G. G. Geyskes

Haemodynamic and hormonal changes during acute and chronic diuretic treatment in essential hypertension

SummaryThe short- and long-term effects of diuretic treatment with chlorthalidone 50 mg/day on haemodynamic and hormonal parameters in patients with essential hypertension (WHO grade I) were investigated. After three days of treatment, all patients showed a rise in plasma renin activity (PRA), plasma aldosterone (PA), urinary norepinephrine excretion (UNE) and heart rate (HR), and a decrease in body weight (BW) and extracellular volume (ECV) and blood volume (BV); the change in blood pressure (BP) was variable. The changes in BP were correlated with those in BV. After three months of therapy, the signs of volume depletion tended to fade, but the lower ECV persisted. In contrast to the 4-day study, after three months the change in BP correlated inversely with changes in ECV and renin dependency (saralasin response), and positively with PRA and changes in UNE. It is concluded that the BP response to diuretic treatment is determined by the adaptation with time of the haemodynamic reactions to the volume-depleted state. Whether this adaptation will take place cannot be predicted from the control values of the parameters studied, or from acute changes observed during the first days of treatment.

Lisinopril in hypertensive patients with and without renal failure

SummaryLisinopril (MK521), a lysine analogue of enalaprilic acid, the bioactive metabolite of enalapril, has a longer half-life than enalaprilic acid, and is excreted unchanged in the urine. Its kinetic profile and antihypertensive and hormonal effects have been investigated in an open study in 3 groups each of 6 hypertensive patients, with normal, moderate and severe impairment of renal function. Serum drug level, blood pressure, converting enzyme activity (CEA), plasma renin activity (PRA), aldosterone concentration (PAC), and serum potassium and creatinine were measured during 1 week following a single oral dose and subsequently following 8 daily doses of 5 mg lisinopril. Accumulation of lisinopril was found in the severe renal failure group. CEA was suppressed to less than 10% of its initial value from 4 to 24 h after the initial dose in all three groups, and the suppression was more marked and lasted longer in patients with severe renal failure. An inverse correlation was found in all patients between log serum lisinopril concentration and log CEA. Lisinopril lowered blood pressure in all three groups over 24 h. PRA rose and PAC fell similarly in the groups. Serum potassium increased in the renal failure groups and creatinine remained unchanged in all groups.Thus, when lisinopril 5 mg is given daily to patients with severe renal failure it may accumulate. The high serum lisinopril concentration does not cause an excessive antihypertensive effect. In patients with severe renal failure, adjustment of the dose or the dosing frequency to the degree of renal failure is recommended to avoid administration of doses in excess of those required to achieve adequate inhibition of converting enzyme.

Pharmacokinetics of lisinopril in hypertensive patients with normal and impaired renal function

SummaryThe pharmacokinetics of lisinopril was studied after administration of single and multiple doses of 5 mg to hypertensive patients with normal and impaired renal function.In patients with severe renal failure the peak concentrations were higher, the decline in serum concentration was slower and the time to peak concentration was extended. Accumulation of lisinopril was highly correlated with the creatinine clearance. The effective half-life was doubled and tripled in patients with mild and severe renal impairment, respectively, as compared to patients with a normal renal function. Lisinopril lowered blood pressure in all three groups over 24 h.It is suggested that smaller doses of lisinopril should be administered to patients with severe renal failure.

Observations on Plasma Renin Substrate in the Nephrotic Syndrome

Literature data on renin in the nephrotic syndrome are conflicting: renin values are reported to be elevated as the rule, but sometimes normal or low; data on renin substrate are scanty and pointing to low values. In the present study, plasma renin activity (PRA) and plasma renin substrates (PRS) were measured in 27 episodes of the nephrotic phase in 24 patients with nephrotic syndrome with various lesions. 10 patients were reinvestigated after remission; 1 patient could be followed during development of the edema phase as well as during prednisone-induced remission. During the nephrotic phase, PRS was suppressed in 8%, normal in 44 and elevated in 48%, while PRA was suppressed in 41%, normal in 48 and elevated in 11% of the patients. After remission, PRA increased in 70% and PRS decreased in 20 and increased in 50% of the cases. The purpose of this study was to investigate PRA and PRS in nephrotic patients; it is concluded that low PRS and high PRA are not as characteristic for the nephrotic syndrome as they are generally thought to be.

One and three doses of propranolol a day in hypertension

In 26 patients with essential hypertension who were on continuous chlorthalidone therapy, 1 and 3 daily doses of propranolol were compared in a crossover study. Plasma propranolol levels and heart rates had larger daily fluctuations on single‐dose therapy than on 3 times daily; plasma renin activity was more constant. There was no significant difference in blood pressures. Once‐daily propranolol dosage was well tolerated and possibly gave less rise to the troublesome side effect of vivid dreaming.

Comparison of enalapril and propranolol in essential hypertension

SummaryIn 40 patients with essential hypertension, enalapril was compared with propranolol as an antihypertensive agent in a double-blind study. The patients were randomly given either enalapril 5–10–20 mg bid or propranolol 40–80–120 mg bid in a treatment consisting of step-by-step increases in dosage. When the diastolic blood pressure remained >90 mm Hg on the highest dosage, hydrochlorothiazide was added. Both enalapril and propranolol reduced blood pressure, although the patients tended to achieve lower blood pressures while on enalapril. More patients on propranolol required additional diuretic therapy than patients on enalapril.Propranolol reduced heart rate; with enalapril there were no changes in heart rate. Both drugs increased serum potassium and urea. Plasma renin substrate was reduced by enalapril, but raised by propranolol. Enalapril increased plasma renin activity and angiotensin I, while propranolol reduced both. Converting enzyme activity was lowered with enalapril but was unchanged with propranolol. Both drugs reduced angiotensin II. Plasma aldosterone concentration was more suppressed with propranolol than with enalapril.

