Mineralocorticoid activity in patients in the early benign phase of essential hypertension.
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Biomedical subjects
Publications and source records attributed to J Genest.
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Urinary excretion of dopamine, norepinephrine and epinephrine was measured in a group of adult men and women of comparable age during recumbency and then during stimulation by upright posture. Urinary norepinephrine was found to be significantly higher in women (30.3 +/- 4.4 ng/min/m2 B.S.) than in men (18.3 +/- 2.7 ng/min/m2 B.S.) during recumbency; there was no significant sex difference in dopamine and epinephrine excretion. There was no apparent trend indicating a difference in urinary catecholamine excretion during the follicular or luteal phase of the menstrual cycle. In response to upright posture, there was a significant decrease in the urinary dopamine-norepinephrine ratio in both sexes; the magnitude of the decrease was, however, significantly higher in men (-9.9 +/- 3.0) than in women (-2.05 +/- 0.72). The mechanisms of the sex differences in urinary catecholamine excretion are unknown. Clinical studies involving catecholamines have to take these sex differences into account.
Deoxycorticosterone pivalate (2.5 mg/kg) given intramuscularly on four occasions 10-15 days apart over a period of 45 days to unilaterally nephrectomized adult male mongrel dogs, receiving as drinking solution 0.9% NaCl in 5% dextrose, resulted in an average sustained rise in the mean arterial blood pressure of 30 mm Hg (1 mm Hg - 133 N/m2) in 60% of the animals. Hypertensive dogs had in their arterial tissues generally more sodium, potassium, magnesium, and calcium than the similarly treated but non-hypertensive dogs, but compared to the tissues of operated untreated or unoperated normotensive dogs, only sodium and calcium were significantly higher. The dogs who were similarly treated but did not develop hypertension had in their arterial tissues less sodium, potassium, and magnesium than operated untreated or unoperated normotensive dogs. Norepinephrine content in the branches of mesenteric arteries of all deoxycorticosterone- and NaCl-treated animals, irrespective of their blood pressure, was significantly lower, and in the myocardium significantly higher, than either the unoperated normotensive or operated but not further treated dogs. It is concluded, therefore, that in deoxycorticosterone + NaCl treatment the dogs which developed hypertension had more arterial sodium, potassium, magnesium, and calcium than those who were similarly treated but remained within the limits of normal blood pressure, and that there was no difference between hypertensive and non-hypertensive dogs in regard to their cardiovascular norepinephrine content.
In dogs made hypertensive renal artery stenosis and contralateral nephrectomy, the arterial and myocardial tissue content of water, cations (sodium, potassium, magnesium, calcium), and norepinephrine was measured 20 and 60 days after the operation. Hypertensive animals autopsied at the earlier stage of hypertension had significantly lower (-25 to-50%, P smaller than 0.01) arterial norepinephrine than either the sham or nonhypertensive animals. The water and cation content of arteries was unchanged, but aortic tissue contained significantly more water, sodium, potassium, and magnesium than the nonhypertensives. Hypertensives autopsied at 60 days also had lower arterial norepinephrine content than sham and nonhypertensive animals, but this refuction was not significant. Their arterial and aortic tissue contained more water and cations than the nonhypertensive, sham, unoperated, and unilaterally nephrectomized dogs. It is suggested that in the initial stage of renovascular hypertension the arterial norepinephrine content is reduced significantly, whereas at a later stage the arterial water and cations may be involved in the maintenance of an elevated blood pressure.
