Kegg Pathway: Angiotensin antagonists

Heart. 2008 Jul 16;
Akat K, Borggrefe M, Kaden JJ

Calcific aortic valve stenosis (CAVS) is one of the most common valvular diseases whose prevalence is likely to increase in the future. The pathologic hallmarks of CAVS are inflammation, fibrous valvular thickening and tissue calcification resembling bone formation. In the last 15 years the view changed from an unmodifiable degenerative disease to an active biological process regulated by highly conserved ubiquitous cellular pathways. Since many mechanisms and risk factors of CAVS are similar to atherosclerosis, statins and Angiotensin II antagonists seemed promising treatment options. Clinical trials, however, mostly failed to support this concept. This review describes the current understanding of major molecular mechanisms and discusses their role in clinical practice and possible therapy.

Prescrire Int. 2008 Jun; 15(33): 115-8

(1) Reliable evidence supports the use of thiazide diuretics (chlortalidone or hydrochlorothiazide) as first-line treatment for uncomplicated arterial hypertension. (2) When patients fail to reach blood pressure targets with well-conducted treatment with thiazide diuretics, or this treatment is poorly tolerated, what are the best second-line options? To answer this question, we reviewed the available evidence, based on our standard in-house methodology. (3) We found no published trials specifically designed to evaluate second-line antihypertensive treatments in cardiovascular prevention. There were no available trials of dual- versus single-agent therapy after failure of a thiazide diuretic. (4) When the blood pressure target is not reached, inadequate drug efficacy is only one of several possible causes. Various other factors affecting blood pressure should also be investigated. (5) Dual-agent therapy carries an increased risk of adverse effects and drug interactions compared to monotherapy. (6) There is no consensus among clinical practice guidelines on second-line antihypertensive therapy. However, to minimise the risk of adverse effects, it is clearly better to select single-agent therapy with a drug that has been shown to prevent cardiovascular events in first-line treatment of otherwise healthy hypertensive patients. Possible options include: Angiotensin-converting-enzyme inhibitors, Angiotensin II antagonists, calcium channel blockers or betablockers. In patients over the age of 60, betablockers seem less effective that the other drugs in preventing strokes. (7) There is too little evidence to choose a specific third-line combination rather than another. However, any adverse effects that the patient experienced during prior treatments should be taken into account.

Kardiol Pol. 2008 Jun; 66(6): 642-649
Banasiak W, Wilkins A, Pociupany R, Ponikowski P

Background: Comprehension of therapeutic methods in patients with stable coronary artery disease (CAD) is mandatory for the introduction of successful prevention. Aim:To gather information regarding individuals with stable coronary artery disease treated by specialists and general practitioners on an outpatient basis. Methods: A representative group of 215 general practitioners and 67 specialists participated in this study. The analysis contains data concerning pharmacotherapy in a group of 2,593 patients with stable CAD (mean age - 65.0+/-9.8 years, women - 44.6%). Results: The patients received the following treatment: acetylsalicylic acid - 75.3%, other antiplatelet drugs - 6.6% (antiplatelet drugs altogether - 81.9%), beta-blockers - 81.1%, ACE-I - 78.8%, statins - 71.9%, fibrates - 4.7%, long-acting nitrates - 53.0%, short--acting nitrates - 33.1%, molsidomine - 18.2%, calcium channel blockers - 23.8%, metabolic drugs (trimetazidine) - 13.4%, diuretics - 43.5%, and Angiotensin receptor antagonists - 1.7% of patients. Drugs classified as non-cardiological were received by 36.2% of patients. The optimal pharmacotherapy including four medications, one from each therapeutic class used in order to improve the prognosis of the patient (an antiplatelet drug, a beta-blocker, an ACE-I, statin), was received by a total of 45.8% of the participants, three medications by 31.7%, two medications by 15.8%, and one medication by 5.5%; 1.2% of the participants did not receive any medication from the four groups of drugs improving prognosis. What is worth noting, however, is the use of relatively small doses of ACE-I and beta-blockers. 69.9% of patients also received at least one symptomatic drug (a long-acting nitrate, a calcium channel blocker, a metabolic drug, molsidomine), including 39.7% - 1 drug, 22.7% - 2 drugs, 6.7% - 3 drugs, and 0.8% - 4 drugs from the classes mentioned above. Conclusions: The results of the RECENT study indicate that great progress has been made in the pharmacotherapy of CAD in Poland within the last few years. Currently, the majority of patients receive drugs that improve prognosis. The awareness of the benefits of the use of combined treatment with all the drug groups and their appropriate doses should be higher. The significant percentage of patients with persisting symptoms of angina pectoris indicates the necessity to improve the efficacy of intervention also in this respect.

