colforsin-daropate and Heart-Failure

In the failing heart, numerous changes occur in cardiac adrenergic receptors (ARs) and intracellular signal transduction pathways. The most striking of these alterations appears at beta1 ARs, and the desensitization is the most prominent. Since malfunctions of beta1 ARs prevent intracellular signal transduction, the desensitization plays an important role in the onset and progression of the heart failure. Currently, several lines of evidence show the efficacy of inotropic agents, such as adenylate cyclase activator, that depend not on the ARs. Thus, it is essential to understand the pathway for the etiologic/pathologic evaluation for appropriate usage of these drugs for an adequate period. A novel water-soluble forskolin derivative, colforsin daropate hydrochloride (CDH) is a positive inotropic agent for treatment of the heart failure, especially in the severe stage with the beta1 AR desensitization. CDH potentiates cAMP activity via its direct action on adenylate cyclase, resulting in cardiotonic action. On the other hand, CDH relaxes vascular smooth muscle, while it antagonizes antidiuretic effects of angiotensin II and noradrenaline, involved in renal protection. In addition, CDH attenuates the mesangial cell proliferation and the inflammatory reaction, related with antiproliferative property of adrenomedullin and ketamine. To gain insights into the CDH action, we should take into account that intracellular signal transduction pathways in myocardium, smooth muscle and mesangial cell are controlled in a distinct manner.

Topics: Adenylyl Cyclases; Animals; Cell Proliferation; Colforsin; Cyclic AMP; Glomerular Filtration Rate; Glomerulonephritis, Membranoproliferative; Heart Failure; Humans; Mesangial Cells; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Contraction; Receptors, Adrenergic, beta-1; Renal Circulation; Signal Transduction

Colforsin daropate hydrochloride (COL) is a water-soluble forskolin derivative for the treatment of acute heart failure. COL, like forskolin, stimulated adenylate cyclase (AC) directly and produced pharmacologic activities accompanied by the increase in cellular cAMP. COL was different from forskolin in water-solubility, duration of action, BBB permeability, oral activity and AC-subtype selectivity. COL was a inodilator with positive inotropic and vasodilator effects and was effective on a beta-receptor desensitized-heart model in which the effects of beta-agonists and PDE inhibitors were attenuated. COL improved cardiac function in some heart failure models. In the clinical studies, COL improved hemodynamics, subjective and objective symptoms of heart failure patients, and was also effective in the catecholamine-resistant heart failure patients. COL is a first clinically available adenylate cyclase activator. Further information from the post-marketing-surveillance will provide information that will enable more adequate usage of this drug.

Topics: Adult; Animals; Colforsin; Drug Evaluation, Preclinical; Heart Failure; Hemodynamics; Humans; Male; Myocardial Contraction; Vasodilator Agents

Colforsin daropate hydrochloride (COL) is a novel drug for the treatment of acute heart failure. COL stimulates adenylate cyclase directly and produces positive inotropic and vasodilator effects accompanied by the increase in cellular cAMP. We investigated its cardiovascular effects for 9 patients who showed low cardiac index (< 3.0 l/min/m2) after open-heart surgery in ICU. After 2 or 3 hours from administration of COL, heart rate and cardiac index increased, and pulmonary artery pressure and central venous pressure decreased significantly, but blood pressure and systemic venous oxygen saturation did not show significant change. In conclusion, COL improved hemodynamics through positive inotropic and vasodilator effects without hypotension. We should investigate more proper usage of this drug to avoid such side effects as tachycardia and arrhythmia, which occurred in some cases.

Topics: Acute Disease; Adenylyl Cyclases; Cardiac Surgical Procedures; Colforsin; Heart Failure; Hemodynamics; Humans; Postoperative Complications; Vasodilator Agents

Increased nitric oxide (NO) in the failing heart attenuates the myocardial contractile response to beta-adrenergic receptor stimulation. However, the physiological effects of NO on the beta-adrenergic post-receptor signaling system are unknown. The objective of the present study was to examine the effects of cardiac NO synthase (NOS) inhibition on left ventricular (LV) hemodynamics and mechanoenergetics in response to adenylyl cyclase stimulation in human heart failure.. The study group comprised 13 patients with heart failure because of idiopathic cardiomyopathy (IDC). Emax was examined as an index of LV contractility, LV external work (EW), pressure-volume area (PVA), myocardial oxygen consumption (MVO2), and mechanical efficiency (EW/MVO2) with the use of conductance and coronary sinus thermodilution catheters before and during colforsin daropate infusion, and during concurrent infusion of colforsin daropate with the NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA; 200 micromol). Colforsin daropate increased Emax by 53% and EW by 18%, and reduced PVA by 14%, without altering MVO2 or mechanical efficiency. The combination of colforsin daropate with L-NMMA further increased Emax by 26% and reduced PVA by 9%, without altering MVO2 or mechanical efficiency.. These findings suggest endogenous NO may modulate beta-adrenergic post-receptor pathways and preserve myocardial efficiency in patients with IDC.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Aged; Biomechanical Phenomena; Cardiomyopathy, Dilated; Colforsin; Female; Heart Failure; Heart Function Tests; Humans; Male; Middle Aged; Myocardial Contraction; Nitric Oxide Synthase Type III; omega-N-Methylarginine