Inhibition of cardiovascular cell proliferation by angiotensin receptor blockers: are all molecules the same?

BACKGROUND: Few studies have directly compared the effects of different angiotensin receptor blockers (ARBs) on mechanisms involved in the pathogenesis of cardiovascular disease. METHODS: We studied the ability of different ARBs to inhibit the proliferation of vascular smooth muscle cells (VSMCs) and cardiac fibroblasts (CFs) in continuous culture and in quiescent cells stimulated to proliferate by platelet-derived growth factor (PDGF) and insulin. We also investigated whether the antiproliferative effects of ARBs depended on their ability to block angiotensin II receptors or activate the peroxisome proliferator-activated receptor gamma (PPAR gamma). RESULTS: Dose-response studies showed that candesartan, eprosartan, and irbesartan had little or no effect on the proliferation of VSMC or CF in continuous culture even when tested at concentrations as high as 10 mumol/l or when tested in cells stimulated with PDGF/insulin. In contrast, telmisartan inhibited VSMC and CF proliferation by 50-70% (P < 0.05) in a dose-dependent and reversible fashion and significantly inhibited the increases in cyclin D1 levels and cell proliferation induced by PDGF/insulin. Antiproliferative effects of telmisartan were also observed in Chinese hamster ovary (CHO-K1) cells that lack functional angiotensin II receptors and in human VSMCs treated with the PPAR gamma antagonist GW9662. CONCLUSION: Telmisartan, but not candesartan, irbesartan, or eprosartan, can significantly inhibit the proliferation of VSMC and CF in culture when tested at concentrations near those that can be achieved in plasma with usual oral dosing. Telmisartan can also inhibit the proliferation of cells that lack angiotensin II receptors and cells treated with a PPAR gamma antagonist suggesting that the antiproliferative effects of telmisartan may involve more than just angiotensin II receptor blockade or activation of PPAR gamma.     

Have angiotensin receptor blockers lived up to expectations?

Angiotensin receptor blockers (ARBs) were introduced after clinical trials showed angiotensin-converting enzyme inhibitors (ACEIs) to have extensive clinical benefits in a wide range of diseases. Consequently, it has been more difficult for clinical trials to demonstrate similar, enhanced or additive benefits of ARBs. However, ARBs were introduced with the hypothesis that they were likely a more effective method of interrupting the renin-angiotensin system and would result in enhanced outcomes. Clinical trials in high-risk vascular patients (after myocardial infarction), patients with heart failure and patients with nephropathy show the benefits of ACE inhibition. ARBs likely have similar benefits as ACEIs when used after myocardial infarction, in patients with heart failure and for management of diabetic nephropathy. However, ARBs generally remain a second-line treatment because it has been more difficult to demonstrate that ARBs prevent acute vascular events, such as myocardial infarction, together with the greater clinical trial evidence for ACE inhibition. The primary application of ACEIs over ARBs is reflected in the Canadian clinical guidelines for the management of patients with diabetes, hypertension, heart failure and following myocardial infarction. Until the completion of clinical trials, such as the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), that examine whether ARBs have vascular protective properties similar to ACEIs, it is unlikely that the clinical guidelines will change.     

Are angiotensin converting enzyme inhibitors and angiotensin receptor blockers becoming the treatment of choice in African-Americans?

African-American patients constitute a significant and important group who are at high risk for developing hypertension-related complications. The proportion of African-American patients succumbing to or suffering from cardiovascular, renal, and neurologic sequelae is unacceptably high. Therefore, it is extremely crucial to develop appropriate therapeutic strategies for this vital subset of our society. The renin-angiotensin system may play a role in the pathophysiology of hypertension-related diseases, and therefore drugs that block this system, ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, may have a special indication for African-American patients. Although these drugs may not be the most efficacious agents in terms of blood pressure reduction, they have a major benefit in offering target organ protection and arresting disease progression in the African-Americans. Hence, contrary to the old notions, drugs blocking the renin-angiotension system have an important place in the management of hypertension and related disorders in African-American patients.     

Renin-angiotensin-aldosterone system blockade and renal protection: angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers?

