Specificity of the hemodynamic indices’ shift in SHR line rats at different age

Specificities of the changes in the systemic hemodynamics indices in the spontaneously hypertensive line SHR rats have been studied in comparison with the normotensive line WKY rats. It was demonstrated that an increase in blood pressure observed in the young hypertensive male rats, which have completed puberty (8 weeks old), is associated with the development of the hyperkinetic type arterial hypertension, which is characterized by increased cardiac minute output. It has been shown that SHR line male rats reveal the establishment of stable arterial hypertension due to a significant increase in the total peripheral resistance with the simultaneous recovery of the cardiac minute output by the 25th week of life. SHR line rats at the age of 15 weeks may be regarded as being in the period of transition from the hyperkinetic type arterial hypertension to stable arterial hypertension.     

Central and peripheral noradrenergic tone in primary hypertension

The contents of norepinephrine (NE), epinephrine (E), dopamine (DA), normetanephrine (NMN), and 4-hydroxy-3-methoxyphenylethylene glycol (MHPG) were measured in the plasma and cerebrospinal fluid (CSF) of 66 patients with primary hypertension and 24 patients with normal blood pressure and minor neurological disorders. Plasma and CSF NE and NMN concentrations were raised in the hypertensive patients. The plasma and CSF NE levels and arterial blood pressure of a small subset of hypertensive patients were normalized after clonidine therapy. In hypertensive patients the content of DA was lower and the ratio of NE/DA was greater; CSF and plasma NE contents were related to the level of arterial blood pressure; and the content of MHPG in CSF was linked strongly with NE content in plasma and CSF and to the level of arterial blood pressure. Thus both central sympathetic nerve tone and peripheral sympathetic nerve tone were enhanced in young patients with uncomplicated hypertension. The elevated levels of neurohormones and their metabolites in some patients with primary hypertension may be related to increased synthesis and release of neural NE and may be pathogenic in the blood pressure elevation.     

Plasma atrial natriuretic factor concentrations in essential and renovascular hypertension.

Plasma atrial natriuretic factor concentrations were measured in 44 patients with mild untreated essential hypertension and 48 normotensive controls. Mean venous plasma atrial natriuretic factor concentrations were 13.2 (SEM 1.5) and 13.0 (1.3) ng/l in the hypertensive patients and controls, respectively. Plasma atrial natriuretic factor concentrations were significantly correlated with age in both groups. Plasma atrial natriuretic factor concentrations were also measured during renal vein catheterisation in a group of 15 hypertensive patients; of these, eight had renovascular hypertension, and in all eight cases plasma atrial natriuretic factor concentrations were increased in the aorta and inferior vena cava. It is concluded that mild essential hypertension is not associated with increased plasma atrial natriuretic factor concentrations, whereas an age related increase in concentrations occurs in hypertensive and normotensive people.     

Role of the baroreceptor reflex in the early phases after removing the renal artery constriction in conscious renal hypertensive rats

Hemodynamic studies in unanesthetized rats with chronic one-kidney-Goldblatt hypertension showed a 25% increase in cardiac output and a 42% increase in peripheral resistance. Removal of renal artery constriction under either anesthesia and minor surgical trauma produced an immediate 20% drop in arterial pressure. At the end of the 6 observation period the pressure dropped 30% but still remained at a moderate hypertensive level. The hemodynamic measurement at that time suggested that the pressure drop was the result of a decrease in cardiac output. However, the data obtained 1 hour after removal of the constriction suggested that a vasodilating mechanism may also contribute to pressure normalization in the early phase of reversal of renal hypertension. In the sham-operated hypertensive rats the pressure remained unchanged, while the cardiac output dropped due to compensation by a proportional increase in peripheral resistance. In contrast, in the unclipped animals the same drop in cardiac output produced an equivalent fall in pressure because no change in peripheral resistance occurred. This was not due to an insufficiency of the baroreceptor reflex since bilateral splanchnicectomy performed at that time produced a striking hypotensive response, indicating an overactivity of the sympathetic system possibly due to the baroreceptor still reset to operate at a hypertensive level.     

Hemodynamic and autonomic correlates of postexercise hypotension in patients with mild hypertension

We investigated the interplay of neural and hemodynamic mechanisms in postexercise hypotension (PEH) in hypertension. In 15 middle-aged patients with mild essential hypertension, we evaluated blood pressure (BP), cardiac output (CO), total peripheral resistance (TPR), forearm (FVR) and calf vascular resistance (CVR), and autonomic function [by spectral analysis of R-R interval and BP variabilities and spontaneous baroreflex sensitivity (BRS)] before and after maximal exercise. Systolic and diastolic BP, TPR, and CVR were significantly reduced from baseline 60-90 min after exercise. CO, FVR, and HR were unchanged. The low-frequency (LF) component of BP variability increased significantly after exercise, whereas the LF component of R-R interval variability was unchanged. The overall change in BRS was not significant after exercise vs. baseline, although a significant, albeit small, BRS increase occurred in response to hypotensive stimuli. These findings indicate that in hypertensive patients, PEH is mediated mainly by a peripheral vasodilation, which may involve metabolic factors linked to postexercise hyperemia in the active limbs. The vasodilator effect appears to override a concomitant, reflex sympathetic activation selectively directed to the vasculature, possibly aimed to counter excessive BP decreases. The cardiac component of arterial baroreflex is reset during PEH, although the baroreflex mechanisms controlling heart period appear to retain the potential for greater opposition to hypotensive stimuli.     

Effect of platelet depletion on lung vasoconstriction in heparin-protamine reactions

In six awake sheep the control heparin-protamine reaction was associated with a 150-fold rise in arterial plasma thromboxane B2 (TxB2) levels, a 4.5-fold increase in pulmonary vascular resistance, a 20% decrease in cardiac output, a 30% decrease in arterial PO2, and a 30% reduction in arterial white blood cell concentrations. Depletion of 99% of circulating platelets by antibodies did not prevent either acute and severe pulmonary hypertension or increased plasma TxB2 levels induced by heparin-protamine administration. We produced sheep platelet aggregation in vitro with bovine thrombin and measured marked TxB2 release (36.3 +/- 16.3 ng/10(9) platelets). In contrast, neither heparin, protamine, nor heparin-protamine complexes over a 10,000-fold range of concentrations induced platelet aggregation and release of thromboxane in vitro. Therefore sheep platelets are not the source of thromboxane production associated with acute pulmonary hypertension during the heparin-protamine reaction, and other cells must produce the thromboxane.     

Clonidine reduces elevated cerebrospinal fluid catecholamine levels in patients with essential hypertension

Cerebrospinal fluid (CSF) catecholamines were measured in normotensive patients and in patients with mild to moderate essential hypertension. CSF-norepinephrine (NE) concentrations were 50% lower in the normotensive individuals (127 ± 28 vs. 240 ± 23 pg/m1) (P<0.01). In hypertensive patients, CSF-NE was inversely related to age (r =-0.68; P<0.01) and directly related to plasma NE (r = 0.61; P<0.05). Clonidine (450 mcg/day for 2 weeks) significantly reduced CSF-NE (?40%) in hypertensive patients. In addition, it decreased blood pressure, plasma and urinary NE. Urinary VMA was not affected by clonidine. No correlation was observed between clonidine effects on BP and on plasma or CSF catecholamines. This study indicates that patients with essential hypertension have elevated levels of CSF-NE which are reduced after treatment with clonidine. The elevation of CSF-NE suggests that central (spinal?) noradrenergic activity may be increased in patients with mild to moderate essential hypertension, and that can be reduced by treatment with clonidine.     

Pharmacologic tools for assessment of adrenergic nerve activity in human hypertension

Measurement of plasma norepinephrine concentration (plasma NE) has not resolved the role of the adrenergic system in the pathogenesis or maintenance of hypertension. A better picture is gained if plasma NE measurement is combined with the assessment of sympathetic drive and reactivity by the use of specific sympathetic antagonists and agonists. In mild hypertension, the decrease in heart rate and cardiac output after beta-adrenoceptor blockade correlates with the level of plasma NE. In established hypertension, the fall in blood pressure or peripheral vascular resistance after alpha-adrenoceptor blockade is related to plasma NE levels. Similarly, changes in forearm vascular resistance induced by local alpha-adrenoceptor blockage correlates with plasma NE in hypertension. Cardiovascular responsiveness to adrenergic agonists is altered in hypertension. The response to cardiac beta-receptor stimulation decreases during the course of the disease. To the contrary, vascular responses to exogenous NE increase with the progression of the hypertensive disease. Results with total autonomic blockade indicate that in some patients with early or borderline hypertension, increased sympathetic tone is involved in the maintenance of blood pressure. In established hypertension, there is no definite indication of increased sympathetic tone, but the sympathetic nervous system may nevertheless play a prominent role in the maintenance of the blood pressure. A vascular hyperreactivity to adrenergic stimulation is characteristically associated with established hypertension. The nature of this hyperreactivity has not been fully elucidated, but it is very likely that it reflects structural vascular changes in hypertension.     

Correlation between cardiac hypertrophy and plasma levels of atrial natriuretic factor in non-spontaneous models of hypertension in the rat

We have compared atrial and plasma concentration of atrial natriuretic factor (ANF) in 4 models of non spontaneous experimental hypertension with different pathogenic mechanisms in the rat: two-kidney, one-clip (2-K, 1-C), one-kidney, one-clip (1-K, 1-C), DOCA-NaCl and adrenal regeneration hypertension (ARH) and their respective normotensive controls. All hypertensive groups developed cardiac hypertrophy. In all hypertensive groups plasma ANF was higher than in controls. Atrial ANF concentration was lower in the right and left atrium of 1-K, 1-C rats and in the left atrium of ARH. A good correlation was found between systolic BP and plasma ANF in 2-K, 1-C (r = 0.82; p less than 0.01) and 1-K, 1-C animals (r = 0.70; p less than 0.01). This correlation was less good in DOCA-NaCl (r = 0.41; p less than 0.05) and non existent in ARH (r = 0.28; NS). A negative correlation between plasma ANF and atrial ANF concentrations was found only in the 1-K, 1-C group (r = 0.41; p less than 0.05). A good correlation between plasma ANF levels and cardiac weight was found in all groups: 2-K, 1-C (r = 0.83; p less than 0.01), 1-K, 1-C (r = 0.73; p less than 0.01), DOCA-NaCl (r = 0.69; p less than 0.01) and ARH (r = 0.71; p less than 0.01). We suggest that the release of ANF in experimental hypertension depends of the pathogenesis and could be related either to the level of BP (hence the magnitude of the left ventricular end-diastolic pressure) or to the existence of an expanded blood volume. The correlation between plasma ANF levels and cardiac hypertrophy suggests that ANF could be partially released by the ventricles.     

Usefulness of determining conjugated amine catecholamines in blood platelets for diagnosis of pheochromocytoma]

The studies included 14 patients with pheochromocytoma (mean age 39.5 years), 32 patients with arterial hypertension (mean age 39.5 years), and 9 healthy volunteers (mean age 39.5 years). Free and conjugated noradrenaline and adrenaline in blood platelets have been assayed with RIA technique. It was shown that mean concentrations of conjugated noradrenaline and adrenaline in blood platelets are significantly higher in patients with pheochromocytoma than those in hypertensive patients and healthy individuals. However, such test may be used with limitations as there is high percentage of increased values in patients with the primary arterial hypertension. A decreased noradrenaline inactivation in blood platelets of patients with pheochromocytoma has also been observed. This may exert some effect on the diversified clinical course of this type of arterial hypertension.     

Longitudinal studies on the effect of hypertension on circadian hemodynamic and autonomic rhythms in telemetered rats

This study dealt with the long-term effects of hypertension on circadian rhythms of hemodynamic and cardiovascular autonomic functions in radiotelemetered rats. Blood pressure (BP), heart rate (HR), spontaneous locomotor activity, and respiration.were monitored in spontaneously hypertensive rats (SHRs), a model of human hypertension, from 14 to 27 weeks of age and in Wistar-Kyoto rats (WKY) as controls. Cardiovascular autonomic changes were determined by time-domain analysis of the variability of BP (standard deviation of mean arterial pressure, SDMAP) and HR (standard deviation of R-R intervals, SDRR, and the root mean square of successive differences in R-R intervals, rMSSD). Compared with WKY rats, the 24-hr MAP and SDMAP were higher at week 14 in SHRs and showed stepwise increases over the study duration, suggesting progressive increases in vasomotor sympathetic activity in hypertensive rats. Also, higher SDRR, rMSSD, and activity and lower HR and respiration were demonstrated in SHRs. Normal circadian rhythms (higher dark-time values) of MAP, HR, SDMAP, and SDRR were evident in WKY rats at week 20 and continued thereafter. Compared with WKY rats, the circadian BP and HR patterns were abolished and inverted, respectively, in SHRs. Lower dark-time, compared with light-time, SDMAP values were observed in SHRs that were associated with temporal increases in HR variability indices. These findings demonstrate that hypertension elicits significant alterations in circadian autonomic and hemodynamic profiles. Further, the steady increases in BP, average level and oscillations, in SHRs may explain the reported progressive age-related vascular and cardiac hypertrophy in these rats.     

Comparison of vascular function and structure of iliac artery in spontaneously hypertensive and hereditary hypertriglyceridemic rats

The aim of this study was to compare the vascular reactivity and morphology of iliac artery (IA) in adult spontaneously hypertensive rats (SHR) and hereditary hypertriglyceridemic (hHTG) rats. The isolated rings of iliac artery (IA) from Wistar rats (controls), SHR and hHTG rats were used for measurement of relaxant responses to acetylcholine (ACh) and contractile responses to noradrenaline (NA). Morphological changes of IA were measured using light microscopy. Systolic blood pressure (BP) measured by plethysmographic method was increased in SHR approximately by 88 % and in hHTG rats by 44 % compared to controls. BP increase was accompanied by cardiac hypertrophy. In both SHR and hHTG groups (experimental groups) reduced relaxation to ACh and enhanced maximal contraction and sensitivity to adrenergic stimuli were observed. The sensitivity to NA in SHR was higher also in comparison with hHTG. Geometry of IA in both experimental groups revealed increased wall thickness and wall cross-sectional area, in SHR even in comparison with hHTG. Inner diameter was decreased in both experimental groups. Thus, independently of etiology, hypertension in both models was connected with impaired endothelial function accompanied by structural alterations of IA. A degree of BP elevation was associated with arterial wall hypertrophy and increased contractile sensitivity.     

Abnormal magnesium metabolism in two rat models of genetic hypertension.

Magnesium concentrations in erythrocyte ghosts and arterial tissue of male, spontaneously hypertensive rats (SHR) were significantly less than in these tissues of male normotensive controls (Wistar-Kyoto; WKY) of the same age, which were also fed rat chow and tap water. The magnesium concentration in SHR erythrocyte ghosts was increased to the control value by incubating SHR erythrocytes with WKY blood plasma; SHR plasma did not affect the magnesium concentration in WKY erythrocyte ghosts. The magnesium concentrations in erythrocyte ghosts, aortas, and mesenteric arteries from female salt-sensitive (SS/JR) and salt-resistant (SR/JR) Dahl-derived rats, both maintained ad libitum on laboratory rat chow and either tap water or 0.9% NaCl, were not different but were significantly less than those of Sprague-Dawley rats considered as controls. While the ingestion of 0.9% NaCl had no effect on the magnesium concentrations measured in these animals, it caused the salt-sensitive rats to become severely hypertensive. It is evident from these observations that the decreased binding of magnesium to the plasma membrane of cells may be an inheritable metabolic defect that may be associated with the development of hypertension. However, in those instances of hypertension in which this defect occurs, it appears to be a contributing cause of the hypertension; by itself the defect is not a cause of hypertension.     

Regulation of the blood circulation system in hypertensive crises using mathematical analysis of the cardiac rhythm

Regulation of the circulatory system in hypertensive crises was studied using mathematical analysis of the cardiac rhythm. The study involved 166 patients from age 29 to 73 years with hypertension stage II–III. The cardiac rhythm variability was assessed for 10-min intervals by parameters of the regulatory system activity (according to R.M. Baevskiiet al.). In hypertensive crisis, the cardiac rhythm variability was decreased, and the activity of systems regulating blood circulation was increased, compared to both the normal and the crisis-free period. Therefore, the determination of parameters of cardiac rhythm variability has an additional diagnostic value. Changes in these parameters in hypertensive crisis depend on the duration of hypertension, the patients’ age, and dysfunction of target organs. Changes in the cardiac rhythm variability persisted after normalization of arterial pressure in the postcrisis period, and this indicates that the patients’ condition was not stabilized during hospital treatment and prolonged supervised hypotensive therapy was required.     

Plasma melatonin concentrations in hypertensive patients with the dipping and non-dipping blood pressure profile

Some patients with hypertension exhibit disturbed circadian organization in the cardiovascular system. Hormone melatonin can synchronize circadian rhythms and its repeated administration can improve synchronization of rhythmicity in blood pressure (BP). In our study we measured endogenous melatonin production in patients with essential hypertension exhibiting a dipping and non-dipping BP profile. Blood pressure was monitored for at least 24-hr with an automatic ambulatory BP monitor and patients with no decline in BP were classified as non-dippers. Plasma melatonin was measured in the middle of the daytime and night-time by radioimmunoassay. As expected night-time systolic (P <0.05), diastolic (P <0.001) and mean arterial (P <0.001) BP was higher in non-dippers than in dippers. No significant difference was found between both groups in BP during the day. Mean melatonin concentrations were higher during the night than during the day in both dippers and non-dippers. When patients were divided into dippers and non-dippers on the basis of mean arterial or diastolic BP a lower ratio of night/day concentration was determined in non-dippers than in dippers. Our study showed a blunted night/day difference in plasma melatonin concentrations in hypertensive patients with the non-dipping profile in diastolic BP indicating disturbances in the circadian system of these patients.     

Effects of Capsaicin and Isoflavone on Blood Pressure and Serum Levels of Insulin-Like Growth Factor-I in Normotensive and Hypertensive Volunteers with Alopecia

Insulin-like growth factor-I (IGF-I) reduces arterial blood pressure. Since administration of capsaicin and isoflavone increases serum levels of IGF-I by sensory neuron stimulation in subjects with alopecia, it is possible that administration of capsaicin and isoflavone reduces arterial blood pressure in patients with hypertension. Systolic and diastolic blood pressure (BP) and serum levels of IGF-I were determined before and at 1, 3, and 5 months after administration of capsaicin and isoflavone in 42 volunteers with alopecia, 29 normotensive and 13 hypertensive volunteers. Neither systolic nor diastolic BP changed in the normotensive volunteers after combined administration of capsaicin and isoflavone. In contrast, systolic and diastolic BP was significantly reduced in hypertensive volunteers after administration of capsaicin and isoflavone. Serum levels of IGF-I significantly increased in both normotensive and hypertensive volunteers after administration of capsaicin and isoflavone. These observations suggest that administration of capsaicin and isoflavone might reduce BP in hypertensive, but not in normotensive subjects, probably by increasing serum levels of IGF-I.     

Role of endothelin and nitric oxide in the pathogenesis of arterial hypertension in autosomal dominant polycystic kidney disease

The pathogenesis of arterial hypertension in autosomal dominant polycystic kidney disease (ADPKD) is complex and likely dependent on interaction of hemodynamic, endocrine and neurogenic factors. We decided to evaluate the role of endothelin (ET1) and nitric oxide (NO) in the regulation of arterial blood pressure (BP) and to determine plasma levels of ET1 and NO in the group of patients with ADPKD. The ADPKD group (18 patients, 6 men + 12 women, mean age 44.6+/-11.7 years, with creatinine clearancecorrig > 1.1 ml/s) was compared with a control group of 27 healthy volunteers of comparable age. Plasma levels of ET1 assessed by direct RIA determination in the group of ADPKD patients (11.03+/-1.8 fmol/ml) were significantly increased (p<0.001) in comparison with the control group (2.66+/-0.58 fmol/ml), while no significant differences were observed between normotensive and hypertensive patients in the ADPKD group. Serum levels of NO were evaluated according to the determination of serum levels of their metabolites - nitrites/nitrates. Serum levels of NO in the group of ADPKD patients (39.85+/-.38 micro mol/l) were significantly higher (p<0.05) in comparison with the control group (22.7+/-1.20 micro mol/l), whereas in the ADPKD group no significant differences were observed between normotensive and hypertensive patients. Thus, our study supports the concept of complex alteration of both vasoconstrictor and vasodilator systems in the pathogenesis of arterial hypertension in ADPKD.     

