Effects of bradykinin on short-term variability in blood pressure and heart rate in rats: a spectral study.

Using a spectral procedure, we studied the effects of two treatment regimens of bradykinin (BK) on the blood pressure (BP) and heart rate (HR) variabilities in conscious Wistar rats. We performed a second series of experiments with hydralazine, at doses equihypotensive to those used in BK treatments, to discriminate between a specific effect of the peptide and those induced by vasodilation. We assessed the activity of the sympathetic nervous system (SNS), using the responses to atenolol and prazosin. First, at a subhypotensive treatment regimen, BK (5 micrograms/min) increased low-frequency (LF, 0.02-0.2 Hz) and mid-frequency (MF, 0.2-0.6 Hz) frequency components of BP variability and also activated the SNS. Lesser enhancements of LF and MF areas were induced by hydralazine (0.15 mg/kg). Second, high-dose treatment regimens of BK (100 micrograms/min) and hydralazine (2 mg/kg), which markedly decreased BP, did not change the areas of the LF and MF components of BP variability, whereas overactivity of the SNS was still assessed with the adrenergic blockers. On the other hand, high-dose BK induced a sixfold increase in the amplitude of the high frequency (HF, respiratory) component of BP. The effect of bradykinin on HF domain was associated with an increase in the depth of respiration in a group of anesthetized rats. Hoe 140 (60 micrograms/kg), a B-2 BK-receptor antagonist, abolished both the effects of BK on HF fluctuations in BP and the effects on breathing pattern. Our results demonstrate that BK induced different effects on LF and MF fluctuations in BP depending on the treatment regimen, whereas the SNS was activated by the two selected treatment regimens. Therefore, the MF component of BP variability should be considered only as a marker of the activity of the SNS when the BP level was not affected. Furthermore, we characterized an amplifying effect of BK on the HF domain of BP variability partly mediated by an increase in the depth of respiration.

Spectral analysis of blood pressure and heart rate variability in response to stress from air-jet in the Lyon rat.

1. Power spectral analysis of the frequency of wave-forms of blood pressure and heart rate was used to characterize short-term fluctuations of these parameters in three strains of conscious Lyon rat, normotensive (LL and LN) and hypertensive LH. 2. A mild stress produced by means of a jet of air elicited blood pressure rises, associated with tachycardia. This response was of similar magnitude in the three strains. The stressor amplified the medium frequency (195-605 mHz) Mayer waves of blood pressure and heart rate which are under autonomic control. 3. Clonidine (10 micrograms kg-1 i.v.) lowered blood pressure and heart rate and dramatically reduced the amplitude of blood pressure and heart rate oscillations in the frequency region of 195-605 mHz. 4. A jet of air applied after clonidine administration led to blood pressure rise associated with tachycardia and enhanced oscillations in the 195-605 mHz region. 5. These results indicate that in Lyon normotensive and hypertensive rats, a mild emotional stressor elicits blood pressure and heart rate rises associated with spectral modifications reflecting sympathetic hyperactivity. Clonidine lowers blood pressure and heart rate and reduces their related variabilities. This effect is more pronounced in LH rats than in their normotensive controls. Clonidine appears to reduce the autonomic response to stress as indicated by the medium frequency oscillations.

Differential effects of enalapril and hydralazine on short-term variability of blood pressure and heart rate in rats.

Using a spectral procedure, we studied the acute and chronic effects of enalapril and hydralazine on the variability of blood pressure (BP) and heart rate (HR) in conscious Wistar rats. In the acute protocol, rats received two injections 25 min apart (saline followed by enalaprilic acid or hydralazine hydrochloride). In the chronic protocol, animals received oral enalapril maleate, hydralazine hydrochloride, or distilled water. A 5-min recording session was initiated on day 12. Acute enalapril and hydralazine amplified the low-frequency (LF) component of the systolic BP (SBP) spectrum. Chronic enalapril reduced the variability of BP, as indicated by the lower variance in SBP distribution. Chronic enalapril preferentially reduced the amplitude of the 400-mHz oscillations of SBP. Acute administration of enalapril or hydralazine resulted in BP variability profiles, suggesting a reflexly mediated vascular sympathetic activation. In contrast, chronic angiotensin-converting enzyme (ACE) blockade with enalapril caused a significant decrease in the LF oscillations of BP. This could reflect a reduced sympathetic outflow to vascular smooth muscles.

