Controlled and uncontrolled studies of phosphodiesterase III inhibitors in contemporary cardiovascular medicine

The phosphodiesterase inhibitors are new inotrope vasodilators that have beneficial hemodynamic effects in patients with congestive heart failure (CHF). The most extensively studied agents are milrinone and enoximone. Both drugs have clearly been shown in numerous studies to improve hemodynamics in patients with CHF when given acutely by either the intravenous or oral route. In long-term studies, milrinone has been shown to have sustained beneficial hemodynamic effects during active treatment. Effects on exercise tolerance have been less clear-cut in several uncontrolled trials, but a recent large-scale randomized trial does show sustained improvement in exercise performance. When milrinone is withdrawn after long-term therapy, some studies show worsened cardiac performance; the exact cause remains ill-defined, but could be due to deterioration of baseline ventricular function or to "rebound." Both uncontrolled studies and a large recently reported randomized trial show that the hemodynamic response to readministration of milrinone after withdrawal is well-preserved, i.e., no tolerance is observed. Studies of enoximone show that its acute hemodynamic effects are similar to those of milrinone, but its long-term efficacy, using both hemodynamic and exercise end points, is less clear-cut, and no large-scale randomized trials of enoximone therapy have yet been reported. The studies of both these agents performed thus far indicate that the phosphodiesterase inhibitors have considerable promise for both acute and long-term treatment of patients with CHF.     

Beta blockade in the compensation for bed-rest cardiovascular deconditioning: physiologic and pharmacologic observations

Beta-adrenergic blockade using intravenous propranolol was evaluated as a countermeasure for bedrest-induced cardiovascular deconditioning. After propranolol administration, tolerance to a maximal lower body negative pressure (LBNP) test after bed rest improved to at least the -70 mm Hg level; following this, there was a sharp decrease in tolerance time. Propranolol decreased mean tolerance time by 36% (17.7 +/- 2.4 to 11.5 +/- 2.3 minutes) before bed rest, and by only half as much (16.6%) after bed rest (14.4 +/- 2.2 to 12.0 +/- 2.3 minutes). Systemic vascular resistance was maintained and even slightly increased after propranolol despite a decrease in cardiac output, indicating beta 2-adrenergic blockade. Heart rates at all levels of LBNP were lower during beta blockade, yet increases occurred with successive LBNP steps, both before and after bed rest, indicating withdrawal of parasympathetic nervous system influences. Results support the use of propranolol in small dosages as a countermeasure after bed rest, and the findings may also be extrapolated to space-flight deconditioning.     

Type 5 phosphodiesterase inhibitors in the treatment of erectile dysfunction and cardiovascular disease

Since the discovery of sildenafil in 1989 as a highly selective inhibitor of the phosphodiesterase type-5 (PDE-5) receptor, 2 additional PDE-5 inhibitors, tadalafil and vardenafil, have emerged as safe and effective treatments of erectile dysfunction (ED). Enzymes in the PDE family catalyze the hydrolysis of the intracellular signaling molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which is the second messenger of nitric oxide (NO) and a principal mediator of smooth muscle relaxation and vasodilation. Sildenafil was initially introduced for clinical use as the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Erection is largely a hemodynamic event, which is regulated by vascular tone and blood flow balance in the penis. Endothelial dysfunction, an early component of atherosclerosis, may inhibit a vascular event such as erection and is rarely confined to the arteries supplying blood to the penis, but more likely occurs throughout the vascular bed. In addition to the effects of the NO-cGMP signaling pathway on cavernosal smooth muscle, clinical findings have suggested that vascular tone in the pulmonary, coronary, and other vascular tissues expressed by PDE-5 is also influenced by this signal transduction mechanism. This has led to the emergence of novel therapeutic indications for sildenafil over a range of cardiovascular conditions that are either well-established risk factors or comorbidities with ED. Recently, the U.S. Food and Drug Administration approved sildenafil as an orally active therapy for the treatment of primary pulmonary hypertension. The drug will be marketed under the trade name of Revatio, not Viagra, the name used for the ED indication. The approved dose for primary pulmonary hypertension is 20 mg 3 times daily.     

