The antagonists of endothelin receptors:results and perspectives.

In 1988 Yanagisawa described endothelins, a new class of vasoconstrictor agents produced by endothelial cells. Further biological effects of these peptides have subsequently been demonstrated, for example, induction of cell proliferation and fibrosis. Two types of endothelin receptors have been described: ETA are responsible for endothelininduced vasoconstriction whereas ETB induce endothelial cells to release nitric oxide (NO) and prostacyclin. Many antagonists of endothelin receptors have been synthesized and evaluated in animal models and in humans. Satisfactory results have been obtained in animal models of arterial hypertension, pulmonary hypertension, stroke and heart failure but clinical trials have failed to demonstrate that these drugs have a beneficial effect in the treatment of heart failure and a dose-dependent reversible hepatic toxicity has been observed. However, the efficacy of bosentan, a mixed antagonist of endothelin receptors, in the treatment of primary pulmonary hypertension has been demonstrated and the drug is now marketed worldwide for this condition. Further studies are ongoing to evaluate other clinical applications of these drugs. Recently it has been reported that atrasentan, a selective ETA antagonist, delayed the progression of hormone-refractory prostate cancer in humans. This review describes the results of the studies performed in animals and in humans and their potential future clinical applications

Non peptidic urotensin II antagonists: perspectives for a new class of drugs.

Urotensin II (U-II) is a cyclic peptide isolated from a fish. Subsequently, human U-II and its receptor were identified. In rat thoracic aorta U-II triggers powerful vasoconstrictor activity. However, the constrictor response to U-II appears to be variable and highly dependent on the vascular bed examined. Vasoconstriction is not its only effect; U-II and its receptor have been demonstrated in the central nervous system, where U-II induces a cardiovascular, behavioural, motor and endocrine response and in the kidney, where it seems to influence renal hemodynamics but also salt and water excretion, in rat pancreas where it inhibits insulin secretion, in the heart where it seems to play a role in cardiac hypertrophy and fibrosis. In humans high plasma or urine levels of U-II have been described in some pathologic conditions. Peptidic and non peptidic UT receptor antagonists have been synthesized and their effects have been evaluated particularly in animal models of diabetes and heart failure. After promising results in animal models, palosuran, a non peptidic U-II antagonist has been administered also in diabetic patients to evaluate its potential nephroprotective activity. This review presents the data available on the U-II system and its role in physiological and pathological conditions, together with data regarding palosuran and other non peptidic and peptidic U-II antagonists

A pheochromocytoma with normal clonidine-suppression test:how difficult the biochemical diagnosis?

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Comparative evaluation of the extended hypotensive effect of slow-released clonidine administered alone or in association with diuretics

Recently two new slow-release preparations (clonidine \u201cperlongetten\u201d 250 mcg CP, and cloni dine \u201cperlongetten\u201d 150 mcg + chlorthalidone 15 mg, CP + D) gave been presented. The prolonged action of CP and CP + D may permit once daily administration of the drug and thus obtain better patient compliance. The hypotensive effect of CP or CP + D and possible side effects have been esamined during a 3-week trial in 19 hypertensive subjects. It was found that in mild and in some cases of moderate hypertension a single daily dose of CP or CP + D is apt to normalize blood pressure for 24 hrs. In patients with moderate and severe hypertension blood pressure is satisfactorily controlled by b.i.d. administration of CP or CP + D. The hypotensive action of the two preparations did not show consistent differences while tolerance was slightly better for CP + D