New strategies in the prevention of restenosis.

Restenosis is a common and serious complication following angioplasty and stent implantation in patients with arterial vascular disease. Restenosis is a form of intimal hyperplasia. Endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) stimulate intimal hyperplasia and may play a role in restenosis. ET-1 and VEGF may act in concert in promoting restenosis following mechanical injury to the vessel wall in angioplasty and stent implantation. An understanding of their mechanism of action may lead to more effective methods for preventing restenosis. ET-1 receptor antagonists may play a prominent role in prophylaxis.

Endothelin-mediated preeclampsia at high altitude.

Preeclampsia is pregnancy-induced hypertension. The hypoxia at high altitude increases the incidence of preeclampsia. Endothelin is released in response to hypoxia and is associated with other hypertensive states at high altitude. Endothelin may play a major role in preeclampsia for individuals residing at high altitude. Endothelin antagonists may prove useful in the treatment of preeclampsia.

Closure of the ductus arteriosus--new insights for critical care.

New insights into the closure of the ductus arteriosus may lead to more effective nonsurgical treatment in patent ductus arteriosus. ET-1 agonists may prove useful in future pharmacologic interventions.

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.

High-altitude pulmonary edema: a clinical crisis.

High-altitude pulmonary edema is a serious clinical condition observed in individuals participating in mountain climbing and skiing at high altitudes. High-altitude pulmonary edema is an oncardiogenic form of pulmonary edema. Atrial natriuretic factor and endothelin are implicated and ventilatory support is important in preventing fatalities.

Pathophysiology of pulmonary edema.

Pulmonary edema is a frequent and common cause of death in patients in critical care settings. It is seen as a complication of myocardial infarcts, hypertension, pneumonia, smoke inhalation, and high-altitude pulmonary edema. Pulmonary edema occurs when there are alterations in Starling forces and capillary permeability, opposition to lymphatic flow in the lungs, decreased plasma oncotic pressure, central nervous system lesions, and following some types of strenuous exercise. Pulmonary edema presents initially with crackles, wheezing, and dry cough and progresses to tachypnea, dyspnea, orthopnea, pink frothy sputum, and cyanosis. Treatment involves supportive therapy, reduction in blood volume, and oxygen therapy.

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.

Role of calcium in U 46619 and PGF2 alpha pulmonary vasoconstriction in rat lungs.

The role of calcium and calmodulin during U 46619 and PGF2 alpha-induced pulmonary vasoconstriction was studied in isolated rat lungs perfused with Krebs-Ringer bicarbonate (KRB) or calcium-free KRB. In lungs perfused with KRB, bolus injections of U 46619 (0.2 microgram) and PGF2 alpha (40.0 micrograms) resulted in a 48.0 +/- 4.0 and 23.9 +/- 2.5% increase in mean pulmonary artery pressure, respectively. During lung perfusion with KRB without calcium, the U 46619 response decreased to 31.1 +/- 7.5% whereas the PGF2 alpha response increased to 34.6 +/- 4.1%. Repeated challenges with PGF2 alpha in the KRB without calcium resulted in reduction of the response to 11.8 +/- 1.2%; the U 46619 response was unaltered. The intracellular calcium blocker, 8-(N,N-diethylamino)-octyl-3,4,5, trimethoxybenzoate HCL (TMB-8) significantly attenuated the pressor response to U 46619 at low doses and PGF2 alpha at high doses. The calmodulin inhibitor trifluoperazine (TFP 100 microM) attenuated the vasoconstrictor response to U 46619 by 54%, whereas the PGF2 alpha was unchanged. However, in the calcium-free KRB, TFP attenuated the pressor response to both U 46619 and PGF2 alpha. The U 46619 pressor response depends on intracellular and extracellular calcium to achieve calmodulin-dependent vasoconstriction. PGF2 alpha requires extracellular calcium to replenish depletable intracellular calcium pools and is independent of calmodulin activation.

Effects of intracellular and extracellular calcium blockers on the pulmonary vascular responses to PGF2 alpha and U46619.

In this study, TMB-8, an intracellular calcium antagonist, and verapamil, an extracellular calcium antagonist, were used simultaneously to elucidate the role of calcium in the pulmonary vasopressor response induced by PGF2 alpha and U46619. The pulmonary vasoconstrictor action of these two agonists was evaluated in the canine isolated lung lobe preparation. Lobar arterial pressure was constantly monitored and changes in arterial pressure were recorded as a percentage from baseline. Control responses to PGF2 alpha (42.0 +/- 8.2%) and U46619 (47.2 +/- 7.0%) were obtained prior to the administration of TMB-8 and verapamil. After administration of TMB-8 and verapamil, the PGF2 alpha (7.4 +/- 3.1%) and U46619 (28.8 +/- 6.2%) responses were significantly attenuated. We conclude that the PGF2 alpha pressor response is dependent on a TMB-8-sensitive intracellular calcium pool and a verapamil-sensitive slow-channel calcium influx. In contrast, the degree of attenuation of the U46619 response was similar to the vasopressor response in the presence of verapamil alone, as described previously. This indicates a direct dependence on extracellular calcium. An additional source of calcium insensitive to verapamil and TMB-8 may also be activated and contribute to the pulmonary vasoconstrictor action. These results suggest that each agonist possesses a mechanism of action distinctly different from the other.

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.

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.