7-Hydroxycoumarin Induces Vasorelaxation in Animals with Essential Hypertension: Focus on Potassium Channels and Intracellular Ca2+ Mobilization

Abstract

Cardiovascular diseases (CVD) are the deadliest noncommunicable disease worldwide. Hypertension is the most prevalent risk factor for the development of CVD. Although there is a wide range of antihypertensive drugs, there still remains a lack of blood pressure control options for hypertensive patients. Additionally, natural products remain crucial to the design of new drugs. The natural product 7-hydroxycoumarin (7-HC) exhibits pharmacological properties linked to antihypertensive mechanisms of action. This study aimed to evaluate the vascular effects of 7-HC in an experimental model of essential hypertension. The isometric tension measurements assessed the relaxant effect induced by 7-HC (0.001 μM–300 μM) in superior mesenteric arteries isolated from hypertensive rats (SHR, 200–300 g). Our results suggest that the relaxant effect induced by 7-HC rely on K+-channels (KATP, BKCa, and, to a lesser extent, Kv) activation and also on Ca2+ influx from sarcolemma and sarcoplasmic reticulum mobilization (inositol 1,4,5-triphosphate (IP3) and ryanodine receptors). Moreover, 7-HC diminishes the mesenteric artery’s responsiveness to α1-adrenergic agonist challenge and improves the actions of the muscarinic agonist and NO donor. The present work demonstrated that the relaxant mechanism of 7-HC in SHR involves endothelium-independent vasorelaxant factors. Additionally, 7-HC reduced vasoconstriction of the sympathetic agonist while improving vascular endothelium-dependent and independent relaxation.

Identification of a Novel Subtype-Selective α1B-Adrenoceptor Antagonist

“…Furthermore, a recent study showed that 7-hydroxycoumarin induces vasorelaxation in hypertensive rats and diminishes rat mesenteric arteries' responsiveness to α 1 -AR agonists challenge. 80 Thus, the potential of the coumarin scaffold for developing novel, selective α 1 -adrenoceptor ligands has precedent.…”

“…Other groups have also described coumarin-piperazine derivatives as serotonin and dopamine receptor binding ligands, and to a lesser extent α 1 -AR ligands, , again focusing only on the α 1A -AR subtype. Furthermore, a recent study showed that 7-hydroxycoumarin induces vasorelaxation in hypertensive rats and diminishes rat mesenteric arteries' responsiveness to α 1 -AR agonists challenge . Thus, the potential of the coumarin scaffold for developing novel, selective α 1 -adrenoceptor ligands has precedent.…”