Direct selective blockade of the vascular angiotensin II receptors in therapy for hypertension and severe congestive heart failure.

ACEIs are widely prescribed antihypertensives and have become the mainstay of therapy for severe CHF. Nevertheless, a focused AII-receptor blockade has compelling intellectual appeal and substantial clinical advantages over the ACEIs (no disruption of the prostaglandin and bradykinin biosystems). Identification and careful characterization of the AII receptors and the recent discovery of their antagonists has led to the extensive clinical investigation of selective AII-receptor blockers in both hypertension and severe CHF. Studies with the first orally active AII-receptor blocker, losartan, have demonstrated safe and effective control of elevated blood pressure and improvement of the abnormal hemodynamics typical of pronounced CHF. Several other oral AII-receptor blockers are currently being evaluated, and early results with these agents are encouraging.

Placebo-controlled evaluation of three doses of a controlled-onset, extended-release formulation of verapamil in the treatment of stable angina pectoris.

This double-blind, placebo-controlled, parallel-group, multicenter study was designed to evaluate the safety and efficacy of a new controlled-onset, extended-release formulation of verapamil hydrochloride called physiologic pattern release (PPR) verapamil. The study was conducted at 24 sites (13 United States, 5 Canada, 6 overseas; see Appendix). Following a 1- to 3-week single-blind placebo lead-in period, 278 patients with chronic stable angina pectoris (247 males, 31 females, mean age 60.8 years, range 32 to 78) were randomly assigned to 1 of 4 once-daily, fixed-dose treatment groups: verapamil 180, 360, or 540 mg, or placebo. PPR verapamil at all doses significantly increased (p < 0.05) time to moderate angina and symptom-limited exercise duration, and verapamil 360 mg significantly increased (p < 0.05) time to > or = 1 mm ST-segment depression, after 4 weeks of treatment when assessed 24 hour after the previous dose. Larger doses of verapamil were associated with proportionately greater improvements in exercise tolerance. Frequency of anginal attacks was also reduced by verapamil. The most frequently observed adverse events were dizziness, headache, constipation, and nausea. The incidence of constipation was high (20.9%) within the 540 mg treatment group. This verapamil formulation can be clinically titrated within a 180 to 540 mg dosing range, permitting effective once-daily administration for the treatment of chronic stable angina.

Amlodipine combined with beta blockade for chronic angina: results of a multicenter, placebo-controlled, randomized double-blind study.

Amlodipine, a potent long-acting dihydropyridine calcium antagonist, was compared with placebo in a parallel, randomized, double-blind study in 134 patients with chronic stable angina pectoris maintained on beta-adrenergic blocking agents. After a single-blind, two-week placebo period, patients were randomized to receive either amlodipine (2.5, 5, and 10 mg) or placebo once daily for four weeks. The effects of amlodipine on maximal exercise time, work, time to angina onset, and subjective indices including angina frequency, nitroglycerin tablet consumption, and patient and investigator ratings were assessed. Each dose of amlodipine produced increases in exercise time and calculated total work accomplished compared to baseline. Improvements at 5 and 10 mg were significantly greater than placebo which produced no significant change (p less than 0.05). Qualitative improvements in the severity of angina were produced by amlodipine at 5 and 10 mg daily assessed by patient-rating questionnaires (p less than 0.05). Reductions in angina frequency attacks per week and weekly nitroglycerin tablet consumption occurred but were not statistically significant when compared with placebo. Adverse effects observed during amlodipine treatment prompted discontinuation of treatment in only 2 out of 100 patients. Three patients discontinued treatment for reported lack of efficacy. No laboratory abnormalities prompted treatment discontinuation and minor side effects of dizziness, nausea, headache, and fatigue were observed infrequently. The results of this controlled, large-scale multicenter trial suggest that amlodipine significantly increased exercise capacity and was well tolerated when added to the antianginal regimen of patients remaining symptomatic while receiving beta-blocking agents.

A cooperative multicenter study of captopril in congestive heart failure: hemodynamic effects and long-term response.

