Calcium channel blockers in the spectrum of antihypertensive agents

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. Through blood pressure reduction, and possibly other mechanisms such as antioxidative effects, they may play a role in diminishing the risk for a variety of cardiovascular outcomes. The combination of CCBs with other newer antihypertensive agents such, as ACE inhibitors and angiotensin receptor blockers, may provide complementary effects on risk reduction in cardiovascular adverse events and renal disease. Although the efficacy of CCBs as antihypertensive agents has been adequately demonstrated, there have been concerns regarding the use of short acting dihydropyridines after acute myocardial infarction. There have also been questions about the role of CCBs with regards to other antihypertensive agents in renal disease. For example, differential effects of dihydropyridine and non-dihydropyridine CCBs may affect progression of renal disease and risk for diabetes. Certain precautions involving drug interactions are needed because of the effects of CCBs on the CYP450 enzyme systems.     

Use of Calcium Channel Blockers in Cardiovascular Risk Reduction

Cardiovascular disease (CVD) is a continuum that begins with the presence of several risk factors for CVD, including smoking, hypertension, obesity, diabetes mellitus, and high levels of cholesterol, and if unaddressed can result in premature death, ischemic heart disease, stroke, congestive heart failure, and end-stage renal disease. Hypertension is associated with a significant increase in cardiovascular (CV) morbidity and mortality, raising the risk of stroke, myocardial infarction, heart failure, kidney disease, and peripheral arterial disease. In Latin America, the prevalence of hypertension and other CV risk factors has become similar to that seen in more developed countries, increasing the proportion of the population at high risk for CVD and congestive heart failure; however, it is hypertension that is a key driving force behind CV risk in Latin America. Despite the existence of a wide range of antihypertensive agents, BP control and reductions in CV risk remain poor in Latin America and in Hispanics living in the US. Ethnic differences in treatment rates and disease awareness have been well documented. Studies have shown that calcium channel blockers (CCBs; calcium channel antagonists) are at least as effective in reducing BP and improving the CV risk profile as other classes of antihypertensive agents when administered as monotherapy. CCBs have also been shown to be effective when administered as part of combination therapy in both low- and high-risk hypertensive patients, suggesting that CCBs can easily be combined with other antihypertensive classes in order to achieve BP control and CV risk reduction. In patients with hypertension, coronary artery disease, and high cholesterol, CCBs have been associated with beneficial effects on a range of other aspects of the CV continuum, including the vasculature, coronary calcification, and progression of atherosclerosis. CCBs have also been shown to preserve renal function. Unlike diuretics and β-adrenoreceptor antagonists, CCBs are metabolically neutral, inducing minimal changes in serum lipids and decreasing the incidence of new-onset diabetes compared with other antihypertensive agents. CCBs are well tolerated when administered as monotherapy or combination therapy, with long-acting formulations minimizing adverse events even further compared with short-acting formulations. These characteristics make CCBs an attractive option for the treatment of hypertension and CV risk in Latin America, which remain significant health issues in this region.     

Calcium channel blockers as the treatment of choice for hypertension in renal transplant recipients: fact or fiction

Posttransplantation hypertension has been identified as an independent risk factor for chronic allograft dysfunction and loss. Based on available morbidity and mortality data, posttransplantation hypertension must be identified and managed appropriately. During the past decade, calcium channel blockers have been recommended by some as the antihypertensive agents of choice in this population, because it was theorized that their vasodilatory effects would counteract the vasoconstrictive effects of the calcineurin inhibitors. With increasing data becoming available, reexamining the use of traditional antihypertensive agents, including diuretics and beta-blockers, or the newer agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, may be beneficial. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit, from both a renal and a cardiovascular perspective. Beta-blockers, diuretics, and ACE inhibitors have all demonstrated significant benefit on morbidity and mortality in patients with cardiovascular disease. Calcium channel blockers have been shown to possess the ability to counteract cyclosporine-induced nephrotoxicity. When compared with beta-blockers, diuretics, and ACE inhibitors, however, the relative risk of cardiovascular events is increased with calcium channel blockers. With the long-term benefits of calcium channel blockers on the kidney unknown and a negative cardiovascular profile, these agents are best reserved as adjunctive therapy to beta-blockers, diuretics, and ACE inhibitors.     