Renal function is closely associated with cardiovascular risk, to the extent that even minor renal abnormalities, which are present in 10% of the general population, carry a greatly elevated risk of cardiovascular disease, target-organ damage and death. Reducing blood pressure by 20 mmHg or more in patients with severe hypertension (>160/100 mmHg) and advanced renal disease is sufficient to ensure a considerable reduction in proteinuria. In patients with less severe disease, however, blockade of the renin-angiotensin-aldosterone system (RAAS) is necessary to restore normal renal function. Clinical studies have shown that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), which both overcome the activity of angiotensin II, provide renoprotection in diabetics and non-diabetic populations. Which class of drugs is more effective remains a subject of debate, but the evidence favours ARBs for providing more effective renoprotection in patients at risk of diabetic nephropathy. The ARBs preserve renal haemodynamics and reduce progression to end-stage renal disease by around 25% in patients with overt nephropathy and prevent progression to overt disease by up to 70% in patients with mild renal impairment. The combination of ARBs and ACE inhibitors is even more protective, halving the number of patients with progression of renal impairment compared with either monotherapy. Long-term clinical studies now under way will help to establish the relative efficacies of the ARBs and ACE inhibitors and provide greater insight into the benefits of combination therapy.     

Are angiotensin II receptor blockers more efficacious than placebo in heart failure? Implications of ELITE-2. Evaluation of Losartan In The Elderly

In the light of the recent randomized controlled trials in chronic heart failure, it is now commonly assumed that treatment with an angiotensin-receptor blocker (ARB) is equivalent to treatment with an angiotensin-converting enzyme (ACE) inhibitor. We performed an imputed placebo analysis using previous placebo-ACE inhibitor trials and the current ACE inhibitor-ARB comparison studies, which shows that ARBs may not even be superior to placebos, let alone an ACE inhibitor.     

The addition of angiotensin receptor blockers to angiotens-inconverting enzyme inhibitors—What has time told us?

The neurohormonal hypothesis for the pathogenesis of heart failure found an early champion in the angiotensinconverting enzyme (ACE) inhibitors. More recently, the β-blockers and aldosterone receptor antagonists have provided significant support by demonstrating marked additive clinical benefit. Within this context, angiotensin receptor blockers (ARBs) were specifically designed to antagonize one of the most potent contributors to the development and progression of heart failure, angiotensin. This review discusses the recent evidence for the addition of ARBs to standard therapy with ACE inhibitors and suggests how this evidence may be used to care for patients.     

Do angiotensin II receptor antagonists substitute angiotensin converting enzyme inhibitors in the treatment of high blood pressure?

Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (AIIA) are both pharmacological groups that inhibit the actions of angiotensin II. ACEI prevent the formation of angiotensin II from angiotensin I, whereas A II A inhibit the final crucial step of angiotensin II binding with the AT1 receptor site. A similar antihypertensive efficacy has been described for both groups but A II A drugs have a better safety profile above all due to the absence of dry cough. Despite the fact that evidence with ACEI is more conclusive, A II A seems to achieve the same protective effects on the target organ damage in hypertensive patients. At present, ACEI are the drugs of choice in the treatment of patients with cardiac dysfunction and failure. The information of ongoing trials with A II A will be of great value in deciding the optimal treatment for hypertensive patients with different cardiovascular diseases.     

Does the antihypertensive response to angiotensin converting enzyme inhibition predict the antihypertensive response to angiotensin receptor antagonism?

To test the hypothesis that the antihypertensive response to angiotensin converting enzyme (ACE) inhibition can predict the response to angiotensin II type I receptor (AT₁R) antagonism, 33 hypertensive patients were randomized to receive lisinopril (20 mg) or losartan (50 mg) for 5 weeks. Patients were then crossed-over to the alternative treatment for a second 5-week period. Twenty-four-hour ambulatory BP (ABP) was measured before randomization and on the final day of each period. The agreement in ABP response between the two drugs was assessed using the following approaches: Subjects were classified as responders and nonresponders using as a threshold an arbitrary level of response (ABP fall ≥ 10 mm Hg systolic or ≥ 5 mm Hg diastolic) or the median ABP response achieved by each of the drugs. Disagreement between the two drugs in the responders-nonresponders classification was expressed as the proportion of subjects whose ABP responded to one of the drugs only. Lisinopril was more effective than losartan in reducing ABP (mean difference 4.7 ± 8.1/3.3 ± 5.7 mm Hg, systolic/diastolic, P < .05). Disagreement in the antihypertensive response between the two drugs was found in 39%/33% of subjects for systolic/diastolic ABP using the arbitrary response criterion (33%/39% using the median response criterion). Significant correlations were found between the responses to lisinopril and losartan (r = 0.47/0.59, systolic/diastolic, P < .01). We conclude that in more than one third of hypertensive subjects, the BP response to ACE inhibition fails to predict the response to AT₁ R antagonism and vice versa. These data suggest that there are differences between these two drug classes that are not only of theoretical but also of practical significance.