Carlo Beretta-Piccoli

Sodium-volume factor, cardiovascular reactivity and hypotensive mechanism of diuretic therapy in mild hypertension associated with diabetes mellitus☆

Abstract Diabetes mellitus is often associated with excess body sodium and frequently accompanied by hypertension. Relationships among blood pressure and various regulatory factors were studied before and after six weeks of diuretic therapy with chlorthalidone, 100 mg/day, in 17 diabetic subjects (aged 32 to 75 years) with borderline to moderate hypertension. Following a four-week placebo phase, mean supine blood pressure was 165/93 ± 26/15 (±SD) mm Hg and exchangeable sodium was increased (49 ± 4 versus 45 ± 4 meq/kg lean body mass in 90 normal subjects; p

Interrelations among blood pressure, blood volume, plasma renin activity and urinary catecholamines in benign essential hypertension☆

Interrelations among blood pressure, circulatory volume, plasma renin activity (PRA) and urinary catecholamine excretion rates were studied in normal subjects and in patients with benign essential hypertension. Mean plasma or blood volumes related to lean body mass, products of blood volume and the logarithm of PRA, and catecholamine excretion rates did not differ significantly between normal and hypertensive subjects. In both normal subjects and hypertensive patients, blood pressure levels correlated positively with the noradrenaline excretion rate (r = 0.40 and 0.36, respectively; p less than 0.025) but not with adrenaline excretion, circulatory volume or the volume-renin product. The logarithm of PRA correlated inversely with mean blood pressure in normal subjects (r = 0.40; p less than 0.001) but not in hypertensive patients; however, there was no convincing evidence for an inappropriate blood pressure-PRA relationship as a prominent feature in the hypertensive patients. PRA did not correlate with blood volume. Patients with low PRA relative to sodium excretion (21 per cent of hypertensive population) were consistently normovolemic, but they tended to be older and excreted less (p less than 0.025) adrenaline than patients with normal or high PRA. The patient subgroup with high PRA relative to sodium excretion (11 per cent of population) was hypovolemic (p less than 0.02); despite this, urinary sodium output was high (172 +/- 64 meq/24 hours). These data reveal no evidence for major roles of PRA, circulatory volume and free peripheral catecholamines in the maintenance of benign essential hypertension. Essential hypertension with low PRA is usually not a hypervolemic state, but it may reflect diminished adrenergic activity, factors associated with aging and effects of a high systemic pressure. High PRA in benign essential hypertension may be at least partly a consequence of hypovolemia resulting from high blood pressure-induced sodium diuresis.

Interrelations between age and plasma renin, aldosterone and cortisol, urinary catecholamines, and the body sodium/volume state in normal man

