Inhibiting the renin-angiotensin-aldosterone system through the use of angiotensin-converting enzyme (ACE) inhibitors has proven very useful in the treatment of hypertension, congestive heart failure (CHF) and progressive renal failure. More recently, agents that directly block the angiotensin II Type 1 (AT1) receptor – angiotensin II receptor antagonists (AIIRAs) – have been developed. These agents are thought to have a more specific mechanism of action since they do not affect other hormone systems as do the ACE inhibitors. Whether such specificity results in a different efficacy profile is still being determined. However, these drugs are extremely well-tolerated and very safe. AIIRAs are effective in the reduction of both systolic and diastolic blood pressure and compare favourably to other classes of agents. Recent results indicate that at least one AIIRA has a favourable effect on stroke in hypertensive patients with left ventricular hypertrophy. Additional studies with other members of the class will provide further information on similar outcomes. In CHF patients, ACE inhibitors remain the drug of choice and AIIRAs are best utilised in patients who cannot tolerate an ACE inhibitor or in those receiving an ACE inhibitor who cannot tolerate a β-blocker and need additional therapy. AIIRAs are effective in slowing the progression of renal failure in patients with Type II diabetes and may be effective in other proteinuric conditions. Whether they are more or less effective than ACE inhibitors is unknown. Overall, AIIRAs represent an important addition to the armamentarium of cardiovascular therapies with an excellent safety record and an emerging profile of utility in multiple cardiovascular conditions.

BACKGROUND:Endothelin is a potent vasoconstrictor that has been implicated in the pathogenesis of radiocontrast nephrotoxicity. Endothelin antagonists may reduce the renal hemodynamic abnormalities following radiocontrast administration.METHODS:One hundred fifty-eight patients with chronic renal insufficiency [mean serum creatinine +/- SD = 2.7 +/- 1.0 mg/dL (242. 3 to +/- 92.8 micromol/L)] and undergoing cardiac angiography were randomized to receive either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. All patients received intravenous hydration with 0.45% saline before and after radiocontrast administration. Serum creatinine concentrations were measured at baseline, 24 hours, 48 hours, and 3 to 5 days after radiocontrast administration. The primary end point was the mean change in serum creatinine concentration from baseline at 48 hours; the secondary end point was the incidence of radiocontrast nephrotoxicity, defined as an increase in serum creatinine of > or =0.5 mg/dL (44 micromol/L) or > or = 25% from baseline within 48 hours of radiocontrast administration.RESULTS:The mean increase in serum creatinine 48 hours after angiography was higher in the SB 209670 group [0.7 +/- 0. 7 mg/dL (63.5 +/- 58.6 micromol/L)] than in the placebo group [0.4 +/- 0.6 mg/dL (33.6 +/- 55.1 micromol/L), P = 0.002]. The incidence of radiocontrast nephrotoxicity was also higher in the SB 209670 group (56%) compared with placebo (29%, P = 0.002). This negative effect of SB 209670 was apparent in both diabetic and nondiabetic patients. Adverse effects, especially hypotension or decreased blood pressure, were more common in the SB 209670 group.CONCLUSIONS:In patients with chronic renal insufficiency who were undergoing cardiac angiography, endothelin receptor antagonism with SB 209670 and intravenous hydration exacerbate radiocontrast nephrotoxicity compared with hydration alone.

We retrospectively performed stepwise logistic regression analysis on 1,509 patients with chronic heart failure in 4 multicenter United States studies and 1 Australia-New Zealand study to examine the effect of digoxin in patients randomized to carvedilol or placebo. Patients receiving digoxin had more advanced heart failure, the incidence of hospitalization for any cause and the combination of all-cause death and all-cause hospitalization were the same in the digoxin versus no-digoxin groups.

Angiotensin-converting enzyme inhibitors have been used extensively in the management of hypertension and related cardiovascular conditions. However, this treatment approach is limited by lack of specificity and continued production of angiotensin II by other routes. Antagonism of the angiotensin II receptor offers the possibility of improved control of hypertension by providing a more complete blockade of the renin-angiotensin system than angiotensin-converting enzyme inhibition without bradykinin-related effects. Eprosartan is the only nonbiphenyl, nontetrazole competitive angiotensin II receptor antagonist clinically available and is highly selective for the AT1 receptor subtype. In clinical trials, eprosartan has been shown to lower blood pressure effectively in a once-daily regimen in hypertensive patients. In the recommended dose range of 600 to 1200 mg once daily, eprosartan is effective in patients with all grades of hypertension irrespective of age, sex, or race. Furthermore, the tolerability profile of eprosartan is comparable to that of placebo, and there are no known clinically relevant drug-drug interactions. A number of large-scale clinical studies are currently underway or planned to determine which of the increasing number of AT1 receptor antagonists may reduce cardiovascular morbidity and mortality rates in different groups of hypertensive patients. Meanwhile, current evidence suggests that the AT1 receptor antagonists represent a significant new approach to cardiovascular therapy and merit a fuller assessment in hypertension and other cardiovascular diseases.