Reevaluating the role of phosphodiesterase inhibitors in the treatment of cardiovascular disease

First developed for clinical use in the late 1980s, the phosphodiesterase inhibitors were found to increase the levels of the ubiquitous second messenger cyclic adenosine monophosphate and could effect changes in vascular tone, cardiac function, and other cellular events. After several early studies using high doses of phosphodiesterase inhibitors in patients with severe heart failure suggested adverse consequences, they fell out of favor. However, recent investigations of phosphodiesterase inhibitors in patients with intermittent claudication have demonstrated profound benefits. Furthermore, these agents have proven useful in prevention of cerebral infarction and coronary restenosis, and their use in the treatment of heart failure is being reevaluated. The reemergence of phosphodiesterase inhibitors can be attributed to a better understanding of dosing and drug-specific pharmacology, the use of concomitant medications, and a recognition of unique ancillary properties; however, their use still requires caution.     

Electrophysiology of phosphodiesterase inhibitors

Phosphodiesterase inhibitors appear to uniformly enhance atrioventricular node conduction, although milrinone seems to have the least effect. Except for digoxin, this effect on atrioventricular node conduction is similar to that noted with other inotropic agents. Other electrophysiologic effects vary among patients, with enoximone being more theophylline-like in response. Because none of these drugs do not have an adverse effect on His-Purkinje conduction, they are safe to use in patients with intraventricular conduction disturbances. Significant proarrhythmia is uncommon, but can occur. The mechanisms causing these electrophysiologic changes are not well defined, but the changes may occur because of increased concentrations of cytosol cyclic adenosine monophosphate secondary to phosphodiesterase inhibition, increased cytosol calcium levels secondary to increased cyclic adenosine monophosphate, or reflex adrenergic stimulation secondary to the peripheral vasodilating effects of these drugs.     

Biochemical aspects of inhibition of cardiovascular low (Km) cyclic adenosine monophosphate phosphodiesterase

Multiple isozymes of cyclic nucleotide phosphodiesterase (PDE) exist in mammalian cells. At least 5 major types of PDE isozymes have been identified; they differ by substrate affinity, maximal activity, intracellular regulation or mechanism of pharmacologic inhibition. A low Michaelis constant (Km) cyclic adenosine monophosphate (cAMP) PDE, whose activity is inhibited by submicromolar concentrations of cyclic guanosine monophosphate and stimulated by cAMP-mediated phosphorylation, is present in both cardiac muscle and vascular smooth muscle. This PDE isozyme (referred to as peak IIIc PDE) is sensitive to selective inhibition by amrinone, milrinone, imazodan, CI-930, piroximone, and numerous other PDE inhibitors. The subcellular distribution of cardiac PDE IIIc varies according to species; it is found in the soluble fraction of guinea pig myocardium, in the particulate fraction of canine myocardium, and in both fractions of primate (simian and human) myocardium. Another PDE isozyme, which is sensitive to inhibition by rolipram and is less sensitive to inhibition by PDE IIIc inhibitors, is found in cardiac muscle of some species (i.e., soluble fractions of rat and canine myocardium) and is apparently not related to direct regulation of positive inotropy. Both positive inotropy and vasorelaxation by milrinone and other PDE IIIc inhibitors can be linked to inhibition of PDE IIIc and activation of the cAMP system. These significant relations are similar to those obtained for other cAMP-related positive inotrope/vasodilators (such as beta-adrenoreceptor agonists). Moreover, an increased rate of ventricular relaxation (lusitropy), which is apparent with PDE IIIc inhibitors, may also be attributable to activation of the cAMP system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct visualization of the coronary microcirculation for pharmacologic and physiologic studies

An isolated, arrested rat heart preparation which has coronary tone similar to that found in vivo and allows direct visualization of the coronary microcirculation is described. The rat hearts are perfused in situ prior to isolation. This procedure obviates any ischemic damage to the heart. The perfusate used is a modified Krebs solution with 40 mM potassium, 2 g% albumin, and washed red cells (20% HCT). To directly view the coronary microcirculation, a fluorescent albumin conjugate is added to the cell-rich perfusate. The epicardial microvessels are illuminated and observed with a fluorescence microscope. It was found that the control intercapillary distance in this model (33 μm) was almost twice that reported by other investigators for working hearts and suggested a 60–70% coronary capillary reserve in the arrested heart. The calcium blocker nisoldipine (Miles Laboratories) caused a dose-dependent coronary vasodilation using either a constant-flow or constant-pressure protocol. The coronary reactivity of this preparation to nisoldipine was 50 times greater than reported for isolated hearts perfused with cell-free Krebs solution. Further, the preparation vasodilated in a dose-dependent manner to histamine, but histamine did not cause a significant increase in coronary permeability to macromolecules. This model is appropriate for both physiologic and pharmacologic studies. It is particularly well suited for determining the direct effects of an intervention on coronary tone and the coronary microcirculation.     

