Mariusz Sikora

Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats.

BACKGROUND Recent evidence suggests that an elevated plasma trimethylamine N-oxide (TMAO) level is associated with an increased risk of adverse cardiovascular events in humans; however, the mechanism is not clear. The aims of this study were to establish the plasma TMAO level in rats and to evaluate the effect of TMAO on arterial blood pressure (BP) and the hemodynamic effects of angiotensin II (Ang II). METHODS Twelve-week-old, Sprague-Dawley rats were implanted with telemetric transmitters, and continuous recordings of heart rate, systolic BP (SBP), and diastolic BP (DBP) were made for 7 days before and 14 days during osmotic minipump-driven subcutaneous infusion of saline (controls), TMAO, low-dose Ang II, or Ang II + TMAO. Plasma TMAO concentration was evaluated using liquid chromatography coupled with triple-quadrupole mass spectrometry. RESULTS The plasma TMAO concentration in controls was 0.57 μmol/L, whereas in TMAO-infused rats it was 58 μmol/L. Neither saline nor TMAO infusion affected SBP and DBP. Infusion of Ang II significantly increased SBP and DBP for the first 5 days of infusion only. In contrast, infusion of Ang II + TMAO produced a hypertensive response that lasted until the end of the experiment. TMAO infusions did not affect body weight and motor activity. CONCLUSIONS We showed that physiological plasma TMAO concentration in rats was approximately 10 times lower than that reported in humans. Furthermore, the new finding of the study is that TMAO does not affect BP in normotensive animals. However, it prolongs the hypertensive effect of Ang II.

Exogenous hydrogen sulfide causes different hemodynamic effects in normotensive and hypertensive rats via neurogenic mechanisms

BACKGROUND Increasing evidence suggests that disturbances in H2S homeostasis may participate in the development of hypertension. In this study we compared hemodynamic responses to intracerebroventricular (ICV) infusions of sodium hydrosulfide (NaHS), a H2S donor, between normotensive rats (WKY), spontaneously hypertensive rats (SHR) and angiotensin II - induced hypertensive rats (WKY-Ang II). METHODS We tested the effects of NaHS on mean arterial blood pressure (MABP) and heart rate (HR) in 12-14-week-old, male rats. MABP and HR were continuously recorded at baseline and during ICV infusion of either vehicle (Krebs-Henseleit buffer) or NaHS. RESULTS ICV infusions of the vehicle did not affect MABP and HR. WKY rats infused with 30 nmol/h of NaHS showed a mild decrease in MABP and HR. ICV infusion of 100 nmol/h produced a biphasic response i.e. mild hypotension and bradycardia followed by an increase in MABP and HR, whereas, the infusion of 300 nmol/h of the H2S donor caused a monophasic increases in MABP and HR. In contrast, SHR rats as well as WKY-Ang II rats showed a decrease in MABP and HR during ICV infusions of NaHS. CONCLUSIONS The results provide further evidence for the involvement of H2S in the neurogenic regulation of the circulatory system and suggest that alterations in H2S signaling in the brain could be associated with hypertension.

Statins, the renin–angiotensin–aldosterone system and hypertension – a tale of another beneficial effect of statins

Background: Statins, a class of lipid lowering drugs, decrease mortality associated with cardiovascular events. As hypercholesterolemia is often accompanied by hypertension, a large number of patients receive therapy with statins and antihypertensive drugs which act via the renin–angiotensin–aldosterone system (RAAS). New guidelines published by the American Heart Association and American College of Cardiology on the treatment of dyslipidaemia and the reduction of atherosclerotic cardiovascular risk, which use a risk prediction algorithm based on risk factors such as hypertension but not low-density lipoprotein (LDL) level, may even further increase the number of patients receiving such concomitant therapy. Method: In this paper we review studies on an interaction between statins, the RAAS and antihypertensive drugs acting via the RAAS. Result: Accumulating evidence suggests that the combination of statins and drugs affecting the RAAS exerts a synergistic effect on the circulatory system. For example, statins may lower arterial blood pressure and augment the effect of antihypertensive drugs acting via the RAAS. Statins may interact with the RAAS in a number of ways i.e. to decrease the expression of receptors for angiotensin II (Ang II), inhibit the Ang II-dependent intracellular signalling, reduce the RAAS-dependent oxidative stress and inflammation as well as inhibit the synthesis of Ang II and aldosterone. Conclusion: Although statins given either alone or together with antihypertensive drugs acting via the RAAS may lower arterial blood pressure, further research is needed to evaluate the mechanisms and their therapeutic significance.

The role of brain gaseous transmitters in the regulation of the circulatory system.

