Reduced tolerance of simulated altitude (4200 m) in young men with borderline hypertension.

BACKGROUND: Primary hypertensives who are acutely exposed to hypoxic hypoxia show an enhanced reactivity of arterial chemoreceptors as well as an exaggerated response of the sympathetic nervous system. Since these phenomena could influence their ability to tolerate sustained hypoxic hypoxia, this study was performed to determine whether persons predisposed to hypertension have a normal tolerance of simulated high altitude. METHODS: Subjects were 18 young men with a family history of hypertension (sons of hypertensives, SOHT) whose BP values were in the upper normal or borderline hypertensive range. Controls were 15 young men without parental hypertension (sons of normotensives, SONT) who had normal BP values. Each subject underwent both a control and an altitude experiment. The latter consisted of an 8-h exposure to hypobaric hypoxia (equivalent to 4200 m) while resting supine in an altitude chamber. Fluids were administered by mouth and by intravenous line to produce sustained diuresis. Variables measured included heart rate, BP, respiratory rate, O2 saturation, urine flow rate, and sodium excretion. RESULTS: All subjects tolerated the control experiment and all SONT also completed altitude exposure. However, 8 of 18 SOHT developed antidiuresis and had to leave the chamber early due to symptoms of mild acute mountain sickness. Compared with SONT, SOHT exhibited more stable cardiorespiratory parameters at altitude. CONCLUSIONS: The data support the hypothesis that borderline hypertensives have stronger cardiorespiratory responses to altitude than controls, a response that is compatible with higher excitability of their arterial chemoreceptors. However, their altitude tolerance is reduced even at rest, probably because of the renal effects of an exaggerated response in the sympathetic nervous system.

Pharmacological stimulation of arterial chemoreceptors in conscious rats produces differential responses in renal cortical and medullary blood flow.

1. There have been no previously published data regarding intrarenal blood flow distribution in acute whole-body hypoxic hypoxia and/or arterial chemoreceptor stimulation in normoxic mammals. 2. Cortical and medullary blood flows were measured simultaneously before and in response to pharmacological stimulation of peripheral arterial chemoreceptors by i.v. injection of almitrine bismesylate (0.25 mg/kg). 3. Arterial chemoreceptor excitation reduced cortical blood flow but only in innervated kidneys. An effect on medullary blood flow was observed in neither innervated nor denervated kidneys. 4. These data indicate that renal cortical and medullary blood flows react differently to arterial chemoreceptor stimulation.

Cardiorespiratory and renal responses to arterial chemoreceptor stimulation by hypoxia or almitrine in men.

1. The cardiorespiratory and renal responses to 3 h of normobaric whole-body hypoxic hypoxia (FiO2 = 0.12) as well as to arterial chemoreceptor stimulation by the oral administration of 100 mg almitrine bismesylate during normoxia were measured in 12 normotensive young men undergoing water diuresis. A third series of responses obtained under comparable conditions in the same subjects served as time controls. 2. No significant changes could be detected over time in the parameters measured in control experiments. The subjects reacted to both whole-body hypoxic hypoxia and to pharmacological chemoreceptor stimulation with significant increases in heart rate, tidal volume, minute ventilation and filtration-fraction. Overall renal vascular resistance rose significantly in hypoxia; increases in renal vascular resistance in almitrine experiments were not significant. 3. Renal fractional lithium excretion decreased significantly in response to whole-body hypoxic hypoxia and increased slightly in response to almitrine. Fractional urine and sodium excretion showed negligible changes. 4. The data indicate that, in humans, both almitrine and whole-body hypoxic hypoxia affect not only alveolar ventilation but also renal haemodynamics. 5. The renal electrolyte excretion pattern suggests that under certain circumstances (e.g. dilated renal vascular bed) acute, but well-tolerated, whole-body hypoxic hypoxia can simultaneously stimulate renal proximal tubular sodium reabsorption and inhibit distal tubular sodium reabsorption. The renal tubular responses also indicate that almitrine may influence renal tubular lithium reabsorption by, thus far, unknown mechanisms.

Cardiorespiratory and renal responses to arterial chemoreceptor stimulation in early hypertension.

