P. Sassano

Systemic hypertension after cardiac transplantation: Effect of cyclosporine on the renin-angiotensin-aldosterone system

Fifteen patients who had undergone cardiac transplantation and who had hypertension (164 +/- 14/112 +/- 13 mm Hg), aged 16 to 57 years (mean 39), were treated with cyclosporine, 8 +/- 3 mg/kg/day, and prednisolone, 0.27 +/- 0.1 mg/kg/day, for 63 to 788 days (mean 288) after transplantation. They were not given antihypertensive drugs. Before treatment, the mean urinary sodium level was 104 +/- 48 mEq/day. Two discrete abnormalities accompanied their high blood pressure (BP): an increase in serum creatinine levels (p less than 0.05) to values exceeding those measured just before transplantation (2.1 +/- 1.0 vs 1.35 +/- 0.54 mg/dl) with low creatinine clearance (61 +/- 28 ml/min X 1.73 m2), and a 15% increase in plasma volume (+445 +/- 686 ml, p less than 0.02). Urinary excretion of vanilmandelic acid and total metanephrines was normal. Supine plasma renin activity was also normal (0.78 +/- 0.32 nmol/ml/hour). The stimulation of renin release after acute inhibition of converting enzyme by captopril was less marked than is usual in hypertensive subjects (0.86 +/- 0.54 nmol/liter/hour). Captopril induced a smaller drop in BP than nifedipine (-8 +/- 13/-6 +/- 10 mm Hg vs -14 +/- 11/-15 +/- 10 mm Hg). Levels of plasma aldosterone, angiotensinogen and converting enzyme activity were all normal, 308 +/- 147 pmol/liter, 712 +/- 164 nmol/ml and 30 +/- 6 mU/ml, respectively. It is concluded that hypertension is common in cardiac transplantation patients treated with cyclosporine, since 13 of our 15 subjects were normotensive before transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of indomethacin on the natriuretic and renin-stimulating effect of bumetanide in essential hypertension.

The effect of bumetanide on absolute and fractional sodium excretion, creatinine clearance, and plasma renin activity (PRA) was studied in eight patients with essential hypertension before and after indomethacin. After bumetanide, urinary sodium excretion increased only in the first 4 hr, creatinine clearance only in the first 2 hr, and PRA rose progressively. After indomethacin, bumetanide caused a smaller increase in urinary sodium excretion, decreased creatinine clearance, and caused a small early and late PRA rise. Prostaglandin inhibition and indomethacin did not, per se, affect the tubular natriuretic mechanism but they abolished both early vascular and sustained PRA‐stimulating effects of bumetanide.

Comparison of Increase in the Enalapril Dose and Addition of Hydrochlorothiazide as Second-step Treatment of Hypertensive Patients Not Controlled by Enalapril Alone

Forty-six patients were randomly allocated to two different groups of treatment if their diastolic blood pressure remained above 90 mm Hg after one month of treatment with 20 mg enalapril mg once daily. In the first group (ENA), 23 patients were given higher daily dosages of enalapril (40 mg and, when necessary, 60 mg). The second group of 23 patients (HCTZ) was given 20 mg/day enalapril and hydrochlorothiazide (25 mg/day and, when necessary, 50 mg). Blood pressure was measured by an automatic device and by the physician with a standard sphygmomanometer. Blood pressure was significantly lower in the HCTZ group, according to both the automatic device (130 ± 9/80 ± 8 vs. 141 ± 5/86 ± 8 mm Hg, p < 0.01/p < 0.05) and the sphygmomanometer (134 ± 10/89 ± 6 vs. 149 ± 16/94 ± 5 mm Hg, p < 0.001/p < 0.01). Plasma renin activity, increased by enalapril at the 20 mg dosage, rose in the HCTZ group but not in the ENA group (22.4 ± 22 vs. 10.2 ± 11 pmol/ml/h, p < 0.05). Plasma aldosterone increased significantly in the HCTZ group (0.44 ± 0.22 vs. 0.30 ± 0.17 pmol/ml, p < 0.05) but did not change in the ENA group (0.31 ± 0.11 vs. 0.30 ± 0.17 pmol/ml, NS). In the ENA group, converting enzyme activity was not reinforced (5.7 ± 8 vs. 6.6 ± 6 mU/ml, NS) despite an increase in plasma enalaprilat levels (172.4 ± 108 vs. 72.1 ± 42 ng/ml, p 0.001). Plasma potassium fell in the HCTZ group (–0.43 ± 0.3 mmol/L, p < 0.001), and was not affected by the higher doses taken by ENA group (+0.11 ± 0.3 mmol/L). The effects of converting enzyme inhibition by enalapril 20 mg o.d. are not reinforced by the administration of 40–60 mg o.d., whereas the addition of hydrochlorothiazide 25–50 mg o.d. decreases blood pressure simultaneously with a rise in plasma renin and aldosterone. Combined therapy with enalapril and hydrochlorothiazide is a more effective antihypertensive approach than increased doses bof enalapril.