A number of neurotransmitters, including biologically active gases namely, nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) have been postulated to play an important role in the control of the cardiovascular system by the brain. The attention of researchers has been focused on NO in particular. It has been shown that pharmacological manipulation of NO concentration in the brain produces significant changes in circulatory parameters. Furthermore, significant alterations in the brain NO system have been found in animal models of human cardiovascular diseases. These findings imply that NO in the brain may become a promising target for new treatment strategies. Although H2S and CO have also been proved to serve as transmitters in the central nervous system, their role in the neurogenic regulation of the cardiovascular system remains more obscure. Interestingly, increased synthesis of NO, H2S and CO is found in inflammation and it appears that the gases mediate some of the circulatory responses to inflammatory stimuli. In this review we discuss the role of brain gaseous transmitters in the control of the circulatory system in health and disease.

Interleukin-1 receptor antagonist reduces the magnitude of the pressor response to acute stress

The purpose of the present study was to establish the effect of chronic central interleukin-1 receptors blockade and central chronic infusion of interleukin-1 beta (IL-1beta) on cardiovascular response to an acute stressor. The experiments were performed on 12-14-week-old, male WKY rats, divided into three experimental groups. Each group was subjected to chronic intracerebroventricular (ICV) infusion of one of the following compounds: saline (control, group C), recombinant rat IL-1 receptor antagonist (IL-ANT group) or interleukin-1 beta (IL-1B group). After 5 days of the ICV infusions mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously under baseline conditions and after the application of an air jet stressor. The stressor was applied three times with 10-min intervals. There were no significant differences in MABP and HR between groups under baseline conditions and immediately before the application of the three consecutive air jets. After the first stressor the IL-ANT group responded with a significantly lower increase in blood pressure than the control and IL-1B group. After the application of the two following air jets only the trend for an intergroup difference was present. The results of the present study provide further evidence that cytokines play an important role in the regulation of the circulatory system. The most important new finding is that the magnitude of the pressor response to the alarming stress is strongly influenced by IL-1 receptors in the brain.

Early high-sodium solid diet does not affect sodium intake, sodium preference, blood volume and blood pressure in adult Wistar-Kyoto rats

A high-Na diet may lead to the development of hypertension in both humans and rats; however, the causes of Na intake in amounts greater than physiologically needed as well as the mechanisms whereby high-Na food elevates blood pressure are not clear. Therefore, we decided to test the hypothesis that a high-Na diet introduced after suckling affects Na intake, food preference, resting blood pressure and blood volume in adult rats. Male Wistar-Kyoto (WKY) rats, 4 weeks old, were divided into three groups and placed on either a high-Na (3.28%), a medium-Na (0.82%) or a regular diet (0.22%) with the same energy content for 8 weeks. Subsequently, food preference, resting arterial blood pressure, blood volume, plasma osmolality and Na blood level were evaluated. When offered a choice of diets, all the groups preferred the regular chow, and there was no significant difference in total Na intake between the groups. When the rats experienced the change from their initial chow to a new one with different Na content, they continued to eat the same amount of food. Body weight, resting arterial blood pressure, blood volume, plasma osmolality and Na blood level were comparable between the groups. In conclusion, the results show that a high-Na diet introduced immediately after suckling does not affect Na preference and Na intake in adult WKY rats. Furthermore, the findings provide evidence that both blood volume and arterial blood pressure are highly protected in normotensive rats on a high-Na diet.

Simvastatin Reduces Pressor Response to Centrally Administered Angiotensin II

BACKGROUND Angiotensin II (Ang II) plays a pivotal role in regulation of the circulatory system. Activation of angiotensin type 1 (AT1) receptors in several brain regions leads to an increase in blood pressure. Accumulating data suggest that statins affect the peripheral action of Ang II; however, their central effects are poorly recognized. The study was aimed to determine whether simvastatin interferes with the brain angiotensin system in rats. METHODS Twelve-week-old, Sprague-Dawley rats were divided into two groups. Untreated group was maintained on tap water, whereas simvastatin group received water containing simvastatin for the following 12 weeks. Later, both groups were subjected to experiments in which mean arterial blood pressure (MABP) and heart rate (HR) were recorded during baseline conditions and after intracerebroventricular (ICV) infusion of either saline, Ang II, or losartan. RESULTS ICV infusion of Ang II elicited a significant increase in MABP in both groups. However, the pressor response in the simvastatin group was significantly smaller than that in the untreated group. There was no significant change in MABP after ICV infusion of saline or losartan. ICV infusion of Ang II elicited a significant increase in HR in the untreated group but not in the simvastatin group. There was no significant change in HR after ICV infusion of saline or losartan. CONCLUSIONS The results show that simvastatin reduces the pressor response to ICV-infused Ang II in rats. This implies that statins may affect the central regulation of the circulatory system, especially when the brain angiotensin system is stimulated.