The acute hemodynamic effects, long-term clinical efficacy, and safety of the oral angiotensin-converting enzyme inhibitor, captopril, were assessed in a multicenter cooperative study of 124 patients with heart failure resistant to digitalis and diuretics. The cardiac status of most patients was deteriorating prior to the study. Favorable acute hemodynamic effects consistently occurred with captopril. Maximal mean percentage increases in cardiac index, stroke index, and stroke work index were, respectively, 35%, 44%, and 34%. Systemic and pulmonary vascular resistances were each decreased by approximately 40%, as were the filling pressures of the right and left heart. Infusion of nitroprusside in some of the same patients to an end point of a pulmonary capillary wedge pressure of 12 to 18 mm Hg (equivalent to that after captopril) revealed no significant difference in the effect of either drug on the other hemodynamic parameters. Recatheterization after 8 weeks of captopril therapy revealed sustained hemodynamic changes. Significant and sustained improvements in clinical status were observed in most patients as measured by changes in New York Heart Association (NYHA) functional classification and exercise tolerance times. Seventy-nine percent of patients for whom there were adequate NYHA class data improved. Twenty percent remained unchanged and 1% deteriorated. Those patients who had both pretreatment and post-treatment exercise stress testing exhibited a highly significant mean increase in exercise tolerance times of 34% (317 +/- 32 seconds pretreatment to 425 +/- 34 seconds, final measurement). There was no evidence of tachyphylaxis over an 18-month period.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of combined nitroglycerin and dobutamine infusion in left ventricular dysfunction.

The immediate therapy of severe left ventricular (LV) failure after acute myocardial infarction (AMI) frequently requires simultaneous preload reduction, pump output augmentation, and maintenance of systemic blood pressure. Therefore the effects of intravenous nitroglycerin (NG) and dobutamine (DB) were evaluated in 12 patients with severe LV failure following AMI. Nitroglycerin achieved salutary lowering of abnormally elevated LV filling pressure (23 to 14 mm Hg, p less than 0.001) while DB markedly augmented LV pump function (cardiac index rose from 1.7 to 2.5 L/min/m2, p less than 0.005). Notably, the combined infusion of NG + DB simultaneously decreased preload (LV filling pressure 23 to 14 mm Hg, p less than 0.001) and markedly enhanced LV pump performance (cardiac index increased from 1.7 to 2.4 L/min/m2, p less than 0.001). Minor decline in mean systemic blood pressure with NG (72 to 66 mm Hg, p less than 0.05) was rapidly reversed by DB addition (69 mm Hg, p greater than 0.05). Both agents were well tolerated without clinical or ECG evidence of myocardial ischemia or dysrhythmias. Thus the principally venodilator effects of NG minimize systemic hypotension while salutary augmentation of cardiac function in AMI with LV failure is achieved by NG + DB.

Vasodilator therapy of severe congestive heart failure: the special importance of angiotensin-converting enzyme inhibition with captopril.

Successful ambulatory afterload reduction therapy of severe chronic congestive heart failure (CHF) required the extensive evaluation of hemodynamic effects of vasodilator agents, precise characterization of differential cardiocirculatory actions, and objective confirmation of extended salutary improvements of the heart failure state. This article describes results of a series of investigations with the angiotensin-converting enzyme (ACE) inhibitor captopril (CPT) in several patients with severe CHF. CPT causes predominant peripheral venodilation, resulting in marked decline in elevated left ventricular preload and modest augmentation of the depressed cardiac output. These hemodymanic effects of oral CPT are similar to the effects of nitroprusside and prazosin on increased ventricular preload, but the latter vasodilators cause greater rise in low cardiac pump output. Importantly, the beneficial cardiocirculatory action of oral CPT provided prolonged cardiac benefits with symptomatic improvements confirmed by objective enhancement in left ventricular function documented by cardiac catheterization, echocardiography, nuclear scintigraphy, and treadmill exercise. Thus, ACE inhibition with oral CPT successfully provides marked long-term augmentation of cardiac performance and clinical status in refractory CHF.