Effect of physiologic and pharmacologic adrenergic stimulation on heart rate variability

Objectives. The aim of this study was to evaluate and compare the effects of physiologic and pharmacologic sympathetic stimulation on time and frequency domain indexes of heart rate variability.Background. Measurements of heart rate variability have been used as indexes of sympathetic tone. To date, the effects of circulating catecholamines on heart rate variability have not been evaluated.Methods. Fourteen normal subjects (eight men, six women, mean (± SD) age 28.5 ± 48 years) were evaluated. Five-minute electrocardiographic recordings were obtained in triplicate after physiologic and pharmacologic sympathetic stimulation: during upright tilt, after maximal exercise, during epinephrine and isoproterenol infusions at 50 ng/kg body weight per min, during beta-adrenergic blockade and during combined beta-adrenergic and parasympathetic blockade.Results. Beta-adrenergic stimulation resulted in a significant decrease in time domain measures of heart rate variability. The frequency domain indexes showed variable responses, depending on the individual stimulus. Tilt caused an increase in low frequency power and in the ratio of low to high frequency power. These changes were not necessarily observed with other conditions of beta-adrenergic stimulation. Double blockade suppressed baseline heart rate variability, but beta-adrenergic blockade had no significant effect. Time domain measures of heart rate variability demonstrated excellent reproducibility over the three recordings, but the frequency domain variables demonstrated fair to excellent reproducibility.Conclusions. These findings suggest that different modes of beta-adrenergic stimulation may result in divergent heart rate variability responses. Thus, current heart rate variability techniques cannot be used as general indexes of “sympthetic” tone. Studies utilizing heart rate variability to quantify sympathetic tone need to consider this.     

Pharmacology of phosphodiesterase 5 inhibitors

The phosphodiesterase enzymes, of at least 11 types, are ubiquitous throughout the body, and perform a variety of functions. Phosphodiesterase type 5 (PDE5) is the predominant enzyme in the corpus cavernosum, and plays a crucial role in penile erection. Inhibitors of PDE5 are the most effective oral agents in the treatment of erectile dysfunction. Sildenafil, tadalafil, and vardenafil are all potent inhibitors of PDE5 and show the same mechanism of action, although they have some pharmacological differences that may translate into varying clinical effects.     

Antiarrhythmic therapy--recent aspects of pharmacologic treatment

Over the last years the indication for antiarrhythmic therapy has changed due to the development of other therapeutic approaches. However, antiarrhythmics are important in the acute treatment as well as the prevention of recurrent rhythm disorders. In line with the antiarrhythmic agents of class IC and III also beta-blockers, ACE inhibitors and AT (1) antagonists can be used primarily with a lower risk of severe cardiac side effects. Recent studies demonstrate that for patients with atrial fibrillation there was no benefit of rhythm control versus rate control. However, rhythm control with antiarrhythmics is beneficial in the treatment of highly symptomatic or hemodynamically compromised patients. Hybrid therapy and the "pill in the pocket"-strategy seem to be potent new therapeutic options.     

Renal lithium reabsorption in man: physiologic and pharmacologic determinants.

In order to evaluate the premise that renal lithium reabsorption may reflect proximal tubular sodium reabsorption, the fractional excretion of lithium (FELi) was measured, during a variety of experimental maneuvers known to affect renal cation reabsorption, in normal volunteers who had been pre-loaded with lithium. Furosemide increased FELi, as well as sodium, calcium, and magnesium excretion, during the first hour following diuretic administration. Subsequently, sodium, calcium, and magnesium excretion continued to remain elevated after furosemide, despite progressive volume depletion, but FELi values usually declined at least to pretreatment levels. Oral glucose ingestion increased lithium, calcium, and magnesium excretion while sodium and potassium excretion decreased concomitantly. Increases in FELi during volume expansion with saline were correlated with changes in fractional flow (V/GFR) in natriuretic subjects. Parathyroid extract (PTE) increased both FELi and fractional phosphate excretion (FEphos). FELi and FEphos were correlated significantly in the studies with furosemide and PTE, but not after saline volume expansion. In persons who previously had undergone unilateral nephrectomy, FELi was not increased over values in normal subjects. These results indicate that changes in lithium reabsorption may be dissociated from the reabsorption of other cations. They are consistent with the hypothesis that FELi may reflect proximal tubular sodium rejection, but do not exclude other more distal sites of lithium reabsorption.     

