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At least 19 recordsLinked to original sources
PubMed2001

Antiinflammatory effects of colforsin daropate hydrochloride, a novel water-soluble forskolin derivative.

BACKGROUND: To evaluate the effects of colforsin daropate hydrochloride (colforsin), a water-soluble forskolin derivative, on hemodynamics and systemic inflammatory response after cardiopulmonary bypass, we conducted a prospective randomized study. METHODS: Twenty-nine patients undergoing coronary artery bypass grafting were randomized to receive either colforsin treatment (colforsin; n = 14) or no colforsin treatment (control; n = 15). Administration of colforsin (0.5 microg.kg(-1).min(-1)) was started after induction of anesthesia and was continued for 6 hours. Perioperative cytokine and cyclic adenosine monophosphate levels, hemodynamics, and respiratory function were measured serially. RESULTS: Marked positive inotropic and vasodilatory effects were observed in patients receiving colforsin. Interleukin 1beta, interleukin 6, and interleukin 8 levels after cardiopulmonary bypass were significantly (p < 0.05) lower in the colforsin group. Plasma levels of cyclic adenosine monophosphate increased significantly (p < 0.05) in the colforsin group, and the levels correlated inversely (r = -0.56, p = 0.002) with the respiratory index after cardiopulmonary bypass. CONCLUSIONS: Intraoperative administration of colforsin daropate hydrochloride had potent inotropic and vasodilatory activity and attenuated cytokine production and respiratory dysfunction after cardiopulmonary bypass. The results indicate that the technique can be a novel therapeutic strategy for the systemic inflammatory response associated with cardiopulmonary bypass.

Aged↗
PubMed1999

Age-related endothelium-dependent vascular relaxation in rat thoracic aorta in response to colforsin.

BACKGROUND: Colforsin, a novel water-soluble forskolin derivative, increases intracellular cyclic AMP by direct stimulation of adenylate cyclase and has strong positive inotropic and vasodilative effects. However, it is not known whether colforsin causes nitric oxide (NO) release and enhances endothelium-dependent vascular relaxation. METHODS: We studied NO production and relaxation on exposure to colforsin in thoracic aorta from rats aged 4, 12 and 60 weeks. RESULTS: When a low concentration of colforsin was added to a solution bathing ring segments of aorta from 12-week-old rats, relaxation was greater in the ring segments with intact endothelium than in those from which the endothelium had been removed. A high concentration of colforsin induced the same degree of relaxation of ring segments with or without endothelium, probably by a direct effect on vascular smooth muscle cells. Production of NO in response to colforsin by cultured endothelial cells from 12-week-old rat aorta was demonstrated by the electron paramagnetic resonance spin trapping method. A low concentration of colforsin relaxed aortic segments with intact endothelium from 4-week-old rats more than those from 12-week-old or 60-week-old rats. Reversal of relaxation by NG-nitro L-arginine, an NO synthesis inhibitor, was most significant in arteries from 4-week-old rats. Production of NO after exposure to colforsin was greater in aortic segments from 4-week-old rats than older rats, as detected by an NO-selective electrode. CONCLUSIONS: Colforsin induces vasodilation in part by releasing NO from the endothelium in rat thoracic aorta. In addition to a direct vasodilative effect on the vascular smooth muscle cells, an endothelium-dependent vasodilative effect is also important in younger arteries.

Aging↗
PubMed2001

Colforsin daropate improves contractility in fatigued canine diaphragm.

