Research on Experimental Hypertension in Prague (1966-2009) (Review).

The study of ontogenetic aspects of water and electrolyte metabolism performed in the Institute of Physiology (Czechoslovak Academy of Sciences) led to the research on the increased susceptibility of immature rats to salt-dependent forms of hypertension since 1966. Hemodynamic studies in developing rats paved the way to the evaluation of hemodynamic mechanisms during the development of genetic hypertension in SHR. A particular attention was focused on altered renal function and kidney damage in both salt and genetic hypertension with a special respect to renin-angiotensin system. Renal damage associated with hypertension progression was in the center of interest of several research groups in Prague. The alterations in ion transport, cell calcium handling and membrane structure as well as their relationship to abnormal lipid metabolism were studied in a close cooperation with laboratories in Munich, Glasgow, Montreal and Paris. The role of NO and oxidative stress in various forms of hypertension was a subject of a joint research with our Slovak colleagues focused mainly on NO-deficient hypertension elicited by chronic L-NAME administration. Finally, we adopted a method enabling us to evaluate the balance of vasoconstrictor and vasodilator mechanisms in BP maintenance. Using this method we demonstrated sympathetic hyperactivity and relative NO deficiency in rats with either salt-dependent or genetic hypertension. At the end of the first decennium of this century we were ready to modify our traditional approach towards modern trends in the research of experimental hypertension.

Gliflozins in the Treatment of Non-diabetic Experimental Cardiovascular Diseases.

A new class of antidiabetic drugs - gliflozins (inhibitors of sodium glucose cotransporter-2; SGLT-2i) stimulate glucose and sodium excretion, thereby contributing to improved glycemic control, weight loss and blood pressure reduction in diabetic patients. Large clinical trials in patients with type 2 diabetes treated with empagliflozin, canagliflozin or dapagliflozin have demonstrated their excellent efficacy in improving many cardiovascular outcomes, including the reduction of death from cardiovascular diseases, non-fatal myocardial infarction or stroke, and hospitalization for heart failure. Moreover, the beneficial effects of SGLT-2i were also demonstrated in the decrease in proteinuria, which leads to a lower risk of progression to end-stage renal disease and thus a delay in initiation of the renal replacement therapy. Unexpectedly, their cardioprotective and renoprotective effects have been demonstrated not only in patients with diabetes but also in those without diabetes. Recently, much effort has been focused on patients with heart failure (either with reduced or preserved ejection fraction) or liver disease. Experimental studies have highlighted pleiotropic effects of SGLT-2 inhibitors beyond their natriuretic and glycosuric effects, including reduction of fibrosis, inflammation, reactive oxygen species, and others. Our results in experimental non-diabetic models of hypertension, chronic kidney disease and heart failure are partially consistent with these findings. This raises the question of whether the same mechanisms are at work in diabetic and non-diabetic conditions, and which mechanisms are responsible for the beneficial effects of gliflozins under non-diabetic conditions. Are these effects cardio-renal, metabolic, or others? This review will focus on the effects of gliflozins under different pathophysiological conditions, namely in hypertension, chronic kidney disease, and heart failure, which have been evaluated in non-diabetic rat models of these diseases. Key words: SGLT-2 inhibitor, hypertension, chronic kidney disease, heart failure, liver disease, rat.

Corrigendum for: Blood Pressure Reduction Induced by Chronic Intracerebroventricular or Peroral Clonidine Administration in Rats With Salt-Dependent or Angiotensin II-Dependent Hypertension.

List of changes: On the basis of author's request the publisher of Physiological Research decided to change the license of the article to CC BY license.

Corrigendum for: Nitric Oxide and Salt Resistance in Dahl Rats: No Role of Inducible NO Synthase.

List of changes: On the basis of author's request the publisher of Physiological Research decided to change the license of the article to CC BY license.

Corrigendum for: Sex Differences in Blood Pressure, Free Radicals and Plasma Cholesterol Fractions in Ren-2 Transgenic Rats of Various Ages.

List of changes: On the basis of author's request the publisher of Physiological Research decided to change the license of the article to CC BY license.

Hypertension after the Menopause: What Can We Learn from Experimental Studies?