The peripheral arterial chemoreceptors (PAC) modify not only cardiorespiratory but also renal hemodynamic and excretory function. There is evidence that in hypertensive animals and humans the reflectoric actions of the PAC on ventilation and circulation differ from those of normotensive subjects. However, the influence of these receptors on kidney function of hypertensive subjects is poorly understood. Cardiorespiratory and renal responses to pharmacological stimulation of PAC by almitrine bismesylate during normoxia were measured in 16 normotensive (NT) and 13 age-matched borderline-hypertensive young men (BHT) undergoing water diuresis. Placebo experiments served as time controls in each subject. NT reacted to almitrine with significant rises in heart rate, minute ventilation, and filtration fraction. Renal vascular resistance tended to increase slightly. In BHT the drug caused a significant rise in heart rate and minute ventilation too, however, this reaction had a longer latency when compared to NT. In contrast to NT, filtration fraction, and renal vascular resistance decreased. Renal fractional sodium and lithium excretion did not show any clear response to almitrine in NT, but decreased in BHT. The results suggest that the weaker ventilatory response in BHT vs. NT might indicate a lower reactivity of their PAC to almitrine. The different reactions of the renal vascular bed to pharmacological chemoreceptor excitation in mild hypertensives might result from a different reactivity of the renal arterioles, whereas the enhanced proximal tubular sodium reabsorption could be due to an exaggerated increase in efferent renal nerve activity.

In vivo diuretic actions of renal vasopressin V1 receptor stimulation in rats.

The specific vasopressin V1 receptor agonist (V1AG; [Phe2,Ile3,Orn8]vasopressin) was infused (2.0 ng.kg-1.min-1) into the renal medullary interstitial space to determine the effects of selective medullary V1 receptor stimulation on sodium and water excretion in normal rats. Responses were compared with those of arginine vasopressin (AVP) and vasopressin V2 receptor stimulation resulting from infusion of a V1 receptor antagonist with AVP. Medullary infusion of V1AG or AVP in euvolemic rats produced no changes in hemodynamics or glomerular filtration rate. V1AG increased urine flow > 60% in euvolemic rats, whereas no change was observed with AVP. This response could not be explained by a rise of arterial pressure or by volume retention. With V2 stimulation in euvolemic rats, urine flow was decreased. In water diuretic rats, V1AG produced no change, whereas AVP infusion decreased urine flow. The results provide in vivo evidence that tubular V1 vasopressin receptor activity results in increased urine flow and thereby modulates the antidiuretic actions of vasopressin in the euvolemic state.

Normotensive normoxic men undergoing water diuresis fail to respond to stimulation of their peripheral arterial chemoreceptors by almitrine with an increase in plasma concentrations of atrial natriuretic factor.

The purpose of this study was to investigate the possible participation of atrial natriuretic factor (ANF) in the natriuretic and diuretic response occurring after stimulation of the peripheral arterial chemoreceptors by almitrine bismesylate in normoxic humans. The experiments were performed in 14 healthy male volunteers undergoing water diuresis. Each subject participated in two experiments. In one of them they ingested 100-mg almitrine at 12 p.m. The other study served as a control. Surprisingly, our subjects responded to almitrine with an elevation of urine flow only, whereas sodium excretion remained almost unchanged over the whole period of the experiments. As regards ANF plasma concentrations, no statistically significant differences between the control and the almitrine group could be observed. Moreover, no direct connection between ANF plasma concentrations and renal volume excretion was detectable. We conclude that a specific stimulation of peripheral arterial chemoreceptors by almitrine in humans undergoing water diuresis did not seem to raise ANF plasma concentrations as is the case at high altitude. Therefore we would suggest that there exists no specific reflex influence of these receptors on ANF release.

[The effect of moderate oxygen deficiency on volume regulation in man]. / Zur Wirkung eines moderaten Sauerstoffmangels auf die Volumenregulation des Menschen.

In acute hypoxia or at pharmacological stimulation of the peripheral arterial chemoreceptors by almitrine, a transient natriuresis and diuresis occurs. Depending on the starting level, e.g. on the state of water diuresis or the osmotic diuresis, the renal excretion responded differently in our examinations. In water diuresis the water excretion increased isolatedly. In the opposite to the osmotic diuresis, the natriuresis did not increase. This response might be based on the proximal inhibition of the sodium and water reabsorption at following augmented distal sodium reabsorption and suppressed distal water reabsorption. In this way the organism is able to respond with increased water excretion at sodium excretion kept constant or with diuresis and natriuresis when arterial chemoreceptors are stimulated.

Influence of infusion of deoxycorticosterone acetate on the responses of kidney function elicited by stimulation of the peripheral arterial chemoreceptors with almitrine bismesylate in anaesthetized rats.

