Thierry Tarrade

KATP channel modulation in working rat hearts with coronary occlusion: effects of cromakalim, cicletanine, and glibenclamide

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. 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. RESULTS All concentrations of cicletanine, similarly to 0.1-10 microM cromakalim, attenuated ischemia-induced deterioration of aortic flow, left ventricular developed pressure, and left ventricular end-diastolic pressure. In contrast to cromakalim, cicletanine did not increase coronary flow. Cicletanine (60 microM) and cromakalim (10 and 60 microM) significantly reduced the incidence of reperfusion-induced VF; however, 60 microM cromakalim triggered VF during ischemia. Lower concentrations of cromakalim and cicletanine did not produce an anti-arrhythmic effect. Cardiac functional parameters were concentration dependently worsened by glibenclamide, and the drug did not change the incidence of VF. Glibenclamide (0.1 microM) did not significantly affect cardiac performance, but it did abolish the anti-ischemic effect of cromakalim (1-10 microM) and cicletanine (60 microM). Glibenclamide suppressed the anti-arrhythmic effect of 10 and 60 microM cromakalim; however, it did not affect the anti-arrhythmic effect of cicletanine. CONCLUSIONS (i) The anti-ischemic but not the anti-arrhythmic effect of cicletanine may involve opening of KATP. (ii) opening of KATP attenuates, inhibition of the channel exacerbates functional consequences of coronary occlusion, and (iii) KATP opening attenuates reperfusion-induced VF, but it triggers ischemia-induced VF. KATP blocking does not affect VF.

Cicletanine attenuates overdrive pacing-induced global myocardial ischemia in rabbits: possible role of cardiac cyclic nucleotides.

BackgroundThis study examined whether cicletanine, an antihypertensive drug with cGMP phosphodiesterase inhibitory effect, could alleviate ventricular overdrive pacing-induced myocardial ischemia in chronically instrumented rabbits. MethodsAn electrode-catheter implanted into the right ventricle was used for pacing (500 bpm over 5 min) and for measuring intracavital ST-segment elevation and ventricular effective refractory period (VERP). PQ and QT intervals were measured in the chest-lead ECG, and dP/dtmax as well as left ventricular end-diastolic pressure (LVEDP) were recorded through a left intraventricular catheter. In separate groups, mean arterial blood pressure (MABP) was monitored from the right carotid artery. Experiments were performed on conscious rabbits after a week of convalescence. In anesthetized, open-chest rabbits, samples were taken from the left ventricle before and after drug treatment and/or overdrive pacing for determination of cGMP and cAMP contents by radioimmunoassay. ResultsIntravenous cicletanine, 30 mg/kg body weight, did not change resting MABP, dP/dtmax, and LVEDP, but it did reduce heart rate and prolonged PQ and QT intervals and VERP. Overdrive pacing produced intracavital ST-segment elevation, increased LVEDP, and decreased dP/dtmax and MABP. Cicletanine administered 15 minutes before pacing significantly attenuated ST-segment elevation, increased LVEDP, and decreased dP/dtmax and MABP. In anesthetized animals, cicletanine itself slightly increased cardiac cGMP and cAMP contents. Overdrive pacing moderately increased cGMP and profoundly elevated cAMP, and in overpaced rabbits, cicletanine further increased cGMO and markedly attenuated cAMP content increased by overdrive pacing. ConclusionsThese results suggest that in correlation with alterations of cardiac cycle nudeotide contents, cicletanine protects the heart against pacing-induced myocardial ischemia.

Zaprinast, cicletanine, and verapamil attenuate overdrive pacing-induced myocardial ischemia in conscious rabbits

In conscious rabbits equipped with right ventricular electrode and left ventricular polyethylene catheters, zaprinast and cicletanine, inhibitors of phosphodiesterase (PDE) V and PDEs I and V, respectively, as well as verapamil, a Ca2+ channel blocker, decreased intracavital ST-segment elevation induced by ventricular overdrive pacing (VOP). Zaprinast and cicletanine attenuated VOP-induced QT reduction and increase in left ventricular end-diastolic pressure (LVEDP), whereas verapamil increased LVEDP. These results suggest that inhibition of cGMP-PDEs can protect heart against ischemia.

