Renovascular hypertension has robust effects on control of blood pressure, including an impairment in baroreflex mechanisms, which involves oxidative stress. Although α-lipoic acid (LA) has been described as a potent antioxidant, its effect on renovascular hypertension and baroreflex sensitivity (BRS) has not been investigated. In the present study we analyzed the effects caused by chronic treatment with LA on blood pressure, heart rate and baroreflex sensitivity (sympathetic and parasympathetic components) in renovascular hypertensive rats. Male Wistar rats underwent 2-Kidney-1-Clip (2K1C) or sham surgery and were maintained untouched for four weeks to develop hypertension. Four weeks post-surgery, rats were treated with LA (60 mg/kg) or saline for 14 days orally. On the 15th day mean arterial pressure (MAP) and heart rate (HR) were recorded. In addition, baroreflex sensitivity test using phenylephrine (8 µg/kg, i.v.) and sodium nitroprusside (25 µg/kg, i.v.) was performed. Chronic treatment with LA decreased blood pressure in hypertensive animals; however, no significant changes in baseline HR were observed. Regarding baroreflex, LA treatment increased the sensitivity of both the sympathetic and parasympathetic components. All parameters studied were not affected by treatment with LA in normotensive animals. Our data suggest that chronic treatment with LA promotes antihypertensive effect and improves baroreflex sensitivity in rats with renovascular hypertension.

TRV027 is a biased agonist for the Angiotensin (Ang)-II type 1 receptor (ATR), able to recruit β-arrestin 2 independently of G-proteins activation. β-arrestin activation in the central nervous system (CNS) was suggested to oppose the effects of Ang-II. The present study evaluates the effect of central infusion of TRV027 on arterial pressure (AP), autonomic function, baroreflex sensitivity (BRS), and peripheral vascular reactivity. Spontaneously hypertensive (SH) and Wistar Kyoto (WKY) rats were treated with TRV027 for 14 days (20 ng/h) delivered to the lateral ventricle via osmotic minipumps. Mechanistic studies were performed in HEK293T cells co-transfected with ATR and Ang converting enzyme type 2 (ACE2) treated with TRV027 (100 nM) or Ang-II (100 nM). TRV027 infusion in SH rats (SHR) reduced AP (~20 mmHg, <0.05), sympathetic vasomotor activity (ΔMAP = -47.2 ± 2.8 compared with -64 ± 5.1 mmHg, <0.05) and low-frequency (LF) oscillations of AP (1.7 ± 0.2 compared with 5.8 ± 0.4 mmHg, <0.05) compared with the SHR control group. TRV027 also increased vagal tone, improved BRS, reduced the reactivity of mesenteric arteries to Ang-II and increased vascular sensitivity to phenylephrine (Phe), acetylcholine, (ACh), and sodium nitroprusside (SNP). , TRV027 prevented the Ang-II-induced up-regulation of ADAM17 and in contrast with Ang-II, had no effects on ACE2 activity and expression levels. Furthermore, TRV027 induced lesser interactions between ATR and ACE2 compared with Ang-II. Together, these data suggest that due to its biased activity for the β-arrestin pathway, TRV027 has beneficial effects within the CNS on hypertension, autonomic and vascular function, possibly through preserving ACE2 compensatory activity in neurones.

Abstract:The cardiovascular effects elicited by the ethanolic extract obtained from the roots of Erythroxylum pungens O.E. Schulz, Erythroxylaceae (EEEP) and the vasorelaxant effect induced by its main tropane alkaloid (pungencine) were investigated. In normotensive rats, administration of EEEP (1, 10, 30 and 60 mg/kg i.v., randomly) produced dose-dependent hypotension (-2±1, -7±0.5 -17.6±1, -24±1 ∆ mmHg, n=5) followed by tachycardia (3±0.5, 7±2, 7.1±1, 10±5 ∆ bpm, n=5). In intact phenylephrine (Phe, 10 μM)-pre-contracted rings, EEEP (0.01-500 μg/mL) induced concentrationdependent vasorelaxation (EC50 13.7±5.5 μg/mL, Maximal Response= 92±2.6%), and this effect was unchanged after the removal of the vascular endothelium (EC50 27.2±4.7 μg/ml, Maximal Response= 88.3±3.3 %). In KCl (80 mM)-pre-contracted-endotheliumdenuded rings, EEEP elicited concentration-dependent relaxation (EC50= 128.2±11.2 μg/mL, Maximal Response 76.8±3.4%). Vasorelaxation has also been achieved with tonic contractions evoked by the L-type Ca 2+ channel agonist Bay K 8644 (EC50 80.2±9.1 μg/mL, Maximal Response 86.3±8.3%). In addition, in a depolarizing medium, EEEP inhibited CaCl 2 (30-500 μg/mL) induced contractions and caused a concentrationdependent rightward shift of the relaxation curves. Lastly, the tropane alkaloid pungencine caused vasorelaxation in mesenteric arteries resembling to the EEEP responses. These results suggests that EEEP induces hypotension and vasorelaxation, at least in part, due to the reduction in [Ca 2+ ]i in vascular smooth muscle cells.

