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 (K_ATP, BK_Ca, and, to a lesser extent, K_v) 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.

Background: Arterial hypertension (AH) remains a global health concern due to its multifactorial etiology, limited therapeutic success, and high cardiovascular risk. In this context, plant-derived compounds such as essential oils have gained attention as alternative strategies. The monoterpene (-)-linalool (LIN) demonstrates antihypertensive effects. However, its clinical application is hampered by poor solubility and low bioavailability. Methods: This study aimed to investigate the chronic cardiovascular effects of free LIN and its inclusion complex with β-cyclodextrin (LIN/β-CD) in spontaneously hypertensive rats (SHR) and normotensive Wistar rats. Results: Pharmacokinetic analysis showed that complexation with β-CD markedly improved LIN plasma exposure, increasing systemic bioavailability by approximately 20-fold and prolonging its circulation time. In acute assays, intravenous LIN and LIN/β-CD (50 mg/kg) reduced blood pressure in SHR, LIN induced bradycardia, and LIN/β-CD elicited a mild, non-significant tachycardia. Orally administered LIN/β-CD exerted superior antihypertensive effects compared to free LIN. In a 60-day chronic regimen, LIN/β-CD consistently maintained reduced arterial pressure, achieving levels comparable to normotensive controls, while free LIN produced transient effects. LIN/β-CD also significantly reduced the cardiac mass index in SHR, suggesting attenuation of hypertrophic remodeling. Vascular reactivity assays revealed enhanced endothelium-dependent and -independent relaxation and diminished vasoconstriction in LIN/β-CD-treated animals, indicating improved endothelial and smooth muscle function. Histological analyses confirmed the absence of cardiac or vascular injury in both treatment groups. Conclusions: In conclusion, the LIN/β-CD complex improves the pharmacokinetic profile and enhances the arterial morphology, antihypertensive and cardioprotective effects of linalool. These findings support its translational potential as a safe and effective oral formulation for the long-term management of hypertension and associated cardiovascular dysfunction.

Sexual dysfunction affects the quality of life for both men and women. Menthol, a TRPM8 agonist, is widely used in products to enhance sexual performance due to its cooling effect. Beyond this, menthol also induces vascular effects in male arteries. To explore its effects on female vasculature, we studied male and female C57BL/6 mice, along with female TRPM8 knockout (KO) mice. We isolated the internal pudendal artery and aorta to assess isometric contractile force. Menthol-induced relaxation of the pudendal artery was reduced in both female TRPM8 KO and male mice compared to female controls. Acetylcholine-induced relaxation was not affected in females, but in males, it was attenuated by menthol and enhanced by M8-B, a TRPM8 inhibitor. Menthol did not alter responses to norepinephrine, serotonin, or histamine in either sex. Notably, menthol-induced relaxation was also reduced in the aortas of female TRPM8 KO mice. In both the aorta and pudendal arteries of female mice, the TRPA1 inhibitor HC030031 significantly diminished menthol-induced relaxation. These findings suggest that TRPM8 modulation plays a role in acetylcholine-induced relaxation in male, but not female, pudendal arteries. Moreover, the menthol vascular effect in female arteries relies on TRPM8 and TRPA1 activation.

Introdução: O monoterpeno linalol (LIN) apresenta várias atividades farmacológicas, inclusive como anti-hipertensivo, porém, apresenta problemas de solubilidade devido ao seu caráter lipofílico. Dessa forma, estratégias de estabilização e melhoria de parâmetros farmacocinéticos e farmacodinâmicos vem sendo estudadas, como a formação de complexos de inclusão com ciclodextrinas (CDs). Objetivo: O objetivo desta revisão é reunir informações sobre os efeitos cardiovasculares do LIN e avaliar a possibilidade do uso de CDs para melhorar as propriedades biológicas do LIN. Metodologia: Esta revisão de literatura abrangeu artigos no período entre 1998 e 2022, coletadas nas bases de dados PUBMED, SciELO, LILACS e MEDLINE. Resultados: Em ratos normotensos, o LIN induziu hipotensão associada à taquicardia, enquanto em ratos hipertensos, reduziu a pressão arterial sem alterar a frequência cardíaca. O LIN tem ação direta sobre a vasculatura promovendo relaxamento vascular e melhora da função cardíaca. Interessantemente, a complexação de LIN com β-CDs melhorou a atividade anti-hipertensiva do monoterpeno. Conclusão: Foi evidenciado nesta revisão o potencial farmacológico do LIN como agente hipotensor, relaxante vascular e anti-hipertensivo. Além disso, há evidências que é possível melhorar o efeito anti-hipertensivo do LIN com a utilização de sistemas de inclusão com CDs, porém, estudos adicionais sobre este tema deverão ser realizados.

BACKGROUND: Emerging evidence suggests a critical interplay between skeletal muscle metabolism and vascular function in the context of hypertension. Elevated plasma lactate levels precede the onset of hypertension and are inversely associated with skeletal muscle mass, highlighting skeletal muscle atrophy and metabolic dysregulation as key contributors to cardiovascular dysfunction. METHODS: Male and female Wistar rats and spontaneously hypertensive rats were studied. Skeletal muscle performance was evaluated using in vivo plantarflexion torque measurements. Femoral arteries with surrounding skeletal muscle were isolated to assess contractility and relaxation. Plasma and muscle lactate levels were quantified using colorimetric assays. Structural remodeling and mitochondrial function were assessed via wheat germ agglutinin staining, succinate dehydrogenase activity, and high-resolution respirometry. Protein lactylation was evaluated by mass spectrometry-based lactylated proteomics. Human translational relevance was examined using publicly available skeletal muscle transcriptomic data RESULTS: Spontaneously hypertensive rats exhibited skeletal muscle dysfunction marked by increased fatigability, reduced muscle mass, impaired mitochondrial activity, and elevated muscle lactate levels. Despite upregulation of oxidative markers, persistent lactate accumulation suggested a maladaptive metabolic shift. Proteomics revealed differential lactylation of key structural proteins (myosins, nebulin) and metabolic enzymes (Nampt, GAPDH [glyceraldehyde-3-phosphate dehydrogenase]). The anticontractile effect of skeletal muscle on femoral arteries was completely lost in spontaneously hypertensive rats, accompanied by impaired vascular relaxation and increased arterial lactylation. Human transcriptomic data supported parallel metabolic alterations in hypertension. CONCLUSIONS: Hypertension disrupts skeletal muscle metabolic homeostasis and muscle-vascular communication, driven in part by persistent lactate accumulation and altered protein lactylation. Targeting lactate-mediated signaling may offer new therapeutic avenues for hypertensive vascular dysfunction.