Renal protection with calcium antagonists: the role of lercanidipine

Abstract

Background:

Clinical research in the field of hypertension is now increasingly focusing on the potential effects of antihypertensive treatments that may go beyond the reduction of blood pressure (BP). In particular, renal protection appears as a desirable goal, especially considering that hypertension is associated with an increased risk of developing kidney damage, which may eventually lead to end-stage renal disease and a higher mortality. Dihydropyridine calcium channel blockers (CCBs) are widely used in the field of hypertension therapy but the different renal effects of the various CCBs have been poorly explored to date.     

Prevention and treatment of diabetic nephropathy in older patients

Renal disease in older diabetic patients is costly in terms of morbidity, mortality and expenditure. Therefore, prevention and treatment of diabetic nephropathy has become a prominent goal in the treatment of patients with diabetes mellitus. Preventive treatment should begin no later than at the stage of microalbuminuria, and regular screening for microalbuminuria is recommended for all patients with diabetes, irrespective of age. Improved metabolic control has been demonstrated to lower urinary albumin excretion. Target glycosylated haemoglobin levels should be below 7%, or 1% above the upper limit of normal of non-diabetic subjects. The use of an intensified treatment regimen is recommended. Insulin therapy has no adverse effects on renal indexes. To preserve renal function in older diabetic patients, blood pressure should be kept at or below 130/80 mm Hg. Treatment with ACE inhibitors or angiotensin II receptor antagonists (angiotensin II receptor blockers; ARBs) is superior to other pharmacological therapy, and should be initiated as first-line treatment. Most of the calcium channel antagonists have been found to increase or to have no effect on microalbuminuria despite blood pressure reduction. Moreover, there is substantial controversy as to whether they may be associated with increased cardiovascular morbidity. Non-dihydropyridine derivatives and calcium channel antagonists, such as nitrendipine, may be nephroprotective and have favourable effects on patients outcomes. A renoprotective action of diuretics may be confined to indapamide. Although beta-adrenoreceptor blockers are effective antihypertensive agents, they may not adequately preserve kidney function in older diabetic patients. However, as add-on treatment to ACE inhibitors or ARBs, they are particularly beneficial in nephropathic patients at risk of cardiovascular disease or with arrhythmias, in whom they may prove life-saving.     

Can the renin-angiotensin system protect against stroke? A focus on angiotensin II receptor blockers

From a patient's perspective, stroke is the most devastating form of cardiovascular disease, representing the number one cause of permanent disability in the United States. Treatment of hypertension significantly reduces the risk of stroke; however, it is unclear whether all antihypertensive agents are equivalent in this regard. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the risk of cardiovascular events, including stroke. Although attenuation of the renin-angiotensin system (RAS) is often credited with the blood pressure-independent effects of this class of agents, this hypothesis has not been confirmed with regard to the end point of stroke. In fact, drugs that activate the RAS, such as diuretics and dihydropyridine calcium channel blockers, are as effective or superior to ACE inhibitors for stroke prevention. Angiotensin II receptor blockers (ARBs) selectively block the angiotensin II subtype I receptor, which results in a reflexive increase in levels of angiotensin II and unopposed activation of angiotensin II subtype 2 receptors. Clinical trials comparing ARBs with active controls have reported significant reductions in stroke in ARB-treated patients. Data on ARBs and other drugs that activate the RAS (diuretics and dihydropyridine calcium channel blockers) support a potential role for the RAS in protecting against stroke. Ongoing trials with ARBs are evaluating stroke as a primary end point, and results should help to further elucidate the role of ARBs in this disease. Until then, it is prudent to treat hypertension with an agent or combination of agents that are likely to result in a rapid and sustained reduction in blood pressure, taking into consideration patient characteristics, comorbidities, tolerability, and cost.     

Calcium channel blockers and treatment of hypertension

Over the past years, research efforts have been focused on the pathophysiologic role of calcium ions, and the implication for the potential role of calcium channel blockers in the management of essential hypertension. Numerous studies have shown that nifedipine and verapamil are effective antihypertensive agents, initial experience with diltiazem is also encouraging. The magnitude of blood pressure reduction with these drugs is related to the pre-treatment blood pressure. In refractory hypertension, combination with other antihypertensive agents provide additive effect. In the elderly population and in patients with ischemic heart disease, supraventricular arrhythmia, bronchospastic disease, peripheral vascular disease or diabetes mellitus, the calcium channel blockers offer potential advantages over other antihypertensive agents. Experimental studies also suggest that these drugs may reverse ventricular hypertrophy. When long-term safety with these drugs is documented from well-controlled clinical trials, the calcium channel blockers may be our first line of therapy for the management of hypertension.     

