The phenanthrenes gymnopusin (1), fimbriol A (2), and erianthridin (3) from Maxillaria densa were found to induce significant relaxant effects in a concentration-dependent and endothelium-independent manner on aortic rings precontracted with norepinephrine (NE, 0.1 μM) and KCl (80 mM). Compound 1 was the most active and also inhibited the cumulative concentration-response contraction of NE or CaCl(2). Contractions induced by FPL 64176, an agonist of L-type voltage-dependent calcium channels, were blocked by 1. The potassium channel blockers glibenclamide and TEA (tetraethylammonium) reduced the relaxations induced by 1. Nevertheless, the effect of 1 was not modified by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a specific soluble guanylate cyclase inhibitor. The functional results obtained suggest that 1 induces relaxation through an endothelium-independent pathway by the control of cationic channels (calcium channel blockade and potassium channel opening) in the myogenic response of rat aortic rings.
Several 4H-pyran derivatives were designed and synthesized previously as
vasorelaxant agents for potential antihypertensive drugs. In this context, the
objective of the present investigation was to determine the functional mechanism
of vasorelaxant action of
6-amino-3-methyl-4-(2-nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
(1) and its in vivo antihypertensive effect. Thus, compound
1 showed significant vasorelaxant action on isolated aorta rat rings
pre-contracted with serotonin or noradrenaline, and the effect was not
endothelium-dependent. Compound 1 induced a significant relaxant effect
when aortic rings were contracted with KCl (80 mM), indicating that the
main mechanism of action is related to L-type calcium channel blockade. Last was
corroborated since compound 1 induced a significant
concentration-dependent lowering of contraction provoked by cumulative
CaCl2 adding. Moreover, compound 1 was capable to block
the contraction induced by FPL 64176, a specific L-type calcium channel agonist,
in a concentration-dependent manner. On the other hand, docking studies revealed
that compound 1 interacts on two possible sites of the L-type calcium
channel and it had better affinity energy
(−7.80+/−0.00 kcal/mol on the
best poses) than nifedipine
(−6.86+/−0.14 kcal/mol).
Finally, compound 1 (50 mg/kg) showed significant
antihypertensive activity, lowering the systolic and diastolic blood pressure on
spontaneously hypertensive rats (SHR) without modifying heart rate.
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