UNLABELLED: We studied the effects of colforsin daropate, a water-soluble forskoline derivative, on contractility in fatigued canine diaphragm. Dogs were randomly divided into 4 groups of 8 each. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. Immediately after the end of a fatigue-producing period, Group 1 received no study drug, Group 2 was infused with small-dose colforsin daropate (0.2 microg. kg(-1). min(-1)), Group 3 was infused with large-dose colforsin daropate (0.5 microg. kg(-1). min(-1)), and Group 4 was infused with nicardipne (5 microg. kg(-1). min(-1)) during colforsin daropate (0.5 microg. kg(-1). min(-1)) administration. After the fatigue-producing period, in each group transdiaphragmatic pressure (Pdi) at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups 2 and 3, during colforsin daropate administration, Pdi to each stimulus increased from fatigued values (P < 0.05). The increase in Pdi was larger in Group 3 than in Group 2 (P < 0.05). In Group 4, the augmentation of Pdi by colforsin daropate was abolished in fatigued diaphragm with an infusion of nicardipine. The integrated diaphragmatic electric activity did not change in any of the groups. We conclude that colforsin daropate improves, in a dose-dependent manner, contractility in fatigued canine diaphragm via its effect on transmembrane calcium movement. IMPLICATIONS: Diaphragmatic fatigue is implicated as a cause of respiratory failure in normal subjects and in patients with chronic obstructive lung disease. Colforsin daropate improves contractile properties during diaphragmatic fatigue.

Animals↗
PubMed1993

Pharmacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma.

The airway and tremor response and cardiovascular and hypokalemic effects of single doses of inhalative fenoterol dry powder capsules (0.4 mg) were compared with the fenoterol metered dose inhaler (0.4 mg) and colforsin (forskolin) dry powder capsules (10.0 mg), a direct activator of the adenylate cyclase system, in 16 patients with asthma. Subjects (FEV1 < or = 60% predicted) were investigated in a randomized, double-masked, placebo-controlled, four-period, crossover trial for a 120 minute period. All active drugs caused a significant increase in specific airway conductance (p < 0.05); the order of potency (mean +/- SEM maximum increase from baseline) was fenoterol metered dose inhaler (0.51 +/- 0.06 sec-1 x kPa-1), fenoterol dry powder capsules (0.49 +/- 0.07), and colforsin dry powder capsules (0.30 +/- 0.03). A marked increase in finger tremor amplitude resulted after fenoterol metered dose inhaler only (62.93% +/- 10.21%; p < 0.05) in contrast to fenoterol dry powder capsules (15.84% +/- 4.35%; p < 0.05) and colforsin dry powder capsules (12.87% +/- 10.44%; p > 0.05). A decrease in plasma potassium was found after fenoterol (metered dose inhaler > dry powder capsules; p < 0.05). In conclusion, fenoterol dry powder capsules caused less tremor response and hypokalemic effects than the metered dose inhaler, although the bronchodilator capacity was similar. Colforsin dry powder capsules resulted in a measurable bronchodilatation in patients with asthma.

Administration, Inhalation↗
PubMed1989

Effect of colforsin on human neutrophil superoxide production and intracellular calcium mobilization.

1. The effects of dibutyryl cyclic AMP (cAMP), isoproterenol and colforsin (forskolin) were evaluated on respiratory burst in human polymorphonuclear neutrophils (PMN). 2. Dibutyryl cAMP showed a dose-dependent inhibition of n-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced superoxide production by human PMN. 3. Administration of isoproterenol induced a dose-dependent inhibition of FMLP-induced superoxide production by human PMN, and the inhibition was blocked by propranolol. 4. Administration of colforsin induced a dose-dependent inhibition of FMLP-induced superoxide production by human PMN, and the inhibition could not be blocked by propranolol. 5. Incubation with colforsin caused a significant increase in the cAMP level in human PMN. 6. Pretreatment with colforsin caused a dose-dependent inhibition in the elevation of intracellular free calcium (monitored by fura-2 fluorescence), which was observed in human PMN stimulated with FMLP. 7. These results suggest that cAMP is an inhibitory factor of superoxide production and intracellular calcium mobilization in human PMN stimulated with FMLP.

Adult↗
PubMed2001

[Effect of colforsin daropate hydrochloride after cardiopulmonary bypass].