We investigated the cardiovascular effects induced by the nitric oxide donor Cyclohexane Nitrate (HEX). Vasodilatation, NO release and the effects of acute or sub-chronic treatment with HEX on cardiovascular parameters were evaluated. HEX induced endothelium-independent vasodilatation (Maximum effect [efficacy, ME] = 100.4 ± 4.1%; potency [pD2] = 5.1 ± 0.1). Relaxation was attenuated by scavenging nitric oxide (ME = 44.9 ± 9.4% vs. 100.4 ± 4.1%) or by inhibiting the soluble guanylyl cyclase (ME = 38.5 ± 9.7% vs. 100.4 ± 4.1%). In addition, pD2 was decreased after non-selective blockade of K+ channels (pD2 = 3.6 ± 0.1 vs. 5.1 ± 0.1) or by inhibiting KATP channels (pD2 = 4.3 ± 0.1 vs. 5.1 ± 0.1). HEX increased NO levels in mesenteric arteries (33.2 ± 2.3 vs. 10.7 ± 0.2 au, p < 0.0001). Intravenous acute administration of HEX (1–20 mg/kg) induced hypotension and bradycardia in normotensive and hypertensive rats. Furthermore, starting at 6 weeks after the induction of 2K1C hypertension, oral treatment with the HEX (10 mg/Kg/day) for 7 days reduced blood pressure in hypertensive animals (134 ± 6 vs. 170 ± 4 mmHg, respectively). Our data demonstrate that HEX is a NO donor able to produce vasodilatation via NO/cGMP/PKG pathway and activation of the ATP-sensitive K+ channels. Furthermore, HEX acutely reduces blood pressure and heart rate as well as produces antihypertensive effect in renovascular hypertensive rats.

The search for new nitric oxide donors is warranted by the limitations of organic nitrates currently used in cardiology. The new organic nitrate 2-nitrate-1,3-dibuthoxypropan (NDBP) exhibited promising cardiovascular activities in previous studies. The aim of this study was to investigate the cardiorespiratory responses evoked by NDBP and to compare them to the clinically used organic nitrate nitroglycerine (NTG). Arterial pressure, heart rate and respiration were recorded in conscious adult male Wistar rats. Bolus i.v. injection of NDBP (1 to 15mg/kg; n=8) and NTG (0.1 to 5mg/kg; n=8) produced hypotension. NDBP induced bradycardia at all doses, while NTG induced tachycardia at three lower doses but bradycardia at higher doses. Hydroxocobalamin (20mg/kg; HDX), a NO scavenger, blunted hypotension induced by NDBP (15mg/kg), and its bradycardic effect (n=6). In addition, HDX blunted both hypotension and bradycardia induced by a single dose of NTG (2.5mg/kg; n=6). Both NDBP and NTG altered respiratory rate, inducing a biphasic effect with a bradypnea followed by a tachypnea; HDX attenuated these responses. Our data indicate that NDBP and NTG induce hypotension, bradycardia and bradypnea, which are mediated by nitric oxide release.

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Diabetic cardiomyopathy (DC) describes diabetes-associated changes in the structure and function of myocardium that are not directly linked to other factors such as hypertension. Currently there are some models of DC; however, they take a large time period to mimic key features. In the present study, we investigated the effects of a short-term high-fat/high salt diet (HFHS) treatment on myocardial function and structure, and vascular reactivity in C57BL/6 male mice. After 14 weeks HFHS induced hypertension (MAP = 144.95 ± 16.13 vs 92.90 ± 18.95 mm Hg), low glucose tolerance (AUC = 1049.01 ± 74.79 vs 710.50 ± 52.57 a.u.), decreased insulin sensitivity (AUC = 429.83 ± 35.22 vs 313.67 ± 19.55 a.u.) and increased adiposity (epididymal fat weight 0.96 ± 0.10 vs 0.59 ± 0.06 OW/BW × 10), aspects present in metabolic syndrome. Cardiac evaluation showed diastolic dysfunction (E/A ratio = 1.20 vs 1.90 u.a.) and cardiomyocyte hypertrophy (cardiomyocyte area = 502.82 ± 31.46 vs 385.58 ± 22.11 μm). Lastly, vascular reactivity was impaired with higher contractile response (136.10 ± 3.49 vs 120.37 ± 5.43%) and lower response to endothelium-dependent vasorelaxation (74.01 ± 4.35 vs 104.84 ± 3.57%). In addition, the diet was able to induce an inward coronary remodeling (vascular total area: SCNS 6185 ± 800.6 vs HFHS 4085 ± 213.7 μm). Therefore, we conclude that HFHS short-term treatment was able to induce metabolic syndrome-like state, cardiomyopathy and vascular injury working as an important tool to study cardiometabolic diseases.