Haemodynamic and renal responses to oral losartan potassium during salt depletion or salt repletion in normal human volunteers.

We examined the haemodynamic and renal response to oral losartan potassium (100 mg) during activation of the renin system in humans. Eight healthy volunteers followed a low-salt (40 mmol sodium) diet for 4 days on four occasions 2 weeks apart. Double-blind salt depletion was achieved by 3-day administration of frusemide (40 mg twice daily, b.i.d.) with placebo salt replacement, salt repletion by placebo frusemide (b.i.d.), and active salt replacement (100 mmol/day). On day 4, subjects received randomised double-blind placebo or losartan. Prestudy salt depletion was associated with nonsignificant decreases in serum sodium (138 +/- 2 mM), potassium (3.5 +/- 0.2 mM) and increased urea (6.5 +/- 1.1 mM), and creatinine (91 +/- 6 microM) as compared with screening. Prestudy (day 3) 24-h urinary volume was similar during deplete preparation (placebo 1.707 +/- 0.81 L, losartan 1.509 +/- 0.626 L) or deplete preparation (placebo 1.726 +/- 0.5 L, losartan 1.764 +/- 0.52 L), but sodium excretion was greater during replete preparation. Salt replete supine blood pressure (BP) profiles showed little effect of losartan (mean maximal supine BP -9 +/- 6 mm Hg) as compared with placebo (-1 +/- 4 mm Hg), with a similar relative result for erect BP. After salt depletion, losartan caused a greater response in both supine (-24 +/- 9) and erect (-33 +/- 15) BP than did placebo (supine -12 +/- 5, erect -14 +/- 9). In this protocol after salt depletion, losartan caused a transient increase in urea and creatinine (143 +/- 40 microML) 8 h after dosing as compared with placebo (105 +/- 13 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Responses to an orally active renin inhibitor, remikiren (Ro 42-5892), after controlled salt depletion in humans.

The biological effects of dose-dependent inhibition of renin have rarely been extensively studied after oral (p.o.) dosing in humans. We studied remikiren (Ro42-4892), a selective renin inhibitor, in normal volunteers after activation of the renin-angiotensin system (RAS) based on salt depletion. Twelve normal men (28 +/- 9 years, 77 +/- 10 kg), comprising three consecutive dose panels of 4 subjects, received four treatments, double-blind and randomised 2 weeks apart: panel I, placebo (P), or 30, 100, and 300 mg, remikiren; panel II, placebo or 300, 600 mg, 1,000; panel III, placebo or 30, 600, and 1,000 mg. The RAS was activated by 40 mmol/day sodium diet plus frusemide (40 mg BDS), for 3 days before each study day. Data (mean +/- SD) were examined by repeated-measures analysis of variance (ANOVA). RAS activation was confirmed by 24-h urinary sodium excretion (screen, 142 +/- 74 mmol/24 h; prestudy, 66 +/- 33, 59 +/- 41, 78 +/- 4, 73 +/- 30 mmol/24 h) and increase in plasma renin activity (PRA) (screen, 0.8 +/- 0.3 ng AI/ml/h; before dosing, P, 6.5 +/- 3.1; 30 mg, 8.2 +/- 3; 100 mg, 9.4 +/- 5.7; 300 mg, 6.5 +/- 2.4; 600 mg, 5.2 +/- 2; 1,000 mg, 6.2 +/- 4.4 ng AI/ml/h).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of angiotensin in the extravascular system.