ZusammenfassungUntersuchungen bei 28 jungen (19–29 Jahre), 16 mittel-alten (32–58 Jahre) und 15 älteren (60–74 Jahre) Normalpersonen zeigten eine mit zunehmendem Alter progressive Abnahme der Plasmareninaktivität und -aldosteronkonzentration sowie eine Zunahme der Noradrenalinexkretionsrate. Mit Ausnahme der im Stehen gemessen Plasmaaldosteronspiegel waren die Korrelationen dieser Parameter mit dem Alter (r≥0,34;p<0.05) sowie die Unterschiede der Mittelwerte zwischen jungen und älteren Personen (p<0,02) signifikant. Die Plasmacortisolkonzentration blieb beim Aufstehen bei jungen und mittel-alten Personen im Mittel unverändert (−10 und −8%), stieg jedoch bei älteren Menschen um 50% an (p<0,02). Der Blutdruck korrelierte (p<0,05) bei Analyse der gesamten Studienpopulation mit dem Alter (r=0,35) und der Noradrenalinexkretionsrate (r=0,34), bei den älteren Personen fand sich auch eine signifikante Beziehung zum Blutvolumen (r=0,68). Austauschbares Körpernatrium, Plasma- und Blutvolumina und Adrenalinexkretionsrate zeigten keine signifikanten altersbezogenen Variationen. Plasmarenin- und -aldosteronspiegel korrelierten weder mit diesen letzteren Parametern noch mit dem Blutdruck. Es wird gefolgert, daß der Einfluß des Alters auf Plasmarenin- und -aldosteronwerte, das freie periphere Noradrenalin und die Stimulierbarkeit von Plasmacortisol durch Orthostase in Betracht gezogen werden sollte, wenn immer diese Faktoren bei Patienten mit arterieller Hypertonie oder anderen klinischen Störungen interpretiert werden müssen. Diese Resultate sind außerdem mit der Möglichkeit vereinbar, daß die altersbezogene Zunahme des Liegendblutdrucks beim normalen Menschen zumindest teilweise auf dem parallelen Anstieg des freien peripheren Noradrenalins beruhen könnte.SummaryInterrelations between age and plasma renin, aldosterone and cortisol levels, urinary catecholamines, plasma and blood volumes, exchangeable body sodium and blood pressure were studied in 28 young (19 to 29 years), 16 middle-aged (32 to 58 years) and 15 elderly (60 to 74 years) healthy subjects. Supine and upright plasma renin and supine aldosterone levels decreased while urinary noradrenaline excretion rate increased progressively with aging (r≥0.34;p<0.05), with significant differences in mean values between young and elderly subjects (p<0.02). There was also an age-related decrease in upright plasma aldosterone concentration, although this was not statistically significant. Furthermore, mean plasma cortisol concentrations increased in response to upright posture in elderly (+50%;p<0.02), but not in young (−10%) or middle-aged (−8%) subjects. Blood pressure correlated with age (r=0.35;p<0.05) or noradrenaline excretion rate (r=0.34) in the entire study population and with blood volume in the elderly (r=0.68), but not in the young or middle-aged study groups. There were no significant age-related differences in the body sodium/volume state, basal plasma cortisol levels or urinary adrenaline excretion rate, and plasma renin or aldosterone levels did not correlate with these parameters or with blood pressure. It is concluded that the influence of age on plasma renin or aldosterone levels, plasma cortisol responsiveness to upright posture, and urinary noradrenaline excretion should be taken into consideration, whenever these factors have to be interpreted in patients with arterial hypertension or other clinical disorders. Furthermore, these data are consistent with the possibility that in normal man increases in supine blood pressure with aging may be related at least partly to concomitant changes in free peripheral noradrenaline.

Hypertension associated with early stage kidney disease: Complementary roles of circulating renin, the body sodium/volume state and duration of hypertension

Interrelations among blood pressure, exchangeable sodium, blood volume and plasma renin activity were studied in 40 normal subjects and in 40 patients with early stage kidney disease (mean plasma creatinine, 2 mg/100 ml). Findings in eight normotensive patients did not differ significantly from those in normal subjects. However, 32 hypertensive patients showed increases (p less than 0.05) in mean exchangeable sodium and in the products of the logarithm of plasma renin activity and exchangeable sodium or blood volume. In normal subjects, blood pressure did not correlate with any of the parameters measured. In the patients, it correlated significantly (p less than 0.05) with duration of hypertension (r = 0.70), exchangeable sodium (r = 0.34) and with sodium-renin (r = 0.38) or volume-renin (r = 0.30) products, but not with blood volume or circulating renin individually. Multiple regression analysis with blood pressure as a dependent variable, and duration of hypertension and the sodium-renin or volume-renin products as independent variables, revealed correlation coefficients of 0.77 and 0.76, respectively. These findings suggest that hypertension accompanying early stage kidney disease may depend at least partly on subtle abnormalities in the sodium volume-renin feedback mechanism as well as on a factor related to the duration of preexisting hypertension.

