Disease relevance of Cicletanine

• We studied the effects of cicletanine, a furopyridine antihypertensive drug, and furosemide, a loop diuretic, on ventricular arrhythmias, such as sustained ventricular fibrillation (VF) and ventricular tachycardia (VT), and myocardial ion content in Langendorff rat hearts subjected to 30 min global ischaemia then 10 min reperfusion [1].
• This mechanism of action may be relevant to the greater potency of cicletanine in salt-sensitive hypertension in which plasma levels of endogenous digitalis-like cardiotonic steroids are elevated [2].
• OBJECTIVES: We studied the effects of ATP-sensitive potassium channel (KATP) modulation on ischemic cardiac performance and reperfusion-induced ventricular fibrillation (VF), and assessed the contribution of KATP to the cardioprotective and anti-arrhythmic effect of the anti-hypertensive drug cicletanine [3].
• Cicletanine (39 mg/kg body weight per day for 6 weeks) ameliorated the development of hypertension in Dahl-S rats fed a high-salt (4% NaCl) diet [4].
• METHODS: Isolated working rat hearts, subjected to a 10-min coronary occlusion followed by reperfusion, were perfused in the presence of vehicle, 0.1-60 microM cromakalim, an opener of KATP; 3-60 microM cicletanine; and 0.1-10 microM glibenclamide, a blocker of KATP, respectively [3].

High impact information on Cicletanine

• In the PepTag PKC assay, cicletanine produced a concentration-dependent inhibition of rat brain PKC activity (IC50 45 +/- 11 micromol/l) [2].
• RESULTS: MBG and ET-1 both induced sustained vasoconstriction in human mesenteric artery rings, and cicletanine relaxed rings pre-contracted with either MBG (EC50 = 11 +/- 2 micromol/l) or ET-1 (EC50 = 6.4 +/- 1.1 micromol/l) [2].
• Cicletanine reverses vasoconstriction induced by the endogenous sodium pump ligand, marinobufagenin, via a protein kinase C dependent mechanism [2].
• In mesenteric artery sarcolemma, 100 nmol/l MBG inhibited the Na/K-ATPase by 68 +/- 5% and cicletanine (100 micromol/l) attenuated this Na/K-ATPase inhibition by 85 +/- 6% [2].
• CONCLUSIONS: (i) The anti-ischemic but not the anti-arrhythmic effect of cicletanine may involve opening of KATP [3].

Chemical compound and disease context of Cicletanine

• Terfenadine, a histamine H(1) receptor antagonist, has been associated with clinical ventricular arrhythmias and in vitro excitation-conduction blocks, whereas anti-ischemic and antiarrhythmic effects have been shown with cicletanine, a prostacyclin generation stimulator [5].
• The following low-dose oral formulations of diuretics constitute effective once-daily monopharmacotherapies for mild-to-moderate uncomplicated essential hypertension: bendrofluazide 1.25 mg, chlorthalidone 12.5 and 15 mg, cicletanine 50 mg, cyclopenthiazide 0.125 mg, HCTZ 12.5 mg, and torasemide 2.5 and 5 mg [6].
• The effect of cicletanine on reperfusion-induced arrhythmias in relation to 6-keto-PGF1 alpha and thromboxane (TXB2) release was studied [7].
• All cicletanine concentrations reduced the incidence of irreversible ventricular fibrillation (VF) during reperfusion, an effect roughly concentration dependent in the range of 3 x 10(-5)-10(-4) M, whereas nitrendipine had no influence on arrhythmias [8].
• Reperfusion-induced arrhythmias and myocardial ion shifts: a pharmacologic interaction between pinacidil and cicletanine in isolated rat hearts [9].

Biological context of Cicletanine

• Moreover, urinary prostacyclin (PGl2) excretion was increased with cicletanine treatment, being inversely related to systolic blood pressure [4].
• However, the changes in renal vascular resistance were parallel to those in mean blood pressure: it was increased with salt loading, reversed by cicletanine and increased by indomethacin [10].
• Inhibition of low Km cGMP phosphodiesterases and Ca+(+)-regulated protein kinases and relationship to vasorelaxation by cicletanine [11].
• 2. Cicletanine increased cardiac output prior to coronary occlusion (P < 0.01) but had no other significant haemodynamic effects at this time and did not significantly alter heart rate, blood pressure or cardiac output during 30 min of ischaemia or 30 min of reperfusion [12].
• In contrast, capillary permeability was reduced after acute cicletanine in the heart (31%), duodenum (49%) and muscle (58%) and after amiloride in the heart (25%) and muscle (63%) [13].