Amlodipine and atorvastatin in atherosclerosis: a review of the potential of combination therapy

Hypertension and hyperlipidaemia are major risk factors for the development of atherosclerosis. Calcium channel blockers (CCBs) have been used for decades and have established antihypertensive effects. Statins have been extensively used because of their potent lipid lowering properties. Amongst other factors, inflammation and oxidation are involved in enhanced progression of atherosclerosis and new lesion development. Therefore, research has been initiated focusing on the antioxidant and anti-inflammatory properties of CCBs and statins, beyond their primary effect, in order to evaluate the possible additive effects of combined treatment of CCBs with statins as antiatherosclerotic therapy. Clinical studies (e.g., the International Nifedipine Trial on Antiatherosclerotic Therapy [INTACT]) have demonstrated that the antiatherosclerotic action of CCBs is limited to the attenuation of the first stage of atherosclerogenesis (fatty streak formation or new lesion growth). The lesions that pre-existed at the start of CCB therapy did not demonstrate progression or regression on angiography. However, because the mechanisms of action of lipid-lowering drugs and CCBs, and their role in preventing the progression of atherosclerosis differ, it is conceivable to conclude that these two classes may have an additive or synergic effect, not only on new lesion formation but also on inhibiting the progression of established coronary atherosclerosis. Indeed, this combined effect of lipid-lowering therapy and CCBs on human coronary atherosclerosis has been reported in the Regression Growth Evaluation Statin Study (REGRESS) trial. This beneficial effect of combining CCBs with statins has now been replicated in transgenic atherosclerotic mice, where the combination of amlodipine and atorvastatin produced an additional 60% reduction of atherosclerosis compared with that observed with the statin alone. Serum markers of atherosclerosis and vascular integrity also improved most in the combination group. Synergistic effects of the combination of atorvastatin and amlodipine on acute nitric oxide release/endothelial function, and additive effects of the combination of amlodipine and atorvastatin in the improvement of arterial compliance in hypertensive hyperlipidaemic patients has been demonstrated. Collectively, these studies support the clinical antiatherosclerotic advantages of combination of CCBs and statins and in particular, of atorvastatin with amlodipine beyond their established antihyperlipidaemic and antihypertensive modes of action.     

Amlodipine and atorvastatin in atherosclerosis: a review of the potential of combination therapy

Hypertension and hyperlipidaemia are major risk factors for the development of atherosclerosis. Calcium channel blockers (CCBs) have been used for decades and have established antihypertensive effects. Statins have been extensively used because of their potent lipid lowering properties. Amongst other factors, inflammation and oxidation are involved in enhanced progression of atherosclerosis and new lesion development. Therefore, research has been initiated focusing on the antioxidant and anti-inflammatory properties of CCBs and statins, beyond their primary effect, in order to evaluate the possible additive effects of combined treatment of CCBs with statins as antiatherosclerotic therapy. Clinical studies (e.g., the International Nifedipine Trial on Antiatherosclerotic Therapy [INTACT]) have demonstrated that the antiatherosclerotic action of CCBs is limited to the attenuation of the first stage of atherosclerogenesis (fatty streak formation or new lesion growth). The lesions that pre-existed at the start of CCB therapy did not demonstrate progression or regression on angiography. However, because the mechanisms of action of lipid-lowering drugs and CCBs, and their role in preventing the progression of atherosclerosis differ, it is conceivable to conclude that these two classes may have an additive or synergic effect, not only on new lesion formation but also on inhibiting the progression of established coronary atherosclerosis. Indeed, this combined effect of lipid-lowering therapy and CCBs on human coronary atherosclerosis has been reported in the Regression Growth Evaluation Statin Study (REGRESS) trial. This beneficial effect of combining CCBs with statins has now been replicated in transgenic atherosclerotic mice, where the combination of amlodipine and atorvastatin produced an additional 60% reduction of atherosclerosis compared with that observed with the statin alone. Serum markers of atherosclerosis and vascular integrity also improved most in the combination group. Synergistic effects of the combination of atorvastatin and amlodipine on acute nitric oxide release/endothelial function, and additive effects of the combination of amlodipine and atorvastatin in the improvement of arterial compliance in hypertensive hyperlipidaemic patients has been demonstrated. Collectively, these studies support the clinical antiatherosclerotic advantages of combination of CCBs and statins and in particular, of atorvastatin with amlodipine beyond their established antihyperlipidaemic and antihypertensive modes of action.     