Exaggerated pressor responsiveness to norepinephrine in nonazotemic diabetes mellitus

Pressor responses to norepinephrine (NE) or angiotensin II (AII) were studied in 27 diabetic patients without heart or renal failure and in 27 normal subjects. Mean plasma or 24-hour urinary sodium, blood volume and preinfusion plasma NE levels were similar in diabetic and normal subjects; exchangeable sodium was higher (p less than 0.02) and preinfusion plasma renin activity (PRA) was slightly lower in diabetic patients. The NE pressor and threshold doses were lower in diabetic patients than in normal subjects (76 versus 141 and 16 versus 41 ng/kg/min, respectively; p less than 0.05). The AII pressor dose also tended to be lower in diabetic patients (7.2 versus 11.9 ng/kg/min; p less than 0.05), but the AII threshold dose did not differ between the two groups (1.1 versus 1.6 ng/kg/min). These findings were similar in the diabetic subgroup without or with retinopathy (N = 13 and 14, respectively) and in those with normal or high blood pressure (N = 17 and 10, respectively). These observations suggest that in nonazotemic diabetes mellitus increases in AII pressor responsiveness are associated with a concomitant reduction in PRA. However, cardiovascular pressor responsiveness to NE tends to be exaggerated despite normal plasma NE levels and this alteration may occur already in the normotensive stage of diabetes mellitus. Cardiovascular hyperresponsiveness in diabetic subjects may be related to excess body sodium or structural alterations in the vasculature, or both.

Curable Hypertension with Unilateral Hydronephrosis: Studies on the Role of Circulating Renin

Among eight patients with unilateral hydronephrosis and hypertension, peripheral plasma renin activity was normal in seven and borderline high in one. Four patients had hydronephrotic/contralateral kidney renin ratios of greater than 1.5, suggesting excessive renin release from the diseased kidney, and ratios between contralateral kidney and peripheral blood of less than 1.2, indicating suppressed renin production in the contralateral kidney. Nephrectomy normalized blood pressure in each of these patients. Two patients had hydronephrotic/contralateral kidney renin ratios of less than or equal to 1.3 or contralateral kidney/periphery ratios of greater than 1.2, suggesting ischemia of the contralateral kidney; pyeloplasty or nephrectomy, or both, failed to improve the hypertension. Postoperative changes in blood pressure correlated with changes in peripheral renin (r = 0.90; P less than 0.01). These data suggest that hypertension associated with unilateral hydronephrosis is partly renin-dependent; and renal vein renin values are helpful in selecting patients for surgery.

Plasma Catecholamines and Renin in Diabetes Mellitus * Relationships with Posture, Age, Sodium, and Blood Pressure