Cicletanine improves myocardial function deteriorated by ischemia/reperfusion in isolated working rat hearts

Summary The effect of cicletanine, a novel furopyridine antihypertensive drug was compared with that of nitren-dipine, a dihydropyridine slow calcium channel blocker, on cardiac function and reperfusion-induced ventricular arrhythmias in isolated working rat hearts subjected to 10-min ischemia induced by ligation of the left main coronary artery followed by 10-min reperfusion. Before ischemia, cicletanine and nitrendipine, perfused at concentrations of 3 ± 10-5, 6 ± 10-5, 10-4, and 2 ± 10-4or 10-8 M, respectively, did not influence heart rate (HR), LV developed pressure (LVDP), its first derivative (LVdP/dtmax) and LV end-diastolic pressure (LVEDP), whereas aortic flow (AF) was decreased by 2 ± 10 -4 M cicletanine only. Coronary flow (CF) remained unchanged by various cicletanine concentrations but was slightly increased by nitrendipine. In the concentration range of 3 ± 10-5–10-4 M, cicletanine improved AF either in ischemia or during reperfusion, whereas 2 ± 10 -4 M had no such effect. Nitrendipine slightly attenuated ischemia/reperfusion-induced decrease in AF. Cicletanine and nitrendipine enhanced LVDP during ischemia. Ischemia-induced deterioration of LVdP/dtmax was reduced by cicletanine, during reperfusion, but this parameter was reduced by nitrendipine and the highest cicletanine concentration. Cicletanine decreased LVEDP significantly during ischemia and reperfusion, but nitrendipine had no such effect. All cicletanine concentrations reduced the incidence of irreversible ventricular fibrillation (VF) during reperfusion, an effect roughly concentration dependent in the range of 3 ± 10-5–10-4 M, whereas nitrendipine had no influence on arrhythmias.

Cromakalim and cicletanine against pacing-induced myocardial ischemia in conscious rabbits

Myocardial ischemia assessed by intracavital ST-segment elevation, shortening of ventricular effective refractory period (VERP), and increase in left ventricular end-diastolic pressure (LVEDP) was provoked by ventricular overdrive pacing (VOP) in conscious rabbits. Cromakalim (10 micrograms/kg), an ATP-sensitive K+ channel opener, and cicletanine (30 mg/kg), a cGMP-phosphodiesterase inhibitor, reduced VOP-induced ST-segment elevation and LVEDP-increase. Under resting conditions, cromakalim lowered blood pressure, increased heart rate (HR), and shortened VERP, whereas cicletanine decreased HR, prolonged VERP without changing blood pressure. Co-administration of cromakalim and cicletanine additively reduced VOP-induced ST-segment elevation, shortening of VERP, and LVEDP-increase. Cicletanine did not change cromakalim-induced hypotension but abolished reflexogenic tachycardia. This suggests that VERP shortening is not a prerequisite for the anti-ischemic effect of cromakalim, and the combination of these drugs may afford a potent and safe anti-ischemic effect without affecting hypotension induced cromakalim.

Protective effect of cicletanine on hypertension-induced decreases in the renal kallikrein-kinin and prostaglandin systems in stroke-prone spontaneously hypertensive rats