Evolution of drugs that preserve renal function

Over the past 50 years, many advances have been made in slowing the progression of renal disease from various causes. These advances have been primarily linked to defining new lower levels for blood pressure goals as well as understanding the importance of proteinuria reduction. To achieve these goals, it is also appreciated that agents that lower blood pressure must also lower proteinuria. This is not true for all antihypertensive drug classes--notably, direct-acting vasodilators, alpha-blockers, and dihydropyridine calcium antagonists. Interestingly, antihypertensive agents that also reduce proteinuria have been associated with cardiovascular risk reduction. Moreover, an understanding of combinations of antihypertensive medications that provide additive reductions in proteinuria may be even more efficacious for slowing renal disease progression. It is hoped that these advances and the projected advances in pharmacogenetics will reduce the current increasing incidence of people going on dialysis.     

Nebivolol: a review

Nebivolol is a vasodilating β-blocker, which can be distinguished from other β-blockers by its haemodynamic profile. It combines β-adrenergic blocking activity with a vasodilating effect mediated by the endothelial L-arginine nitric oxide (NO) pathway. The blood pressure lowering effect of nebivolol is linked to a reduction in peripheral resistance and an increase in stroke volume and preservation of cardiac output. The effects of nebivolol have been compared with other β-blockers and also with other classes of antihypertensive agents. In general, response rates to treatment are higher and the frequency and severity of adverse events are either comparable or lower with nebivolol. Endothelium-derived NO is important in the regulation of large arterial stiffness, which in turn is a major risk factor for cardiovascular disease. Therefore, antihypertensive drugs, such as nebivolol, that also improve endothelial function and decrease arterial stiffness, may contribute to a reduction in cardiovascular risk.     

Discordant effects of beta-blockade on central aortic systolic and brachial systolic blood pressure: considerations beyond the cuff

The role of beta-blockers in uncomplicated hypertension has been challenged recently. Compared with other antihypertensives, beta-blockers are less effective for preventing cardiovascular events in patients with uncomplicated hypertension. Moreover, a recent meta-analysis of placebo-controlled clinical trials concluded that atenolol is not more efficacious than placebo for preventing cardiovascular events in patients with hypertension. Although these agents lower blood pressure measured conventionally over the brachial artery with a blood pressure cuff, they do not exert a commensurate effect on blood pressure in the central aorta. Central aortic blood pressure and aortic augmentation index are strong predictors of left ventricular hypertrophy, an independent risk factor for cardiovascular events. Emerging data are illuminating the antihypertensive paradox whereby antihypertensive agents may elicit discordant effects on central and peripheral blood pressure and hemodynamics. Vasodilatory antihypertensives, such as renin-angiotensin-aldosterone system inhibitors and calcium channel blockers, elicit reductions in central aortic blood pressure equal to or greater than that in the brachial artery. Conversely, beta-blockers lower central aortic blood pressure to a lesser degree even when blood pressure measured by sphygmomanometry is reduced substantially. Given the strong relationship between central aortic blood pressure and target organ damage, the effectiveness of beta-blockers may be overestimated in practice on the basis of conventional blood pressure measurements alone. Differences in central and peripheral blood pressure may account for the lack of cardiovascular protection afforded by beta-blockers in clinical trials and could account for a portion of the apparent "benefit beyond blood pressure" reduction with other classes of antihypertensive agents. Future studies should aim to better clarify the role of central aortic blood pressure in the treatment of hypertension. In the meantime, the effects of antihypertensive drugs on blood pressure "beyond the brachial blood pressure cuff" should be considered when prescribing antihypertensive agents for a patient.     

Eprosartan for the treatment of hypertension

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT₁) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT₁ receptors (postsynaptically) and at presynaptic AT₁ receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.     

Eprosartan for the treatment of hypertension

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT(1)) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT(1) receptors (postsynaptically) and at presynaptic AT(1) receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.     

