min before irradiation showed no depression in vascular reactivity to U46619 compared to control. The abolition of the radiation-induced decrease in vascular responsiveness was not caused by a direct vasoconstrictor action of WR2721 or its metabolites. The vascular response of rat abdominal aortic rings to KCl was unchanged after in vivo exposure to ionizing radiation. WR2721 did not alter the vascular response to KCl. These studies confirm that exposure to whole-body ionizing radiation decreased abdominal aortic vascular responsiveness to U46619. This depressed vascular reactivity can be abolished by pretreatment with the radioprotectant, WR2721. These observations may provide a rapid initial screening method for evaluating the in vivo efficacy of radioprotectant drugs.

Regional release of cyclooxygenase products after radiation exposure of the rat.

The present study evaluated the regional release of cyclooxygenase products 4 h following 20 Gy gamma irradiation. Thoracic shielding reduced the radiation-induced increase in immunoreactive thromboxane B2 (iTxB2) excretion to control levels while abdominal shielding partially attenuated the altered excretion of this cyclooxygenase product. To assess the role the kidneys play in the radiation-induced increase in iTxB2 excretion, an in situ isolated perfused rat kidney model was developed. The excretion rate of iTxB2 from irradiated isolated perfused kidneys was not significantly different from sham-irradiated perfused kidneys. Radiation exposure did alter renal cyclooxygenase product release in that the excretion of immunoreactive prostaglandin E2 (iPG2) and immunoreactive 6-keto-PGF1 alpha was significantly increased (P less than 0.05) in irradiated isolated perfused kidneys. These data show that radiation-induced increases in iTxB2 excretion are primarily due to altered extrarenal synthesis and/or metabolism of this arachidonate metabolite.

Pulmonary hydraulic impedance responses to hypoxia and hypercapnia in newborn pigs.

The purpose of this study was to determine the cumulative effects of brief intervals of hypoxia and hypercapnia on the pulsatile characteristics of the pulmonary arterial circulation of 48-h-old compared with 2-wk-old open-chest Yorkshire pigs while using two different anesthetic regimens: 1) azaperone and ketamine (4 and 12 mg/kg im, respectively) and 2) thiopental sodium (25 mg/kg i.v.). Animals 48 h old were randomly allocated to undergo mild hypoxia (inspired O2 fraction = 0.15), severe hypoxia (inspired O2 fraction = 0.05), or hypercapnia (inspired CO2 fraction = 0.20), whereas animals 2 wk old underwent severe hypoxia or hypercapnia. With use of Fourier analysis, characteristic impedance (Zo), mean input impedance (Zm), impedance moduli, and phase angles were determined. In 48-h-old pigs anesthetized with azaperone-ketamine, neither mild nor severe hypoxia altered Zo, Zm, or pulmonary vascular resistance (PVR), whereas hypercapnia increased Zo by 22% (P < 0.001), which persisted despite a return to normocapnia. In 48-h-old animals anesthetized with thiopental, baseline control Zo and Zm were lower than those in same-age pigs anesthetized with azaperone-ketamine. In thiopental-anesthetized 48-h-old pigs, both severe hypoxia and hypercapnia increased Zm and PVR but Zo was unaltered. In 2-wk-old pigs anesthetized with thiopental, severe hypoxia but not hypercapnia elevated Zm and PVR, whereas Zo was not changed with either stress. Results indicate age- and anesthetic-dependent responses of Zo, Zm, and PVR to severe hypoxia and hypercapnia. The persistent elevation in Zo caused by hypercapnia indicates a prolonged decrease in arterial compliance or a reduction in effective proximal pulmonary arterial radius.

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

BACKGROUND: This study determined the pulmonary vascular responses to intravenous (IV) administration of endothelin-1 (ET-1) before and after an IV bolus of bosentan (Ro 47-0203), an endothelin receptor antagonist, in anesthetized open-chest 48-hour-old and 2-week-old Yorkshire pigs. METHODS: Eighteen 48-hour-old and 25 2-week-old pigs were randomly allocated to receive either (1) 400 ng x kg(-1) x min(-1) of ET-1 or (2) 5 mg/kg or 10 mg/kg of Ro 47-0203 followed by 400 ng x kg(-1) x min(-1) of ET-1 over a 10-minute interval. Pulmonary vascular resistance (PVR, dyne sec/cm(-5)), elastic modulus (E(Yo), dyne/cm2), and characteristic impedance (Zo) were determined (+/- SEM). RESULTS: In 48-hour-old pigs, ET-1 decreased pulmonary artery pressure (PAP, dyne/cm2; 21,317 +/- 1,833 versus 17,757 +/- 1,823; p = 0.003). In 2-week-old pigs, ET-1 elevated PAP (19,009 +/- 1,834 versus 21,935 +/- 2,104; p = 0.003) and PVR (1,624 +/- 254 versus 2,302 +/- 416; p = 0.001), whereas bosentan abolished the ET-1 induced pulmonary and systemic vasoconstriction. Neither agent altered E(Y) or Z(o). CONCLUSIONS: ET-1 caused a pulmonary depressor response in 48-hour-old pigs and a constrictor response in 2-week-old pigs, whereas bosentan inhibited the ET-1 induced pulmonary arteriolar vasoconstriction in 2-week-old pigs. The response to ET-1 changes from dilation in 48-hour-old pigs (neonates) to constriction in 2-week-old pigs (infants) suggests a maturational dependent alteration in ET receptors during the first 2 weeks of life. These data suggest that bosentan may have potential clinical application in the treatment of newborn pulmonary hypertensive episodes as it ablated ET-1 induced pulmonary vasoconstriction, while maintaining systemic pressure.