Hypertension is the most prevalent cardiovascular disease of the adult population and is closely associated with serious cardiovascular events. The burden of hypertension with respect to vascular and other organ damage is greater in women. These sex differences are not fully understood. The unique feature in women is their transition to menopause accompanied by profound hormonal changes that affect the vasculature that are also associated with changes of blood pressure. Results from studies of hormone replacement therapy and its effects on the cardiovascular system are controversial, and the timing of treatment after menopause seems to be important. Therefore, revealing potential sex- and sex hormone-dependent pathophysiological mechanisms of hypertension in experimental studies could provide valuable information for better treatment of hypertension and vascular impairment, especially in postmenopausal women. The experimental rat models subjected to ovariectomy mimicking menopause could be useful tools for studying the mechanisms of blood pressure regulation after menopause and during subsequent therapy.

Sex differences in blood pressure, free radicals and plasma cholesterol fractions in Ren-2 transgenic rats of various ages.

Sex-related cardiovascular differences were observed in humans as well as in experimental animals. Our previous study demonstrated a marked sexual dimorphism in blood pressure (BP) of 9-month-old heterozygous transgenic Ren 2 rats (TGR), in which mouse Ren-2 renin gene was inserted into the genome of normotensive Hannover Sprague-Dawley rats (HanSD). We found significantly elevated BP only in male TGR, whereas BP of TGR females was similar to that of HanSD females. The aim of our present study was to compare BP of 3- and 6-month-old heterozygous TGR with age- and sex-matched HanSD under the same conditions as we measured in 9-month-old rats. We also monitored the amount of oxidative stress marker, thiobarbituric acid-reactive substances (TBARS), and a main intracellular antioxidant, reduced glutathione in the heart, kidneys and liver. We also measured plasma triglycerides and cholesterol levels. We found an increased mean arterial pressure in both female and male 3-month-old TGR (172±17 vs. 187±4 mm Hg, respectively) compared to HanSD (115±5 vs. 133±3 mm Hg, respectively) but there was a marked sexual dimorphism of 6 month-old TGR where only males were hypertensive (145±5 mm Hg) while females became normotensive (123±7 mm Hg). We did not find any relationship between BP values and concentrations of TBARS or glutathione or plasma lipid levels. Our results demonstrated that 6-month-old TGR exhibited a marked sexual BP dimorphism, which was not dependent on the abnormalities in oxidative stress or cholesterol metabolism.

Nitric oxide and salt resistance in Dahl rats: no role of inducible NO synthase.

Inducible NO synthase (NOS II) was proposed to play an important role in salt resistance of Dahl salt-resistant (SR/Jr) rats. Its chronic inhibition by specific inhibitors was accompanied by blood pressure (BP) elevation in animals subjected to high salt intake. The aim of our study was to evaluate 1) whether such inhibitors affect BP and/or its particular components (sympathetic tone and NO-dependent vasodilation) only under the conditions of high salt intake, and 2) whether similar BP effects are elicited after systemic or intracerebroventricular (icv) application of these inhibitors. Wistar rats fed Altromin diet (0.45 % NaCl) and SR/Jr rats fed either a low-salt (LS, 0.3 % NaCl) or a high-salt (HS, 4 % NaCl) diet were studied. Aminoguanidine (AMG) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) were used as NOS II inhibitors. BP and its responses to acute blockade of renin-angiotensin system (captopril), sympathetic nervous system (pentolinium) and NO synthase (L-NAME) were measured in conscious cannulated rats. There were no significant changes of BP or its components in either Wistar rats or SR/Jr rats subjected to chronic inhibition of NOS II by peroral aminoguanidine administration (50 mg/kg/day for 4 weeks). This was true for SR/Jr rats fed either LS or HS diets. Furthermore, we have studied BP effects of chronic icv administration of both NOS II inhibitors in SR/Jr rats fed HS diet, but we failed to find any BP changes elicited by such treatment. In conclusion, inducible NO synthase does not participate in the resistance of SR/Jr rats to hypertensive effects of excess salt intake.

Blood pressure reduction induced by chronic intracerebroventricular or peroral clonidine administration in rats with salt-dependent or angiotensin II-dependent hypertension.