Influence of Age and Sodium Intake on Plasma Renin Activity of Normal Subjects

Supine and upright plasma renin activity (PRA) were measured i 104 normal subjects (age range 13-74 years, 71 males and 33 females) on a constant diet of normal potassium (60-80 mEq/day) and of varying but constant, sodium content (range 10-260 mEq/day). Both supine and upright PRA values were inversely related to the 24-hour urinary sodium excretion, while only upright PRA values showed a significant inverse correlation with age. Through a multiple regression analysis it was shown that age increased the significance of the PRA/sodium relationship by about 10%. Besides posture, two other factors seem to influence the PRA-age relationship: the age range and the sodium intake. In fact, the PRA-age relationship was not detectable either when subjects below 20 and above 50 were excluded, or when sodium intake was increased above 140 mEq/day. These data can explain the contrasting reports on the age influence on renin secretion. The relationship between PRA and urinary sodium confirms the dependance of PRA on the state of sodium balance. Age significantly influences the PRA/sodium relationship of normal subjects on normal or low sodium intake and in the upright position. Therefore, the decline of PRA with age may be explained by the decrease either of renin storage or of sympathetic nervous system activity on renin release.

Effect of captopril on renal function in patients with essential hypertension.

The glomerular filtration rate (creatinine clearance), glomerular permeability (qualitative and quantitative proteinuria), tubular reabsorption (k-lambda chains of immunoglobulins and lysozyme) and indexes of tubular cell lysis (alpha-glucosidase and gamma-glutamyltranspeptidase) were measured in the urine of 10 patients with moderate, uncomplicated essential hypertension during placebo therapy and after captopril given at increasing doses of 25, 50, 100 and 200 mg twice daily, the first three doses being given for 3 days and the last one for 4 weeks in all patients and for an additional 6 months in 5 patients. During placebo therapy, proteinuria was absent in eight patients and detectable (glomerular and selective) in two; selective proteinuria appeared in two and a decrease in selectivity was observed in two patients with previous proteinuria after 4 weeks of captopril therapy. No proteinuria was detectable in the five patients followed up to 6 months, not even in the one in whom a decrease in glomerular selectivity had occurred after 4 weeks. The glomerular filtration rate was unchanged as were lysozyme and gamma-glutamyltranspeptidase values, while light chains were always undetectable. Alpha-glucosidase showed some increase; however, increments were transient and always much lower than those observed with known tubular toxic drugs. These data show that under our experimental conditions captopril caused no evident changes in glomerular and tubular function.

Humoral and hemodynamic effects of increasing doses of captopril in patients with essential hypertension

To compare the hemodynamic and humoral effects of increasing doses of captopril, blood pressure, heart rate, plasma renin activity, plasma aldosterone and angiotensin-converting enzyme activity were measured in 10 patients with mild uncomplicated essential hypertension before and after captopril given in an increasing dose of 25, 50 and 100 mg twice a day, with each dose given for 3 days. The maximal decrease in blood pressure, which was predicted both by basal plasma renin activity values and by the hypotensive response to the first dose, was found after the lowest (25 mg) dose; this effect was detectable for 12 hours independently of the dose administered. Similarly, plasma renin activity was already maximally increased and plasma aldosterone maximally decreased at the lowest dose, while angiotensin-converting enzyme activity showed a dose-dependent inhibition. These data suggest that (1) neither the magnitude nor the duration of the hypotensive effect nor the resin-stimulating and aldosterone-inhibiting actions of captopril are enhanced by drug doses above 25 mg (at least up to 100 mg), and (2) there was no apparent correlation between the degree of angiotensin-converting enzyme inhibition with increasing doses of captopril and the hypotensive effects of the drug.