Naunyn Schmiedebergs Arch Pharmacol. 2008 Jul 15;
Mehrotra S, Gupta S, Chan KY, Villalón CM, Centurión D, Saxena PR, Maassenvandenbrink A

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, alpha-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT(1B/1D) receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT(2) receptor antagonists, Ca(2+) channel blockers, and beta-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT(1-7)), adrenergic (alpha(1), alpha(2,) and beta), calcitonin gene-related peptide (CGRP(1) and CGRP(2)), adenosine (A(1), A(2), and A(3)), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, Angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

Mol Cell Endocrinol. 2008 Jun 21;
Van Liefde I, Vauquelin G

Sartans are non-peptide AT(1) receptor antagonists used to treat hypertension and related pathologies. Their effects on the G protein-dependent responses of Angiotensin II (Ang II) were the same in vascular tissues and in isolated cell systems. All are competitive but, when pre-incubated, they act surmountably (only rightward shift of the Ang II concentration-response curve) or insurmountably (also decreasing the maximal response). Insurmountable behaviour reflects the formation of tight sartan-receptor complexes; it is often partial due to the co-existence of tight and loose complexes. Their ratio positively correlates with the dissociation half-life of the tight complexes and depends on the sartan: i.e. candesartan>olmesartan>telmisartan approximately EXP3174>valsartan>irbesartan>>losartan. When AT(1) receptors display sufficient basal activity (in case of receptor over-expression, mutation and, especially, tissue stretching) sartans may also act as inverse agonists. This rather affects long-term, G protein-independent hypertrophic responses leading to cardiovascular remodelling.

J Clin Pharm Ther. 2008 Aug; 33(4): 349-56
Mariotti R, Borelli G, Coceani M, Zingaro S, Barison A, Morelli I, Rondinini L

OBJECTIVE: In randomized clinical trials, aldosterone antagonists have been shown to reduce mortality and morbidity in heart failure (HF). The aim of the present study was to examine the risk-benefit profile of aldosterone antagonists in routine clinical practice. METHODS: A retrospective analysis, extending over a 1-year period, of the clinical, instrumental and laboratory data of 264 HF outpatients was performed. All patients were on a beta-blocker and an ACE-inhibitor (or Angiotensin-II receptor-blocker) and 151 were taking an aldosterone antagonist. RESULTS: At baseline, subjects treated with aldosterone antagonists had a higher NYHA class, a larger left-ventricular end-diastolic volume, a worse ejection fraction and a higher systolic pulmonary arterial pressure (sPAP). During follow-up, a greater reduction in sPAP and a tendency towards improved systolic and diastolic function were observed in subjects treated with aldosterone antagonists. Moreover, clinical and laboratory parameters did not deteriorate in patients taking aldosterone antagonists. Mortality rates were similar in the two groups (8.6% vs. 8.8%, P = NS). CONCLUSIONS: The use of aldosterone antagonists in HF is associated with an improvement in cardiac function and is well tolerated. In the present study, patients administered these agents had a comparable clinical outcome to that of the control group, despite important differences in baseline risk.

Stress. 2008 Jun 13; 1
Bregonzio C, Seltzer A, Armando I, Pavel J, Saavedra JM

Spontaneously hypertensive rats, a stress-sensitive strain, were pretreated orally for 14 days with the AT(1) receptor antagonist candesartan before submission to 2 h of cold-restraint stress. In non-treated rats, stress decreased AT(1) receptor binding in the median eminence and basolateral amygdala, increased AT(2) receptor binding in the medial subnucleus of the inferior olive, decreased AT(2) binding in the ventrolateral thalamic nucleus and increased tyrosine hydroxylase mRNA level in the locus coeruleus. In non-stressed rats, AT(1) receptor blockade reduced AT(1) receptor binding in all areas studied and enhanced AT(2) receptor binding in the medial subnucleus of the inferior olive. Candesartan pretreatment produced a similar decrease in brain AT(1) binding after stress, and prevented the stress-induced AT(2) receptor binding decrease in the ventrolateral thalamic nucleus. In the locus coeruleus and adrenal medulla, AT(1) blockade abolished the stress-induced increase in tyrosine hydroxylase mRNA level. Our results demonstrate that oral administration of candesartan effectively blocked brain AT(1) receptors, selectively increased central AT(2) receptor expression and prevented the stress-induced central stimulation of tyrosine hydroxylase transcription. The present results support a role of brain AT(1) and AT(2) receptors in the regulation of the stress response, and the hypothesis that AT(1) receptor antagonists may be considered as potential therapeutic compounds in stress related disorders in addition to their anti-hypertensive properties.

