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Experimental and clinical pharmacology of carvedilol and other drugs combining vasodilation and beta-adrenoceptor antagonism in a single molecule.

Combinations of beta-adrenoreceptor blocking agents and vasodilators have been widely used because of their favorable hemodynamic actions and their high efficacy. In comparison with the free combination of the two active principles, substances that combine vasodilation and beta-blockade in a single molecule may lead to a simplification of therapy and thus to an improvement in compliance. Substances that show clear beta-blocking and vasodilating actions at therapeutic doses have already been introduced to therapy or are in an advanced stage of clinical development. The vasodilating action of amosulalol, carvedilol and labetalol is achieved by blockade of the alpha 1-receptors. In contrast, partial agonistic action on beta 2-receptors is responsible for the vasodilatation with dilevalol. This mechanism probably also plays an important role in the vasodilatation induced by celiprolol. While classical beta-blocker lead to a rise in peripheral resistance and to a marked fall in cardiac output, peripheral resistance falls during treatment with vasodilating beta-blockers. The cardiac output is either only slightly reduced or virtually unchanged. Surprisingly, three months' treatment with the vasodilating beta-blocker bucindolol in patients with severe heart failure led to a rise in cardiac output and in ejection fraction and to a reduction of the heart rate and pulmonary wedge pressure. An improvement of left-ventricular function was also obtained on administration of carvedilol in patients with coronary heart disease. Theoretically, it is conceivable that substances with additional alpha 1-blocking actions, such as labetalol, carvediolol or amosulalol, or with partial agonistic activity such as celiprolol or dilevalol, would have a clearly more favourable effect on the blood lipid profile than the classical beta-blocking agents. Initial results appear to confirm this, but final conclusions will only be possible when the results of prospective comparative studies are available.