The agonists of alpha(2)-adrenergic receptors such as clonidine, rilmenidine or monoxidine are known to lower blood pressure (BP) through a reduction of brain sympathetic outflow but their chronic antihypertensive effects in rats with low-renin or high-renin forms of experimental hypertension were not studied yet. Moreover, there is no comparison of mechanisms underlying BP reduction elicited by chronic peroral (po) or intracerebroventricular (icv) clonidine treatment. Male salt-sensitive Dahl rats fed 4% NaCl diet and Ren-2 transgenic rats were treated with clonidine administered either in the drinking fluid (0.5 mg/kg/day po) or as the infusion into lateral brain ventricle (0.1 mg/kg/day icv) for 4 weeks. Basal BP and the contributions of renin-angiotensin system (captopril 10 mg/kg iv) or sympathetic nervous system (pentolinium 5 mg/kg iv) to BP maintenance were determined in conscious cannulated rats at the end of the study. Both peroral and intracerebroventricular clonidine treatment lowered BP to the same extent in either rat model. However, in both models chronic clonidine treatment reduced sympathetic BP component only in rats treated intracerebroventricularly but not in perorally treated animals. In contrast, peroral clonidine treatment reduced angiotensin II-dependent vasoconstriction in Ren-2 transgenic rats, whereas it lowered residual blood pressure in Dahl rats. In conclusions, our results indicate different mechanisms of antihypertensive action of clonidine when administered centrally or systemically.

Contribution of sympathetic nervous system to high blood pressure in salt hypertensive dahl rats.

The important participation of sympathetic nervous system in various forms of experimental hypertension is well known. This is also true for salt hypertension elicited by excess salt intake in Dahl salt-sensitive rats (for review see Zicha et al. 2012). Two recent studies in Dahl rats (Zicha et al. 2019, Puleo et al. 2020) evaluated the hypothesis on the role of beta-adrenergic WNK4-NCC pathway in salt-sensitive hypertension which has been proposed by Mu et al. (2011). Although these studies differed in many experimental details, both of them demonstrated a major importance of alpha1- rather than beta-adrenergic mechanisms for the development of salt hypertension in this rat strain.

The abnormalities of adrenomedullary hormonal system in genetic hypertension: Their contribution to altered regulation of blood pressure.

It is widely accepted that sympathetic nervous system plays a crucial role in the development of hypertension. On the other hand, the role of adrenal medulla (the adrenomedullary component of the sympathoadrenal system) in the development and maintenance of high blood pressure in man as well as in experimental models of hypertension is still controversial. Spontaneously hypertensive rats (SHR) are the most widely used animal model of human essential hypertension characterized by sympathetic hyperactivity. However, the persistence of moderately elevated blood pressure in SHR subjected to sympathectomy neonatally as well as the resistance of adult SHR to the treatment by sympatholytic drugs suggests that other factors (including enhanced activity of the adrenomedullary hormonal system) are involved in the pathogenesis of hypertension of SHR. This review describes abnormalities in adrenomedullary hormonal system of SHR rats starting with the hyperactivity of brain centers regulating sympathetic outflow, through the exaggerated activation of sympathoadrenal preganglionic neurons, to the local changes in chromaffin cells of adrenal medulla. All the above alterations might contribute to the enhanced release of epinephrine and/or norepinephrine from adrenal medulla. Special attention is paid to the alterations in the expression of genes involved in catecholamine biosynthesis, storage, release, reuptake, degradation and adrenergic receptors in chromaffin cells of SHR. The contribution of the adrenomedullary hormonal system to the development and maintenance of hypertension as well as its importance during stressful conditions is also discussed.

Pharmacological suppression of endogenous glucocorticoid synthesis attenuated blood pressure and heart rate response to acute restraint in Wistar rats.