In two groups of male, normotensive, spontaneously breathing rats in chloralose-urethane anaesthesia the peripheral arterial chemoreceptors were stimulated by intravenous infusion of almitrine bismesylate (0.25 mg/kg). The experiments were carried out in moderate osmotic diuresis. In one series desoxycorticosterone acetate (DOCA) was infused at a rate of 35-40 ng/min.100 g body weight. Urine was collected via a bladder catheter. Kidney hemodynamics as well as tubular and excretory function were determined using the clearance-technique. In both groups of animals administration of almitrine caused an increase of breathing rate as well as an increase of the oxygen tensions and the pH-values in the arterial blood. Mean systemic arterial blood pressure, effective renal plasma flow and glomerular filtration rate decreased slowly with the time of the experiments, whereas renal hemodynamic resistance tended to increase both in the control and in the DOCA treated group. In both groups of animals intravenous infusion of almitrine was followed by an inhibition of renal tubular sodium reabsorption and an increase of both the absolute and the fractional salt excretion. The data indicate that arterial chemoreceptor stimulation in rats causes an inhibition of renal tubular sodium reabsorption which does not result from a reduced tubular action of mineralocorticoid hormones.

Renal hemodynamics and excretory function of healthy young men during stimulation of their peripheral arterial chemoreceptors by almitrine bismesylate.

Renal hemodynamics and excretory function were studied using clearance-techniques in 13 healthy, normotensive, normoxic young men undergoing moderate osmotic diuresis. Each subject was measured in two experiments both lasting from 7:30 a.m. to 6:00 p.m. In one of them 50 mg almitrine bismesylate (Vectarion) was ingested at 12:00 o'clock, whereas the other test served as control. There were only negligible changes of the parameters measured in the control experiments. Immediately after ingestion of the drug a renal vasodilation occurred, but 2-3 h later renal hemodynamic resistance tended to increase. Urinary sodium excretion rose after administration of almitrine. Initially this increase seemed to be caused by the kidney vasodilation but between the 3rd and 6th hour after giving the agent a natriuresis occurred that resulted from inhibition of renal tubular sodium reabsorption. The maximum of this renal tubular response was apparently not reached at the end of the experiments, i.e. 6 h after oral administration of the drug. Almitrine did not increase the renal potassium excretion. The data indicate that pharmacological stimulation of the peripheral arterial chemoreceptors by almitrine bismesylate in normoxic healthy humans causes reflectorically a slight renal vasoconstriction and a long-lasting inhibition of renal tubular sodium reabsorption. These findings are in good agreement with previously published data obtained in animal experiments.

Plasma vasopressin levels in healthy young men in response to stimulation of the peripheral arterial chemoreceptors by almitrine bismesylate.

The plasma arginine vasopressin (AVP) concentration, the plasma osmolality as well as the systemic arterial blood pressure, the heart rate, and the minute ventilation were determined in four healthy, normotensive, normoxic young men undergoing moderate osmotic diuresis. Each subject was measured in two experiments, both lasting from 7:30 a.m. to 6:00 p.m.. In one of them they obtained 50 mg almitrine bismesylate (Vectarion) at 12:00 o'clock, whereas the other test served as control experiment. There were only negligible changes of the parameters measured in the control experiments and also only weak responses of the cardiorespiratory values in the almitrine treated group. Compared with the data obtained 30 min before administration of the drug, measurements carried out 90 min after the ingestion showed a decrease of plasma AVP in all four subjects through plasma osmolality was increased in three of the four cases. A comparison of the mean values of all data obtained in the morning, i.e. before the oral administration of the drug, with those determined in the afternoon revealed that three out of four subjects had responded to almitrine with a fall of plasma AVP regardless of an increase of plasma osmolality in all these three cases. One person did not react to almitrine ingestion, neither with plasma AVP nor with plasma osmolality. In the control experiments the corresponding reaction pattern was uncharacteristic. The data do not support the assumption that arterial chemoreceptor stimulation increases plasma AVP. They rather indicate that excitation of these pO2-sensors in normoxic humans suppresses plasma AVP by mechanisms so far unknown.

Kidney function during arterial chemoreceptor stimulation. I. Influence of unilateral renal nerve section, bilateral cervical vagotomy, constant artificial ventilation, and carotid body chemoreceptor inactivation.

The reactions of renal hemodynamics and excretory function elicited by perfusion of the vascularly isolated carotid bodies with venous blood were studied in four groups of chloralosed cats in which the Nn. vagi, the breathing reactions, and the carotid body chemoreceptors were excluded successively. The kidney function was determined using clearance-techniques in both the innervated right and denervated left kidneys. In the animals with intact carotid chemoreceptors perfusion of the carotid bifurcations with venous blood caused a weak (4-6 mm Hg on the average) and transient increase of the mean systemic arterial blood pressure as well as a vasoconstriction and a fall of the blood flow and glomerular filtration rate in the innervated kidneys. In the spontaneously breathing animals carotid body chemoreceptor stimulation effected a rise of fractional sodium excretion only in the denervated kidneys whereas the relaxed and constantly ventilated cats showed a natriuretic response both at the innervated and denervated side. The reactions of renal excretory function did not correlate with those of renal hemodynamics. Vagotomy, relaxation, and constant artificial ventilation failed to abolish the responses elicited by stimulation of the chemoreceptors. Inactivation of the carotid body chemoreceptors by injecting acetic acid into the vascularly isolated carotid sinuses prevented both the hemodynamic and tubular reactions due to hypoxic-hypercapnic perfusion of the carotid bodies. The findings suggest that the arterial chemoreceptors control kidney function by specific reflex mechanisms. The influence of the carotid body chemoreceptors on kidney vasculature is mediated by the efferent renal nerves, whereas the control of renal tubular sodium reabsorption requires hormone action.

