Background: Quercetin (QCT) was shown to exert beneficial cardiovascular effects in young healthy animals. The aim of the present study was to determine cardiovascular benefits of QCT in older, 6-month and 1-year-old Zucker diabetic fatty (ZDF) rats (model of type 2 diabetes). Methods: Lean (fa/+) and obese (fa/fa) ZDF rats of both ages were treated with QCT for 6 weeks (20 mg/kg/day). Isolated hearts were exposed to ischemia-reperfusion (I/R) injury (30 min/2 h). Endothelium-dependent vascular relaxation was measured in isolated aortas. Expression of selected proteins in heart tissue was detected by Western blotting. Results: QCT reduced systolic blood pressure in both lean and obese 6-month-old rats but had no effect in 1-year-old rats. Diabetes worsened vascular relaxation in both ages. QCT improved vascular relaxation in 6-month-old but worsened in 1-year-old obese rats and had no impact in lean controls of both ages. QCT did not exert cardioprotective effects against I/R injury and even worsened post-ischemic recovery in 1-year-old hearts. QCT up-regulated expression of eNOS in younger and PKCε expression in older rats but did not activate whole PI3K/Akt pathway. Conclusions: QCT might be beneficial for vascular function in diabetes type 2; however, increasing age and/or progression of diabetes may confound its vasculoprotective effects. QCT seems to be inefficient in preventing myocardial I/R injury in type 2 diabetes and/or higher age. Impaired activation of PI3K/Akt kinase pathway might be, at least in part, responsible for failing cardioprotection in these subjects.

Aliskiren, a renin inhibitor, has been shown to have cardioprotective and blood pressure (BP) lowering effects. We aimed to determine the effects of nanoparticle-loaded aliskiren on BP, nitric oxide synthase activity (NOS) and structural alterations of the heart and aorta developed due to spontaneous hypertension in rats. Twelve week-old male spontaneously hypertensive rats (SHR) were divided into the untreated group, group treated with powdered or nanoparticle-loaded aliskiren (25 mg/kg/day) and group treated with nanoparticles only for 3 weeks by gavage. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions, and collagen content were determined in both the heart and aorta. Vasoactivity of the mesenteric artery and wall thickness, inner diameter, and cross-sectional area (CSA) of the aorta were analyzed. After 3 weeks, BP was lower in both powdered and nanoparticle-loaded aliskiren groups with a more pronounced effect in the latter case. Only nanoparticle-loaded aliskiren increased the expression of nNOS along with increased NOS activity in the heart (by 30%). Moreover, nanoparticle-loaded aliskiren decreased vasoconstriction of the mesenteric artery and collagen content (by 11%), and CSA (by 25%) in the aorta compared to the powdered aliskiren group. In conclusion, nanoparticle-loaded aliskiren represents a promising drug with antihypertensive and cardioprotective effects.

The inhibitory action of perivascular adipose tissue (PVAT) in modulation of arterial contraction has been recently recognized and contrasted with the prohypertensive effect of obesity in humans. In this study we demonstrated that PVAT might have opposing effect on sympatho-adrenergic contractions in different rat conduit arteries. In superior mesenteric artery isolated from normotensive Wistar-Kyoto rats (WKY), PVAT exhibited inhibitory influence on the contractions to exogenous noradrenaline as well as to endogenous noradrenaline released from arterial sympathetic nerves during transmural electrical stimulation or after application of tyramine. In contrast, the abdominal aorta with intact PVAT responded with larger contractions to transmural electrical stimulation and tyramine when compared to the aorta after removing PVAT; the responses to noradrenaline were similar in both. This indicates that PVAT may contain additional sources of endogenous noradrenaline which could be responsible for the main difference in the modulatory effect of PVAT on adrenergic contractions between abdominal aortas and superior mesenteric arteries. In spontaneously hypertensive rats (SHR), the anticontractile effect of PVAT in mesenteric arteries was reduced, and the removal of PVAT completely eliminated the difference in the dose-response curves to exogenous noradrenaline between SHR and WKY. These results suggest that in mesenteric artery isolated from SHR, the impaired anticontractile influence of PVAT might significantly contribute to its increased sensitivity to adrenergic stimuli.

The aim of this study was to investigate the effect of high fructose intake associated with moderate increase in adiposity on rat arterial adrenergic responses and their modulation by perivascular adipose tissue (PVAT). After eight-week-lasting substitution of drinking water with 10 % fructose solution in adult normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), their systolic blood pressure, plasma triglycerides, and relative liver weight were elevated when compared to their respective control groups. Moreover, in SHR, body weight and relative heart weight were increased after treatment with fructose. In superior mesenteric arteries, PVAT exerted inhibitory influence on adrenergic contractile responses and this effect was markedly stronger in control WKY than in SHR. In fructose-administered WKY, arterial adrenergic contractions were substantially reduced in comparison with the control group; this was caused mainly by enhancement of anticontractile action of PVAT. The diminution of the mesenteric arterial contractions was not observed after fructose treatment in SHR. We conclude that the increase in body adiposity due to fructose overfeeding in rats might have pro-hypertensive effect. However, in WKY it might cause PVAT-dependent and independent reduction in arterial contractile responses to adrenergic stimuli, which could attenuate the pathological elevation in vascular tone.

