This review summarizes our findings concerning the altered balance of vasoactive systems (namely sympathetic nervous system and nitric oxide) in various forms of experimental hypertension – genetic hypertension (SHR, HTG rats), salt hypertension (Dahl rats) and NO-deficient hypertension (L-NAME-treated rats). An attempt is made to define relative NO deficiency (compared to the existing level of sympathetic vasoconstriction), to describe its possible causes and to evaluate particular indicators of its extent. A special attention is paid to reactive oxygen species, their interaction with NO metabolism, cell Ca2+ handling and blood pressure regulation. Our current effort is focused on the investigation of abnormal regulation of cytosolic Ca2+ levels in smooth muscle and endothelium of hypertensive animals. Such a research should cl
arify the mechanisms by which genetic and/or environmental factors could chronically modify blood pressure level.
Red wine polyphenols have been reported to exert beneficial effects in preventing cardiovascular diseases but their molecular mechanisms of hemodynamic effects on functional cardiovascular and renal changes were studied much less. The review is focused on in vitro as well as in
vivo effects of red wine extract containing polyphenolic compounds
(Provinols™) on cardiovascular systems and kidney in relation to the molecular and biochemical mechanisms of these compounds. This review provides the evidence that Provinols™ is able to produce ex vivo
endothelium-dependent relaxation as a result of enhanced NO synthesis. Administration of Provinols™ partially prevents the development of hypertension during NO deficiency and accelerates the decrease of blood pressure in already established hypertension. The effects of Provinols™ include prevention and/or attenuation of myocardial fibrosis, reduction of aortic wall thickening and improvement of vascular functions. These functional and structural alterations are associated with significant augmentation of NO production, seen as the increase of NO synthase activity and eNOS protein expression. Moreover, it has been documented that Provinols™ decreased the oxidative stress within the cardiovascular system and kidney.
The effect of the angiotensin converting enzyme (ACE) inhibitor, captopril, on proteosynthesis in the aorta, acetylcholine-stimulated aortic relaxation and endothelaemia (circulating endothelial cells) was investigated in rabbits with aortic insufficiency. The animals were studied 28 days after experimental intervention. Cardiac volume overload stimulated proteosynthesis in the aorta as reflected by increased ribonucleic acid (RNA) concentration and [14C] leucine incorporation into proteins of the aorta. Moreover, the number of endothelial cells in the blood was increased. The administration of captopril starting from the second day of the haemodynamic overload, partially prevented the increase both in aortic proteosynthesis and in endothelaemia. Despite these alterations, the relaxing ability of the aorta to acetylcholine was not changed either by the haemodynamic overload or by captopril. We conclude that the increase of proteosynthesis in the aorta and of endothelaemia in the early period of chronic cardiac volume overload in rabbits were partially prevented by chronic captopril treatment. Neither aortic insufficiency nor captopril changed the acetylcholine-induced relaxation of the aorta.
The aim of the study was to assess whether angiotensin converting enzyme (ACE) inhibition with captopril prevents the development of hypertension and myocardial hypertrophy and affects nitric oxide synthase (NOS) activity in rats. Animals were divided into five groups: control, two groups receiving NG-nitro-L-arginine methyl ester (L-NAME) 20 or 40 mg/kg/day, a group receiving captopril 100 mg/kg/day and a group concomitantly treated with 40 mg/kg/day L-NAME plus 100 mg/kg/day captopril. After four weeks, systolic blood pressure (SBP) significantly increased in both L-NAME groups by 30 % and 34 %, respectively. In the captopril group, SBP significantly decreased by 30 % and in the captopril plus L-NAME group SBP was not changed as compared to the controL Although left ventricular weight/body weight (LVW/BW) ratio in both L-NAME groups was significantly elevated by 19 % and 29 %, respectively, no alterations in LVW/BW ratio were found in the captopril group and captopril plus L-NAME group. In both groups receiving L-NAME, NOS activity significantly decreased by 17 % and 69 % in the heart, by 14 % and 26 % in the aorta, by 60 % and 73 % in the brain and by 13 % and 30 % in the kidney, respectively. Captopril did not influence NO synthase activity in any of the studied tissues. We conclude that captopril prevents the development of hypertension and LV hypertrophy without affecting NO formation.
Gasotransmitters represent a subfamily of the endogenous gaseous signaling molecules that include nitric oxide (NO), carbon monoxide
(CO), and hydrogen sulphide (H2S). These particular gases share many common features in their production and function, but they fulfill their physiological tasks in unique ways that differ from those of classical signaling molecules found in tissues and organs. These gasotransmitters may antagonize or potentiate each other’s cellular effects at the level of their production, their downstream molecular targets and their direct
interactions. All three gasotransmitters induce vasodilatation, inhibit apoptosis directly or by increasing the expression of anti-apoptotic genes, and activate antioxidants while inhibiting inflammatory actions. NO and CO may concomitantly participate in vasorelaxation, anti-inflammation and angiogenesis. NO and H2S collaborate in the regulation of vascular tone. Finally, H2S may upregulate the heme oxygenase/carbon monoxide
(HO/CO) pathway during hypoxic conditions. All three gasotransmitters are produced by specific enzymes in different cell types that include cardiomyocytes, endothelial cells and smooth muscle cells. As translational research on gasotransmitters has exploded over the past years, drugs that alter the production/levels of the gasotransmitters themselves or
modulate their signaling pathways are now being developed. This review is focused on the cardiovascular effects of NO, CO, and H2S. Moreover, their donors as drug targeting the cardiovascular system are briefly described.