Comparative analysis of the hemodynamic actions of captopril and sodium nitroprusside in severe chronic congestive heart failure.

The hemodynamic actions of the systemic vasodilators parenteral sodium nitroprusside (NP) and oral captopril (CPT) were compared in 11 patients with severe chronic congestive heart failure (CHF). While two agents produced similar reductions in mean blood pressure (NP, 90 to 70 mm Hg vs CPT, 88 to 74 mm Hg, p greater than 0.05) and left ventricular (LV) filling pressure (NP, 27 to 14 mm Hg vs CPT, 24 to 15 mm Hg, p greater than 0.05), they produce disparate effects on LV pump performance. NP raised cardiac index 35% (2.0 to 2.7 L/min/m2, p less than 0.005), whereas CPT increased this index 16% (1.9 to 2.2 L/min/m2, p less than 0.001). Concomitantly, the 31% elevation of stroke index produced by NP (26 to 34 ml/beat/m2, p less than 0.001) was greater (p less than 0.05) than the 15% rise produced by CPT (26 to 30 ml/beat/m2, p less than 0.001). Simultaneously, stroke work index showed similarly greater augmentation, and total systemic vascular resistance declined more with NP. These findings suggest that oral CPT is a predominant ventricular preload-lowering agent primarily likely to improve dyspnea related to severe pulmonary congestion in patients with advanced chronic CHF.

Complementary combined captopril and terbutaline therapy in severe chronic congestive heart failure.

The hemodynamic effects of captopril (CPT) alone and in combination with the beta-adrenergic receptor agonist terbutaline (TBT) were evaluated in 10 patients with severe chronic congestive heart failure (CHF). The heart rate remained unchanged, while CPT lowered mean systemic blood pressure from 86 to 64 mm Hg (p less than 0.001) and decreased left ventricular filling pressure markedly from 27 to 19 mm Hg (p less than 0.001). The addition of TBT produced no further change in these variables (p greater than 0.05). Simultaneously, CPT augmented cardiac index (CI) from 2.1 to 2.9 L/min/m2 (p less than 0.001) and stroke index (SI) from 27 to 37 ml/beat/m2 (p less than 0.001). Concomitant CPT-TBT further raised CI to 3.2 L/min/m2 and SI to 40 ml/beat/m2 (both less than 0.001). Further, the CPT-effected decline in total systemic vascular resistance from 1577 to 841 dynes . sec . cm-5 (p less than 0.001) was not reduced additionally by CPT-TBT combination (p greater than 0.05). These results indicate than both CPT and TBT markedly augment cardiac function in CHF. Moreover, the salutary effects of the systemic vasodilator appear additive to the beneficial actions of the beta-adrenergic receptor agonist, thereby providing substantial augmentation of the function of the failing heart.

Long-term hemodynamic and clinical efficacy of captopril therapy in ambulatory management of severe chronic congestive heart failure.

The 6-month extended vasodilator efficacy of the oral angiotensin converting enzyme (ACE) inhibitor, captopril (CPT), was evaluated by sequential cardiac catheterization, nuclear scintigraphy, echocardiography, treadmill exercise, and symptomatology in nine patients with severe chronic left ventricular (LV) failure (CHF). CPT lowered LV filling pressure (from 23 to 14 mm Hg acutely (p less than 0.001) and to 14 mm Hg (p less than 0.01) with continuous 6-month therapy; concomitantly CPT raised cardiac index from 2.03 to 2.46 L/min/m2 initially (p less than 0.02) and to 2.33 L/min/m2 (p less than 0.02) at 6 months. Simultaneously CPT raised LV ejection fraction from 0.21 to 0.25 acutely (p less than 0.01) and to 0.30 (p less than 0.001) and to 60 mm (p less than 0.001) at 6 months. These beneficial actions of CPT on LV pump function raised treadmill exercise duration (from 339 to 426 seconds initially (p less than 0.05) and to 499 seconds (p less than 0.05) at 6 months, while considerably reducing CHF symptomatology (p less than 0.001). Thus ACE inhibition by CPT provides markedly beneficial sustained hemodynamic and clinical improvement in advanced LV failure without fluid accumulation or late vasodilator drug tolerance.

