Volume 2, Number 4, December 2001

POPULAR
TOPICPAPEREffects of candesartan on cardiac and arterial structure and function in hypertensive subjects
James CS Spratt, David J Webb, Annette Shiels, Bryan Williams

Objectives: To study the effect of candesartan cilexetil on left ventricular mass index (LVMI), left ventricular systolic and diastolic function, arterial structure and function and blood pressure (BP) in hypertensive patients.
Design and methods: Patients (n=35), aged >20 years, with hypertension and average baseline LVMI of 89 g/m² were treated for 24 weeks with candesartan, 16 mg o.d., following a four-week placebo run-in period. If diastolic BP remained above 95 mmHg, hydrochlorothiazide, 12.5 mg o.d., was added. Left ventricular structure and function were assessed using transthoracic echocardiography. Arterial function and structure were assessed using pulse wave analysis to calculate augmentation index (AIx) and forearm plethysmography to calculate minimum vascular resistance. BP was measured in the office and by 24-hour ambulatory BP monitoring (ABPM).
Results: The mean reduction in LVMI was 4.4 g/m² (p=0.022). Left ventricular systolic function was not significantly altered from baseline, but diastolic function significantly improved: the mean change in diastolic time was 54 ms (p=0.037), in peak velocity filling 6.3 cm/s (p=0.023); E:A ratio improved by 0.08 (p=0.049). The mean reduction in forearm vascular resistance was 15 units at rest (p=0.001) and 1.3 units after limb ischaemia (p=0.006). AIx decreased significantly, with a mean reduction of 9% (p<0.001). Central BP also significantly reduced (systolic blood pressure/ diastolic blood pressure 31/20 mmHg; p<0.001). BP was significantly reduced, both in the office (22/16 mmHg; p<0.001) and by 24-hour ABPM (18/12 mmHg; p<0.001).
Conclusions: Treatment with candesartan, 16 mg o.d., with or without hydrochlorothiazide, for 24 weeks, significantly reduced left ventricular mass and arterial hypertrophy in patients with hypertension. In parallel, there were significant improvements in left ventricular diastolic function and arterial function.

JRAAS 2001;2:227-232.

PAPERRenin-angiotensin blockade improves renal cGMP production via non-AT₂-receptor mediated mechanisms in hypertension-induced by chronic NOS inhibition in rat
Nina Uhlenius, Olli Vuolteenaho, Ilkka Tikkanen

Background: To investigate the changes in the angiotensin II (Ang II) receptors and nitric oxide (NO)-cGMP pathway in the rat kidney after nitric oxide synthase (NOS) blockade.
Methods: Captopril, an angiotensin-converting enzyme (ACE) inhibitor, 20 mg/100 ml; and/or L-158,809 (an Ang II AT₁-receptor antagonist, 5 mg/100 ml) and L-NAME (NOS inhibitor, 50 mg/100 ml) were administered orally for 12 weeks. Blood pressure (BP), urinary albumin, urinary cGMP excretion, plasma ANP, and plasma renin activity were measured. In vitro autoradiography was used to locate the Ang II receptors in the kidney.
Results: Captopril and L-158,809 treatments normalised BP and prevented the appearance of albuminuria in rats receiving L-NAME. Urinary cGMP excretion was significantly increased in L-158,809-treated rats compared with the non-treated group, suggesting that the dysfunctional NO system may be activated by the treatment. AT₁-receptor binding in the kidney was inhibited to about 40% of the control value after administration of L-158,809. The AT₂-receptor binding was inhibited to less than 15% of the control value. NOS inhibition had no effect on receptor binding.
Conclusion: Blockade of NOS causes hypertension and renal damage. Treatment with an ACE inhibitor and/or Ang II receptor antagonist prevented these changes equally effectively. The stimulatory effect of AT₁-receptor antagonism on cGMP production was not mediated by AT₂-receptor-dependent mechanisms, since renal AT₂-receptor binding density was suppressed following treatment with L-158,809. AT₁-receptor blockade per se favours activation of humoral pathways that stimulate cGMP production potentially contributing to renal and vascular protection in hypertension and chronic renal disease.