The question was addressed whether short-term (4 hour) NO deficiency, inducing an increase in blood pressure in anaesthetized dogs, does influence proteosynthesis in the myocardium and coronary arteries. A potentially positive answer was to be followed by the study of the supporting role of ornithine decarboxylase for the polyamines pathway. NG-nitro-L-arginine-methyl ester (L-NAME) (50 mg/kg per hour) was administered i.v. to inhibit NO synthase. After the first L-NAME dose diastolic blood pressure increased from 131.8 ±2.0 to 149.4 ±3.9 mm Hg (p< 0.001) and was maintained at about this level till the end of the experiment. Systolic blood pressure only increased after the first dose (from 150.8 ±1.1 to 175.0 ±5.8 mm Hg, p<0.01), returning thereafter to the control level. Similarly, the heart rate declined only after the first dose (from 190.4±5.3 to 147.6±4.5 beats/min, p<0.01). Total RNA concentrations increased in the left cardiac ventricle (LV), the left anterior descending coronary artery (LADCA) and left circumflex coronary artery (LCCA) by 15.9 ±0.7, 29.7 ±1.3 and 17.6 ±1.0%, p<0.05, respectively. The same applied to [14C]leucine incorporation (by 86.5 ±5.0, 33.5 ±2.6, 29.3±4.1 %, p<0.05, respectively). The above parameters indicated an increase of proteosynthesis in the LV myocardium and both coronary arteries LADCA and LCCA after short-term NO deficiency. Surprisingly, the ornithine decarboxylase activity in the LV myocardium decreased significantly by 40.2± 1.6 % (p<0.01) but the changes were not significant in the coronary arteries. This unexpected finding makes the role of polyamines in increasing proteosynthesis during a pressure overload due to NO deficiency questionable.
We investigated the effect of captopril on the growth of the left ventricle in an experimental model of aortic insufficiency. Four groups of rabbits were studied 28 days after experimental intervention: 1. control, 2. control with captopril (10 mg/kg/day), 3. aortic insufficiency, 4. aortic insufficiency with captopril (10 mg/kg/day). Aortic insufficiency induced hypertrophic growth of the left ventricle demonstrated by increased weight and ribonucleic acid (RNA) concentration. Administration of captopril only slightly attenuated the weight increase of the left ventricle and the increase in concentration of left ventricular RNA. However, captopril reduced the concentration of left ventricular deoxyribonucleic acid (DNA) both in the control and even more in the group with aortic insufficiency. The chronic haemodynamic overload enhanced mitochondrial respiration in the left ventricle which was not influenced by captopril. We conclude that captopril in the dose 10 mg/kg/day did not prevent hypertrophy of the left ventricle but reduced left ventricular DNA concentration.
The effect of 4 weeks’ inhibition of NO synthase by nitro-L-arginine methyl ester (L-NAME) on haemodynamic parameters and cGMP and cAMP content was studied in rat tissues. L-NAME in both 20 mg/kg/day and 40 mg/kg/day doses significantly increased systolic blood pressure by 28 % and 30 % and decreased the heart rate by 14 % and 23 %, respectively, after the first week. These changes persisted during the following three weeks. Left ventricular weight/body weight (LVW/BW) ratio was significantly elevated in both L-NAME-treated groups by 19 % and 29 %, respectively. Radioimmunoassay was used to determine the cGMP and cAMP content Cyclic GMP content in animals treated by L-NAME (20 mg/kg/day and 40 mg/kg/day) decreased significantly by 13 % and 22 % in the left ventricle, by 28 % and 62 % in the aorta, by 20 % and 34 % in the brain, and by 10 % and 15 % in the kidney, respectively. On the other hand, the cAMP content increased in both L-NAME treated groups by 8 % and 9 % in the left ventricle, by 28 % and 46 % in the aorta, and by 23 % and 32 % in the brain, respectively. There were no significant changes in kidney cAMP content as compared to control animals. The results suggest a simultaneous decrease of cGMP and increase of cAMP content in the majority of studied tissues during NO-deficient hypertension.
Hypertriglyceridemia and hypertension seem to be very important cardiovascular risk factors. The Prague hereditary hypertriglyceridemic (hHTG) rat was developed as a model of human hypertriglyceridemia. It was demonstrated that these rats are not obese, they are hypertensive and insulin resistant and they have some disturbances in glucose
metabolism. Several QTLs were identified for blood pressure, its particular components (dependent on major vasoactive systems) and plasma triglycerides throughout the genome of hHTG rats by using of F2 hybrids strategy. It is evident that hHTG rats are a suitable model for the study of metabolic disturbances in relation to blood pressure as well as for the
search of genetic determinants of these abnormalities. Numerous abnormalities of blood pressure regulation as well as alterations in the structure and function of cardiovascular apparatus (heart, conduit and resistance arteries) were found in hHTG rats. A special attention was paid to possible changes in the efficiency of various vasoactive systems such as
nitric oxide, renin-angiotensin-aldosterone system and sympathetic nervous system, which seem to contribute substantially to cardiovascular and/or metabolic abnormalities observed in Prague hereditary hypertriglyceridemic rats.