Effects of clonidine on blood pressure and heart rate responses to an emotional stress in the rat: a spectral study.

1. The fluctuations that underlie the spontaneous variability of blood pressure (BP) and heart rate (HR) were investigated in conscious normotensive rats using power spectral analysis. 2. Air jet stimulation determined a significant BP rise associated with a tachycardia. This environmental mild stressor amplified the 195-605 mHz oscillations of HR which are under autonomic control. No habituation to this stressor was observed since a second stimulation determined similar responses. 3. Clonidine (10 micrograms/kg, i.v.) prevented the BP rise normally associated with air jet stimulation. In addition, clonidine dramatically reduced the amplitude of BP and HR oscillations in the frequency region of 195-605 mHz. 4. It is concluded that a mild emotional stressor elicits in normotensive rats a rise in BP and HR associated with modified spectral profiles reflecting sympathetic hyperactivity. Clonidine minored the effects of stress on BP and HR variability and also prevented BP elevation.

Clonidine reduces blood pressure and heart rate oscillations in the conscious rat.

We investigated the effects of clonidine on the fluctuations that underlie the spontaneous variability of blood pressure (BP) and heart rate (HR) in conscious rats. Analog-to-digital conversion of the intrafemoral BP was used to determine systolic, diastolic, and mean BP and HR every 200 ms. The equidistant sampling allowed a direct spectral analysis using a fast Fourier transform algorithm. An i.v. dose of 10 micrograms/kg of clonidine markedly reduced the variability of BP and HR after 20 min as indicated by a reduction in the variances by approximately one-half of the control value for BP and to one-third of the control value for HR. At this time, clonidine had not significantly altered BP or HR. Spectral profiles of systolic BP and HR illustrated the alterations in the spontaneous oscillations underlying these variance changes. Clonidine dramatically reduced the amplitude of BP and HR oscillations in the frequency region of 195-605 mHZ, which depends on the activity of the autonomic nervous system. We suggest that an increased sensitivity of the baroreflex is responsible for the apparent better control of BP and HR with clonidine.

[Nervous mechanisms of spontaneous oscillations of systolic blood pressure and heart rate]. / Mécanismes nerveux des oscillations spontanées de la pression artérielle systolique et de la fréquence cardiaque.

The phenomenon of rhythmic fluctuations in cardiovascular variables such as heart rate (HR) or arterial blood pressure (BP) has attracted the attention of workers in both pure and applied research. In recent years, the possibility of quantifying these oscillations by using power spectral analysis has aroused a growing interest. We investigated the fluctuations which underly the spontaneous variability of BP and HR in conscious rats. Intrafemoral pulsatile BP was computed to generate evenly spaced signals (systolic, diastolic, mean BP, HR) at 200 ms intervals. This equidistant sampling allowed a direct spectral analysis using a Fast Fourier Transform algorithm. Systolic Blood Pressure (SBP) and HR exhibited low frequency oscillations (Mayer waves, 20-605 mHz) and a high frequency oscillation related to respiration (1,855 mHz). The respiratory fluctuations in HR were almost abolished by vagal blockade (atropine). HR fluctuations in the low frequency regime were diminished by vagal blockade or cardiac sympathetic blockade (atenolol). The respiratory frequency fluctuations in SBP were markedly increased by alpha sympathetic blockade (prazosin). On the contrary the low frequency oscillations in SBP were reduced by alpha sympathetic blockade. These data indicate that in conscious rats: 1) the HR oscillation with respiration is vagally mediated, 2) the HR fluctuation in the low frequency regime is jointly mediated by beta sympathetic and parasympathetic activities, 3) the respiratory oscillation in SBP depends on fluctuations in cardiac output and is normally counteracted by the sympathetic tone, 4) the low frequency oscillations in SBP reflect the sympathetic activity to the resistance vessels.

