Vasodilator and antihypertensive effects of a novel N‐acylhydrazone derivative mediated by the inhibition of L‐type Ca²⁺ channels

Abstract

New bioactive N-acylhydrazone derivatives synthesized from safrole previously have been found to promote intense vasodilation and antihypertensive activity. In this study, we describe the synthesis and the cardiovascular effects of the new N-acylhydrazone derivative (E)-N-methyl-N'-(thiophen-3-ylmethylene)benzo[d][1,3]dioxole-5-carbohydrazide (LASSBio-1289). Thoracic aorta and left papillary muscles from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were prepared for isometric tension recording. LASSBio-1289 promoted relaxation of endothelium-intact and denuded aortic rings with respective pIC₅₀ (-log IC₅₀) values of 5.07 ± 0.09 and 4.26 ± 0.09 (P < 0.001) for WKY rats and 5.43 ± 0.05 and 5.58 ± 0.07 (P > 0.05) for SHR. The vasodilator activity of LASSBio-1289 was increased in the KCl-contracted aorta. LASSBio-1289 attenuated the contracture elicited by Ca(2+) in depolarized aorta from both WKY rats and SHR. In endothelium-intact aorta from WKY rats, LASSBio-1289-induced relaxation was unchanged after incubation with propranolol, ZM 241385, atropine, diphenhydramine, and HOE140, but was significantly reduced by L-NAME and ODQ. LASSBio-1289 decreased papillary muscles contractility only at concentrations above 200 μm. Acute intravenous injection of LASSBio-1289 (3 mg/kg) produced a significant hypotensive response in SHR but not in WKY rats, suggesting its antihypertensive profile. The antihypertensive effect was also observed in SHR during 14 days of intraperitoneal and oral administration. In conclusion, our data demonstrated that LASSBio-1289 induces both endothelium-independent vasorelaxation involving the inhibition of Ca(2+) influx through L-type Ca(2+) channels in aorta from WKY rats and SHR, and endothelium-dependent relaxation mediated by the NO/cyclic GMP pathway in WKY rats.

Relaxation Induced by Atrial Natriuretic Peptide Is Impaired in Carotid but Not Renal Arteries from Spontaneously Hypertensive Rats Due to Reduced BK_Ca Channel Activity

“…[36][37][38][39] To test our hypothesis, we performed vascular functional studies as well as experiments to identify the molecular mechanisms involved. Animals and Experimental Design Male SHR and control WKY were obtained at the age of 4 weeks (Hoshino Laboratory Animals, Inc., Ibaraki, Japan).…”

The Novel Analogue of Hirsutine as an Anti-Hypertension and Vasodilatary Agent Both In Vitro and In Vivo

“…Then as we all know, high K + -induced (80mM) contraction in endothelium-denuded aortic rings is due to cell membrane depolarization and activation of the voltage-dependent Ca 2+ channel, especially for L-type Ca 2+ channel which could promote Ca 2+ influx[ 16 , 17 ]. According to our present study, both compound 1 and nifedipine can inhibit high K + -induced contraction in a concentration-dependent manner.…”

Structural characterization of LASSBio-1289: a new vasoactive N-methyl-N-acylhydrazone derivative

“…[16][17][18] After the planning and synthesis of LASSBio-1289, its cardiovascular properties were evaluated. Pereira et al 20 demonstrated that LASSBio-1289 induces both endothelium-independent vasorelaxation involving the inhibition of Ca 2+ influx through L-type Ca 2+ channels in aorta from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), as well as endotheliumdependent relaxation mediated by the nitric oxide/cyclic GMP (Guanosine Monophosphate) pathway in WKY rats.…”

“…In addition, LASSBio-1289 was 90-fold more potent than the precursor LASSBio-897 in aorta from SHR. 20 Many factors are involved in the task of describing the relationship between chemical structure and pharmacological activity of a new drug prototype. Among these factors, the study of atomic-level structure can be included.…”