JRAAS 2001;2:233-239.

PAPERHigh serum enalaprilat in chronic renal failure
Thomas Elung-Jensen, Jens Heisterberg, Anne-Lise Kamper, Jesper Sonne, Svend Strandgaard, Niels Erik Larsen

Background: Most angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure.
Methods: Fifty nine out-patients with plasma creatinine >150 μmol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design.
Results: Median glomerular filtration rate (GFR) was 23 (range 6–60) ml/minute/1.73 m². The daily dose of enalapril was 10 (2.5–20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5–584.7) ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10–42) ml/minute/1.73 m². The median clearance of enalaprilat was 28 (16–68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%.
Conclusion: Patients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.

JRAAS 2001;2:240-245.

POPULAR
TOPICPAPEREvaluation of the safety and efficacy of telmisartan and enalapril, with the potential addition of frusemide, in moderate-renal failure patients with mild-to-moderate hypertension
Thierry Hannedouche, Jacques Chanard, Bertrand Baumelou, on behalf of the French Collaborative Telmisartan Study Group

The effect on renal function and efficacy of the angiotensin II AT₁-receptor blocker (ARB), telmisartan, were compared with those of the angiotensin-converting enzyme inhibitor, enalapril, for the treatment of mild-to-moderate hypertension (diastolic blood pressure [DBP] 95–114 mmHg) in the presence of moderate renal failure (creatinine clearance [Ccr] 30–80 ml/minute). The study was multicentre, double-blind, double-dummy and active-controlled in design, with patients randomised in a 2:1 ratio to receive telmisartan or enalapril. After a two-week placebo run-in period, the 71 eligible patients received either telmisartan, 40 mg, or enalapril, 10 mg, once-daily for four weeks. Thereafter, doses were titrated to telmisartan 80 mg or enalapril 20 mg once-daily if supine trough DBP was still >90 mmHg. After a further four weeks, dose titration was again performed, as required, to telmisartan, 80 mg, or enalapril, 20 mg, or frusemide was given in addition if the double dose was already being administered. Mean Ccr decreases of 4.6% for telmisartan and 2.8% for enalapril were not clinically significant. Adverse events occurred in 12 (26.7%) telmisartan-treated patients and in 12 (46.2%) patients receiving enalapril. The mean reduction in supine trough DBP from baseline to the last available value was 12.5 mmHg for telmisartan, compared with 11.9 mmHg for enalapril. A full (reduction of >10 mmHg) or partial (reduction of 7–9 mmHg) response occurred in 78% of telmisartan patients and 65% of enalapril patients. In the enalapril group, 43% of patients required frusemide, compared with 29% of those in the telmisartan group. In conclusion, telmisartan lacks detrimental effect on renal function, is effective in the treatment of mild-to-moderate hypertension in patients with moderate renal failure, and is comparable to enalapril.

JRAAS 2001;2:246-254.

POPULAR
TOPICPAPERLosartan may modulate erythropoietin production
Sandra M Donnelly, Judith A Miller

Erythropoietin (Epo) is distinct amongst haematopoietic hormones, in that it is produced remote from the bone marrow. The tissue oxygen pressure required to trigger the Epo gene under physiological conditions is uniquely sited at a restricted area in the kidney termed the critmeter. Angiotensin II (Ang II) increases sodium reabsorption and hence oxygen consumption at any given blood flow rate; therefore, it may affect the balance of renal oxygen supply vs. demand and hence Epo production. The purpose of this study was to determine whether Epo production is modulated by the renin-angiotensin system (RAS). Twenty normal subjects on a controlled sodium and protein diet had glomerular filtration rate (GFR) and renal plasma flow (RPF) assessed by standard methods of inulin and para-aminohippurate clearance, respectively, at baseline, hourly after the administration of losartan (25 mg) and after each 30 minute period of the infusion of Ang II at doses of 0.5, 1.5 and 2.5 ng/kg/minute. The baseline GFR was 115±4.0 ml/minute/1.73 m², RPF 650±29 ml/minute/1.73 m² and Epo 12.4±0.8 U/L. In spite of a marked increase in filtration fraction (FF) with Ang II, no changes in serum Epo levels were observed at two hours (11.7±1.3 U/L, p=n.s. compared with baseline). After the administration of losartan, there was a variable effect on FF, but a strong correlation of the change in serum Epo concentration and the change in FF (r=0.648, p=0.002), suggesting that the RAS may modulate Epo production.