Heart Fail Monit. 2008; 6(1): 9-19
Cotter OM, Sasimangalam AN, Arumugham PS, Kaluski E, Weatherley B, Cotter G

Diuretics have been the cornerstone of acute heart failure (AHF) therapy for >200 years, although the treatment of chronic heart failure has changed dramatically over the past decades with the introduction of Angiotensin-converting enzyme inhibitors, Angiotensin II receptor antagonists, beta-blockers, and aldosterone inhibitors. These treatment modalities were never tested prospectively in the acute setting. Furthermore, there is a significant lack of prospective data on the use of diuretics in both chronic (CHF) and AHF. Hence, despite lack of knowledge on their efficacy and safety, diuretics remain an essential component of the current management of AHF and CHF. In the present manuscript we will address the practical concerns regarding diuretic selection, dosage, combination regimens, and the importance of achieving clinical improvement with minimal changes to kidney function in patients with AHF. Heart Fail Monit 2008;6(1):9-19.

Arq Bras Endocrinol Metabol. 2008 Jun; 52(4): 581-8
Zanatta CM, Canani LH, Silveiro SP, Burttet L, Nabinger G, Gross JL

Diabetic Nephropathy (DN) is a major chronic complication of diabetes mellitus (DM), and one of the main causes of new cases for dialysis, being associated with increasing mortality. The main risk factors for DN are hypertension, hyperglycemia, dyslipidemia, and genetic susceptibility. The renin-Angiotensin system (RAS) plays an important role in genesis and progression of DN and there is evidence of an interrelationship between this system and the endothelins. Endothelins are powerful vasoconstrictor peptides and act as modulators of vasomotor tone, cell proliferation, and hormone production. These peptides act through two types of receptors (ET-A and ET-B) and are expressed on endothelial cells and vascular smooth-muscle cells. Activation of this receptor in renal cells leads to a complex signaling cascade resulting in stimulation of mesangial cell hypertrophy, proliferation, contraction, and extracellular matrix accumulation. These hemodynamic renal alterations are associated with the onset and progress of renal disease in DM. Elevated endothelin-1 (ET-1) levels have been reported in patients with DM. There is evidence suggesting that an increase in the production of ET-1 leads to glomerular damage. The use of ET receptor antagonists has been reported as renoprotective, correcting the early hemodynamic abnormalities in experimental DM, reinforcing the importance of this system in DN.

J Thorac Cardiovasc Surg. 2008 Jul; 136(1): 58-64
Tsukashita M, Marui A, Nishina T, Yoshikawa E, Kanemitsu H, Wang J, Ikeda T, Komeda M

OBJECTIVE: Although left ventricular restoration is effective for treating ischemic cardiomyopathy caused by left ventricular remodeling and redilation, the initial improvement in left ventricular function is not always sustained. We have reported that the inhibition of the renin-Angiotensin-aldosterone system by Angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers is effective in preventing late remodeling after left ventricular restoration. However, the effects of spironolactone--an aldosterone blocker--after left ventricular restoration have not been elucidated. METHODS: Myocardial infarction was induced by ligating the left anterior descending artery. The rats developed left ventricular aneurysms and underwent left ventricular restoration by the plication of the left ventricular aneurysm 4 weeks after the ligation. Thereafter, the rats were randomized into a left ventricular restoration (vehicle) group and left ventricular restoration with spironolactone (100 mg/kg/d, by mouth) group. RESULTS: Echocardiography revealed that in the left ventricular restoration with spironolactone group, late cardiac redilation was significantly attenuated (left ventricular end-diastolic area: 0.51 +/- 0.03 cm(2) vs 0.63 +/- 0.03 cm(2), P < .05) and late left ventricular function was preserved (fractional area change: 48.8% +/- 3.0% vs 35.8% +/- 2.4%, P < .01). Hemodynamically, rats in the left ventricular restoration with spironolactone group exhibited improved systolic function (maximal end-systolic pressure-volume relationship: 0.38 +/- 0.03 mm Hg/microL vs 0.11 +/- 0.04 mm Hg/microL, P < .01) and diastolic function (tau: 18.5 +/- 1.5 sec vs 23.1 +/- 1.4 sec, P < .05) than those in the LVR group. Histologically, interstitial fibrosis in the remote area was significantly reduced (5.6% +/- 1.3% vs 12% +/- 1.0%, P < .01), and fibrosis around the pledgets (near area) was also attenuated in the left ventricular restoration with spironolactone group. The myocardial messenger ribonucleic acid expressions of transforming growth factor-beta1 and brain natriuretic peptide measured using the real-time polymerase chain reaction were lower in the left ventricular restoration with spironolactone group (transforming growth factor-beta1: 0.13 +/- 0.02 vs 0.28 +/- 0.02, P < .01; brain natriuretic peptide: 0.99 +/- 0.14 vs 1.54 +/- 0.18, P < .05). The systemic blood pressure and heart rate did not differ between the 2 groups. CONCLUSION: Spironolactone reduced the gene expression of transforming growth factor-beta1 and brain natriuretic peptide and alleviated not only cardiac redilation but also the deterioration of left ventricular function late after left ventricular restoration without inducing hypotension, a major side effect of Angiotensin-converting enzyme inhibitors or Angiotensin receptor blocker. Spironolactone is a promising therapeutic option for alleviating remodeling after left ventricular restoration.