Kidney function during arterial chemoreceptor stimulation. II. Suppression of plasma aldosterone concentration due to hypoxic-hypercapnic perfusion of the carotid bodies in anaesthetized cats.

The reactions of the mean systemic arterial blood pressure, kidney function (clearance technique) and plasma aldosterone concentration (radio-immuno-assay) elicited by perfusion of the vascularly isolated carotid bodies with venous blood were studied in two series of chloralosed, vagotomized, relaxed, and constantly ventilated cats undergoing saline diuresis. In one group of animals the carotid body chemoreceptors were left intact; in the other one, they were abolished by injecting acetic acid into the glomera carotici. In the cats with intact chemoreceptors perfusion of the carotid bodies with venous blood immediately caused a small and transient increase of the blood pressure, whereas renal plasma flow tended to fall despite continuous chemoreceptor stimulation. Renal fractional sodium excretion already increased in the first 25 min of chemoreceptor stimulation, whereas plasma aldosterone concentration showed a significant decrease only after 45 min of venous perfusion of the glomera carotici. Plasma electrolytes changed only little at that time. No clear relationships between the responses of plasma aldosterone and those of the other parameters measured could be obtained. On subsequent perfusion of the carotid bodies with arterial blood plasma aldosterone returned to the values determined before chemoreceptor stimulation. Inactivation of the carotid body chemoreceptors per se already enhanced plasma aldosterone concentration. Perfusion of the glomera carotici with venous blood in the cats with abolished chemoreceptors did not suppress plasma aldosterone content. The data show that plasma aldosterone changes are not involved in the development of the initial phase (first hour) of the inhibition of renal tubular sodium reabsorption provoked by arterial chemoreceptor stimulation, but during long-lasting chemoreceptor stimulation they might contribute to the maintenance of this type of natriuresis. Furthermore the experiments suggest that the decrease of plasma aldosterone repeatedly observed during exposure of mammals to acute hypoxic hypoxia is possibly the reflex result of the stimulation of the arterial chemoreceptors.

Kidney function during arterial chemoreceptor stimulation. III. Long-lasting inhibition of renal tubular sodium reabsorption due to pharmacologic stimulation of the peripheral arterial chemoreceptors with almitrine bismesylate.

The reactions of the mean systemic arterial blood pressure, arterial acid-base balance kidney function (clearance-technique), and plasma aldosterone concentration (radio-immunoassay) elicited by stimulation of the peripheral arterial chemoreceptors with almitrine bismesylate were determined in chloralosed, non-vagotomized, spontaneously breathing cats in moderate mannitol-saline diuresis. The left renal nerves were cut; urine was collected separately from both the innervated and denervated kidneys. Intravenous injection of 0.2 mg/kg of the drug caused the expected long-lasting increase of the pO2 and pH and a decrease of pCO2 in the arterial blood, whereas the mean systemic arterial blood pressure slightly rose by an average of 2-4 mm Hg in the first hour of chemoreceptor stimulation but afterwards considerably decreased below the pre-injection values. The renal responses were characterized by a moderate vasoconstriction particularly in the innervated kidneys and a pronounced increase of sodium and urine excretion especially in the denervated kidneys. The inhibition of renal tubular sodium reabsorption underlying these natriuretic and diuretic reactions was fully demonstrable even at the end of the experiments, i. e. 4 h after the administration of the agent. Plasma aldosterone increased with the time of the experiments but did not show any clear relationships to the activity of the arterial chemoreceptors. The results show that the intravenous injection of almitrine bismesylate is connected with a renal response pattern which is typical for an excitation of the peripheral arterial chemoreceptors, i. e. moderate vasoconstriction (efferently mediated by the renal nerves) and an inhibition of renal tubular sodium reabsorption (efferently mediated by hormonal mechanisms). Furthermore, the data suggest that, on the one hand, under certain conditions these reactions of the kidney function could play the role of undesirable side effects but, on the other hand, the inhibition of renal tubular sodium reabsorption caused by almitrine bismesylate might possibly be used to treat diseases that are connected with a reduced ability of the kidneys to sufficiently excrete sodium.