eprosartan and Kidney-Diseases

Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Humans; Hypertension; Imidazoles; Kidney Diseases; Renin-Angiotensin System; Sympathetic Nervous System; Thiophenes

It is clear that the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) play key roles in sustaining elevated blood pressure, subsequently resulting in increased risks of cardiovascular (CV), cerebrovascular and kidney disease. Modifying these systems with antihypertensive agents has led to the discovery that their effects may indeed extend beyond controlling blood pressure. Within blood vessels, angiotensin II type 1 receptor blockers (ARBs) inhibit postsynaptic angiotensin II type 1 receptors (AT1). The ARB eprosartan, in contrast to other ARBs, also inhibits prejunctional AT1 receptors, which regulate noradrenaline release. The positive effects of eprosartan on blood pressure have been studied extensively, and are due to modulation of both the RAS and the SNS (through stimulation of the angiotensin II type 2 [AT2] receptor). Of importance to isolated systolic hypertension, trough sitting systolic blood pressure (SBP) is also significantly reduced with eprosartan. In addition, many studies have shown how the benefits of eprosartan go beyond that of blood pressure control alone. Eprosartan has shown positive effects on vascular inflammation and resistance to oxidation and/or modification of low-density lipoprotein. A wealth of other positive actions are associated with eprosartan treatment, including effects on platelet aggregation, kidney function and structure, progressive left ventricular dysfunction and central SBP. Clinical studies have clearly demonstrated the benefits of RAS blockade alongside the additional effects beyond blood pressure control with eprosartan treatment. These data place eprosartan as an effective agent to prevent CV, cerebrovascular and renal complications associated with high blood pressure.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atherosclerosis; Humans; Imidazoles; Kidney Diseases; Platelet Aggregation; Renin-Angiotensin System; Sympathetic Nervous System; Thiophenes; Ventricular Dysfunction, Left

The ARBs are a new class of drugs with broad therapeutic potential in cardiovascular disease. These agents act by selectively inhibiting the AT1 subtype of the angiotensin II receptors. They are effective antihypertensive agents with promise, theoretically, in the prevention and regression of ventricular hypertrophy. They are safe and well tolerated in patients with CHF and might be effective in improving survival and reducing morbidity. ARBs also might have a similar role in improving the clinical outcomes of patients with coronary artery disease and chronic nephropathy. Their precise role in the treatment and prevention of cardiovascular and renal disease should be established by several ongoing clinical trials.

Topics: Acrylates; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biological Availability; Biphenyl Compounds; Cardiovascular Diseases; Humans; Imidazoles; Irbesartan; Kidney Diseases; Losartan; Metabolic Clearance Rate; Patient Selection; Renin-Angiotensin System; Telmisartan; Tetrazoles; Thiophenes; Treatment Outcome; Valine; Valsartan

Topics: Acrylates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Diuretics; Dizziness; Drug Combinations; Drug Interactions; Heart Failure; Humans; Hypertension; Imidazoles; Irbesartan; Kidney Diseases; Losartan; Olmesartan Medoxomil; Telmisartan; Tetrazoles; Thiophenes; Valine; Valsartan

The effects of the angiotensin type 1 (AT(1)) receptor antagonist, eprosartan, were studied in a model of severe, chronic hypertension. Treatment of male spontaneously hypertensive stroke prone rats (SHR-SP) fed a high-fat, high-salt diet with eprosartan (60 mg/kg/day i.p.) for 12 weeks resulted in a lowering of blood pressure (250 +/- 9 versus 284 +/- 8 mm Hg), renal expression of transforming growth factor-beta mRNA (1.5 +/- 0.2 versus 5.4 +/- 1.4) and the matrix components: plasminogen activator inhibitor-1 (5.2 +/- 1.4 versus 31.4 +/- 10.7), fibronectin (2.2 +/- 0.6 versus 8.2 +/- 2.2), collagen I-alpha 1 (5.6 +/- 2.0 versus 23.8 +/- 7.3), and collagen III (2.7 +/- 0.9 versus 7.6 +/- 2.1). Data were corrected for rpL32 mRNA expression and expressed relative to Wistar Kyoto (WKY) rats [=1.0]. Expression of fibronectin protein was also lowered by eprosartan (0.8 +/- 0.1 versus 1.9 +/- 0.5), relative to WKY rats. Eprosartan provided significant renoprotection to SHR-SP rats as measured by decreased proteinuria (22 +/- 2 versus 127 +/- 13 mg/day) and histological evidence of active renal damage (5 +/- 2 versus 195 +/- 6) and renal fibrosis (5.9 +/- 0.7 versus 16.4 +/- 1.9) in vehicle- versus eprosartan-treated rats, respectively. Our results demonstrated that AT(1) receptor blockade with eprosartan can reduce blood pressure and preserve renal structure and function in this model of severe, chronic hypertension. These effects were accompanied by a decreased renal expression of transforming growth factor-beta1, plasminogen activator inhibitor-1, and several other extracellular matrix proteins compared with vehicle-treated SHR-SP.

Topics: Acrylates; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Blotting, Western; Body Weight; Dietary Fats; Disease Progression; Extracellular Matrix; Fibrinolysin; Gene Expression Regulation; Heart Rate; Hypertension; Imidazoles; Kidney Diseases; Male; Organ Size; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Serine Proteinase Inhibitors; Sodium Chloride, Dietary; Stroke; Thiophenes; Thrombosis

The role of ANG II on renal and cardiac gene expression of matrix proteins was studied in rats with progressive renal disease. Induction of renal failure by five-sixths nephrectomy of Sprague-Dawley rats resulted in hypertension (163 +/- 19 vs. control pressures of 108 +/- 6 mmHg), proteinuria (83 +/- 47 vs. 14 +/- 2 mg/day), and increased renal expression of fibronectin, thrombospondin, collagen I and III, transforming growth factor-beta (TGF-beta), and plasminogen activator inhibitor-1 (PAI-1) mRNA. Treatment with the ANG II receptor antagonist, eprosartan (60 mg. kg(-1).day(-1)), lowered blood pressure (95 +/- 5 mmHg) and proteinuria (19 +/- 8 mg/d) and abrogated the increased TGF-beta, fibronectin, thrombospondin, collagens I and III, and PAI-1 mRNA expression. An increase in left ventricular weight was observed in five-sixths nephrectomized rats (0.13 +/- 0.01 vs. 0.08 +/- 0.01 g/100 g body wt), a response that was inhibited by eprosartan treatment (0.10 +/- 0.01 g/100 g). Left ventricular expression of TGF-beta and fibronectin was also increased in rats with renal disease; however, the small decreases in expression observed in eprosartan-treated rats did not reach statistical significance. These data suggest that eprosartan may be beneficial in progressive renal disease and that the mechanism of action includes inhibition of cytokine production in addition to antihypertensive activity.

Topics: Acrylates; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Gene Expression Regulation; Hypertension; Imidazoles; Kidney Diseases; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Thiophenes