J Physiol. 2008 Jul 3;
Lu R, Alioua A, Kumar Y, Kundu P, Eghbali M, Weisstaub NV, Gingrich JA, Stefani E, Toro L

Serotonin (5-HT) receptors (5-HTRs) play critical roles in brain and cardiovascular functions. In the vasculature, 5-HT induces potent vasoconstrictions, which in aorta are mainly mediated by activation of 5-HT2AR subtype. We previously proposed that one signaling mechanism of 5-HT induced vasoconstriction could be c-Src, a member of the Src tyrosine kinase family. We now provide evidence for c-Src central role in 5-HT2AR mediated contraction. Inhibiting Src kinase activity with 10 microM PP2 prior contraction, resulted in ~90% to 99% inhibition of 5-HT or of alpha-methyl-5-HT (5-HT2R agonist)-induced contractions. In contrast, PP2-pretreatment only partially inhibited thromboxane A2 mimetic U46619- and Angiotensin II-induced contractions, and had no significant action on phenylephrine-induced contractions. 5-HT increased Src kinase activity and PP2-sensitive tyrosine-phosphorylated proteins. As expected for c-Src identity, PP2 pretreatment inhibited 5-HT-induced contraction with an IC50 of ~1 microM. Ketanserin (10 nM), a 5-HT2A antagonist but not antagonists of 5-HT2BR (100 nM SB204741) or 5-HT2CR (20 nM RS102221) prevented 5-HT-induced contractions mimicking PP2 and pointing 5-HT2AR as the major receptor subtype coupled to c-Src. In HEK 293T cells, c-Src and 5-HT2AR were reciprocally co-immunoprecipitated and colocalized at the cell periphery. Finally, 5-HT-induced Src activity was unaffected by inhibition of Rho kinase, supporting a role of c-Src upstream Rho kinase. Together the results highlight c-Src activation as one of the early and pivotal mechanisms in 5-HT2AR contractile signaling in aorta.

Int J Impot Res. 2008 Jul 3;
Baumhäkel M, Schlimmer N, Böhm M

Pathogenesis of erectile dysfunction (ED) is related to endothelial dysfunction and therefore associated with cardiovascular risk factors. Patients with a combination of risk factors, as in metabolic syndrome, are thus likely to have an increased risk of developing endothelial and ED. The Angiotensin receptor antagonist irbesartan has been shown to improve endothelial function in cardiovascular high-risk patients, which suggests a beneficial effect of treatment with irbesartan on ED. The aim of the present study was to determine the influence of irbesartan on ED in patients with a metabolic syndrome. A total of 1069 consecutive hypertensive patients with a metabolic syndrome from the Documentation of hypertension and metabolic syndrome in patients with Irbesartan Treatment survey were included. Patients were treated with irbesartan or the combination of irbesartan/hydrochlorothiazide for 6 months. ED was assessed using the international index of erectile function. The Cologne Evaluation Questionnaire of Erectile Dysfunction served as a control. Erectile function increased significantly (P<0.0001) after 6 months of treatment with irbesartan, irrespective of dosage and independent of additional treatment with hydrochlorothiazide. Prevalence of ED declined to 63.7% from 78.5% at baseline, along with a significant increase in orgasmic function (P<0.001) and intercourse satisfaction (P<0.001). Treatment with irbesartan alone, as well as in combination with hydrochlorothiazide is associated with an improvement of sexual desire, frequency of sexual contacts and erectile function in hypertensive patients with the metabolic syndrome. These results suggest a beneficial role of Angiotensin receptor antagonists in the treatment of metabolic syndrome, and ED.International Journal of Impotence Research advance online publication, 3 July 2008; doi:10.1038/ijir.2008.28.

Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2007 Dec; 29(6): 792-6
Hua CX, Hua L, Li N, Wang L, Pang HM, Ming GH, Huang Y, Cheng XR, Liu H, Wu Y, Xu L, Kang J, Xu ZM, Li YS

OBJECTIVE: To evaluate the efficacy of the monotherapy of 15 agents in treating essential hypertension. METHODS: After 2-week wash-out, a total of 370 patients with seated diastolic blood pressure 95-114 mmHg and seated systolic blood pressure < 180 mmHg were randomized to different therapeutic groups. 24-hour ambulatory blood pressure monitoring was performed before medication and at the end of 8 weeks. RESULT: All the agents significantly reduced the 24 hour mean blood pressures after treatment except doxazosin, terazosin, and torasemide. CONCLUSION: The result suggested that the Angiotensin-converting enzyme inhibitors, Angiotensin II receptor blockers, beta-blockers and long-acting calcium antagonists were effective in treating essential hypertension, while the low-dose doxazosin, terazosin and torasemide can be used for combination therapy but not for monotherapy.

Clin Ter. 2008 May-Jun; 159(3): 151-4
Morano S, Cipriani R, Santangelo C, Fallarino M, Carnovale A, Mandosi E, Gatti A, Sensi M, Di Mario U

Aims. Angiotensin converting enzyme inhibitors (ACEIs) and Angiotensin II receptor-1 (AT-1) antagonists are used in the treatment of proteinuria of diabetic nephropathy. One of the major pathogenic events in this condition is represented by the alteration of the extracellular matrix protein synthesis by glomerular epithelial cells. Materials and Methods. We evaluated the effects of the Angiotensin converting enzyme inhibitor, Enalaprilat, and the AT-1 receptor antagonist, Losartan, on mRNA fibronectin and laminin synthesis by glomerular epithelial cells, in conditions mimicking hyperglycemia. Results. In high glucose conditions, Enalaprilat reduced significantly the mRNA expression of fibronectin (p 0.03), but not significantly that of laminin. Losartan addition to high glucose incubated cells reduced (-30%) mRNA expression of fibronectin, and significantly (p 0.05) the mRNA expression of laminin.Conclusions. In addition to the known hemodynamic effects, the improvement of renal function in diabetic patients treated with these compounds may also be due to a modulator effect on extracellular matrix content and composition. Clin Ter 2008; 159(3):151-154.

Minerva Endocrinol. 2008 Jul 3;
Mazza A, Armigliato M, Zamboni S, Rempelou P, Rubello D, Pessina AC, Casiglia E

This review describes the therapeutic approach of endocrine arterial hypertension in clinical practice. In mineralocorticoid-related hypertension, adrenalectomy is the treatment of choice for aldosterone-producing adenomas and monolateral primary aldosteronism, whereas pharmacologic blood pressure (BP) control is indicated for the other forms of primary aldosteronism such as bilateral adrenal hyperplasia. Spironolactone is the drug of choice, but intolerable side effects limit its use; amiloride or eplerenone are a valid alternative. If BP remains uncontrolled, Angiotensin converting enzyme inhibitors (ACE-I), Angiotensin II receptor antagonists (AII-RA) and calcium channel blockers (CCB) may be added. Hypertension accompanying Cushing's syndrome can be approached with surgery, but antihypertensive treatment both pre- and postoperative is required as well. Eplerenone, AII-RA and ACE-I are indicated, while peroxisome proliferator activated receptor gamma-agonists may help for the insulin resistance syndrome. Drugs that suppress steroidogenesis should be used with care because of their serious side effects. Subjects with catecholamine-dependent hypertension due to a neuroendocrine neoplasm need to undergo preoperative alpha-adrenergic blockade with phenoxybenzamine or doxazozine. When adequate alpha-adrenergic blockade is achieved, beta-adrenergic blockade with low dose propranolol may be added. If target BP is not achieved, CCB and/or metyrosine are indicated. Laparoscopic adrenalectomy is the procedure of choice for solitary intra-adrenal neoplasms <8 cm. Acute hypertensive crises that may occur before or during surgery should be treated intravenously with sodium nitroprusside, phentolamine, nicardipine or labetalol. For malignant neoplasms, chemo- and radiopharmaceutical therapy may be considered.