Nebivolol: a review

Nebivolol is a vasodilating beta-blocker, which can be distinguished from other beta-blockers by its haemodynamic profile. It combines beta-adrenergic blocking activity with a vasodilating effect mediated by the endothelial L-arginine nitric oxide (NO) pathway. The blood pressure lowering effect of nebivolol is linked to a reduction in peripheral resistance and an increase in stroke volume and preservation of cardiac output. The effects of nebivolol have been compared with other beta-blockers and also with other classes of antihypertensive agents. In general, response rates to treatment are higher and the frequency and severity of adverse events are either comparable or lower with nebivolol. Endothelium-derived NO is important in the regulation of large arterial stiffness, which in turn is a major risk factor for cardiovascular disease. Therefore, antihypertensive drugs, such as nebivolol, that also improve endothelial function and decrease arterial stiffness, may contribute to a reduction in cardiovascular risk.     

Sexual dysfunction in male patients with hypertension: influence of antihypertensive drugs

Evidence suggests that arterial hypertension, in addition to being a cardiovascular and renal risk factor, may also be associated with an impairment of male sexual function. Since other cardiovascular risk factors, especially diabetes mellitus, have also been shown to correlate with impaired sexual function it has been proposed that sexual and especially erectile dysfunction may, at least in part, represent just another manifestation of atherosclerotic vascular disease. In addition to hypertension itself, sexual function in male hypertensive patients may also be affected by antihypertensive drug treatment. Available evidence suggests that centrally acting sympatholytic agents, beta-adrenoceptor antagonists (beta-blockers) and diuretics may have the potential to further impair sexual function. Calcium channel antagonists and ACE inhibitors may be neutral with respect to this endpoint. Preliminary data from several randomised and open studies have suggested that angiotensin II (AT)(1)-receptor antagonists may even be associated with an improvement of sexual function. However, many aspects of the interaction between hypertension, antihypertensive drug treatment and male sexual function remain unclear. Among other factors, the relative contribution of disease labelling both to the higher incidence of sexual dysfunction in hypertensive versus normotensive males and to the negative impact of treatment remains an open question. Furthermore, dose dependence of the observed effects of antihypertensive agents on sexual function, the role of combination therapy and the anticipation of proposed adverse effects of treatment are unresolved issues. Thus, more data from studies of high quality using standardised definitions and procedures are urgently needed to at least partially resolve some of the many open questions.     

Renal protection in hypertensive patients: selection of antihypertensive therapy

Hypertension is common in chronic renal disease and is a risk factor for the faster progression of renal damage, and reduction of blood pressure (BP) is an efficient way of preventing or slowing the progression of this damage. International guidelines recommend lowering BP to 140/90 mm Hg or less in patients with uncomplicated hypertension, and to 130/80 mm Hg or less for patients with diabetic or chronic renal disease. The attainment of these goals needs to be aggressively pursued with multidrug antihypertensive regimens, if needed. The pathogenesis of hypertensive renal damage involves mediators from various extracellular systems, including the renin-angiotensin system (RAS). Proteinuria, which occurs as a consequence of elevated intraglomerular pressure, is also directly nephrotoxic. As well as protecting the kidneys by reducing BP, antihypertensive drugs can also have direct effects on intrarenal mechanisms of damage, such as increased glomerular pressure and proteinuria. Antihypertensive drugs that have direct effects on intrarenal mechanisms may, therefore, have nephroprotective effects additional to those resulting from reductions in arterial BP. Whereas BP-lowering effects are common to all antihypertensive drugs, intrarenal effects differ between classes and between individual drugs within certain classes. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have beneficial effects on proteinuria and declining renal function that appear to be mediated by factors additional to their effects on BP. These RAS inhibitors are recommended as a first-line antihypertensive approach in patients with chronic kidney disease. The addition of diuretics and calcium channel antagonists to RAS inhibitor therapy is also considered to be a rational strategy to reduce BP and preserve renal function. Calcium channel antagonists are a highly heterogeneous class of compounds, and it appears that some agents are more suitable for use in patients with chronic renal disease than others. Manidipine is a third-generation dihydropyridine (DHP) calcium channel antagonist that blocks both L and T-type calcium channels. Unlike older-generation DHPs, which preferentially act on L-type channels, manidipine has been shown to have beneficial effects on intrarenal haemodynamics, proteinuria and other measures of renal functional decline in the first clinical trials involving hypertensive patients with chronic renal failure. Preliminary results from a trial in diabetic patients who had uncontrolled hypertension and microalbuminuria despite optimal therapy with an ACE inhibitor or an ARB suggest that manidipine may be an excellent antihypertensive drug in combination with RAS inhibitor treatment in order to normalise BP and albumin excretion in patients with diabetes.     

