Hemodynamic and neuroendocrine response to acute administration of the phosphodiesterase inhibitor BM 14.478 in patients with congestive heart failure

Abstract

: The benzimidazol analogue BM 14.478 is a phosphodiesterase inhibitor with both vasodilator and positive inotropic properties. Hemodynamic parameters and plasma hormone levels of 8 patients (1 female, 7 male) with chronic congestive heart failure NYHA Classes II‐IV (1 patient with coronary artery disease, 7 patients with primary dilated cardiomyopathy) were assessed before and until 6 h after the intravenous application of 1.0 mg BM 14.478. There was a significant decrease of mean pulmonary artery pressure (28±11 vs. 23±11 mmHg; p>0.05), mean right atrial pressure (8.6±5.2 vs. 5.0±4.7 mmHg; p>0.02), and systemic vascular resistance (1651±484 vs. 1206±252 dynes$$s$$cm–5; p>0.05) as early as 10 min after injection of BM 14.478. Pulmonary vascular resistance also was reduced (128±86 vs. 61±39 dynes$$s$$cm–5, 30 min after injection; p>0.02). Simultaneously there was a significant increase of cardiac index (2.3±0.7 vs. 3.1±0.8 1$$min–5$$m–2, 10 min after injection; p>0.02), and stroke volume index (28.8±11.7 vs. 33.9±8.5 ml$$min–1$$m–2; 30 min after injection; p>0.05). Although mean heart rate did not change significantly, some patients reacted with a transient increase. There was also a slight but insignificant increase of the double product. No serious side effects were observed. The hemodynamic improvement was followed by a delayed reduction of plasma levels of epinephrine (51±20 vs. 41±21 pg/ml; p>0.02; 30 min after injection) and atrial natriuretic peptide (229±283 vs. 121±168 pg/ml; p>0.05; 1 h after injection). Mean levels of plasma norepinephrine, however, did not change significantly and individual responses showed large variations, which could not be predicted by the behavior of the hemodynamic parameters. Three of eight patients (2 of these with elevated baseline filling pressures) even showed a marked increase of plasma norepinephrine levels after BM 14.478. Response of plasma renin activity and plasma vasopressin levels to BM 14.478 also was heterogeneous. According to the results of this study, acute administration of the phosphodiesterase inhibitor BM 14.478 has an immediate beneficial hemodynamic effect in patients with severe congestive heart failure by reducing both preload and afterload, and by increasing cardiac index and stroke volume. However, this improvement of hemodynamic parameters is not necessarily accompanied by a favorable short‐term response of plasma hormones, and therefore does not allow any conclusions on survival of these patients.

Risk of Heart Failure Hospitalization Associated With Cilostazol in Diabetes: A Nationwide Case–Crossover Study

“…On the other hand, elevated cAMP levels enables L-type Ca2+ channels and a component of a delayed-rectifier potassium channel signal transduction pathway in the sinoatrial node (Kodama-Takahashi et al, 2003). Therefore, drugs that inhibit PDE 3 pathways would cause a positive chronotropic effect and inotropic action which have been demonstrated to increase left ventricular ejection fraction and stroke volume (Baim et al, 1983; Jaski et al, 1985; Rauch et al, 1991). However, clinical studies [such as the Prospective Randomized Milrinone Survival Evaluation (PROMISE) (Packer et al, 1991) and the Vesnarinone trial (VEST) (Feldman et al, 1993) studies] have evaluated the long-term effects of PDE 3 administration in congestive HF patients and reported increased cardiovascular mortality.…”

Effects of cilostazol in the heart

“…The binding of this increased cytoplasmic Ca 2þ concentration to troponin C activates actin-myosin cross-bridge formation, thus, eliciting the contractile function [25]. In many studies, the benefits of inotropic action of PDE3 inhibitors such as amrinone, enoximone and milrinone in chronic heart failure patients have been demonstrated, for example, the reduction of left ventricular end-diastolic pressure and the increase in ejection fraction and stroke volume [26][27][28][29][30][31]. It has been observed that the use of PDE3 inhibitors actually produce desirable effects in the short term, however, deleterious effects arise over time [26][27][28].…”