[Effects of colforsin daropate hydrochloride on myocardium, smooth muscle and renal function].
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.
Ogata
Junichi
J
Division of Anesthesia, Kyushu Rosai Hospital, Kitakyushu 800-0296.
Segawa
Kayako
K
Minami
Kouichiro
K
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000242:Cyclic AMP / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy / Q000209:etiology; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D050527:Mesangial Cells / Q000166:cytology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D018342:Receptors, Adrenergic, beta-1; C122001:colforsin daropate; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases