Jürg Nussberger

Renal effects of selective cyclooxygenase‐2 inhibition in normotensive salt‐depleted subjects

To compare the renal hemodynamic and tubular effects of celecoxib, a selective inhibitor of cyclooxygenase‐2 (COX‐2) to those of naproxen, a nonselective inhibitor of cyclooxygenases in salt‐depleted subjects.

Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II.

BackgroundThe purpose of the present study was to assess the inhibitory effect of DuP 753, an orally active angiotensin II receptor antagonist, on the pressor action of exogenous angiotensin I and II in healthy male volunteers. Methods and ResultsIn the first study (single-dose study), eight volunteers were included in a 2-day protocol repeated four times at 1-week intervals. In each phase, a different dose of drug (2.5, 5, 10, 20, or 40 mg) or placebo was given. The peak systolic blood pressure response to a test-dose of angiotensin I was determined serially before and after oral administration of DuP 753 by continuously monitoring finger blood pressure using a photoplethysmographic method. DuP 753 reduced the systolic blood pressure response to angiotensin I in a dose-dependent fashion. Three, 6, and 13 hours after the 40-mg dose, blood pressure response decreased to 31±5%, 37±6%, and 45 ±3% of the control values (mean±SEM, n = 7), respectively. In the second study, 29 volunteers were treated for 8 days with either a placebo or DuP 753 (5, 10, 20, or 40 mg p.o. q.d.) and challenged on the first, fourth, and eighth days with bolus injections of angiotensin II. Again, the inhibitory effect on the systolic blood pressure response to angiotensin II was clearly dose dependent. Six hours after 40 mg DuP 753, the systolic blood pressure response to the test-dose of angiotensin II was reduced to 37 + 7%, 40±4%, and 38±6% of baseline values (mean + SEM, n = 6) on days 1, 4, and 8, respectively. With this latter dose, there was still a blocking effect detectable 24 hours after the drug. Similar to angiotensin converting enzyme and renin inhibitors, DuP 753 induced a dose-dependent increase in plasma renin that was more pronounced on the eighth than on the first day of drug administration. In these normal volunteers, no consistant clinically significant side effects were observed. There was no evidence for an agonist effect. ConclusionsDuP 753 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of angiotensin II in men.

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Bradykinin and the pathophysiology of angioedema

Angioedema has different causes and different clinical presentations. Some types of angioedema may be mediated by bradykinin. We measured plasma levels of bradykinin-(1-9)nonapeptide by radioimmunoassay after high-performance liquid chromatography in patients with different types of angioedema during acute attacks and/or in remission, i.e. hereditary C1-inhibitor deficiency, angiotensin converting enzyme (ACE) inhibitor treatment, idiopathic non histaminergic and responders to antihistamines. Eleven patients with the deficiency of C1-inhibitor had very high levels of bradykinin during acute attacks of angioedema (18.0-90.0 pM) (normal range 0.2-7.1 pM). In three patients with history of ACE inhibitor-related angioedema, plasma bradykinin was high during ACE inhibitor treatment (62.0, 8.9 and 27.0 pM) and in a fourth patient was 47.0 pM during an acute attack and decreased by 93% to 3.2 pM after withdrawal of the ACE inhibitor. The patient with idiopathic angioedema, during an acute attack involving the right arm, had high levels of bradykinin in the venous blood refluent from the angioedematous arm (20.0 pM) while in the contralateral arm bradykinin levels were normal (6.6 pM), similarly to what we previously observed in cases of brachial angioedema due to C1-inhibitor deficiency. The four patients with angioedema responsive to antihistamines had normal levels of bradykinin even during acute attacks (5.7, 3.4, 4.7 and 1.2 pM). In one of these patients who had a brachial angioedema, bradykinin levels were normal in the venous blood refluent from both arms. Bradykinin is involved in hereditary C1-inhibitor deficiency angioedema, in ACE inhibitor-related angioedema, and in idiopathic non-histaminergic angioedema, while bradykinin is not related to allergen-dependent or idiopathic angioedema that are responsive to antihistamines.

Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans.

Background— Pharmacological interruption of the renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF ≈95 mL · min−1 · 1.73 m−2), greater renal vasodilation with angiotensin receptor blockers (≈145 mL · min−1 · 1.73 m−2) suggested more effective blockade. We predicted that blockade with the direct oral renin inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Methods and Results— Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197±27 mL · min−1 · 1.73 m−2) and exceeded responses to captopril (92±20 mL · min−1 · 1.73 m−2; P<0.01). Furthermore, significant residual vasodilation was observed 48 hours after each dose (P<0.01). The RPF response on a high-sodium diet was also higher than expected (47±17 mL · min−1 · 1.73 m−2). Plasma renin activity and angiotensin levels were reduced in a dose-related manner. As another functional index of the effect of aliskiren, we found significant natriuresis on both diets. Conclusions— Renal vasodilation in healthy people with the potent renin inhibitor aliskiren exceeded responses seen previously with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects were longer lasting and were associated with significant natriuresis. These results indicate that aliskiren may provide more complete and thus more effective blockade of the renin-angiotensin system.

Treating the individual hypertensive patient: considerations on dose, sequential monotherapy and drug combinations.

For the general practitioner to be able to prescribe optimal therapy to his individual hypertensive patients, he needs accurate information on the therapeutic agents he is going to administer and practical treatment strategies. The information on drugs and drug combinations has to be applicable to the treatment of individual patients and not just patient study groups. A basic requirement is knowledge of the dose-response relationship for each compound in order to choose the optimal therapeutic dose. Contrary to general assumption, this key information is difficult to obtain and often not available to the physician for many years after marketing of a drug. As a consequence, excessive doses are often used. Furthermore, the physician needs comparative data on the various antihypertensive drugs that are applicable to the treatment of individual patients. In order to minimize potential side effects due to unnecessary combinations of compounds, the strategy of sequential monotherapy is proposed, with the goal of treating as many patients as possible with monotherapy at optimal doses. More drug trials of a crossover design and more individualized analyses of the results are badly needed to provide the physician with information that he can use in his daily practice. In this time of continuous intensive development of new antihypertensive agents, much could be gained in enhanced efficacy and reduced incidence of side effects by taking a closer look at the drugs already available and using them more appropriately in individual patients.

Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2

FGF-2 has been implicated in the cardiac response to hypertrophic stimuli. Angiotensin II (Ang II) contributes to maintain elevated blood pressure in hypertensive individuals and exerts direct trophic effects on cardiac cells. However, the role of FGF-2 in Ang II-induced cardiac hypertrophy has not been established. Therefore, mice deficient in FGF-2 expression were studied using a model of Ang II-dependent hypertension and cardiac hypertrophy. Echocardiographic measurements show the presence of dilated cardiomyopathy in normotensive mice lacking FGF-2. Moreover, hypertensive mice without FGF-2 developed no compensatory cardiac hypertrophy. In wild-type mice, hypertrophy was associated with a stimulation of the c-Jun N-terminal kinase, the extracellular signal regulated kinase, and the p38 kinase pathways. In contrast, mitogen-activated protein kinase (MAPK) activation was markedly attenuated in FGF-2-deficient mice. In vitro, FGF-2 of fibroblast origin was demonstrated to be essential in the paracrine stimulation of MAPK activation in cardiomyocytes. Indeed, fibroblasts lacking FGF-2 expression have a defective capacity for releasing growth factors to induce hypertrophic responses in cardiomyocytes. Therefore, these results identify the cardiac fibroblast population as a primary integrator of hypertrophic stimuli in the heart, and suggest that FGF-2 is a crucial mediator of cardiac hypertrophy via autocrine/paracrine actions on cardiac cells.