Anatomical context of Cicletanine

• METHODS: The effects of cicletanine on vascular tone were studied in isolated, endothelium-denuded rings of 2nd-3rd-order branches of human mesenteric arteries pre-contracted with bufodienolide marinobufagenin (MBG), an Na/K-ATPase inhibitor, or endothelin-1 (ET-1) [2].
• In the present studies we sought to determine if cicletanine, which is an antihypertensive agent of unknown mechanism, could alter cGMP metabolism via inhibition of cGMP phosphodiesterases (PDE) in vascular smooth muscle [11].
• Effects of cicletanine on whole-cell currents of single smooth muscle cells from the guinea-pig portal vein [14].
• 6. The results show that cicletanine inhibits contractile responses of human isolated inferior epigastric arteries by a mechanism unrelated to endothelial factors but associated with inhibition of calcium metabolism [15].
• 5. These findings indicate that cicletanine attenuates arrhythmias and preserves myocardium in the early phase of ischaemia and this effect appears to be independent of an established antihypertensive action [12].

Associations of Cicletanine with other chemical compounds

• CONCLUSIONS: Cicletanine antagonizes vasoconstriction induced by Na/K-ATPase inhibition via a PKC-dependent mechanism that does not involve inhibition of cyclic GMP phosphodiesterase (cGMP-PDE) [2].
• Methylene blue attenuated a component of cicletanine-induced vasorelaxation, but did not completely obviate relaxation [11].
• In summary, these data demonstrate that cicletanine inhibits vascular cGMP PDEs, potentiates vasorelaxation, and to a limited extent, cGMP formation by guanylate cyclase activators in vascular smooth muscle [11].
• Finally, cicletanine sulfate (30 mumol/L) partially inhibited serum-dependent A10 cell growth [16].
• This study investigated the mechanisms of the acute vasodilator actions of 5-OH-indapamide, indapamide, hydrochlorothiazide and cicletanine and their interaction with ion channels in isolated guinea pig mesenteric arteries [17].

Gene context of Cicletanine

• A selective blockade of AII induced contractions in kidney vascular beds can be one factor explaining both the greater antagonistic potency of (-)-cicletanine against AII compared with AVP in pithed rats, and the renal protective properties of cicletanine in both hypertensive and aged rats [18].
• Consistently with maintenance of UKE during the course of hypertension, the level of tissue kallikrein was higher in hypertensive cicletanine-treated than in untreated SHR [19].
• Histamine contracted both types of vessels in a concentration-dependent manner and this effect was antagonized by the H1 receptor antagonists mepyramine and cicletanine [20].
• 1. The aim of the study was to investigate whether cicletanine (CIC), as a potential inhibitor of cyclic GMP phosphodiesterase, is able to restore glomerular response to atrial natriuretic factor (ANF) in rats under conditions of diet deprived of sodium [21].
• Cicletanine was determined to be a mixed (competitive, noncompetitive) inhibitor of both calmodulin-regulated and cGMP-specific PDEs from monkey aortic smooth muscle with Ki values of 450 to 700 microM [11].

Analytical, diagnostic and therapeutic context of Cicletanine

• Effects of cicletanine on kidney function. 1. Clearance and micropuncture studies in anesthetized rats [22].
• Effects of cicletanine on haemodynamics, arrhythmias and extent of necrosis during coronary ligation in rabbits [12].
• Group 1 was a control group, groups 2 and 3 were orally treated with cicletanine at 30 and 100 mg/kg [23].
• Determination of cicletanine enantiomers in plasma by high-performance capillary electrophoresis [24].
• The HPCE method required less than half the time taken by the HPLC method, making HPCE a useful alternative technique for the routine determination of cicletanine in plasma [25].

References