Int J Cardiol. 2008 Jun 25;
Ntaios G, Savopoulos C, Hatzitolios A, Chatzinikolaou A, Karamitsos D

In a recent article by Fernandez-Miranda et al., it was shown that daily administration of 2.5 mg of folate did not significantly alter carotid-intima media thickness (IMT) in patients with coronary heart disease in respect to coronary patients who did not receive folate, although there was indeed a net reduction of IMT in the former group. This reduction of IMT in the first group would be possibly statistically significant if the control group did not exhibit a similar reduction. The authors attributed the IMT reduction of the control group to the fact that all patients were on hypolipidaemic treatment with statins, whereas the vast majority of them were also on treatment with either beta-blockers or Angiotensin-converting enzyme inhibitors or calcium-channels antagonists. As the authors indicate, all these medications have been shown to decrease IMT. It is possible that the effect of folate on IMT was overshadowed by the powerful effect of the combined treatment of statins with the aforementioned cardiovascular drugs.

J Renin Angiotensin Aldosterone Syst. 2008 Jun; 9(2): 75-88
Dietze GJ, Henriksen EJ

Recent evidence suggests a coordinated regulation by the local renin-Angiotensin system (RAS) and tissue kallikrein-kinin system (TKKS) of blood flow and substrate supply in oxidative red myofibres of skeletal muscle tissue during endurance exercise. The performance of these myofibres is dependent on the increased oxidation of substrates facilitated by augmenting nutritive blood flow and glucose uptake. Humoral factors released by the contracting fibres, such as adenosine and kinins, are suggested to be responsible for this metabolic adjustment. The considerable drain of blood volume and the enormous consumption of glucose during endurance exercise require a control mechanism for the maintenance of blood pressure (BP) and glucose homeostasis. This is achieved by the sympathetic nervous system and its subordinate RAS, which is located in the nutritive vessels and parenchyma of the red myofibres. The Angiotensin-converting enzyme (ACE) is the primary enzyme responsible for kinin degradation during exercise, underscoring the important interrelationship between the RAS and the TKKS in the critical role of kinins in the multifactorial regulation of muscle bioenergetics and glucose and BP homeostasis. Importantly, overactivity of the ACE, as occurs in individuals displaying risk factors such as overweight, causes exaggerated BP response and reduced glucose disposal. If they persist over years, compensatory responses to this ACE overactivity, such as hypersecretion of insulin and compliance of the vessel walls, will inevitably be exhausted, leading ultimately to the manifestation of type 2 diabetes and hypertension. This concept also provides a unifying explanation for the beneficial effects of ACE-inhibitors and Angiotensin II receptor antagonists in the treatment of hypertension and insulin resistance.

N Engl J Med. 2008 Jun 26; 358(26): 2829-31
Pyeritz RE

N Engl J Med. 2008 Jun 26; 358(26): 2787-95
Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC

BACKGROUND: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including Angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. METHODS: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. RESULTS: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. CONCLUSIONS: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.

Trends Pharmacol Sci. 2008 Jul; 29(7): 367-74
Marchesi C, Paradis P, Schiffrin EL

Angiotensin (Ang) II, the main effector of the renin-Angiotensin system (RAS), is one of the major mediators of vascular remodeling in hypertension. Besides being a potent vasoactive peptide, Ang II exerts proinflammatory effects on the vasculature by inducing integrins, adhesion molecules, cytokines and growth and profibrotic mediators through activation of redox-sensitive pathways and transcription factors. Clinical findings suggest that inflammation participates in the mechanisms involved in the pathophysiology of hypertension and its complications. antagonists of the RAS have been shown to exert cardiovascular protection, in part through their vascular anti-inflammatory effects. However, further studies are needed to better understand whether inflammatory biomarkers might be clinically useful for cardiovascular risk stratification and whether targeting inflammation pharmacologically will improve cardiovascular outcomes beyond blood pressure reduction. The present review addresses recent findings regarding the pathophysiology of vascular inflammation in hypertension, focusing specifically on the role of Ang II.