We evaluated the effects of colforsin daropate hydrochloride (CDH) after cardiopulmonary bypass (CPB) in comparison with milrinone. CDH or milrinone were given during and after CPB combined with cathecholamines so as to maintain mean arterial pressure (mABP > 60 mmHg) and cardiac index (CI > 3.0 l.min-1.m-2). Hemodynamics measurement was done immediately after CPB (A 1), one hour after CPB (A 2) and after the chest closure (A 3). In CDH group, mABP was significantly higher compared with milrinone group. Also, CDH group showed a significant reduction in the cases of combined use of dobutamine (at A 2, A 3) and norepinephrine (at A 1, A 2) compared with milrinone group. In conclusion, colforsin daropate hydrochloride exerts more inotropic effect and could reduce the necessity of combined use of cathecholamine compared with milrinone.

Aged↗
PubMed1987

Effects of dibutyryl cyclic adenosine monophosphate and colforsin on mucociliary transport using frog palate.

For the determination of mucociliary transport, a method was developed to assess the mucociliary transport force (MCTF). Using this method, effects of isoprenaline (isoproterenol), theophylline, dibutyryl cyclic adenosine monophosphate (AMP) and colforsin on mucociliary transport were investigated for 15 min after the drug application. These agents induced a significant, dose-related increase in MCTF. Propranolol, a beta-adrenergic antagonist, inhibited the effect of isoprenaline, and 9-(tetrahydro-2-furyl)adenine, an inhibitor of adenylate cyclase, inhibited the effect of colforsin. These results indicated that mucociliary transport was stimulated by the agents which increased intracellular cyclic AMP level, and that intracellular cyclic AMP played an important role in the maintenance and/or regulation of mucociliary transport.

Animals↗
PubMed1987

Topical forskolin (colforsin) and aqueous flow in humans.

A 1% forskolin (nonproprietary name, colforsin) suspension was instilled in one eye each of 15 normal human subjects in a single-dose experiment under the following three conditions: during the day, during the night while asleep, and following pretreatment with timolol maleate. The rate of flow was 2.6 +/- 0.13 microL/min (mean +/- SE) in the afternoon in both the treated and the untreated eyes. During sleep at night the flow was lower than in the afternoon in both the placebo-treated eye, 1.5 +/- 0.09 microL/min, and the forskolin-treated eye, 1.3 +/- 0.09 microL/min. Timolol pretreatment reduced the flow to 1.6 +/- 0.08 microL/min in the placebo-treated eye and 1.6 +/- 0.10 microL/min in the forskolin-treated eye. No statistically significant effects of forskolin on flow were observed under any of the conditions. Forskolin caused transient hyperemia in all subjects. The experiment confirmed previous reports of differences in the rate of aqueous flow at different times of day and the effect of the beta-adrenergic blocker timolol on the rate of aqueous humor flow.

Administration, Topical↗
PubMed1999

[Cardiovascular effects of colforsin daropate hydrochloride, a novel drug for the treatment of acute heart failure].

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.

Adult↗
PubMed1999

Characterization of positive inotropic effect of colforsin daropate [correction of dapropate] hydrochloride, a water-soluble forskolin derivative, in isolated adult rat cardiomyocytes.

The present study was undertaken to characterize the positive inotropic action of colforsin daropate [corrected] hydrochloride (NKH477), a novel water-soluble forskolin derivative, on isolated cardiomyocytes of adult rats. Simultaneous measurements of cellular contraction and intracellular calcium concentration ([Ca2+]i) were carried out. The effects of isoprenaline and ouabain on these parameters were also determined for comparison. The contraction and maximum [Ca2+]i of NKH477-, isoprenaline-, or ouabain-treated cells were increased concentration dependently. Peak shortening of NKH477-treated cells was positively correlated with the shortening velocity and inversely with the time to peak shortening. Maximum, but not minimum, [Ca2+]i in NKH477-treated cells was correlated with the rate of increase in [Ca2+]i and inversely with the time to maximum [Ca2+]i. Similar results were obtained with isoprenaline. In contrast, ouabain increased both maximum and minimum [Ca2+]i. Treatment with either NKH477 or isoprenaline increased cellular cAMP content, but treatment with ouabain did not. These results suggest that the positive inotropic action of NKH477 is associated with an increase in [Ca2+]i and acceleration of its kinetics.

