Pharmaceutical Interventions for the Management of No-Reflow

Tim A. Fischell, MD

J Invasive Cardiol. 2008;20(7):374-379. 

In This Article

Endothelin Antagonists

The potent vasoconstricting and proliferative properties of the endothelins (ETs), a family of three 21-amino acid peptides (ET-1, ET-2 and ET-3), were discovered in the 1980s.[58] ET-1 is physiologically most significant[59] and exerts a wide spectrum of biologic actions (Figure 1). Intravenous administration causes rapid and transient vasodilatation followed by a sustained increase in blood pressure.[58] The pressor response is secondary to increased total peripheral resistance with no change in heart rate or cardiac output. It is blocked by the administration of ETAR antagonists. In addition to its direct vasoconstrictor effect, ET-1 amplifies the contractile response to other vasoactive agents including norepinephrine and serotonin. In a similar manner, these agents can potentiate the vasoconstrictor response to ET-1. Thus, ET-1 plays an important role in regulating vascular reactivity. In healthy individuals, administration of a mixed ETAR-ETBR antagonist causes increased forearm blood flow and a small decrease in blood pressure, providing further evidence that ET-1 is involved in regulating vascular tonus.

Coronary artery and cerebral arterial vasospasm have the same physiologic effect on their destination vascular beds, myocardial ischemia and cerebral ischemia, resulting in cellular hypoxia and death. No-reflow through the myocardium after angiographic patency is reestablished has been successfully treated, while cerebrovascular arteries pose a different challenge, but no less of a threat to the integrity of the matrix.

Successful treatment of cerebral vasospasm remains elusive to this day, particularly in light of the mixed results of the Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage (CONSCIOUS-1) study. Although clazosentan, an endothelin receptor antagonist, reduced the relative risk of angiographic vasospasm by 65% in patients treated with the highest dose, there was only a small reduction in the number of delayed neurological deteriorations, and no effect on clinical outcome at 3 months.[60]

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