ZusammenfassungBei 90 Normalpersonen und 100 Patienten mit nicht-azotämischem Diabetes mellitus (18- bis 76jährig) wurden Plasmanoradrenalin (PNA), -adrenalin, Urinkatecholamine, Plasmareninaktivität (PRA) und Blutdruck, sowie ihre Beziehungen zu Körperlage, Alter und Körpernatrium-Volumen-Status untersucht. 46 Diabetiker hatten im Liegen einen normalen Blutdruck, 54 eine Hypertonie. Die Diabetiker hatten ein signifikant (p<0,01) erhöhtes austauschbares Körpernatrium (NaEx), das Blutvolumen war normal. Plasmaadrenalin war bei Diabetikern im Mittel normal und unabhängig von Körperlage oder Alter. Die orthostatische Stimulierbarkeit von PNA war bei Normalpersonen und Diabetikern vergleichbar, die PRA-Stimulierbarkeit war bei Diabetes im Mittel vermindert (p<0,001). In beiden Populationen korrelierte PNA positiv und PRA invers mit dem Alter (p<0,05), jedoch nicht mit dem Urinnatrium. Im Vergleich zu dynamischen Normbereichen für PNA und PRA in Beziehung zum Alter hatten 14% der Diabetiker im Stehen ein niedriges PNA, 12% hatten eine niedrige PRA und 6% eine erhöhte PRA. Die Niedrig-PNA-Subgruppe hatte ein höheres NaEx und niedrigere PRA-Werte als die Normal-PNA-Subgruppe (p<0,025); Niedrig-Renin-Patienten hatten ein höheres NaEx und niedrigeres Urinnoradrenalin als Normal- oder Hoch-Renin-Patienten. Ein orthostatischer Blutdruckabfall wurde bei Niedrig- oder Normal-Renin-Patienten, nicht aber bei Hoch-Renin-Patienten beobachtet. Diese Befunde weisen darauf hin, daß bei Diabetikern ohne wesentliche Nierenfunktionseinschränkung meist eine normale adrenerge Antwort auf Körperlagewechsel besteht und daß die physiologischen Beziehungen zwischen zirkulierendem Noradrenalin oder Renin und dem Alter weitgehend intakt sind. Der orthostatische Anstieg von Renin ist dagegen oft vermindert. Die beobachtete Körpernatriumretention könnte eine wichtige Rolle sowohl für die bei gewissen Patienten vorhandene Noradrenalin- und Reninsuppression als auch für das häufige Auftreten einer Hypertonie bei Diabetes mellitus spielen.SummaryPlasma and urinary norepinephrine (PNE, UNE) and epinephrine, plasma renin activity (PRA) and their interrelations with posture, age, the body sodium-volume state and blood pressure were analyzed in 90 normal and 100 non-azotemic diabetic subjects. Ages ranged from 18 to 76 yrs, urinary sodium from 51 to 249 mEq/24h. Fortysix patients had a normal supine blood pressure, 54 had hypertension. Diabetics had an increased (p<0.01) mean exchangeable sodium, while blood volume was normal. Upright posture caused a comparable increase in PNE in normal and diabetic subjects; but the response of PRA was blunted (p<0.001) in diabetics, with subnormal responsiveness in 32% of cases. Epinephrine levels in diabetics were normal and unchanged with posture or age. In both groups supine and upright PNE and PRA correlated (p<0.05) positively with age, but not with urinary sodium. Comparison with dynamic normal ranges relative to age revealed low upright PNE in 14% and low or high PRA in 12 and 6% of diabetics, respectively. The low-norepinephrine subgroup had a higher exchangeable sodium and lower PRA than the normal-norepinephrine patients (p<0.025). Low-renin patients had a higher exchangeable sodium and lower UNE than normal or high-renin patients. Orthostatic decrease in blood pressure was noted in low or normal-renin, but not in high-renin patients. These findings suggest that patients with non-azotemic diabetes mellitus have usually a normal adrenergic response to postural changes; and physiological variations of PNE and PRA with age are largely maintained. However, diminished renin-responsiveness is common. Distinct sodium retention could contribute to norepinephrine or renin suppression in some patients and possibly also to the frequent development of hypertension in diabetes mellitus.

Antihypertensive Therapy With Ca2+: Antagonist Verapamil and/or ACE Inhibitor Enalapril in NIDDM Patients

Objective To assess the efficacy and tolerance of a diuretic-free antihypertensive therapy with a Ca2+ antagonist and an angiotensin-converting enzyme (ACE) inhibitor in patients with non-insulin-dependent diabetes mellitus (NIDDM). Research Design and Methods After a 2-wk washout and a 4-wk placebo phase, 47 hypertensive patients with NIDDM randomly received verapamil or enalapril alone and, if blood pressure remained elevated, both agents combined over 30 wk. Results Verapamil or enalapril alone normalized blood pressure to < 90 mmHg diastolic in 30 patients; verapamil decreased mean ± SE blood pressure from 159/98 ± 3/1 to 146/87 ± 3/2 mmHg (n = 18, P < 0.001) and enalapril from 166/99 ± 5/2 to 146/86 ± 3/1 mmHg (n = 12, P < 0.001). In 17 patients who were still hypertensive after 10 wk of monotherapy, combination of both drugs decreased blood pressure from 170/104 ± 4/2 to 152/90 ± 4/2 mmHg (P < 0.001). Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total lipids, high-density and low-density lipoprotein cholesterol, apolipoproteins A-I and B, creatinine, and urinary albumin-creatinine ratio were not significantly modified. Conclusions In hypertensive patients with NIDDM, a diuretic-free therapy based on the Ca2+ antagonist verapamil and/or the ACE inhibitor enalapril can effectively decrease blood pressure without adversely affecting carbohydrate and lipid metabolism.

Relation of blood pressure with body and plasma electrolytes in Conn's syndrome.