Thromboxane release from irradiated perfused rat lungs: role of oncotic agents.

Isolated lungs from 20 Gray (Gy) whole body irradiated rats were perfused with Krebs-Ringer bicarbonate plus 3% bovine serum albumin (KRB-BSA). The pulmonary effluent showed a 99% (p less than .05) increase in immunoassayable thromboxane B2 (iTXB2) release compared with non-irradiated lungs. Since both arachidonic acid and cyclooxygenase products bind to albumin, studies were performed to determine if omission or substitution of this protein oncotic agent would alter the radiation-induced increase in pulmonary iTXB2 release. Irradiated, isolated lungs perfused with media from which the BSA was omitted (KRB) did not demonstrate the radiation-induced increase in pulmonary iTXB2 release. Similarly, irradiated lungs perfused with media in which Dextran 70 (KRB plus 3% Dextran 70, KRB-Dextran 70) was substituted for BSA also did not show the radiation-induced increase in pulmonary effluent iTXB2 levels. These studies demonstrate the importance of including albumin as the oncotic agent in perfused organ systems when studying cyclooxygenase product release.

Measure of blood flow by the multiple radioactive microsphere technique in radiated gastrointestinal tissue.

In this study, two different radioactive microspheres were used to measure blood flow of an irradiated segment of small intestine in four dogs before, and 12 days after, irradiation with 2000 rad. The technique and implications are discussed. Using multiple radioactive microspheres, the study demonstrated an increased blood flow in irradiated tissues twelve days after a single dose of 2000 rad. There was also an increase in blood flow to adjoining nonradiated segments of intestine in the same animal. These observations may be of significance in clinical applications of radiation therapy and surgery. A major surgical concern is the impaired healing of irradiated tissue in the immediate postradiation period. The mechanism of this has generally implicated decreases in the perfusion of irradiated tissue. No decrease in blood flow was shown in this study, suggesting that other mechanisms, e.g., stem cell depletion, should be considered. Further studies of this type are recommended to increase understanding of the blood flow in irradiated tissue.

Endothelin-1: possible implications in pulmonary vascular disease.

The vasoactive properties of endothelin-1 (ET-1) in the animal model very with the tone of the pulmonary vessels, the dose level of ET-1, and the maturation of the vessels. The action of ET-1 is mediated by endothelium-derived nitric oxide, prostaglandins, and electrolytes. Plasma levels of ET-1 are elevated in pulmonary hypertension in both animals and humans. ET-1 antagonists may prove useful in treating pulmonary hypertension in children and adults.

Vasodilator effects of hydroxylamine in the isolated rodent lung.

Hydroxylamine is a natural product of cellular metabolism that possesses vasodilating properties similar to those of endothelium-derived relaxing factor (EDRF). In the rodent pulmonary circulation preconstricted with the endoperoxide analog U-46619, hydroxylamine relaxed the vasculature in a concentration-dependent manner. Blockade of the hydroxylamine vasodilator response by methylene blue indicated that the mechanism of vasorelaxation is similar to that of EDRF. In this preparation, hydroxylamine is a more potent vasodilator than nitroglycerin.

Calcium utilization associated with U-46619 and PGF2a vascular responses in rat lungs.

The pulmonary vasoconstrictor responses to U-46619 and PGF2a are calcium dependent. The purpose of this investigation was to determine to what extent extracellular and intracellular calcium pools are utilized during the dose-dependent pulmonary vasopressor responses induced by multiple doses of U-46619 and PGF2a. Increasing doses of these agonists were administered to isolated rat lungs perfused with Krebs-Ringer bicarbonate (KRB) or KRB not containing CaCL2. The data indicate that U-46619 uses predominantly extracellular calcium at low doses (0.1 microgram) and depends solely on intracellular calcium at the highest dose (0.4 microgram). In contrast PGF2a appears to use depletable intracellular calcium stores to achieve contraction.