Animals↗
PubMed2001

[Effects of colforsin daropate hydrochloride in patients undergoing coronary artery bypass surgery].

The effects of Adehl, colforsin daropate hydrochloride, on hemodynamics were studied in patients undergoing cardiac surgery. Twenty-six patients who underwent coronary artery bypass grafting were divided into two groups according to the intraoperative administration of Adehl. The control group (n = 14) received no Adehl treatment and the Adehl group (n = 12) received Adehl infusion immediately after anesthesia induction (0.5 microgram.kg-1.min-1) for 6 hours. Hemodynamic measurements and clinical results were accessed perioperatively. The Adehl group resulted in significantly (p < 0.05) lower pulmonary capillary wedge pressure and systemic vascular resistance, and significantly (p < 0.05) greater cardiac indices and left ventricular stroke work indices than those in the control group. No significant difference was found in the rate pressure product between the groups. The Adehl group resulted in significantly shorter duration of intubation and ICU stay. Adehl was not associated with a significant increase in the prevalence of adverse effects. The results suggest that Adehl has positive inotropic and vasodilator effects without increasing myocardial oxygen consumption. Thus, it is suggested that Adehl can be a useful agent for the perioperative management in patients undergoing cardiac surgery.

Aged↗
PubMed1988

Effects of colforsin, trequinsin and isoprenaline on norepinephrine-induced contractions and cyclic nucleotide levels of isolated vascular tissue.

Recent observations imply the involvement of an endothelium-derived relaxing factor (EDRF) in the vasodilation of isolated vascular preparations accompanied by an increase of cyclic guanosine 3',5'-monophosphate (cGMP). To investigate the changes of cGMP and cyclic adenosine 3',5'-monophosphate (cAMP) in endothelium-dependent relaxation of isolated rabbit thoracic aortic rings we used colforsin (forskolin, FOR) as an adenylate cyclase stimulator, trequinsin (TRE) as a phosphodiesterase inhibitor and isoprenaline (ISO) as a beta-adrenoceptor agonist. Norepinephrine (NE, 10(-8) mol/l) evoked a contractile response in intact rings of rabbit aorta. In these precontracted rings with endothelium, acetylcholine (ACh) induced a concentration-dependent relaxation at 10(-8)-10(-6) mol/l. FOR, TRE and ISO reduced NE-vasoconstrictor responses in a concentration-dependent manner with an IC50 of 4.1 x 10(-8) mol/l, 8.5 x 10(-7) mol/l and 4.0 x 10(-7) mol/l, respectively, in rabbit aortic rings with endothelium. These effects were associated with elevations (p less than 0.05) in cAMP and cGMP in vascular tissue. In segments with disrupted endothelium the IC50 for FOR and TRE were increased about 3.5- and 2.3-fold, without changes in cyclic nucleotides. All three compounds attenuated ACh-induced relaxations of aortic rings in a concentration-dependent manner. High concentrations of FOR (10(-7) mol/l) and TRE (10(-5)) which increased cAMP even reversed ACh-induced relaxations, comparable to ACh effects in de-endothelialized vascular tissue. It is suggested that FOR-, TRE- and ISO-induced relaxations of isolated aortic preparations, accompanied by increased cAMP, interact with EDRF-dependent relaxations.

Acetylcholine↗
PubMed1994

Colforsin or imidazolidione potentiates cAMP elevation caused by endothelin-1 in rat aorta.