Spectral analysis of blood pressure and heart rate in conscious rats: effects of autonomic blockers.

We investigated the fluctuations which underly the spontaneous variability of blood pressure and heart rate in conscious rats. Intrafemoral blood pressure was computed to generate evenly spaced signals (systolic, diastolic, mean blood pressure, heart rate) at 200 ms intervals. This equidistant sampling allowed a direct spectral analysis using a Fast Fourier Transform algorithm. Systolic blood pressure and heart rate exhibited low-frequency oscillations (Mayer waves, 20-605 mHz) and a high- frequency oscillation related to respiration (1855 mHz). The respiratory fluctuations in heart rate were almost abolished by vagal blockade (atropine). Heart rate fluctuations in the low-frequency regime were diminished by vagal blockade or cardiac sympathetic blockade (atenolol). The respiratory frequency fluctuations in systolic blood pressure were markedly increased by alpha-sympathetic blockade (prazosin). In contrast, the low-frequency oscillations in systolic blood pressure were reduced by alpha-sympathetic blockade. These data indicate that in conscious rats: (1) the heart rate oscillation with respiration is vagally mediated; (2) the heart rate fluctuation in the low-frequency range is jointly mediated by beta-sympathetic and parasympathetic activities; (3) the respiratory oscillation in systolic blood pressure depends on fluctuations in cardiac output and is normally counteracted by the sympathetic tone; (4) the low-frequency oscillations in systolic blood pressure reflect the sympathetic activity to the resistance vessels.

[Spectrum analysis of blood pressure and cardiac rate in the conscious rat]. / Analyse spectrale de la pression artérielle et de la fréquence cardiaque du rat conscient.

Intrafemoral pulsatile blood pressure of conscious rats was computed to generate evenly spaced signals (systolic, diastolic, mean blood pressure, heart rate) at 200 ms intervals. This equidistant sampling allowed a direct spectral analysis using a Fast Fourier Transform algorithm. Systolic blood pressure and heart rate exhibited low frequency oscillations (Mayer waves, 20-605 mHz) and a high frequency peak related to respiration (1,765 mHz). The diastolic blood pressure and the mean blood pressure only exhibited low frequency oscillations. This procedure could be useful to analyze the various components of blood pressure variability.

Platelet 5-HT content and uptake in essential hypertension: role of endogenous digitalis-like factors and plasma cholesterol.

A decrease in platelet 5-HT content linked to partial inhibition of 5-HT uptake has been described in essential hypertension. Transport of 5-HT through platelet membrane is dependent upon transmembranal Na+ and K+ gradients. It is inhibited by Na+, K+-ATPase inhibitors such as ouabain and endogenous digitalis-like compounds isolated from hemodiafiltrate. The activity of such compounds in plasma extracts, measured by inhibition of Na+,K+-ATPase or ouabain binding to human erythrocytes, and platelet 5-HT content were determined in parallel in essential hypertensive patients. Significant negative correlations were observed between these parameters in men, suggesting that high levels of digitalis-like compounds can affect platelet 5-HT content. In addition, in essential hypertensive patients, total plasma cholesterol was inversely related to both platelet 5-HT content (n = 15, r = -0.594, P less than 0.02) and maximal velocity of 5-HT uptake (n = 15, r = -0.717, P less than 0.003). In normotensive control subjects, no variation of platelet 5-HT content with cholesterol was observed. This suggests that the platelet membranes of essential hypertensive patients are more sensitive to increases in plasma cholesterol than those of normotensive subjects.

Endogenous digitalislike circulating substances in spontaneously hypertensive rats.

Circulating digitalislike compounds have been proposed to be involved in some Na+-dependent types of experimental hypertension and in human essential hypertension. The level of circulating Na+-K+ pump inhibitor(s) was investigated in the spontaneously hypertensive rat of the Okamoto strain (SHR), its normotensive control, Wistar-Kyoto rat (WKY), and the regular Wistar rat using the following criteria: the ability of whole plasma to inhibit the total active Na+ efflux from Wistar rat erythrocytes and to cross-react with digoxin antibodies and the ability of plasma extracts to inhibit Na+,K+-adenosine triphosphatase (ATPase) activity of membranes from rat kidney. SHR plasma inhibited the net Na+ efflux from Wistar erythrocytes by up to 27% compared with WKY or Wistar plasma. For a given number of cells, the inhibition increased with the amount of available plasma. Cross-reactivity with digoxin antibodies was twice as high in SHR as in WKY or Wistar plasma. It was already enhanced in 3- to 4-week-old rats. Plasma extracts from SHR significantly inhibited Na+,K+-ATPase activity when compared with WKY extracts (75.6 +/- 2.6 vs 89.3 +/- 2.4 mumol Pi/mg/hr; p less than 0.01) but did not differ from Wistar plasma extracts. These results strongly suggest that circulating digitalislike compound(s) are present in elevated amounts in SHR as early as 3 to 4 weeks of age, but their exact participation in blood pressure elevation or maintenance remains to be clarified.

Antihypertensive effect of canrenone in a model where endogenous ouabain-like factors are present.

The effect of canrenone, an antialdosterone and partial ouabain-agonist drug, was studied in rats that developed volume expansion and hypertension after renal mass reduction and excess Na+ intake (RRM-salt). The RRM-salt was characterized by: (1) increased endogenous "digitalis-like" compounds in plasma [cross reactivity with digoxin-antibodies (57.5 +/- 5.0 vs. 42.1 +/- 3.8 pg/ml, p less than 0.02); inhibition of kidney Na+, K+-ATPase activity (135 +/- 5 vs. 154 +/- 5 mumol/mg/h, p less than 0.01); and inhibition of Na+ extrusion from normal erythrocytes (5.96 +/- 0.40 vs. 7.68 +/- 0.34 mmol/L cells/h, p less than 0.01)]; (2) reduced Na+, K+-pump activity (7.34 +/- 0.29 vs. 10.88 +/- 0.41 mmol/L cells/h, p less than 0.001) and increased Na+ content (4.66 +/- .08 vs. 4.16 +/- 0.11 mmol/L cells, p less than 0.01) in erythrocytes; and (3) low plasma renin activity (2.1 +/- 0.9 vs. 12.6 +/- 1.6 ng/ml/h). Ninety minutes after the administration to RRM-salt of a single oral dose of 60 mg/kg of canrenone, the systolic blood pressure decreased by 36 +/- 4 mm Hg (mean +/- SEM). Chronic canrenone administration (60 mg/kg/day) resulted in a marked antihypertensive effect associated to a correction of volume expansion, a decrease in endogenous "digitalis-like" compounds, and a partial recovery of Na+, K+-pump activity and Na+ content in erythrocytes. Our results suggest that the antihypertensive effect in RRM-salt rats results, at least in part, from antagonism with endogenous "digitalis-like" compounds.

An endogenous digitalis-like compound extracted from human urine: biochemical and chemical studies.

Plasma and urine levels of an endogenous digitalis-like compound (EDLC) are increased in low renin Na+-dependent experimental hypertension, in some normotensive offspring of hypertensive patients and in some essential hypertensive patients. Urine-drived EDLC was purified from 550 L of urine from essential hypertensive patients (n = 8) and from normotensive subjects with a family history of hypertension (n = 27), using flash chromatography on C18 reversed-phase, anion exchange chromatography and various reversed-phase high performance liquid chromatographies. The mechanism of Na+-K+ ATPase inhibition and the related effects of semipurified urine-derived EDLC were studied and compared with those of ouabain. Its action was similar to that of ouabain in 8 out of 10 of the tests applied. The main effects of such a compound were the depression of Na+-K+ pump activity of human erythrocytes, the inhibition of 5-hydroxytryptamine reuptake by human platelets, and the induction of natriuresis in urethanized rats. Therefore, EDLC may be considered as one of the natriuretic hormones whose mechanism of action closely resembles that of ouabain.

[Genetic hypertension in the SHR rat and circulating digitalis compounds]. / Hypertension génétique du rat SHR et composés "digitaliques" circulants.

Circulating digitalis-like compounds have been found elevated in some experimental sodium--and volume--dependent hypertensions, as well as in human essential hypertension. As few studies have been undertaken to assess their enhancement in the genetic hypertension of Okamoto (SHR) we have investigated their presence in plasma using 4 criteria: their apparent immunoreactivity with antidigoxin antibodies, their competition with tritiated ouabain binding to the sodium pump of human red blood cells,-their ability to inhibit the Na+, K+ ATPase activity of rat kidney membranes, and the Na+ fluxes from rat red blood cells. When compared to ordinary Wistar (W) and Wistar Kyoto rats (WKY), SHR exhibited a markedly enhanced apparent immunoreactivity with antidigoxin-antibodies (138 +/- 8; 59 +/- 3; 61 +/- 4 pg/ml, n = 15, 6 et 15, p less than 0.001, and p less than 0.001 respectively). The inhibition of ouabain binding by plasma extracts of the three strains did not differ (10.3 +/- 1.6, 9.9 +/- 1.7 and 12.9 +/- 1.4 ng/ml, n = 9, 18 and 14 respectively). When compared to WKY, SHR plasma extracts inhibited the renal Na+, K+ ATPase activity (75.6 +/- 2.6 vs 89.3 +/- 2.4 mumoles Pi . mg-1 . h-1, n = 11 and 10, p less than 0.01, respectively). When incubated in SHR plasma for one hour, net sodium effluxes from Wistar erythrocytes were inhibited compared to that measured in the presence of W or WKY plasma: (5.91 +/- 0.20 vs 7.68 +/- 0.25 and 7.52 +/- 0.15 mmol/l cells, n = 5, 3 and 5, p less than 0.001, and p less than 0.001 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous Na+ transport inhibitor in human hypertension: further biochemical and chemical studies.

Endogenous digitalis-like compound(s) (endalin) has(ve) been reported to be involved in some diseases. Endalin activity is increased in plasma and urine of some essential hypertensives, and in Na+-dependent experimental hypertension. The aims of this study are to compare the biological properties of one endalin extracted from urine of hypertensive patients and of normotensive offspring of hypertensive subjects to those of ouabain and to determine the chemical nature of such an urine-derived endalin. The donors were selected on the basis of the highest Na+,K+-ATPase inhibition produced by extract from their 24-h urine. They consisted of 8 hypertensive patients, 21 normotensive subjects with family history of hypertension and 6 normotensive subjects with no known family history of hypertension. Endalin was semi-purified from 500 liters of pooled urine by flash chromatography on RP 18 packing (40 microns) followed by anion exchange chromatography and two HPLCs on RP 18 reversed phase. Endalin was traced by its capability of inhibiting dog kidney Na+,K+-ATPase activity and 3H-ouabain binding to the enzyme, by its cross-reaction with anti-digoxin antibodies and by its natriuretic effect in rat bioassay. The mechanism of Na+,K+-ATPase inhibition by a semi-purified urine-derived endalin and its consequences on Na-transport were studied and compared to those of ouabain. Semi-purified urine-derived endalin was similar to ouabain in that: it reversibly and specifically inhibited Na+,K+-ATPase activity; it inhibited Na+,K+-ATPase non-competitively with ATP; its inhibitory effect was facilitated by Na+; K+ decreased its inhibitory effect on Na+,K+-ATPase.(ABSTRACT TRUNCATED AT 250 WORDS)

Further biochemical characterization of an Na+ pump inhibitor purified from human urine.

An increase in endogenous Na+,K+-ATPase inhibitor(s) with digitalis-like properties has been reported in chronic renal insufficiency, in Na+-dependent experimental hypertension and in some essential hypertensive patients. The present study specifies some properties and some biochemical characteristics of a semipurified compound from human urine having digitalis-like properties. The urine-derived inhibitor (endalin) inhibits Na+,K+-ATPase activity and [3H]-ouabain binding, and cross-reacts with anti-digoxin antibodies. The inhibitory effect on ATPases of endalin is higher on Na+,K+-ATPase than on Mg2+-ATPase and Ca2+-ATPase. The mechanism of endalin action on highly purified Na+,K+-ATPase was compared to that of ouabain and was similar in that it reversibly inhibited Na+,K+-ATPase activity; it inhibited Na+,K+-ATPase non-competitively with ATP; its inhibitory effect was facilitated by Na+; K+ decreased its inhibitory effect on Na+,K+-ATPase; it competitively inhibited ouabain binding to the enzyme; its binding was maximal in the presence of Mg2+ and Pi; it decreased the Na+ pump activity in human erythrocytes; it reduced serotonin uptake by human platelets; and it was diuretic and natriuretic in rat bioassay. The endalin differed from ouabain in only three aspects: its inhibitory effect was not really specific for Na+,K+-ATPase; its binding to the enzyme was undetectable in the presence of Mg2+ and ATP; it was not kaliuretic in rat bioassay. Endalin is a reversible and partial specific inhibitor of Na+,K+-ATPase, its Na+,K+-ATPase inhibition closely resembles that of ouabain and it could be considered as one of the natriuretic hormones.

Structural and functional alterations of the cell membrane in the prehypertensive rat of the Okamoto Aoki strain.

Plasma membrane properties of 3 to 4-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were investigated in both excitable cells, i.e. cardiomyocytes and platelets, and non-excitable cells, i.e. erythrocytes. Cardiac sarcolemma from SHR exhibited: lowered capacity of high-affinity Ca2+-binding sites; higher Ca2+ pump activity; higher Na+K+-ATPase activity due to increased density of Na+ pump units; suppression of the above three effects by the Ca2+-calmodulin complex, and increased Na+Ca2+ exchange. No difference in platelet cytosolic free Ca2+ concentration was observed between SHR and WKY. In both substrains, erythrocyte intracellular Na+ content was similar in spite of reduced Na+ and K+ net fluxes. Isolated membranes from SHR erythrocytes were also characterized by: lowered phosphoinositide turnover; decreased ATP-dependent Ca2+-transport, and lowered capacity of high affinity Ca2+-binding sites. Structural alterations detected by fluorescence polarization of diphenylhexatriene were observed in SHR cardiac sarcolemma, erythrocyte and brain synaptosomal membranes. Membrane organization and activity of transport systems controlling the intracellular Na+ and Ca2+ level were thus already modified in the prehypertensive animals whereas the resulting intracellular ion contents were still unaltered.

[Compounds of the digoxin type in essential and experimental hypertension]. / Composés de type digoxine dans l'hypertension artérielle et expérimentale.