Effect of the alpha-adrenoblocker pyrroxan on systemic hemodynamics in puppies and dogs with vasorenal hypertension]

Vasorenal hypertension was induced in 2--3-month-old puppies and adult dogs by stricture of both renal arteries. 1.5 mg/kg of pyrroxan was injected intravenously 3 and 14 days later. A reduction of increased arterial pressure was noted both in adult dogs and in puppies, to the subnormal level in the latter. Hypotensive effect of the preparation was connected in adult animals with diminution of the general peripheral vascular resistance and in puppies, besides, with reduction of cardiac output. Pyrroxan injection was accompanied in all the animals with tachycardia, reduction of the phase of isometric contraction and activation of myocardial contractility.     

Endothelin antagonism suppresses plasma and cardiac endothelin-1 levels in SHRSPs at the typical hypertensive stage

Endothelin-1 (ET-1) has been implicated in hypertension, heart failure, atherosclerosis, and pulmonary hypertension. In all these conditions, plasma immunoreactive ET-1 levels are elevated, and tissue ET-1 expression is increased. Clinical trials have demonstrated potentially important benefits of ET antagonism among patients with essential hypertension, pulmonary hypertension, and heart failure. It is unknown whether ET antagonism affects the production of ET-1 in stroke-prone spontaneously hypertensive rat (SHRSP) heart at the typical hypertensive stage. The objective of this study was to investigate the effects of ET blockade on the expression levels of plasma and cardiac ET-1 in SHRSPs. SHRSPs were treated for 3 months with SB209670 (ET(A)/ET(B) dual receptor antagonist) or with saline (vehicle) commencing at the prehypertensive stage (age 6 weeks). Plasma and left ventricular ET-1 peptide levels were measured using enzyme-linked immunoabsorbent assay. Compared with age-matched control Wistar-Kyoto rats, peptide levels of ET-1 were significantly upregulated in vehicle-treated SHRSP heart; this upregulation was reversed by long-term ET antagonism. Plasma ET-1 levels were also significantly increased in vehicle-treated SHRSPs and were normalized by ET antagonism. mRNA expression of preproET-1, which is the source of ET-1 peptide production, was significantly increased in vehicle-treated SHRSP heart and was normalized by ET antagonism. Marked cardiac hypertrophy and fibrosis at the histologic level in SHRSPs were ameliorated by ET antagonism, and left ventricular hypertrophy as seen on echocardiography in SHRSPs was suppressed by ET blockade. After ET antagonism, systolic blood pressures were reduced in SHRSPs; diastolic blood pressures were unchanged. The reversal effect of the upregulated ET system in SHRSP heart by ET antagonism might be independent of blood pressure change. By suppressing the upregulated ET system, ET antagonism might be beneficial in arresting cardiac remodeling.     

Age dependence of the levels of plasma norepinephrine, aldosterone, renin activity and urinary vanillylmandelic acid in normal and essential hypertensives

In the present study the upper reference limits (URLs) for resting plasma norepinephrine, epinephrine, serum aldosterone, plasma renin activity, aldosterone/renin activity ratio, as well as urinary vanillylmandelic acid in healthy Egyptian normotensive subjects over a range of ages (5-60 yr) were established. There was a significant age effect on plasma norepinephrine, UVMA, serum aldosterone and PRA, whereas a single URL for plasma epinephrine level is satisfactory. In uncomplicated untreated essential hypertensive subjects (5-60 yr), the average prevalence of elevation in the plasma norepinephrine, epinephrine and urinary vanillylmandelic acid above their corresponding URLs was 85.10, 62.15 and 83.20%, respectively. This suggests that elevation in plasma catecholamine concentrations is more likely a common consequence than playing a possible role in the pathogenesis of hypertension, supported by insignificant correlation coefficients between the plasma catecholamine levels and resting systolic and diastolic blood pressure values (SBP & DBP) in all hypertensive age groups. Primary hyperaldosteronism was not detected among the normokalemic essential hypertensives at any age using aldosterone/plasma renin activity ratio as a primary screening method. In the present study, 7 statistically significant positive coefficient correlations are reported for SBP or DBP values with UVMA levels in hypertensive children and adolescents, serum aldosterone in old hypertensives, and PRA in adult hypertensives.