Endothelin-1 (ET-1) caused slow-developing and stable vasoconstrictions in isolated rings of rat thoracic aortae with a pD2 value of 7.55 +/- 0.10 compared to pD2 values of 9.30 +/- 0.10 and 8.36 +/- 0.30 for angiotensin II and norepinephrine, respectively. Although the potency of ET-1 was somewhat lower than those of norepinephrine and angiotensin II, the maximal tension generated by ET-1 was comparable to that of norepinephrine and considerably greater than that of angiotensin II. Incubation of aortic rings in the absence of extracellular Ca2+ or in the presence of the Ca2+ channel blocker nifedipine (100 nmol.L-1) greatly attenuated ET-1-induced vasoconstriction. ET-1 (20 nmol.L-1, approximately the ED50 for vasoconstrictions) also caused elevation of cAMP levels in aortic rings after 15 and 25 min of exposure. The cAMP phosphodiesterase inhibitor imidazolidione (Imi, Ro 20-1724, 100 mumol.L-1) potentiated the cAMP responses to ET-1. Rings incubated for 25 min with ET-1 (20 nmol.L-1) showed much larger cAMP elevations caused by colforsin (Col, forskolin 1 mumol.L-1), a direct adenylate cyclase activator and potentiator, than with Col or ET-1 alone. Therefore, ET-1 may utilize at least 2 signal transduction mechanisms, one involving the opening of nifedipine-sensitive Ca2+ channels and the other involving the elevation of cAMP levels, to produce the unusually slow-developing and stable vasoconstrictions in rat aortae.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1995

Calcium entry attenuates adenylyl cyclase activity. A possible mechanism for calcium-induced catecholamine resistance.

In experimental animals, coadministration of calcium (Ca) salts with beta-adrenergic receptor agonists reduces the increased blood pressure and cyclic AMP (cAMP) produced by beta-adrenergic receptor agonists alone. In patients, coadministration of these drugs reduces the increased cardiac output and blood glucose produced by selective administration of beta-adrenergic agonists. The mechanism by which Ca might produce catecholamine resistance remains unclear. Healthy volunteers donated venous blood from which lymphocytes were isolated. The cAMP production was measured by radioimmunoassay under control conditions and after incubation with epinephrine or colforsin (forskolin) in the presence and absence of inhibitors. Epinephrine and colforsin produced concentration-dependent increases in cAMP production. Extracellular Ca concentration over the range from 0 to 8 mM did not inhibit basal cAMP production or that stimulated by either colforsin or epinephrine. The calcium channel agonist Bay K 8644 (50 microM) combined with normal extracellular Ca concentration significantly attenuated colforsin-induced increases in cAMP production. When barium was substituted for Ca in the extracellular fluid, the cAMP response to colforsin was restored, despite Bay K 8644. Inhibition of Ca channel permeability with cadmium or cobalt ions partially restored colforsin-stimulated cAMP production, despite the presence of extracellular Ca and Bay K 8644. These results suggest that entry of Ca ions through Ca channels attenuates adenylyl cyclase. The inhibition appears specific for Ca ions over other permeant divalent cations, and favors a possible physiologic role for the recently cloned Ca-inhibited adenylyl cyclase.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Beta-adrenergic regulation of gap-junctional intercellular communication in cultured rabbit gastric epithelial cells.

The effect of a beta-adrenergic agonist, isoproterenol, on gap-junctional intercellular communication (GJIC) and intracellular cyclic AMP (cAMP) content was investigated in cultured rabbit gastric epithelial cells. Isoproterenol rapidly enhanced GJIC determined by the Lucifer yellow transfer at 10(-6) and 10(-5) M but the effect at 10(-6) M was variable. The enhancement of GJIC by 10(-5) M isoproterenol, which disappeared within 10 or 30 min, was inhibited by a beta blocker, propranolol. Isoproterenol (10(-6) M) greatly increased cAMP at 5 min and much more so at 20 min after its addition. Colforsin (also known as forskolin) and 3-isobutyl-1-methylxanthine (IBMX) enhanced GJIC until 16 and 20 min after their addition, respectively. Both colforsin and IBMX increased the cAMP content by a lesser extent than 10(-6) M isoproterenol. Isoproterenol (10(-5) M) inhibited the GJIC enhanced by colforsin or IBMX. Propranolol abolished the inhibition of GJIC by isoproterenol in the presence of IBMX. Both amiloride, an inhibitor of the Na+/H+ exchanger, and nigericin, a K+/H+ antiporter, inhibited the GJIC enhanced by isoproterenol, IBMX, colforsin and irsogladine. An inhibitor of cAMP-dependent protein kinase A, H-89 (N-[2-((3-(4- bromophenyl)-2-propenyl)-amino)-ethyl]-5-isoquinolinesulfonamide), abolished the enhancement of GJIC by colforsin and IBMX but did not abolish that by isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1994