The aim of this study was to investigate the effects of chronic social stress on endothelium-dependent relaxation in the superior mesenteric artery (SMA) and its first branches (1MA) as well as on neurogenic contractions of SMA in adult, male Wistar-Kyoto (WKY) rats. Mesenteric arteries were isolated from control (living space: 480 cm(2)/rat) or stressed rats exposed to 8-week-lasting crowding stress (living space: 200 cm(2)/rat). Blood pressure (BP) and heart rate, determined by tail-cuff plethysmography, were not affected by crowding. Stress increased neurogenic contractions of SMA elicited by electrical stimulation of perivascular nerves and significantly elevated vasoconstriction induced by exogenous noradrenaline in SMA, without modulation of its endothelial function. In 1MA, nitric oxide (NO)-dependent component of endothelium-dependent relaxation to acetylcholine was investigated. In 1MA, stress failed to affect noradrenaline- and phenylephrine-induced vasoconstriction, total acetylcholine-induced relaxation as well as its NO-dependent and NO-independent components. Moreover, endothelium-independent sodium nitroprusside-induced relaxations of 1MA from the stressed rats did not differ from those of controls. In conclusion, chronic stress produced by crowding failed to induce an increase of BP, presumably because endothelial function of SMA and vascular function of small mesenteric arteries, which are rather important in BP regulation, remained preserved.

The aim of this study was to evaluate the involvement of nitric oxide (NO) system damage in the deleterious effects of high-fructose intake in rats. Fructose was administered as 10% solution in drinking water to twelve-week-old male Wistar rats for the period of 8 weeks. Blood pressure was measured by tail-cuff plethysmography. After sacrificing the rats at the end of the treatment, relative weights of heart and liver and biochemical parameters in blood plasma were determined. Reactivity of isolated conduit arteries was measured using a force-displacement transducer for recording isometric tension. Fructose drinking rats had increased blood pressure and impaired acetylcholine-induced relaxation of the thoracic aorta in comparison with control rats drinking just tap water. Relative liver weight and plasma concentrations of glucose and triglycerides were also elevated after fructose administration. In a further group of Wistar rats, inhibition of NO production by administration of NG-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg/day) was performed throughout fructose intake. L-NAME treatment itself induces increase in blood pressure and relative heart weight as well as impairment in arterial relaxation and contractility. However, in these rats, fructose administration did not cause further elevation of blood pressure and other abnormalities observed in rats receiving fructose without L-NAME. Our results showed that in the state of NO deficiency (induced by L-NAME administration) fructose does not induce cardiovascular and metabolic alterations which develop in rats with a functional NO system. This indicates that impairment of the NO system may participate in many of the adverse effects induced by high-fructose intake.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects host cells through angiotensin-converting enzyme 2 (ACE2). Concurrently, the product of ACE2 action, angiotensin 1–7 (Ang 1–7), binds to Mas receptors within the cardiovascular system and provides protective effects. Therefore, it is crucial to reveal the role of ACE2 inhibition, especially within pre-existing cardiovascular pathologies. In our study, we imitated the action of SARS-CoV-2 in organisms using the low dose of the ACE2 inhibitor MLN-4760 with the aim of investigating to what degree ACE2 inhibition is detrimental to the cardiovascular system of spontaneously hypertensive rats (SHRs), which represent a model of human essential hypertension. Our study revealed the complex action of MLN-4760 in SHRs. On the one hand, we found that MLN-4760 had 1) (pro)obesogenic effects that negatively correlated with alternative renin-angiotensin system activity and Ang 1–7 in plasma, 2) negative effects on ACE1 inhibitor (captopril) action, 3) detrimental effects on the small arteries function and 4) anti-angiogenic effect in the model of chick chorioallantoic membrane. On the other hand, MLN-4760 induced compensatory mechanisms involving strengthened Mas receptor-, nitric oxide- and hydrogen sulfide-mediated signal transduction in the aorta, which was associated with unchanged blood pressure, suggesting beneficial action of MLN-4760 when administered at a low dose.

The aim of this study was to evaluate the mutual relationship among perivascular adipose tissue (PVAT) and endogenous and exogenous H2S in vasoactive responses of isolated arteries from adult normotensive (Wistar) rats and hypertriglyceridemic (HTG) rats, which are a nonobese model of metabolic syndrome. In HTG rats, mild hypertension was associated with glucose intolerance, dyslipidemia, increased amount of retroperitoneal fat, increased arterial contractility, and endothelial dysfunction associated with arterial wall injury, which was accompanied by decreased nitric oxide (NO)-synthase activity, increased expression of H2S producing enzyme, and an altered oxidative state. In HTG, endogenous H2S participated in the inhibition of endothelium-dependent vasorelaxation regardless of PVAT presence; on the other hand, aortas with preserved PVAT revealed a stronger anticontractile effect mediated at least partially by H2S. Although we observed a higher vasorelaxation induced by exogenous H2S donor in HTG rats than in Wistar rats, intact PVAT subtilized this effect. We demonstrate that, in HTG rats, endogenous H2S could manifest a dual effect depending on the type of triggered signaling pathway. H2S within the arterial wall contributes to endothelial dysfunction. On the other hand, PVAT of HTG is endowed with compensatory vasoactive mechanisms, which include stronger anti-contractile action of H2S. Nevertheless, the possible negative impact of PVAT during hypertriglyceridemia on the activity of exogenous H2S donors needs to be taken into consideration.