Splanchnic blood flow (SBF) was measured simultaneously with cardiac output (dye dilution) and intrarterial blood pressure by constant infusion of indocyanine green in 11 control subjects, 13 patients with essential hypertension (EH) and seven hypertensive patients with renal artery stenosis (RAS). The cardiac index (CI) was lower (P less than 0.05) in patients with EH (3.17 plus or minus 0.07 L/min/m-2) (mean plus or minus SEM) than in control subjects (3.43 plus or minus 0.09). Associated with the lower CI was a significantly (P less than 0.01) lower SBF (0.797 plus or minus 0.02 L/min/m-2 vs 0.889 plus or minus 0.04). Patients with RAS presented with higher (P less than 0.01 vs EH, nonsignificant vs control subjects) cardiac index (3.66 plus or minus 0.17) and even lower SBF (0.749 PLUS OR MINUS 0.02). Furthermore, there was a negative correlation (r = - 0.652) between the mean arterial pressure and the SBF when results for all patients were considered. The correlation remained (r = - 0.568) in the EH group and the slope of regression line was not different from that for all subjects. The CI and SBF were weakly correlated (r = 0.423) in control subjects and patients with EH, whereas in patients with RAS, a negative correlation was found (r = - 0.778). This study indicates that the SBF, although significantly decreased in patients with EH, remains proportional to the CI in control subjects and in essential hypertensive patients. No redistribution of CI in regard to the splanchnic circulation occurs in EH. In contrast, in patients with RAS a dissociation of CI and SBF occurs and the fraction of the CI which passes through the splanchnic vascular bed is markedly reduced. The close correlation between mean arterial pressure and SBF suggests that both parameters are influenced by a common pathophysiological factor.
Labile hypertension in patients under 50 years of age (the non-atherosclerotic form) was found to be characterized by higher urinary excretion of catecholamines and particularly of homovanillic acid; when further analyzed it was shown to be a heterogeneous entity with two types of patients clinically and biochemically distinguishable from each other, from control subjects and from patients with stable hypertension. Reactivity to assuming an upright posture distinguishes one type of labile hypertension having a normal postural pulse rate response from another having an excessive postural increase in pulse rate. The first group also showed normal responses of plasma norepinephrine concentration and of urinary cyclic AMP to posture. The group with excessive pulse rate response, in contrast, showed a decrease in plasma norepinephrine and an excessive increase of urinary cyclic AMP excretion in response to upright posture. The results suggest that not only circulating catecholamines but also the reactivity of their target tissues (as probably reflected by cyclic AMP measurements) are important in bringing about signs of adrenergic excess. The hypothesis that cyclic AMP changes reflect beta-adrenergic receptor reactivity is strongly favoured by data indicating qualitative differences in cyclic AMP responses to beta-adrenergic stimulation or inhibition between control subjects and those labile hypertensive patients with clinical signs of excessive sympathetic reactivity. The study stresses the need for more precise definition of labile hypertension, for dynamic clinical and biochemical correlative studies, and for consideration not only of the circulating hormones but also of the "second messengers" (such as cyclic AMP and cyclic GMP) which reflect the cellular action of hormones. Blood pressure is a very labile parameter in health and disease. In one sense, therefore, hypertension can be considered "labile" in every hypertensive patient. Usually, however, labile (or borderline) hypertension is regarded as characterized by a blood pressure over 140/90 mmHg, falling below these values with physical and emotional rest. This clinical entity, which affects some 20% (variously estimated between 16 and 30%) of the adult population, gives rise to uncertainties in both definition and prognosis. In some patients labile hypertension represents the precursor of a fixed hypertensive state, whereas in many others it remains labile throughout life, never progressing to the stable phase nor becoming associated with hypertensive cardiovascular disease.(ABSTRACT TRUNCATED AT 400 WORDS)
Urinary excretion and plasma concentrations of adenosine 3',5'-monophosphate were determined in idiopathic edema patients both at rest and after assumption of the upright position. Patients and normal subjects responded similarly to upright posture with decreases in urinary volume and creatine excretion and their urinary excretion of cyclic AMP was not significantly different. The plasma concentration of cyclic AMP was high in patients, both in the recumbent and upright positions, and its renal clearance (unlike that of creatinine) was low. Plasma cyclic AMP increased in response to upright posture both in patients and normal subjects. Even if the significance of elevated plasma cyclic AMP is unknown, its presence without an increase in urinary cyclic AMP suggests that the renal handling of cyclic AMP is abnormal is idiopathic edema; this may be related to an excessive beta-adrenergic tone.