Endotoxin disrupts beta-adrenergic signal transduction in the heart.

BACKGROUND: Nonsurvivors of septic shock demonstrate impaired myocardial function refractory to the administration of beta-agonists. METHODS: Using the isolated rat heart preparation, the integrity of the beta-adrenergic transduction pathway was tested (rate pressure product, rate of contraction, rate of relaxation, and cyclic adenosine monophosphate content) using isoproterenol hydrochloride (beta-receptor agonist) or colforsin (forskolin) (adenylyl cyclase activator) stimulation following intracoronary endotoxin infusion. RESULTS: Basal rate pressure product, rate of contraction, rate of relaxation, and cyclic adenosine monophosphate concentrations were unaffected by endotoxin infusion. Endotoxin impaired, increases in rate pressure product, rates of contraction and relaxation, and cyclic adenosine monophosphate to isoproterenol (P < .05), but the response to colforsin was unaffected by endotoxin. CONCLUSIONS: Endotoxin disrupts the myocardial response to direct beta-receptor stimulation but not to adenylyl cyclase stimulation in the isolated rat heart. CLINICAL RELEVANCE: Alteration of the proximal beta-adrenoreceptor complex by endotoxin suggests that therapy of the failing heart during refractory septic shock may be directed to intact sites distal in the beta-adrenergic pathway.

Adenylyl Cyclases↗
PubMed1998

Modulation of cAMP-mediated vasorelaxation by endothelial nitric oxide and basal cGMP in vascular smooth muscle.

Recent in vitro evidence shows a role of endothelial nitric oxide (NO) in the modulation of isoproterenol-induced vasorelaxation. To elucidate roles of endothelial cells and NO in cyclic adenosine monophosphate (cAMP)-mediated vasodilators we examined the effects of removal of endothelium and a NO synthase (NOS) inhibitor on relaxant responses in vitro of rat aortic strips to beta-adrenoceptor stimulants and colforsin dapropate, a water-soluble forskolin, and changes in cAMP and cyclic guanosine monophosphate (cGMP) contents. Relaxant responses of rat aorta to isoproterenol, denopamine, salbutamol, colforsin, and dibutyryl cAMP (dbcAMP) were blunted by removal of endothelial cells or treatment with NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Relaxant response of endothelium-intact segments to isoproterenol was associated with increases in tissue cAMP and cGMP contents. Removal of endothelium or treatment with L-NAME markedly reduced basal cGMP and abolished the isoproterenol-induced increase in cGMP but not cAMP content. In endothelium-removed segments, pretreatment with sodium nitroprusside (SNP) restored the diminished relaxant response to isoproterenol and increased basal cGMP (from 0.08 +/- 0.01 to 0.16 +/- 0.02 pmol/mg protein), whereas it did not affect the isoproterenol-induced increase in cAMP. The diminished relaxant response of endothelium-removed segments to dbcAMP was not restored by SNP pretreatment. The results suggest that relaxant response of rat aorta to cAMP-mediated vasodilators is mediated, in part, by NO production in endothelium and subsequent increase in cGMP in vascular smooth-muscle cells.

Adrenergic beta-Agonists↗