Proximal Sodium Reabsorption An Independent Determinant of Blood Pressure Response to Salt

The purpose of this study was to evaluate the contribution of renal sodium handling by the proximal tubule as an independent determinant of blood pressure responsiveness to salt in hypertension. We measured blood pressure (BP), renal hemodynamics, and segmental renal sodium handling (with lithium used as a marker of proximal sodium reabsorption) in 38 hypertensive patients and 27 normotensive subjects (15 young and 12 age-matched) on a high and low sodium diet. In control subjects, changing the diet from a low to a high sodium content resulted in no change in BP and increases in glomerular filtration rate (P <0.05), renal plasma flow (P <0.05), and fractional excretion of lithium (FELi, P <0.01). In hypertensive patients, comparable variations of sodium intake induced an increase in BP with no change in renal hemodynamics and proximal sodium reabsorption. When analyzed by tertiles of their BP response to salt, salt-insensitive hypertensive patients of the first tertile disclosed a pattern of adaptation of proximal sodium reabsorption comparable to that of control subjects, whereas the most salt-sensitive patients of the third tertile had an inverse pattern with a high FELi on low salt and a lower FELi on high salt, suggesting an inappropriate modulation of proximal sodium reabsorption. The BP response to salt correlated positively with age (r =0.34, P =0.036) and negatively with the changes in FELi (r =−0.37, P =0.029). In a multivariate analysis, the changes in FELi were significantly and independently associated with the salt-induced changes in BP. These results suggest that proximal sodium reabsorption is an independent determinant of the BP response to salt in hypertension.

Pharmacokinetics of the converting enzyme inhibitor cilazapril in normal volunteers and the relationship to enzyme inhibition: development of a mathematical model

Summary: The pharmacokinetics of the new converting enzyme inhibitor cilazapril were investigated in 12 healthy male volunteers. Single oral doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects, each of whom received two different doses. A 2-week interval was allowed between treatments. Plasma levels of cilazaprilat, the active form of cilazapril, were measured for up to 3 days after drug administration. Peak plasma levels and 24-h areas under the curve (AUCs) were almost directly proportional to dose, and the elimination half-life (t½) during the first 8 h after dosing was 1.5 h. From 24 h on, there was a prolonged terminal phase with a t½ of ˜50 h, and there was only slight dosedependency during this phase. These data suggest that the pharmacokinetics of cilazapril are nonlinear. A physiologically realistic model based on saturable binding to converting enzyme was developed to account both for the drug kinetics and for the relationship of the kinetics to the dynamics of plasma converting enzyme inhibition. A number of conclusions relevant to the therapeutic application of cilazapril in hypertension are drawn from the data and from the pharmacokinetic-pharmacodynamic model.

Short-term and Sustained Renal Effects of Angiotensin II Receptor Blockade in Healthy Subjects

We investigated the short-term and sustained hormonal and renal effects of angiotensin II (Ang II) receptor blockade in normotensive healthy volunteers. Twenty-four subjects maintained on a fixed sodium diet were randomized to receive for 8 days a placebo or 10 or 50 mg doses of the Ang II antagonist irbesartan (SR 47436, BMS 186295) according to a double-blind, parallel group design. Plasma renin activity, plasma immunoreactive Ang II and aldosterone levels, blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 8 hours after the first and eighth administration of each dose of irbesartan or placebo. Ang II receptor blockade with irbesartan induced a dose-dependent compensatory increase in plasma renin activity and plasma angiotensin levels and a significant decrease in plasma aldosterone levels. The compensatory rise in plasma renin activity and Ang II levels was more pronounced on day 8, reflecting a long duration of the blocking effect of irbesartan. Irbesartan induced small changes in blood pressure and did not significantly modify renal blood flow and glomerular filtration rate. However, a significant decrease in filtration fraction was observed during receptor blockade on days 1 and 8. The tubular effects of irbesartan were characterized by a dose-dependent increase in sodium and chloride excretions. Interestingly, the cumulative natriuretic response to Ang II receptor blockade was similar on days 1 and 8, suggesting that in these subjects, renal Ang II receptors are not blocked over 24 hours during repeated administration even though this antagonist has a long duration of action (t1/2 of 15 to 17 hours).(ABSTRACT TRUNCATED AT 250 WORDS)