ABSTRACT
Rapid progress in the understanding and treatment of unstable angina and acute coronary syndrome are prompting occasional revisions to current treatment guidelines. The recommendations contained in this paper are based on the consensus reached during discussions at the 'International Cardiology Forum' in September 1998. Consensus was reached on significant major points, although some aspects remain controversial. A substantial body of data accumulated in a host of studies justify changes to current treatment habits.
Subject(s)
Angina, Unstable/diagnosis , Angina, Unstable/therapy , Coronary Disease/diagnosis , Coronary Disease/therapy , Myocardial Infarction/diagnosis , Myocardial Infarction/therapy , Practice Guidelines as Topic , Acute Disease , Angina, Unstable/drug therapy , Angioplasty, Balloon, Coronary , Anticholesteremic Agents/therapeutic use , Clinical Trials as Topic , Coronary Disease/drug therapy , Diagnosis, Differential , Electrocardiography , Fibrinolytic Agents/therapeutic use , Humans , Myocardial Revascularization , Outpatients , Platelet Aggregation Inhibitors/therapeutic use , Prognosis , Randomized Controlled Trials as Topic , Risk Assessment , Syndrome , Time FactorsABSTRACT
OBJECTIVES: To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF). BACKGROUND: Nonselective ET(A/B( receptor antagonists improve hemodynamics in patients with CHF. Since ET(B( receptors mediate the release of nitric oxide and the clearance of ET-1, selective ET(A) antagonists are of special interest. METHODS: The hemodynamic effects of a single oral dose of the selective ET(A) receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II-III) with an ejection fraction < or = 35%. RESULTS: Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37-0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = -0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03-0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035- < 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant. CONCLUSIONS: In patients with CHF, a single oral dose of the selective ET(A) receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.
Subject(s)
Endothelin Receptor Antagonists , Heart Failure/drug therapy , Phenylpropionates/therapeutic use , Pyrimidines/therapeutic use , Catecholamines/blood , Dose-Response Relationship, Drug , Endothelin-1/blood , Female , Heart Failure/blood , Heart Failure/physiopathology , Hemodynamics/drug effects , Humans , Male , Middle AgedABSTRACT
Human parathyroid hormone (hPTH (1-38)) induced concentration-dependent relaxations in prostaglandin F2 alpha-preconstricted pig coronary arteries in vitro. Removal of endothelial cells or pretreatment with nitro-L-arginine, a specific inhibitor of the endothelium-derived relaxing factor (EDRF) synthesis, impaired, although to a small extent, hPTH-induced relaxations. Human PTH-, but not bradykinin- or nitroglycerin-induced relaxations were potentiated in the presence of the cyclic AMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Human PTH also relaxed preconstricted human inferior epigastric arteries in vitro. In accordance to pig coronary arteries, this relaxation was potentiated in the presence of IBMX. However, the human internal thoracic (mammary) artery did not respond to hPTH (1-100 nM). Thus, acute vasodilatory effects of hPTH may not be present in all human arteries. The physiological significance of this phenomenon is not known. This relaxation, at least in pig arteries, is mediated to a small extent by the release of EDRF. In addition, this relaxation appears to be mainly mediated in both pig and human arteries by a smooth muscle cyclic AMP pathway.