The effect of beta-adrenergic blockade on patterns of urinary sodium excretion, blood pressure and plasma renin activity in patients with essential and renovascular hypertension.

Abstract. The effects of β‐adrenergic blockade, using oxprenolol, were studied on plasma renin activity, urinary sodium excretion and blood pressure in ten normal subjects and in 120 patients with essential and renovascular hypertension.

The effect of indomethacin on plasma renin activity and urinary aldosterone of patients with essential hypertension

The effect of indomethacin on plasma renin activity (PRA), urinary aldosterone, 17 OH ketogenic steroids and plasma Cortisol was studied in twenty-three patients with essential hypertension and compared in eleven patients to Oxprenolol effect by 2 x 2 factorial trial. Indomethacin decreased PRA and urinary aldosterone: its effect was maintained when the drug was given for three days and it was related to basal PRA and aldosterone values. Therefore in patients with low PRA (renin-sodium index) PRA and aldosterone were unchanged, while they decreased in the normal high PRA group. Aldosterone changes were related to those of PRA, while 17 OH ketogenic steroids and plasma Cortisol were unchanged. Both indomethacin and Oxprenolol decreased PRA, but no interaction or additive effect was found between the two drugs. The present data indicate that indomethacin can decrease both PRA and aldosterone to an extent which is related to basal values and that aldosterone changes are mainly explained by those of PRA. The PRA unresponsiveness to indomethacin found in low renin patients may suggest renal prostaglandin deficiency. Finally the lack of interaction or of additive effect between indomethacin and Oxprenolol may be explained by postulating either that the two drugs act on a common pathway or that an additive effect on PRA cannot be detected renin being maximally suppressed by full renal beta-receptors blockade.

Mediation of renin release in essential hypertension by alpha-adrenoreceptors.

We studied the role of alpha-adrenoceptors in controlling renin release by infusing increasing doses of phentolamine into six patients with essential hypertension. Furthermore, in order to evaluate the relative importance of alpha 1- and alpha 2-adrenoceptors, phentolamine infusion was repeated in the same patients after pretreatment with prazosin, a selective alpha 1-blocking agent, and oxprenolol, a nonselective beta-blocker. After placebo, phentolamine infusion did not change mean blood pressure or heart rate and increased plasma renin activity (PRA) in a dose-dependent fashion. This finding suggests that the drug acts directly on the intrarenal renin producing apparatus and seems to confirm the inhibitory role of alpha-adrenoceptors in the control of renin release. After prazosin and oxprenolol pretreatment, PRA was respectively increased and decreased but it was unmodified by phentolamine infusion. This latter finding may indicate that both alpha 1- and alpha 2-adrenoceptors are involved in renin release or that alpha-adrenoceptors cannot be clearly differentiated into alpha 1- and alpha 2-subtypes.

Efficacy and Influence on Quality of Life of Enalapril as a First Step Treatment of Hypertension

205 patients with mild to moderate uncomplicated hypertension participated in a six-month double-blind parallel study performed in a unique center. After a two-week single-blind placebo period, the patients were randomly allocated to receive either Enalapril 20 mg once-a-day or placebo as the first step treatment. They were then followed-up every two weeks and successive doses of hydrochlorothiazide, oxprenolol, and dihydralazine were added until the diastolic pressure was lower than 90 mmHg. After six months, the systolic and diastolic blood pressures were lower in the Enalapril than in the control group (129/82 +/- 12/6 mmHg versus 136/86 +/- 10/5 mmHg; p less than 0.001). Drug withdrawal was necessary for 8 patients in the Enalapril group and for 16 patients in the control group (p less than 0.05). The number of daily tablets was 2.7 +/- 1.8 in the Enalapril group and 4.4 +/- 2.4 in the control group (p less than 0.01). Therefore, a stepped-care program based on Enalapril appears significantly more effective than a stepped-care program based on a diuretic.