Stroke prevention with losartan in the context of other antihypertensive drugs

Several large clinical trials have demonstrated that successful control of blood pressure decreases the incidence of strokes. Also, drugs that stimulate the production of angiotensin II, such as diuretics, calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs), provide additional stroke reduction than drugs that suppress angiotensin II production such as beta-blockers and angiotensin converting enzyme (ACE) inhibitors. Since the stroke-protective effect of angiotensin II is mediated through stimulation of the AT2 receptors, drugs that selectively block the AT1, such as the ARBs, provide greater stroke protection than the other antihypertensive drugs. The blockade of the AT1 receptors lessens local brain ischemia, whereas the stimulation of the AT2 receptors increases local blood flow through recruitment of collateral vessels. Among the ARBs, losartan possesses certain unique properties not shared by other members of its class, which enhance its stroke-protective effects. These include the prevention of platelet adhesiveness and aggregation and the decrease of serum uric acid levels, which both lead to reduction in cardiovascular and cerebrovascular events. (     

Calcium-channel blockers for treatment of diabetic nephropathy.

The use of calcium-channel blockers (CCBs) to reduce proteinuria associated with nephropathy in patients with diabetes mellitus is discussed. Metabolically induced damage to the nephrons in diabetic nephropathy decreases the filtration rate and increases the glomerular plasma flow rate and transcapillary hydraulic pressure. Microalbuminuria, which is predictive of nephropathy in patients with insulin-dependent diabetes mellitus, is associated with the development of clinical proteinuria and increased mortality. Micro-albuminuria should be evaluated periodically in diabetic patients, and antihypertensive therapy should be initiated when proteinuria is present or blood pressure control is needed. CCBs lower blood pressure because they prevent the action of angiotensin II by blocking the entry of calcium into renal vascular smooth muscle. Some CCBs, such as diltiazem and nicardipine, decrease glomerular pressure by increasing efferent arteriolar dilation. Others, such as nifedipine, may dilate both the afferent and efferent arterioles, thus causing increased excretion of protein. Studies in patients with diabetic nephropathy have shown that individual CCBs vary in their effects on proteinuria; this variation is attributable to their different sites of action and different effects on intrarenal activity. The choice of a CCB or an angiotensin-converting-enzyme inhibitor should be based on concomitant disease states and adverse-effect profiles. For control of hypertension in patients with diabetic nephropathy, diltiazem should be considered initially. Nicardipine is effective for short-term use but has not been tested in long-term studies; it should be considered a reasonable alternative.     

A practical guide to the management of hypertension in renal transplant recipients

Hypertension as well as hypotension can be harmful to a newly transplanted renal allograft. Elevated blood pressure is also a major risk factor for cardiovascular death, which is a frequent occurrence despite successful renal transplantation. Renal artery stenosis, immunosuppressive drugs, chronic rejection, retained native kidneys, and excessive extracellular fluid volume may all contribute to post-transplant hypertension. Antihypertensive agents are widely used in the management of post-transplant hypertension. Careful clinical judgement and knowledge of the pharmacology, pharmacodynamics, pharmacokinetics, adverse drug reaction profiles, potential contraindications, and drug-drug interactions of antihypertensive agents are important when therapy with antihypertensive drugs is initiated in renal transplant recipients. Since blood pressure elevation in any individual is determined by a large number of hormonal and neuronal systems, the effect of antihypertensive agents on the allograft should be considered a critical factor in the management of hypertension in renal transplant recipients. Most renal transplant recipients have other risk factors for premature cardiovascular death such as diabetes mellitus, hypercholesterolemia, insulin resistance, obesity, left ventricular hypertrophy and ischaemic heart disease. Initial antihypertensive therapy should be tailored individually according to the patient's risk factors. A realistic therapeutic goal for blood pressure management in the initial post-operative state is a systolic blood pressure <160 mm Hg and a diastolic blood pressure <90 mm Hg with lower pressure targets becoming applicable late post-transplantation.