Thirty-four patients with untreated Conns syndrome were studied in a metabolic ward. The final diagnosis in each case was based on the finding and removal of an adrenal cortical adenoma with histological features typical of the disorder. Compared with 34 age and sex-matched normal controls the untreated patients had increased plasma aldosterone concentration, increased blood pressure (183/112 mmHg), increased exchangeable sodium (116.7% of normal), hypokalaemia and increased plasma sodium concentration. Exchangeable potassium was lower than normal and plasma concentrations of active renin, total renin and angiotensin II were lower than normal mean values. Arterial pressure correlated significantly and positively with plasma and exchangeable sodium and there was a significant negative correlation with plasma potassium concentration. Partial regression analysis showed that the relation of exchangeable sodium with blood pressure did not depend on age or renal function but that the relation of blood pressure and plasma potassium could be attributed to the correlation of exchangeable sodium and blood pressure. Multiple regression analysis suggested that exchangeable and plasma sodium were the most important determinants of blood pressure in untreated patients. Spironolactone, amiloride and surgical removal of the adenoma corrected the electrolyte abnormality and usually lowered blood pressure. The fall in exchangeable sodium was related to the fall in blood pressure. The pattern of correlation found by multiple regression analysis in postoperative patients was similar to that in normal subjects. The findings are relevant to some of the mechanisms proposed for the hypertension of mineralocorticoid excess.

Effects of tyramine on blood pressure and plasma catecholamines in normal and hypertensive subjects

SummaryResponses of blood pressure and plasma catecholamines to intravenous injection of tyramine at increasing dosage (30, 45, and 60 µg/kg, respectively) were evaluated in 25 normal subjects and 20 patients with mild essential hypertension. Basal plasma norepinephrine and epinephrine concentrations before tyramine injections were similar in the two groups. Following tyramine injection, plasma epinephrine was unchanged. Responses of plasma catecholamines and blood pressure to tyramine were similar in the two groups. Plasma norepinephrine increased significantly 2 min after a dose of 30 µg/kg, but higher tyramine doses failed to produce a further increase in plasma norepinephrine. In contrast, pressor responses to tyramine were dose-dependent. Maximal pressor responses were observed within 2 min after injection. These findings reveal a dissociation between changes in blood pressure and plasma norepinephrine following injection of tyramine. Lack of steady state may limit the value of tyramine bolus injections as a tool for the quantitation of pressor responsiveness to variations in endogenous sympathetic output. Alternatively, it is possible that the pressor effects of tyramine may be mediated at least in part by a norepinephrine independent mechanism.ZusammenfassungBei 25 Normalpersonen und 20 Patienten mit leichter essentieller Hypertonie wurde das Verhalten von Blutdruck und Plasmakatecholaminen unter intravenösen Tyramin-Injektionen in steigenden Dosen von 30, 45 und 60 µg/kg untersucht. Die Basalwerte der Plasmakatecholamine waren in beiden Gruppen vergleichbar. Nach Tyramininjektion blieb Plasma-Adrenalin unverändert. Der Effekt von Tyramin auf Plasma-Noradrenalin und Blutdruck war in beiden Gruppen gleich. Obschon bereits eine Dosis von 30 µg/kg Tyramin 2 min nach Injektion einen signifikanten Anstieg von Plasma-Noradrenalin bewirkte, nahm letzteres unter den höheren Tyramindosen nicht weiter zu. Dagegen waren die Tyramininduzierten Blutdruckanstiege dosisabhängig. Der maximale Pressoreffekt ergab sich innerhalb der ersten 2 min nach Tyramin-Injektion. Diese Befunde zeigen eine Diskrepanz zwischen dem Verhalten von Blutdruck und Plasma-Noradrenalin nach Tyramin-Bolusinjektionen. Das Nichterreichen eines Gleichgewichtzustandes zwischen freigesetzten Neurotransmittern und Noradrenalin im Blut könnte den Wert einer Tyramin-Injektion als Methode zur quantitativen Erfassung der Reaktivität gegenüber Variationen der endogenen Sympathikusaktivität beim Menschen einschränken. Andererseits erscheint es möglich, daß die pressorische Wirkung von Tyramin teilweise durch einen Noradrenalin-unabhängigen Mechanismus vermittelt wird.