Plasma arginine vasopressin (PAV) concentration was determined by radioimmunoassay during the diurnal cycle in 8 recombent healthy male subjects. Two subjects were studied again 3 weeks later while receiving 1 mycles. In 8 out of 10 cycles, a nocturnal increase in PAV was found; there was a progressive rise during the night in 5 subjects and a peak occurred at 2400 or 3400 h. In 1 subject no variation was detected and in another, the pattern was compleetly different. The mean PAV in the 10 cycles was significantly (P less than 0.001) higher during the night than during the day. Dexamethasone did not modify the pattern of variation, but induced a significant (P less than 0.001) decrease in PAV. Hematocrit remained stable throughout the study as did osmolality, except at 2000 h, when a significant (P less than 0.001) increase (5 mOsm) on average occurred in every subject. Blood sugar, sodium or chloride did not account for the observed rise in osmolality and no simultaneous change in PAV occurred. A rise in PAV explains, to some extent, the known nocturnal decrease in urine output. Diurnal variations in PAV must be taken into account in clinical investigations involving vasopressin.
The renin-angiotensin system was studied in experimental renal hypertension produced by ligation of the poles of the left kidney followed by contralateral nephrectomy. Plasma renin concentration of renin substrate was lower and that of angiotensin I converting enzyme was higher in hypertensive animals. The juxtaglomerular index decreased in the medial zone of the kidney, while heavily granulated areas appeared in the poles. Ligated kidneys of rats that remained normotensive showed juxtaglomerular indices intermediate between the control and the hypertensive rats. Differences in renal renin content between the groups correspond to those for the juxtaglomerular index, but were smaller. No differences between the experimental groups were observed in iso-renin content in the brain; however in all animals with ligated kidney poles, hypertensive or normotensive, there was a tendency for iso-renin in the adrenals, left ventricular myocardium, and especially aorta to be lower than in controls.
Propranolol administration to rats was studied for its effects on plasma renin activity, renal renin content, and adrenal and brain isorenins. Propranolol was given intraperitoneally at 6 and 30 mg/kg/day for a 15-day period. Pulse rate was significantly decreased. There were no effects on the isorenin content of adrenal or brain tissue or on renal renin content. Rats responded in two completely different ways with respect to plasma renin activity. Two-fifths had a total suppression of plasma renin activity; the rest had concentrations similar to those in controls. These observations are consistent with those seen during chronic administration of propranolol to hypertensive patients and suggest that its antihypertensive effect may in some patients be through the suppression of renin release. Its mechanism of action in most patients remains at present unclear.
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Renin, iso-renin, angiotensin I. angiotensin-converting enzyme, and angiotensinases were measured in plasma and in various extrarenal tissues of rats. Despite complete suppression of plasma renin in rats bearing pituitary tumors iso-renin and all other components of the renin-angiotensin system were found to be at or above control concentrations. The results strongly suggest that there is local synthesis of iso-renin in extrarenal tissues.
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In a previous study we observed an increase in urinary cyclic AMP in labile hypertension in the upright position and during isoproterenol infusion, in contrast to a decrease in control subjects. In the present study we measured the plasma level of cyclic AMP in control subjects and patients with various types of hypertension. We obtained the following results: (1) plasma cyclic AMP increases in response to upright posture in control subjects and hypertensive patients; (2) values of cyclic AMP in the recumbent and upright positions are comparable in control subjects and patients with essential hypertension, but are significantly higher in those with true renovascular hypertension due to bilateral renal artery stenosis; (3) propranolol inhibits the increase of plasma cyclic AMP in response to posture in control subjects, but has an opposite effect in labile hypertension where there is a further increase; (4) the rise in blood pressure in pheochromocytoma is associated with a considerable increase in plasma cyclic AMP.Present and previous data suggest that kidney handling of cyclic AMP is abnormal in hypertension, and that the specific defect may be related to the type of hypertension.
MAJOR SCREENING PROGRAMS FOR HYPERTENSION ARE NECESSARY FOR THE FOLLOWING REASONS: (a) the 12 to 15% prevalence of hypertension in the North American population; (b) the high proportion of hypertensive patients who are inadequately treated or whose disease is not even recognized; (c) the fact that in too many medical centres hypertension is poorly investigated or considered an insignificant finding; (d) the demonstration by many groups, especially the Framingham study, of hypertension as the major factor in the occurrence of severe cardiovascular disease; and (e) the achievement of a marked decrease in severe cardiovascular complications following adequate treatment. But such screening programs are of little value if unaccompanied by a major educational effort directed not only to the public but also to the medical profession, and a parallel increase in the funding of biomedical research into the basic physiopathological mechanisms of hypertension.