The effect of simvastatin and pravastatin on arterial blood pressure, baroreflex, vasoconstrictor, and hypertensive effects of angiotensin II in Sprague–Dawley rats

Research suggests that statins affect the regulation of arterial blood pressure (BP), however, the mechanisms remain obscure. We maintained male, 12-week-old, Sprague-Dawley rats on tap water (controls) or water containing simvastatin or pravastatin for 4 weeks. Subsequently, we measured mean arterial blood pressure and heart rate at baseline and after intravenous infusion of either saline or angiotensin II (Ang II). Additionally, we tested baroreflex function and the effect of statins on vasoconstrictor response to Ang II on isolated femoral artery branches. Controls and simvastatin and pravastatin groups showed a significant increase in mean arterial BP and heart rate in response to Ang II. The increase was significantly smaller in the simvastatin group than in controls and in the pravastatin group. In contrast, when pretreated with hexamethonium, a ganglionic blocker, simvastatin and pravastatin groups showed a similar hypertensive response to Ang II, which was smaller than in controls. Likewise, the Ang II-induced vasoconstrictor response of femoral artery branches was comparable between simvastatin and pravastatin groups and smaller than in controls. We found no effect of statins on the baroreflex. This study shows that simvastatin and pravastatin differ in their effects on the Ang II-dependent mechanisms controlling BP.

Oral simvastatin reduces the hypertensive response to air-jet stress

Brain angiotensin (Ang) II and vasopressin play important roles in the neurogenic regulation of the circulatory system, such as in cardiovascular responses to stress. Recently, it has become evident that the positive effects of statins are not limited to their lipid‐lowering actions; for example, it has been found that statins interact with angiotensin peptides. In the present study we tested the hypothesis that simvastatin affects haemodynamic responses to air‐jet stress and intracerebroventricular infusions of vasopressin and AngII. We maintained 12‐week‐old male Sprague‐Dawley rats either on tap water (control) or on water containing simvastatin (20, 40 or 60 mg/L) for 4 weeks. Subsequently, we measured arterial blood pressure and heart rate (HR) at baseline and after air‐jet stress or intracerebroventricular infusions over 30 s of 10 ng AngII, 20 ng vasopressin or their antagonists (10 μg losartan and 400 ng d(CH2)5[Tyr(Me)2,Ala‐NH29] vasopressin, respectively). There were no significant differences between the control and simvastatin groups in terms of baseline mean arterial blood pressure (MAP) and HR. In rats given 60 mg/L simvastatin, the hypertensive response to air‐jet stress was significantly smaller than in controls, as was the increase in MAP in response to AngII. In contrast, there was no significant difference between the groups in terms of the hypertensive response to vasopressin. These findings show that simvastatin affects the hypertensive response to air‐jet stress and provide evidence that statins may affect the brains regulation of the circulatory system.

Repeated restraint stress produces acute and chronic changes in hemodynamic parameters in rats

Abstract Noninvasive hemodynamic measurements in rats require placing animals in restrainers. To minimize restraint stress-induced artifacts several habituation protocols have been proposed, however, the results are inconclusive. Here, we evaluated if a four-week habituation is superior to a shorter habituation, or no habituation. This is the first study comparing different habituation protocols with the use of four-week continuous telemetry measurements. We did the experiments on male, 16-week old, Sprague–Dawley rats. Continuous recordings of mean arterial blood pressure (MABP) and heart rate (HR) were made before and during habituation protocols. Rats were subjected either to control (four weeks of restraint-free recordings, n = 5) or two-week (seven restraints, n = 6) or four-week (14 restraints, n = 6) restraint sessions. The restraint protocols included placement of rats in the middle of the dark phase into plastic restrainers as used for tail-cuff measurements. Restraint lasted for 60 min, and was repeated every second day. Each restraint significantly increased MABP (by 15–25 mmHg) and HR (by 40–120 beats/min). Exposure to the restraint protocols decreased diurnal variation in MABP. There was no hemodynamic adaptation to repeated restraint, and no significant difference in hemodynamic response to restraint among controls, the two-week and the four-week groups. In conclusion, our study indicates that measurements in restrained rats are not likely being made without stress-induced changes in MABP. Moreover, in hemodynamic studies in repeatedly restrained rats longer habituation is not superior to shorter habituation.