Cardiocirculatory actions of trimazosin and sodium nitroprusside in ischemic heart disease.

Although postload-reducing drugs are effective vasodilators in chronic congestive heart failure, the clinical application of the approach to ambulatory patient management remains difficult. We compared the hemodynamic effects of the new oral systemic vasodilator trimazosin (TZ) with those of nitroprusside (NP). Both TZ (172 mg) and NP (46 microgram/min) decreased mean blood pressure modestly (P less than 0.001), while causing considerable decline in elevated left ventricular filling pressure (TZ from 30 to 24 mm Hg; NP from 31 to 20 mm Hg; both P less than 0.001). TZ also raised the low cardiac index (CI) of 2.02 to 2.59 1/min/M2 (P less than 0.001), whereas NP elevated CI from 2.16 to 2.96 1/min/M2 (P less than 0.001). Both drugs lowered (P less than 0.05) total systemic vascular resistance and pressure time/minute while enhancing (P less than 0.01) stroke work index. The drugs diminished forearm venous tone (P less than 0.02) and forearm vascular resistance (P less than 0.01) concomitantly with elevation of forearm blood flow (P less than 0.05). Thus, TZ induced qualitatively similar marked augmentation of cardiac function to that by NP. These encouraging hemodynamic findings indicate that TZ may be beneficial to patients undergoing ambulatory vasodilator therapy of severe chronic congestive heart failure.

Assessment of oral quinidine effects on sinus node function in sick sinus syndrome patients.

The effects of therapeutic doses of orally administered quinidine sulfate on sinus rhythmicity and automaticity were observed in 11 patients with sick sinus syndrome (SSS). Evaluation of sinus node (SN) function was undertaken by assessing sinus nodal recovery time (SNRT), treadmill exercise testing, and 24-hour ambulatory ECG monitoring before and after quinidine administration (25 mg/kg) (range 800 to 1600 mg daily). Corrected SNRT ranged from 100 to 1320 msec (average 551) before quinidine and was not significantly (p greater than 0.05) altered after quinidine to 346 to 660 msec (average 481). Further, quinidine did not induce accelerated infrasinus pacemaker activity. Spontaneous sinus rate evaluated with ambulatory monitoring revealed average rate of 57 bpm (range 53 to 63) before quinidine without significant increase to average 59 bpm (range 52 to 80) after quinidine therapy. Similarly, the maximal SN response to exercise was not significantly affected by quinidine (average 129 bpm before and 129 bpm after drug therapy). It is concluded that therapeutic doses of quinidine do not exert adverse effects on SN function in SSS patients. Chronic oral quinidine therapy can therefore be used safely with caution in patients with chronic SN disease when indicated for control of tachyarrhythmias.

Importance of neuroendocrine regulators of vascular tone and integral adrenoreceptor interaction during oral vasodilator therapy of severe congestive heart failure with prazosin.

The cardiocirculatory actions of the oral vasodilator prazosin were evaluated by cardiac catheterization, forearm plethysmography, echocardiography, treadmill exercise, and symptoms in patients with advanced long-standing congestive heart failure. The administration of oral prazosin (2-7mg) reduced forearm venous tone and forearm vascular resistance. Concomitantly, mean systemic arterial pressure and left ventricular filling pressure decreased, and the cardiac index increased. These effects of a single dose of prazosin on left ventricular function were rapid in onset, maximal at 1 h, and sustained for the entire 6-h period of observation. After 2 weeks of outpatient therapy with 2-7 mg of prazosin four times daily, echographic end-diastolic dimension decreased, whereas the duration of treadmill exercise increased. Symptoms (dyspnea, fatigue, angina) were diminished throughout the course of prazosin therapy, and there was an improvement in the New York Heart Association functional class from 3.7 to 2.2. Thus, prazosin possesses sustained nitroprusside-like balanced dilator actions on the systemic arterial and venous beds, which are effectively translated into the beneficial hemodynamic effects of augmenting cardiac output and relieving excessive left ventricular end-diastolic pressure. The delayed vasodilator tolerance that occurs in 30% of the patients is prevented by the prior use of aldosterone antagonists, and is easily treated when present. Subacute hemodynamic suppression of beneficial prazosin vasodilator actions is transient and does not preclude successful sustained prazosin therapy of severe heart failure.