JRAAS 2001;2:255-260.

POPULAR
TOPICEDITORIAL REVIEWBioactive angiotensin peptides: focus on angiotensin IV
Tomris Mustafa, Joo Hyung Lee, Siew Yeen Chai, Anthony L Albiston, Sharon G McDowall, Frederick AO Mendelsohn

Angiotensin II (Ang II) is widely regarded as the major active peptide of the renin-angiotensin system (RAS), exerting effects on the cardiovascular system and on fluid and electrolyte homeostasis, including neural and long-term trophic effects. However, recent studies indicate that other angiotensin peptides such as angiotensin III (Ang III), Ang II (1-7) and angiotensin IV (Ang IV), may also have specific actions. Ang IV binds to a specific binding site and may be involved in memory retention, neuronal development and cardiovascular actions. It now appears, that the RAS is more complex than previously thought and is capable of generating multiple, bioactive peptides that elicit numerous diverse actions.

JRAAS 2001;2:205-210.

EDITORIAL REVIEWAldosterone-induced vasculopathy: a new reversible cause of cardiac death
Allan D Struthers

The idea arising is that the key culprit mechanism with regard to aldosterone may well be its ability to produce a vasculopathy characterised by nitric oxide (NO) deficit, and that aldosterone-induced fibrosis and aldosterone-induced autonomic imbalance could be a consequence of aldosterone vasculopathy.
Aldosterone thus exerts harmful effects on the key processes which promote cardiac death; on endothelial dysfunction, on myocardial fibrosis and on sympathovagal imbalance. It is possible that they are all attributable, to some extent, to a novel aldosterone-induced vasculopathy, which produces a relative deficit of vascular NO. The future should now explore whether aldosterone-induced vasculopathy is a phenomenon only occurring in chronic heart failure, or whether this also occurs in other diseases.

JRAAS 2001;2:211-214.

EDITORIAL REVIEWProspects for ARB in the next five years
Hicham Skali, Marc A Pfeffer

Based on multiple well-conducted randomised clinical outcome trials (RCT), inhibition of the renin-angiotensin system (RAS) with an angiotensin-converting enzyme inhibitor (ACE-I) has become a firmly established therapeutic approach for reducing morbidity and the risk of death across a broad spectrum of cardiovascular diseases. More recently angiotensin II type 1 (AT₁) receptor blockers (ARBs), another pharmacologic class of agents that inhibits RAS, has become clinically available.
We are fortunately in the midst of an impressive series of RCTs, which collectively will evaluate and quantitate the role of ARBs in clinical practice. Based on the ACE-I experience, we provide a framework to consider the completed and ongoing clinical outcomes RCT with ARBs.

JRAAS 2001;2:215-218.

EDITORIAL REVIEWIntracellular angiotensin II: from myth to reality?
Catalin M Filipeanu, Robert H Henning, S Adriaan Nelemans, Dick de Zeeuw

Recent studies show that angiotensin II (Ang II) has complex actions from within the cell, possibly via intracellular receptors that are pharmacologically different from the typical plasma membrane angiotensin receptors. Specific effects of intracellular Ang II have been described ranging from modulation of gap junctions to effects on cell growth, MAP kinase and calcium signalling. This paper summarises the evidence for this system to be acknowledged as a new entity separate from the circulating or local renin-angiotensin-aldosterone system (RAAS), by reviewing intracellular production of Ang II, the pharmacology and possible origin of intracellular angiotensin receptors and the signal transduction pathways involved in its functional effects.

JRAAS 2001;2:219-226.