Changes in blood pressure and body fluid volumes during diuretic therapy in patients with essential hypertension who receive enalapril.

We evaluated the effect of additional chlorthalidone therapy on blood pressure and body fluid volumes in 10 patients with essential hypertension who did not respond to chronic converting enzyme inhibition with enalapril. Values assessed after 3 days and 6 weeks of combined enalapril and chlorthalidone therapy were compared with initial values during enalapril monotherapy. After 3 days the mean arterial pressure (MAP), plasma volume (PV), blood volume (BV), and extracellular fluid volume (ECFV) decreased. There was a positive correlation between the percentage decreases in MAP and BV. After 6 weeks the MAP decreased further, but the decreases in PV, BV, and ECFV were less pronounced. At this time there was a positive correlation between the percentage decreases in MAP and ECFV. Our results support the hypothesis that contraction of the ECFV is an antihypertensive mechanism of diuretics. The antihypertensive effect of diuretics is enhanced during converting enzyme inhibition, while the body remains protected against volume deficits, possibly by the lower blood pressure itself.

The Effect of Converting Enzyme Inhibition on the Enhanced Proximal Sodium Reabsorption Induced by Chronic Diuretic Treatment in Patients with Essential Hypertension

During chronic chlorthalidone treatment of patients with essential hypertension, distal tubular sodium reabsorption is continuously inhibited. At the same time, sodium balance is maintained by an increase of the proximal tubular sodium reabsorption. In the present study, we investigated whether this increase is caused by a stimulated renin-angiotensin system (RAS). For this purpose, the renal effects of converting enzyme inhibition (CEI) were evaluated in 12 patients with essential hypertension who remained hypertensive despite chronic chlorthalidone treatment. After 6 weeks of chlorthalidone, an intravenous injection of 10 mg enalaprilic acid decreased the mean arterial pressure (MAP) from 110 to 102 mm Hg. The effective renal plasma flow (ERPF) increased. However, glomerular filtration rate (GFR) and the fractional excretions of sodium, lithium and free water did not change significantly. After 2 additional weeks of chlorthalidone combined with enalapril 20 mg b.i.d., MAP fell to 90 mm Hg, ERPF remained elevated and plasma aldosterone concentration decreased. As in the acute study, no significant changes were detected in the GFR and the fractional excretions of sodium, lithium or free water. Extracellular fluid volume was not diminished during these 2 weeks. Fractional proximal sodium reabsorption during chronic chlorthalidone therapy was higher when calculated from free water clearance (91%) than from the lithium clearance (71%), but neither of the two were affected by acute or chronic CEI. The results of this study suggest that during chronic diuretic treatment, maintenance of sodium balance by increased proximal reabsorption is not dependent on the stimulated RAS, or alternatively, that this function of the RAS is exactly counterbalanced by another effect of CEI, possibly by the fall in blood pressure.

Changes in haemodynamics and body fluid volume due to enalapril in patients with essential hypertension on chronic diuretic therapy

SummaryIn 12 patients with essential hypertension who remained hypertensive despite chronic chlorthalidone treatment, the effect of 2 weeks of additional therapy with the converting enzyme inhibitor (CEI) enalapril on blood pressure and body fluid volumes has been evaluated. The objective was to examine the influence of a diuretic-stimulated renin-angiotensin-aldosterone system (RAAS) on haemodynamics and body fluid volume. Mean arterial pressure (MAP −21%), total peripheral resistance index (TPRI −22%) and plasma aldosterone concentration (PAC −39%) were decreased, and plasma renin activity (PRA 660%) was increased. The average heart rate (HR), cardiac index (CI), plasma volume (PV), blood volume (BV), extracellular fluid volume (ECFV) and body weight (BW) remained unchanged. A negative correlation was found between the per cent changes in ECFV and PAC. Thus, body fluid volumes during chronic diuretic treatment are well preserved even when the RAAS with its sodium retaining properties is suppressed by CEI. Possible mechanisms are a volume (not angiotensin II) — dependent stimulation of aldosterone and a fall in blood pressure.

Blood to interstitial fluid volume ratio in chronic hypokalaemic states

Abstract. The distribution of extracellular fluid over the intra‐ and extravascular spaces was determined in hypokalaemic and normokalaemic patients. In six patients with Bartters syndrome, four with pseudo‐Bartters syndrome, and twenty with essential hypertension (EH) chronically treated with chlorthalidone, serum potassium (serum K+) and extracellular fluid volume (ECFV) were decreased, while plasma volume (PV) and blood volume (BV) were normal (see Table 1 for means, standard deviations, and levels of significance). Consequently, the ratio of BV to interstitial fluid volume (IFV) was increased. In ten patients with EH on long‐term combined enalapril/chlorthalidone therapy, eight EH patients on long‐term spironolactone treatment, and twenty‐three EH patients treated by short‐term sodium restriction, PV, BV, and ECFV were decreased, but serum K+ and BV/IFV were normal. In six patients with primary hyperaldoster‐onism (PHA) serum K+ was decreased, while PV, BV, and BV/IFV were elevated. Significant negative correlations between sK and BV/IFV were found in the Bartter patients (r= ‐0·88) and the pooled data of all patients (r= ‐0·50). These findings suggest an association between chronic hypokalaemia and a fluid shift from the extra‐ into the intravascular space. The hypothesis that this phenomenon is due to a decreased venous resistance as a consequence of chronic hypokalaemia is discussed.