Glucocorticoids (GCS) are known to modulate cardiovascular response during stress conditions. The present study was aimed to test the hypothesis that permissive and/or stimulating effect of GCs is essential for the maintenance of peripheral vascular resistance and for the adequate response of cardiovascular system to stressor exposure. The effects of acute pharmacological adrenalectomy (PhADX) on humoral and cardiovascular parameters were studied in adult Wistar rats under the basal conditions and during the acute restraint stress. Acute PhADX was performed by the administration of metyrapone and aminoglutethimide (100 mg/kg s.c. of each drug) resulting in a suppression of endogenous glucocorticoid synthesis. Blood pressure (BP), heart rate (HR) and core body temperature were measured using radiotelemetry. BP responses to administration of vasoactive agents were determined in pentobarbital-anesthetized animals. PhADX considerably attenuated stress-induced increase of BP, HR and core body temperature. PhADX did not abolish BP and HR lowering effects of ganglionic blocker pentolinium indicating preserved sympathetic function in PhADX rats. BP response to exogenous norepinephrine administration was attenuated in PhADX rats, suggesting reduced sensitivity of cardiovascular system. Suppression of corticosterone synthesis by PhADX increased basal plasma levels of ACTH, aldosterone and plasma renin activity in unstressed animals but there was no further increase of these hormones following stressor exposure. In conclusion, PhADX attenuated stress-induced rise of blood pressure, heart rate and core body temperature indicating an important permissive and/or stimulating role of glucocorticoids in the maintenance of the adequate response of cardiovascular system and thermoregulation to several stimuli including acute exposure to stressor.

Contribution of selected vasoactive systems to blood pressure regulation in two models of chronic kidney disease.

It is generally accepted that angiotensin II plays an important role in high blood pressure (BP) development in both 2-kidney-1-clip (2K1C) Goldblatt hypertension and in partial nephrectomy (NX) model of chronic kidney disease (CKD). The contribution of sympathetic nervous system and nitric oxide to BP control in these models is less clear. Partial nephrectomy or stenosis of the renal artery was performed in adult (10-week-old) male hypertensive heterozygous Ren-2 transgenic rats (TGR) and normotensive control Hannover Sprague Dawley (HanSD) rats and in Wistar rats. One and four weeks after the surgery, basal blood pressure (BP) and acute BP responses to the consecutive blockade of renin-angiotensin (RAS), sympathetic nervous (SNS), and nitric oxide (NO) systems were determined in conscious rats. Both surgical procedures increased plasma urea, a marker of renal damage; the effect being more pronounced following partial nephrectomy in hypertensive TGR than in normotensive HanSD rats with a substantially smaller effect in Wistar rats after renal artery stenosis. We demonstrated that the renin-angiotensin system does not play so fundamental role in blood pressure maintenance during hypertension development in either CKD model. By contrast, a more important role is exerted by the sympathetic nervous system, the activity of which is increased in hypertensive TGR-NX in the developmental phase of hypertension, while in HanSD-NX or Wistar-2K1C it is postponed to the established phase. The contribution of the vasoconstrictor systems (RAS and SNS) was increased following hypertension induction. The role of NO-dependent vasodilation was unchanged in 5/6 NX HanSD and in 2K1C Wistar rats, while it gradually decreased in 5/6 NX TGR rats.

Sex differences in blood pressure of aged Ren-2 transgenic rats.

Sex-related differences were observed not only in human but also in experimental hypertension. The aim of our study was to compare blood pressure (BP) of aged male and female heterozygous transgenic rats (TGR) harboring Ren-2 mouse gene, with their normotensive Hannover Sprague-Dawley (HanSD) controls. At the age of 9 months, systolic (SBP) and diastolic blood pressure (DBP) were measured by a direct puncture of carotid artery in rats awaking from isoflurane anesthesia. Thiobarbituric acid-reactive species (TBARS) formation was monitored as indicator of lipid peroxidation damage in heart, kidney and liver, whereas intracellular content of reduced glutathione was determined in the same organs as the main intracellular antioxidant. Furthermore, plasma triglycerides and total cholesterol as well as high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions of cholesterol were measured. As compared to HanSD rats, we found significantly elevated BP only in male TGR (MAP: 123±1 vs. 171±5, SBP: 150±2 vs. 208±7, and DBP: 99±3 vs. 140±4 mm Hg), but not between TGR and HanSD females, which were both normotensive. We also did not find any significant differences in TBARS and reduced glutathione in the three above mentioned organs as well as in plasma cholesterol or its HDL and LDL fractions between transgene-negative HanSD and TGR animals of either sex. However, we found significant sex differences in TBARS, glutathione and plasma lipids in both rat strains. Our results confirmed that aged TGR exhibit a marked sexual BP dimorphism, which does not seem to be dependent on oxidative stress or abnormal cholesterol metabolism.

Is renal ß-adrenergic-WNK4-NCC pathway important in salt hypertension of Dahl rats?