The prescription of cardiac glycosides is usually controlled by immunological measurement of their plasma concentration. The observation of false positive digoxin measurements in patients free of this drug and the hypothesis that endogenous digitalis-like compounds might participate in body sodium and water homeostasis have led us to investigate the presence in plasma of compounds interacting with digoxin-antibodies under various physiological and pathological conditions in man and rats. The apparent levels of digoxin-equivalents in plasma of healthy control subjects (n = 21) and patients with essential hypertension (n = 48) or end-stage renal failure (n = 13) were 24.7 +/- 3.2, 34.4 +/- 4.4 and 98.7 +/- 17.4 pg/ml, p less than 0.05 and p less than 0.01 respectively. Positive correlations were observed between systolic and diastolic blood pressure and the apparent immunoreactivity of either whole or deproteinized plasma, in particular when only male subjects were considered. No relationship was found with the renal Na+ excretion or the plasma renin activity and the apparent immunoreactivity of the plasma. Its levels were however correlated with its ability to inhibit ouabain binding to the erythrocyte Na+ pump and to its capacity to reduce the renal Na+, K+-ATPase activity. In rats with experimental hypertension, induced by chronic excess salt intake either alone or associated with reduced renal mass, the cross reactivity with antidigoxin antibodies was also enhanced when compared to control rats (71.6 +/- 10.2 pg/ml, n = 12 and 57.3 +/- 5.0 pg/ml, n = 33 respectively compared to 43.4 +/- 3.7 pg/ml, n = 36, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[Canrenone: an effective antihypertensive in an experimental model of hypertension in which the active transport of sodium is diminished]. / La canrénone: un antihypertenseur efficace dans un modèle expérimental d'hypertension où le transport actif du sodium est diminué.

Recent studies in essential hypertensive patients and rats with genetic hypertension strongly suggested that the development of primary hypertension results from a transient and chronic "cascade" of events; I) excess Na+ intake, II) secretion of natriuretic factors, III) abnormal cell Na+ homeostasis in the vascular wall, due to the presence of inherited and induced abnormalities in different Na+ transport system and IV) increase in cytosolic free Ca2+ content and sympathetic drive. In vitro studies have previously shown that canrenone, an antihypertensive antialdosterone drug, behaves like a partial agonist at the digitalis-receptor site of the Na+, K+-pump. In particular, it has been shown that canrenone counterbalances the increases in internal Na+ and cytosolic free Ca2+ contents induced by ouabain in cultured smooth muscle cells. We thus investigated the effect of canrenone administration in a model of experimental hypertension with increased endogenous "ouabain-like" factors (rats with reduced renal mass under excess Na+ intake: RRM-salt rats). Results presented here confirm that RRM-salt rats exhibit: volume expansion, strongly decreased plasma renin activity, increased endogenous "ouabain-like" factors and (IV) decreased Na+, K+-pump activity and increased Na+ content in erythrocytes. In addition, we found that canrenone is antihypertensive in this model and this is associated with a tendency to normalize volume expansion, plasma levels of endogenous "ouabain-like" factors, Na+, K+-pump activity and Na+ content in erythrocytes. In conclusion, our results suggest that administration of canrenone to RRM-salt rats may induce a lowering of blood pressure by antagonism with endogenous "ouabain-like" factors at the vascular wall.

Active Na+ and Ca+ transport, Na+-Ca2+ exchange, and intracellular Na+ and Ca2+ content in young spontaneously hypertensive rats.

The activity of Na+-Ca+-exchange and ATP-dependent Na+ and Ca2+ transport by heart sarcolemmal membranes from male 3-4-week-old spontaneously hypertensive rats (SHR) and their normotensive controls (WKY) were compared. Differences in active Ca2+ and Na+ transport between the two substrains were suppressed by addition of exogenous calmodulin. Calmodulin was active only in the presence of Ca2+. The rate of the Na+-dependent Ca2+ efflux, reflecting the activity of the Na+-Ca2+ exchange, was significantly higher in SHR than in WKY vesicles. An alteration of the intracellular calmodulin activity or content might thus be responsible for the modifications in Ca2+ handling, and limit the activity of the Na+ pump in SHR membranes. The platelet cytosolic free Ca2+ concentration of young SHR and WKY was measured by using the fluorescent indicator Quin-2/AM. In the absence or presence of added external Ca2+, no difference in the intracellular concentration of Ca2+ was observed between platelets of either origin. The intraerythrocytic sodium content, measured by flame spectrophotometry, was similar in SHR and WKY. This study, performed before the onset of hypertension, shows that membrane mechanisms controlling the intracellular ion content were already modified, whereas the resulting intracellular concentrations remained within the normal range.