The pleiotropic effects of phosphodiesterase 5 inhibitors on function and safety in patients with cardiovascular disease and hypertension

J Clin Hypertens (Greenwich). 2012; 14:644–649. © 2012 Wiley Periodicals, Inc. Phosphodiesterase 5 (PDE‐5) inhibitors are selective blockers of PDE‐5, which catalyzes the hydrolysis of cyclic guanosine monophosphate (cGMP) to its corresponding monophosphates. cGMP is a potent vasodilator and nitric oxide donor. Since PDE‐5 is widely distributed in the body, it was hypothesized that inhibition of its actions could lead to significant vasodilation, which could benefit patients with coronary artery disease. This hypothesis led to the development of PDE‐5 inhibitors, the first being sildenafil citrate. Studies of sildenafil in patients with coronary artery disease demonstrated a modest cardiovascular effect but a potent action on penile erection in men, resulting in sildenafil becoming first‐line treatment of erectile dysfunction. Two more PDE‐5 inhibitors are now US Food and Drug Administration–approved (vardenafil and tadalafil) for the treatment of erectile dysfunction. Recent studies have demonstrated several beneficial pleiotropic cardiovascular effects of PDE‐5 inhibitors in patients with erectile dysfunction and multiple comorbidities, including coronary artery disease, heart failure, hypertension, and diabetes mellitus. Treatment of these conditions with PDE‐5 inhibitors has been very effective, safe, and well tolerated. Drug interactions have been minimal with the exception of nitrates, where coadministration may result in severe vasodilation and hypotension. These beneficial pleiotropic and safe cardiovascular effects of PDE‐5 inhibitors will be discussed in this concise review.     

Severe hemophilia and physiologic inhibitors of coagulation.

Patients with hemophilia demonstrate quite variable clinical phenotype even in cases with the same level of deficient factor or the same molecular abnormality. Different interacting factors including congenital and acquired alterations of coagulation inhibitors can modulate both clinical expression and severity of hemophilia. In this study, plasma levels of factor VIII (FVIII), factor IX (FIX) as well as protein C (PC), protein S (PS), and antithrombin (AT) plasma levels were measured in 80 patients with severe hemophilia A and B. Patients were divided into two groups according to the risk of bleeding: the first group (n = 32) with mild bleeding (< 2 bleeds/year), and the second group (n = 48) with severe bleeding (> or = 2 bleeds/year). Both hemophilia groups showed significantly decreased PC plasma levels compared to levels in healthy control subjects (the first group: p < 0.0001 and second group: p < 0.01). The difference in PC plasma levels between the first and second hemophilia group was significant (p < 0.05). Moreover, there was positive correlation between age and the functional PC in both hemophilia groups. Our results suggest that decreased PC plasma levels can testify to a slightly protective effect of the PC pathway on the severity and frequency of bleeding in patients with severe hemophilia A and B.     

The esophagus in Chagas' disease: physiologic, pharmacologic and clinical studies

Intramural denervation confirmed anatomopathologically and by means of a pharmacological test is the main factor responsible for achalasia of the cardia and for the absence of peristalsis in the esophageal body in Chagas' disease. The resulting difficulty in transit and stasis cause the main symptoms and complications of megaesophagus. Among the recent phenomena observed in the physiopathology and pharmacology of megaesophagus by the manometric method, we may mention: delayed pharyngo-esophageal time, concomitance of peristalsis and aperistalsis and abnormal responses of the lower sphincter to caerulein, atropine, nifedipine and isosorbitol dinitrate. Gammascintillography was shown to be useful in the study of esophageal transit in megaesophagus by permitting the detection of unsuspected abnormalities, especially when deglution is done with the patient lying down, and by affording a dynamic and quantitative view of the changes in esophageal emptying.