In 2011 Fujita and coworkers proposed that ß-adrenergic stimulation causes decreased serine/threonine-protein kinase WNK4 transcription leading to the activation of Na-Cl cotransporter (NCC) which participates in salt sensitivity and salt hypertension development in rodents. The aim of our study was to investigate whether the above hypothesis is also valid for salt hypertension of Dahl rats, which are characterized by high sympathetic tone and abnormal renal sodium handling. Male 8-week-old salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats were fed either low-salt diet (LS, 0.4 % NaCl) or high-salt diet (HS, 4 % NaCl) for 6 weeks. Half of the animals on either diet were chronically treated with non-selective ß-blocker propranolol (100 mg/kg/day). At the end of the experiment diuresis and sodium excretion were measured prior and after hydrochlorothiazide injection (HCTZ, 10 mg/kg i.p.). Furthermore, blood pressure (BP), heart rate (HR), sympathetic (pentolinium 5 mg/kg i.v.) and NO-dependent (L-NAME 30 mg/kg i.v.) BP components were determined. Chronic HS diet feeding increased BP through sympathoexcitation in SS/Jr but not in SR/Jr rats. Concomitant propranolol treatment did not lower BP in either experimental group. Under the conditions of low salt intake HCTZ increased diuresis, natriuresis and fractional sodium excretion in SR/Jr but not in SS/Jr rats. HS diet feeding attenuated renal response to HCT in SR/Jr rats, whereas no HCTZ effect was observed in SS/Jr rats fed HS diet. Propranolol treatment did not modify diuresis or natriuresis in any experimental group. In conclusions, our present data do not support the idea on the essential importance of renal ß-adrenergic-WNK4-NCC pathway in pathogenesis and/or maintenance of salt hypertension in Dahl rats.

Distinct effects of bosentan on NO-dependent vasodilation and calcium influx in heterozygous Ren-2 transgenic rats on high-salt diet.

Our studies in hypertensive Ren-2 transgenic rats (TGR) demonstrated that chronic administration of atrasentan (ETA receptor antagonist) decreased blood pressure by reduced Ca2+ influx through L-type voltage-dependent calcium channels (L-VDCC) and attenuated angiotensin II-dependent vasoconstriction. We were interested whether bosentan (nonselective ET(A)/ET(B) receptor antagonist) would have similar effects. Young 4-week-old (preventive study) and adult 8-week-old (therapeutic study) heterozygous TGR and their normotensive Hannover Sprague-Dawley (HanSD) controls were fed normal-salt (NS, 0.6 % NaCl) or high-salt (HS, 2 % NaCl) diet for 8 weeks. An additional group of TGR fed HS was treated with bosentan (100 mg/kg/day). Bosentan had no effect on BP of TGR fed high-salt diet in both the preventive and therapeutic studies. There was no difference in the contribution of angiotensin II-dependent and sympathetic vasoconstriction in bosentan-treated TGR compared to untreated TGR under the condition of high-salt intake. However, bosentan significantly reduced NO-dependent vasodilation and nifedipine-sensitive BP component in TGR on HS diet. A highly important correlation of nifedipine-induced BP change and the BP after L-NAME administration was demonstrated. Although bosentan did not result in any blood pressure lowering effects, it substantially influenced NO-dependent vasodilation and calcium influx through L-VDCC in the heterozygous TGR fed HS diet. A significant correlation of nifedipine-induced BP change and the BP after L-NAME administration suggests an important role of nitric oxide in the closure of L-type voltage dependent calcium channels.

The absence of sympathoexcitation during the development of hypertension in Cyp1a1 Ren-2 transgenic rats.