Introduction: Carvedilol, a chiral compound possessing nonselective β- and α1-blocking activity, is used for the treatment of hypertension and congestive heart failure (CHF). The enantiomers of carvedilol exhibit similar α1-blocking activity; only S-carvedilol possesses β-blocking activity. Carvedilol is primarily hepatically metabolized, with less than 2% of the dose excreted renally as unchanged drug.

BACKGROUND The beta-blocker/vasodilator carvedilol is found to have beneficial effects in patients with chronic heart failure. However, the safety and efficacy of this agent in the presence of concomitant amiodarone therapy has not been previously determined. METHODS AND RESULTS We retrospectively analyzed the Australia/New Zealand Carvedilol Heart Failure Research Collaborative Group study of 415 patients with mild to moderate ischemic heart failure where amiodarone was administered as part of the treatment therapy (in 52 patients). After the open-label carvedilol run-in, patients received carvedilol (target dose 25 mg twice daily) or placebo for an average of 19 months. The main adverse events during this double-blind period were worsened heart failure, hypotension/dizziness, bradycardia/atrioventricular block, and aggravation of angina. By Chi square analysis, carvedilol and amiodarone together were not associated with a greater overall incidence of adverse effects than either drug alone. The beneficial effects of carvedilol on left ventricular ejection that were observed in the main trial were preserved in the presence of amiodarone. CONCLUSIONS Carvedilol is a useful additional therapy for patients with chronic heart failure already receiving amiodarone. Carvedilol can be added to amiodarone in these patients without expectation of increased adverse effects or loss of clinical efficacy.

BACKGROUND:We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a "third-generation" beta -blocking agent with vasodilator properties, in chronic heart failure.METHODS AND RESULTS:Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, and high-dose carvedilol groups, respectively, compared with 2 EF units with placebo, P < .001 for linear dose response) and survival (respective crude mortality rates of 6.0%, 6.7%, and 1.1% with increasing doses of carvedilol compared with 15.5% in the placebo group, P < .001). When the three carvedilol groups were combined, the all-cause actuarial mortality risk was lowered by 73% in carvedilol-treated subjects (P < .001). Carvedilol also lowered the hospitalization rate (by 58% to 64%, P = .01) and was generally well tolerated.CONCLUSIONS:In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose-related reductions in mortality and hospitalization rate.

Of 13 chronic hemodialysis end-stage renal disease (ESRD) patients undergoing open-heart surgery, 7 received intraoperative hemodialysis (IHD) during cardiopulmonary bypass and 6 received hemodialysis on a routine basis (RHD). Within the groups, IHD patients had significantly lower post-operative mean serum potassium and mean plasma creatinine concentrations compared to mean preoperative values. Postoperative mean BUN tended to decrease and mean serum bicarbonate concentration was unchanged as compared to mean preoperative values. In the RHD group, however, post-operative mean serum potassium concentration tended to increase, mean serum bicarbonate concentration significantly declined and mean BUN was unchanged as compared to mean preoperative values. An average of 2.1 +/- 0.5 liters of fluid was removed from the IHD patients during cardiopulmonary bypass. Post-operatively, 0 of 7 IHD patients versus 4 of 6 RHD patients required parenteral sodium bicarbonate therapy (chi-2, p < 0.01). On average, RHD patients required hemodialysis 1 day after surgery, whereas IHD patients were hemodialyzed 2 days after surgery (p = 0.009). We conclude that IHD lessened postoperative hyperkalemia and metabolic acidosis and delayed postoperative hemodialysis by an additional day. IHD should be considered as an adjunct to RHD therapy in the management of ESRD patients undergoing open-heart surgery.

Cyclosporine causes renal vasoconstriction and reduced renal blood flow that may contribute to chronic nephrotoxicity. This effect has not been consistently reversed by available pharmacologic agents. The efficacy of orally administered fenoldopam, a dopamine-1 (DA-1) agonist with renal vasodilator properties, was evaluated in six patients whose condition was stable 3 to 6 months following renal transplantation. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and p-aminohippurate (PAH) clearances, respectively, at baseline, after the acute oral administration of 100 mg of fenoldopam, and following 3 weeks of chronic oral fenoldopam therapy (100 mg thrice daily). Mean ERPF increased from 3.15 ± 0.17 mL/s/1.73 m2 (189 ± 10 mL/min/1.73 m2) at baseline to 3.48 ± 0.17 mL/s/1.73 m2 (209 ± 10 mL/min/1.73 m2) 4 hours after acute administration of fenoldopam (P = 0.04). Urine flow rate and fractional excretion of sodium also increased after acute administration, but not significantly. Mean systolic (SBP) and diastolic blood pressure (DBP) decreased maximally by 18 and 6 mm Hg, respectively, and mean pulse rate increased maximally by 8 bpm between 75 and 90 minutes after both acute and chronic administration. GFR was unchanged following both acute and chronic administration. The increase in ERPF was not maintained to the end of the dosing interval during chronic administration, probably due to the short half-life of fenoldopam, However, the renal vasodilatory response was still observed 3 to 4 hours after readministration of the drug following 3 weeks of oral dosing. Thus, fenoldopam significantly reverses the renal vasoconstriction caused by cyclosporine in renal transplant recipients. Further evaluation of fenoldopam in preventing cyclosporine-induced nephrotoxicity appears warranted.