The hemodynamic actions of prenalterol in left ventricular failure.

The hemodynamic effects of prenalterol, a parenteral cardioselective beta 1-receptor agonist, were evaluated by cardiac catheterization in patients with refractory severe congestive heart failure (CHF). Prenalterol (PN) (4 mg i.v.) did not alter (p greater than 0.05) heart rate (HR), mean blood pressure (MBP) or left ventricular filling pressure (LVFP). Concomitantly PN markedly augmented cardiac index (CI) from 1.9 to 2.6 l/min/m2 (p less than 0.01) and substantially elevated stroke index (SI) from 24 to 30 ml/beta/m2 (p less than 0.001). In addition PN raised stroke work index (SWI) from 21 to 26 g . m/m2 (p less than 0.005) and decreased total systemic vascular resistance (TSVR) from 1702 to 1260 dyn . s. cm-5 (p less than 0.001). An important finding was that the heart rate x systolic blood pressure product was unchanged (p greater than 0.05) and precipitation of cardiac dysrhythmias or myocardial ischemia were not observed. Further PN 1 mg, 4 mg and 8 mg i.v. was sequentially injected and peak hemodynamic effects were determined 10 min after drug administration. PN 1 mg raised CI from 2.1 to 2.5 1/min/m2 (p less than 0.01), elevated SI from 24 to 29 ml/beat/m2 (p less than 0.01), and augmented SWI from 21 to 25 g . m/m2 (p less than 0.01), however, TSVR declined from 1702 to 1392 dyn . s. cm-5. Subsequent incremental PN doses of 4 and 8 mg did not provide (p greater than 0.05) additional enhancement of cardiac function. Thus, prenalterol produced markedly beneficial enhancement of cardiocirculatory function without untoward effects and may be useful in the management of patients with severe congestive heart failure. Moreover, dose-response analysis indicates these salutary improvements can be maximally produced by the small dose of 1 mg obviating the need for larger doses.

Cardiocirculatory and myocardial energetic effects of prostaglandin E1 in severe left ventricular failure due to chronic coronary heart disease.

The cardiocirculatory actions of brief (69 +/- 5 minutes) infusions of prostaglandin E1 were evaluated in nine chronic coronary heart disease patients with severe left ventricular (LV) failure caused by previous myocardial infarction. Prostaglandin E1 infusion did not alter heart rate (HR) and produced modest declines in mean systemic blood pressure (BP) (85 +/- 6 to 76 +/- 5 mm Hg, P less than 0.025) and LV filling pressure (19 +/- 3 to 15 +/- 2 mm Hg, P less than 0.01). Simultaneously, prostaglandin E1 augmented LV pump function raising cardiac index from 1.9 +/- 0.2 to 2.5 +/- 0.1 L/min/m2 (p less than 0.005), elevating stroke index from 28 +/- 2.4 to 35 +/- 2.9 ml/beat/m2 (p less than 0.01), and increasing stroke work index from 26 +/- 4.3 to 30 +/- 4.4 gm . m/m2 (p less than 0.02). Additionally, total systemic vascular resistance decreased from 1862 +/- 192 to 1282 +/- 100 dynes-sec-cm-5 (p less than 0.02) and double product LV aerobic index of HR . systolic BP diminished from 9492 +/- 666 to 8278 +/- 492 (p less than 0.02). Concomitantly, in the forearm, vascular resistance fell, blood flow rose, and venous tone remained unchanged. These results indicate that prostaglandin E1 is a potent systemic arteriolar dilator with markedly beneficial effects on cardiac function in chronic coronary patients having severe ischemic LV failure refractory to conventional therapy.