Angiotensin receptors are present in many tissue types, including adrenal cortex, renal glomeruli, heart, hypothalamus, liver, pancreas, pituitary, platelets, renal tubules, uterus and vascular smooth muscle. Two high-affinity receptor subtypes have been identified by radioligand binding with antagonists: losartan (DuP 753/MK954) identifies AT1 receptors; PD123177 and CGP42112A are markers for AT2 receptors. Angiotensin II may be produced locally in tissues outside the humoral system. For example, it is found in the brain, kidney and heart. Within the brain, the heptapeptide angiotensin(1-7) mimics some effects of angiotensin II, but may be formed directly from angiotensin I. Evidence for non-ACE-mediated angiotensin II production has been reported in the heart. Intravascular angiotensin II receptors are implicated in the central release of vasopressin and other hypophyseal hormones, in increasing sympathetic outflow, in the thirst response and, possibly, in cognitive function; in the inotropic and chronotropic effects of angiotensin II on the heart as well as in growth/hypertrophy; in the control of aldosterone release and in the balance between cortisol and aldosterone secretion; and in modulating sodium, chloride and bicarbonate transport within the kidney. Effects on the reproductive system, liver and pancreas have not been established. The pharmacological effects of angiotensin II antagonists will depend on their distribution characteristics as well as affinity for specific receptor subtypes. At present, however, the physiological role of AT2 receptors has not been defined.

Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man.

In a dose-ranging study, the angiotensin type I receptor antagonist losartan (DuP753/MK954) was administered orally to normal volunteers in whom the renin-angiotensin system (RAS) had been activated by a low sodium diet (40 mmol) and frusemide (40 mg twice daily) for 3 days before study. On the fourth day, subjects (n = 12) received placebo and three active doses (5, 10, 25, 50, or 100 mg) in a randomized, double-blind, three-panel, dose-ranging design. On the study day, 24-h urinary sodium excretion was approximately 10-20 mmol Na, with an increase in renin and aldosterone levels at baseline. Dose-dependent decreases in supine and erect blood pressures (BP) were statistically significant for 50 and 100 mg and were associated with a modest increase in supine heart rate (HR) at the higher dose. The peak BP decreases observed suggested that the highest dose studied (100 mg) was not necessarily the maximal response. Active treatments caused no increase in the sodium loss on the study day. Renin was significantly increased by doses > 10 mg in a dose-dependent fashion but there was little change in plasma aldosterone profile. Increase in renin was evident at doses (10 mg) below those significantly affecting overall BP (50 mg). Adverse symptoms were uncommon and limited to postural lightheadedness which was largely dose related. Our results indicate a BP and plasma renin dose-response relation for the orally active angiotensin II (AII) receptor blocker losartan in normotensive subjects with an activated RAS.

Neurohormonal and blood pressure responses to low-dose infusion of an orally active renin inhibitor, Ro 42-5892, in salt-replete men.

Renin inhibitors are an alternative means of blockade of circulating and tissue-based renin-angiotensin systems (RAS). We studied a new renin inhibitor, Ro 42-5892, by low-dose (0.1 mg/kg) intravenous (i.v.) infusion in 10 min (fast) or 6 h (slow) or placebo in a double-blind cross-over study to assess the relationship between drug concentration and response. Fasting salt-replete normotensive male volunteers (n = 9) aged 18-32 years were studied supine. There were no significant changes in blood pressure (BP) or heart rate (HR) between drug and placebo infusion. Drug concentration peaked (482 +/- 140 ng/ml) at the end of the fast infusion or showed a sustained plateau (25.9 +/- 6.1 ng/ml) with the slow infusion (mean time to peak 121 +/- 99 min). Both fast (135.2 +/- 26 ng/ml/h2) and slow (121.0 +/- 31.1 ng/ml/h2) infusions had similar area under the curve (AUC)0-24-values. Plasma renin activity (PRA) was dramatically reduced by both strategies, but AUC0-10 for PRA was significantly less for slow (1.7 +/- 0.6 ngAI/ml/h2) than fast (4.9 +/- 2.5 ngAI/ml/h2) infusions. Mean peak plasma active renin (AR) concentration was increased by both fast (102.2 +/- 65.9 pg/ml) and slow (195.2 +/- 110.5 pg/ml) infusions as compared with placebo (49.9 +/- 18.6 pg/ml). Similarly, AUC0-10 for AR was greater for slow (990.2 +/- 582.1 pg/ml/h) than fast (512.4 +/- 189.4 pg/ml/h) infusions. Plasma angiotensin-converting enzyme (ACE) activity was unaltered. Our results indicate that protracted low concentrations of Ro 42-5892 may provide more effective and long-lasting inhibition of renin.(ABSTRACT TRUNCATED AT 250 WORDS)