The insertion of mouse renin gene (Ren-2) into the genome of normotensive rats causes a spontaneous rise of blood pressure (BP), leading to an angiotensin II (Ang II)-dependent form of hypertension in transgenic (mRen-2)27 rats (TGR). However, enhanced sympathetic BP component was demonstrated in heterozygous TGR aged 20 weeks. In the present study we used another model, i.e. Cyp1a1-Ren-2 transgenic rats (iTGR) in which hypertension can be induced by natural xenobiotic indole-3 carbinol (I3C) added to the diet. We investigated whether the development of high blood pressure (BP) in 5-month-old iTGR animals fed I3C diet for 10 days is solely due to enhanced Ang II-dependent vasoconstriction or whether enhanced sympathetic vasoconstriction also participates in BP maintenance in this form of hypertension. Using acute sequential blockade of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and NO synthase (NOS) we have demonstrated that the observed gradual increase of BP in iTGR fed I3C diet was entirely due to the augmentation of Ang II-dependent BP component without significant changes of sympathetic BP component. Thus, the hypertension in iTGR resembles to that of homozygous TGR in which high BP was entirely dependent on Ang II-dependent vasoconstriction. Moreover, our measurements of acute BP response to Rho kinase inhibitor fasudil in animals subjected to a combined blockade of RAS, SNS and NOS indicated the attenuation of basal calcium sensitization in both iTGR and homozygous TGR.

Renoprotective effects of ET(A) receptor antagonists therapy in experimental non-diabetic chronic kidney disease: Is there still hope for the future?

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ET(A)) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ET(A) receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ET(A) blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ET(A) antagonists, at least under certain pathological conditions.

Human genome evolution and development of cardiovascular risk factors through natural selection.

Impressive advances in molecular genetic techniques allow to analyze the effects of natural selection on the development of human genome. For example, the trend towards blonde hair and blue eyes was documented. The approach to analyze possible effects of natural selection on the evolution of recent phenotypes with high risk of cardiovascular disease has not been described yet. A possible effect on the evolution of two main risk factors - hypercholesterolemia and hypertension - is presented. The close relationship of non-HDL cholesterol blood concentration to the proportion of pro-inflammatory macrophages in human visceral adipose tissue might be a result of long-lasting natural selection. Individuals with higher proportion of this phenotype might also display a higher ability to fight infection, which was very common in human setting from prehistory until Middle Ages. Successful battle against infections increased the probability to survive till reproductive age. Similar hypothesis was proposed to explain frequent hypertension in African Americans. A long-lasting selection for higher ability to conserve sodium during long-term adaptation to low sodium intake and hot weather was followed by a short-term (but very hard) natural selection of individuals during transatlantic slave transport. Only those with very high capability to retain sodium were able to survive. Natural selection of phenotypes with high plasma cholesterol concentration and/or high blood pressure is recently potentiated by high-fat high-sodium diet and overnutrition. This hypothesis is also supported by the advantage of familial hypercholesterolemia in the 19th century (at the time of high infection disease mortality) in contrast to the disadvantage of familial hypercholesterolemia during the actual period of high cardiovascular disease mortality.

Lack of reactive oxygen species deteriorates blood pressure regulation in acute stress.

This study investigated the contribution of reactive oxygen species (ROS) to blood pressure regulation in conscious adult male Wistar rats exposed to acute stress. Role of ROS was investigated in rats with temporally impaired principal blood pressure regulation systems using ganglionic blocker pentolinium (P, 5 mg/kg), angiotensin converting enzyme inhibitor captopril (C, 10 mg/kg), nitric oxide synthase inhibitor L-NAME (L, 30 mg/kg) and superoxide dismutase mimeticum tempol (T, 25 mg/kg). Mean arterial pressure (MAP) was measured by the carotid artery catheter and inhibitors were administered intravenously. MAP was disturbed by a 3-s air jet, which increased MAP by 35.2+/-3.0 % vs. basal MAP after the first exposure. Air jet increased MAP in captopril- and tempol-treated rats similarly as observed in saline-treated rats. In pentolinium-treated rats stress significantly decreased MAP vs. pre-stress value. In L-NAME-treated rats stress failed to affect MAP significantly. Treatment of rats with P+L+C resulted in stress-induced MAP decrease by 17.3+/-1.3 % vs. pre-stress value and settling time (20.1+/-4.2 s). In P+L+C+T-treated rats stress led to maximal MAP decrease by 26.4+/-2.2 % (p<0.005 vs. P+L+C) and prolongation of settling time to 32.6+/-3.3 s (p<0.05 vs. P+L+C). Area under the MAP curve was significantly smaller in P+L+C-treated rats compared to P+L+C+T-treated ones (167+/-43 vs. 433+/-69 a.u., p<0.008). In conclusion, in rats with temporally impaired blood pressure regulation, the lack of ROS resulted in greater stress-induced MAP alterations and prolongation of time required to reach new post-stress steady state.