Modulation of sympathoadrenergic contractions by perivascular adipose tissue in mesenteric arteries of rats with different level of body adiposity.

Obesity is associated with increased sympathetic nervous system activation, possibly contributing to higher cardiovascular risk. The aim of this study was to assess the relationship between body adiposity and sympathoadrenergic contractions in rat isolated mesenteric arteries, and the modulatory effect of mesenteric perivascular adipose tissue (PVAT). Experiments were performed on male 38-week-old Wistar, Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Paired rings of isolated rat superior mesenteric arteries with or without PVAT were prepared and connected to a force-displacement transducer for the recording of isometric tension. Contractile responses were elicited by increasing doses of exogenous noradrenaline and by endogenous noradrenaline released during electrical stimulation of perivascular adrenergic nerves. In ZDF rats, mesenteric PVAT had marked anticontractile effect leading to significant reduction in adrenergic contractions of their superior mesenteric arteries; however, in arterial preparations without PVAT, obese rats showed significantly increased sensitivity in their contractile responses to adrenergic stimulation when compared to other rat groups. In Wistar rats, ranging in the level of body adiposity between ZL and ZDF rats, neurogenic contractions in arterial preparations with preserved PVAT were higher compared to those without PVAT. No vasomodulatory effect of PVAT was detected in mesenteric arteries from ZL rats. The results of this study indicate that the modulatory effect of mesenteric PVAT on arterial adrenergic contractions did not change in proportion with increasing adiposity; however, it could be influenced by the rat strain-specific distribution of sympathetic nerves between PVAT and the proper mesenteric arterial wall. In ZDF rats, characterized by higher vascular sympathetic tone, the mesenteric arteries might be specifically regulated by the anticontractile effect of PVAT, leading to higher mesenteric blood flow. This could be associated with hyperphagia and increased nutrient-induced mesenteric vasodilatation in this rat strain.

Effect of low dose L-NAME pretreatment on nitric oxide/reactive oxygen species balance and vasoactivity in L-NAME/salt-induced hypertensive rats.

Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase-dependent reactive oxygen species (ROS) overproduction and decreased nitric oxide (NO) bioavailability lead to vascular dysfunction and development of hypertension. The goal of our study was to analyze an effect of salt diet and NO synthase (NOS) inhibition with NG-nitro-L-arginine methyl ester (L-NAME) on blood pressure (BP), arterial reactivity, NO production, as well as ROS level in adult rats pretreated with low dose of L-NAME (2 mg/kg/day) for three weeks. Higher dose of L-NAME (40 mg/kg/day), or salt diet (8% NaCl), or combination of both were applied for the following four weeks. The administration of L-NAME in low dose had no effect on BP but enhanced the expression of eNOS. Both higher dose of L-NAME and salt diet elevated BP, decreased NOS activity, and impaired the endothelium-dependent arterial relaxation. However, salt diet did not increase ROS production and sympathoadrenergic arterial contractions in low dose L-NAME-pretreated rats. Combination of salt diet with higher dose of L-NAME did not evoke additive decrease of NOS activity, but it caused elevation of conjugated dienes (CD) concentration and NADPH oxidase 2 (Nox-2) protein expression. In conclusion, these findings indicate that chronic low dose of L-NAME treatment has a potential to trigger adapting mechanisms to attenuate some cardiovascular disorders.

Effect of perivascular adipose tissue on arterial adrenergic contractions in normotensive and hypertensive rats with high fructose intake.

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 prehypertensive 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.

Interaction of perivascular adipose tissue and sympathetic nerves in arteries from normotensive and hypertensive rats.

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.

[Urotensin II--a newly discovered modulator of cardiovascular functions in vertebrates]. / Urotenzín II--novo objavený modulátor kardiovaskulárnych funkcií u stavovcov.

Peptide urotensin II was originally isolated from the urophysis of teleost fishes; later it was identified also in higher vertebrates in various organs and tissues, including cardiovascular structures. Since its discovery it has been considered as a highly potent vasoconstrictor inducing contraction of smooth muscle in subnanomolar concentrations. Its wide distribution as well as its high interspecies homology indicates that this peptide is involved in regulation of many important physiological functions in vertebrates. An effort to discover other possible functions of urotensin II was intensified by the identification of its G-protein coupled receptor and its identification in humans. Furthermore, altered levels of expression of urotensin II and its receptor were found in various disease states including hypertension, diabetes, heart and renal failure, in experimental animal models as well as in humans. Therefore, there is widely discussed question regarding the possible role of urotensin II in etiopathogeneses of these diseases, however the exact mechanisms are still unknown. The aim of this review is to summarize the current knowledge about urotensin II with emphasis to its direct and undirect effects in cardiovascular system.

[Programming of cardiovascular phenotype by pharmacological intervention in early developmental stages: prevention of hypertension]. / Programovanie kardiovaskulárneho fenotypu farmakologickým ovplyvnením v skorých stádiách vývinu: prevencia hypertenzie.

Cardiovascular diseases, including hypertension, represent serious medical and social problem because they affect many people in industrialized countries in the world and, unfortunately, their incidence has not decreasing tendency. Human essential hypertension is a chronic, slowly developing disease, which is a consequence of abnormalities in the development of cardiovascular system and its regulation, which are subsequently reflected in pathological rise of blood pressure. In general, blood pressure increases slowly and gradually and this may last several years. Myocardial hypertrophy and structural alterations of the vessel system frequently occur. As hypertension is already established, then complete normalization of blood pressure is difficult to obtain. Therefore, it is necessary to focus on its prevention, this means, to intervene before blood pressure elevation in individuals with significant genetic predisposition to this disease. Moreover, it is well known that cardiovascular system of the young organism is very sensitive to various environmental influences, and one can expect that it may also be more susceptible to vasoactive substances in prevention and treatment of cardiovascular diseases. Hypertension and its pharmacological treatment should therefore be studied with regard to the maturity of an individual. In accordance with the hypothesis of developmental plasticity of organisms, it may be possible (by pharmacological intervention in early ontogenetic stages of predisposed individual) to achieve such a setting of structural and functional parameters which could reduce the subsequent clinical manifestation of genetically induced hypertensive state.

Effect of chronic nifedipine treatment on blood pressure and adrenergic responses of isolated mesenteric artery in young rats with developing spontaneous hypertension.

It is documented that in chronic hypertensive state there is an increased vasodepressor response to calcium channel antagonists such as the dihydropyridine derivate nifedipine. This effect is generally proportional to initial blood pressure as was demonstrated in several models of experimental hypertension. In the present study we investigated the effect of chronic nifedipine treatment on the development of cardiovascular system in young spontaneously hypertensive rats (SHR) in order to evaluate whether it could prevent the abnormalities leading to hypertensive state. Four- and eight-week-old rats were treated with nifedipine (50 mg/kg/day) for 4 weeks. Blood pressure of nifedipine-treated SHR remained at the initial level in contrast to their untreated controls where it continued to increase. In both age groups, chronic nifedipine administration reduced neurogenic contractions of isolated superior mesenteric artery, but did not significantly affect the dose-response curve to exogenous noradrenaline in 8-week-old rats. In contrast, maximum response to noradrenaline was significantly attenuated in mesenteric artery of 12-week-old nifedipine-treated SHR. We can presume that the antihypertensive effect of nifedipine is similar in both stages of spontaneous hypertension development, but the mechanisms involved might be different. It seems that chronic reduction of calcium influx during the rapid phase of pathological blood pressure increase in SHR may eliminate the effect of enhanced sympathetic tone, which may have unfavorable consequences on cardiovascular structure and function.

Inactivation of G(i) proteins by pertussis toxin diminishes the effectiveness of adrenergic stimuli in conduit arteries from spontaneously hypertensive rats.

Treatment with pertussis toxin (PTX) which eliminates the activity of G(i) proteins effectively reduces blood pressure (BP) and vascular resistance in spontaneously hypertensive rats (SHR). In this study we have compared the functional characteristics of isolated arteries from SHR with and without PTX-treatment (10 microg/kg i.v., 48 h before the experiment). Rings of thoracic aorta, superior mesenteric artery and main pulmonary artery were studied under isometric conditions to measure the reactivity of these vessels to receptor agonists and to transmural electrical stimuli. We have found that the treatment of SHR with PTX had no effect on endothelium-dependent relaxation of thoracic aorta induced by acetylcholine. In PTX-treated SHR, the maximum contraction of mesenteric artery to exogenous noradrenaline was reduced and the dose-response curve to cumulative concentration of noradrenaline was shifted to the right. Similarly, a reduction in the magnitude of neurogenic contractions elicited by electrical stimulation of perivascular nerves was observed in the mesenteric artery from PTX-treated SHR. PTX treatment of SHR also abolished the potentiating effect of angiotensin II on neurogenic contractions of the main pulmonary artery. These results indicate that PTX treatment markedly diminishes the effectiveness of adrenergic stimuli in vasculature of SHR. This could importantly affect BP regulation in genetic hypertension.