Allan D. Angerio

Cardiovascular Responses to PGD2 in the Dog

Summary The cardiac and peripheral vascular effects of PGD2 and PGE2 were investigated in dogs with an intact circulation and during left ventricular bypass. PGE2 had a positive inotropic effect, whereas PGD2 produced a negative inotropic effect on the heart that was independent of reflex effects or changes in ventricular preload or afterload. Both PGE2and PGD2 produced a systemic depressor response which was due to the direct peripheral vasodilating action of these compounds.

The role of endothelin in heart failure.

Current treatments for heart failure extend the life of the patient but do not stop the progression of the disease process. These treatments may not be addressing the underlying cause of cellular injury. The role of endothelin in cardiac remodeling and inflammation may be important in the progression of failure, and endothelin antagonists may be beneficial in treatment in combination with drugs already in use.

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.

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.

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.

Effects of Intracellular and Extracellular Calcium Blockers on the Pulmonary Vascular Responses to PGF2α 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 PGF2α 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 PGF2α (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 PGF2α (7.4±3.1%) and U46619 (28.8±6.2%) responses were significantly attenutated. We conclude that the PGF2α 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.

Interferon and heart disease.

Heart disease is the leading cause of morbidity and mortality in the United States. Atherosclerosis is the major cause of heart disease. It is a chronic inflammatory response. Many factors contribute to this chronic inflammation. This review looks at the role of interferon γ in atherosclerosis.

Sickle cell crisis and endothelin antagonists.

&NA; Sickle cell crisis may be more complex than a vaso‐occlusive event in response to hypoxia. Endothelin‐1 (ET‐1) is a potent vasoconstrictor and mitogen secreted in response to hypoxia. ET‐1 contributes to the vaso‐occlusion and inflammation in sickle cell crisis. ET‐1 antagonists may be useful in the prevention and treatment of crisis.

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.

Endothelin-1-mediated inflammation in acute renal failure.

Acute renal failure presents a serious and life-threatening problem in hospitalized patients. Current therapies address the systemic alterations in renal failure. Cellular changes also occur. These changes affect the glomerular filtration rate and the integrity of the glomerular membrane. ET-1, the most potent vasoconstrictor known, has a negative effect on both the rate of filtration and the integrity of the filtering membrane in renal failure. Using ET-1 antagonists along with the current therapies may prove useful in patients.