Summary: We investigated the effect of two oral (p.o.) doses of cicletanine (5 and 30 mg/kg/day) for 4 weeks on urinary excretion (UKE), renal concentration (RKC) of kallikrein, and prostaglandin E2 (PGE2) and 6-keto-PGFlα urinary excretion of stroke-prone (SP) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) rats submitted to a high sodium intake (1%). Both doses of cicletanine induced a significant antihypertensive effect in treated SHR as compared with hypertensive untreated controls (HC). After 4-week treatment, a significant difference in mortality was observed between normotensive controls (NC) (0%) and HC (84%). Both doses of cicletanine reduced the mortality of hypertensive animals (8% SHR with 5 mg and 24% SHR with 30 mg vs. 84% in HC). Whereas UKE and RKC were decreased in HC during the progression of untreated hypertension from week 1 to week 4, both doses of cicletanine administration significantly prevented this decrease. 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. This increased RKC was associated with a significantly higher rate of kallikrein biosynthesis. The increased level of the urinary excretion and tissue concentration of PGE2 and 6-keto-PGFlα in cicletanine-treated SHR as compared with untreated animals was also of interest. This protective effect on PG excretion correlated with that on kallikrein excretion. The results confirm the efficiency of cicletatine as an antihypertensive treatment. The antihypertensive action includes protective effects on potential vasodepressor kallikrein-kinin and prostaglandin systems. Furthermore, the effect on the renal kallikrein-kinin system may also indicate a functional improvement in the intracellular homeostasis of the distal connecting tubular cells, the major site for renal kallikrein production. Whereas the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors through a kinindependent mechanism has already been documented in ischemic hearts, the present data support similar effects in kidney by a new antihypertensive agent not belonging to the ACE inhibitor family.

Effects of cicletanine on vasoactive systems in conscious sinoaortic-denervated dogs

Summary— The present study investigates the antihypertensive action of cicletanine, a new antihypertensive compound with diuretic properties (or placebo), on vasopressor (catecholamines, renin‐aldosterone) as well as vasodepressor (prostaglandins, kallikrein‐kinin) systems in conscious chronic sinoaortic denervated (SAD) dogs. Cicletanine (10 mg/kg twice a day, per os, for one month) lowered blood pressure and heart rate. The antihypertensive action does not involve an effect on sympathetic tone (since plasma catecholamine levels were unmodified) or on plasma aldosterone levels. By contrast, urinary 6 keto PGF1 or PGE2 levels and kallikrein activity were enhanced. This result indicates that the antihypertensive effect of cicletanine is associated with a stimulation of potential vasodepressor systems (such as prostaglandins or kinins).

A mechanical stress increases sodium ion content in vascular smooth muscle cells through a calcium-dependent pathway: prevention by cicletanine via a cyclo-oxygenase product

The non-laminar (rather turbulent) flow induced by cell washings was able to reversibly increase the sodium ion (Na+) content in cultured A10 aortic smooth muscle cells. Similar changes, although to a lesser extent, were observed in cardiocytes but not in fibroblasts, erythrocytes, thymocytes or macrophages, suggesting that the changes are specific to excitable cells. The increase in vascular sodium content had the following properties: (1) It was inhibited by nitrendipine; (2) it was accompanied by an increase in the free cytosolic Ca2+ content; (3) it was unable to stimulate the sodium pump; and (4) it reflected the qualitative and quantitative composition of the incubation media. These observations suggested that a non-laminar flow is able to open potential-dependent calcium channels, with secondary internalization of high amounts of extracellular ions. These ionic perturbations were blocked by low concentrations of cicletanine; the half-maximal inhibitory concentration (IC50) was about 10(-9) mol/l on internal sodium. The protective effects of cicletanine were inhibited by indomethacin, suggesting that they are mediated by a cyclooxygenase metabolite, perhaps prostacyclin. Captopril and diuretic drugs such as hydrochlorothiazide, furosemide, spironolactone or acetazolamide were unable to protect vascular cells against the harmful effects of cell washings.

Dexamethasone and PAF Receptor Antagonists Do Not Modify Asphyxia-Induced Changes in Mesenterial Blood Flow in Newborn Pigs 88

Dexamethasone and PAF Receptor Antagonists Do Not Modify Asphyxia-Induced Changes in Mesenterial Blood Flow in Newborn Pigs 88

1 PLATELET-ACTIVATING FACTOR IS INVOLVED IN THE PATHOGENESIS OF NECROTIZING ENTEROCOLITIS IN ASPHYXIATED NEWBORN PIGLETS: PROTECTIVE EFFECT OF BN 50727 AND BN 50730

Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal complication in leonates. We investigated the effect of BN 50727 and BN 50730, two hetrazepine-type platelet-activating factor (PAF)-antagonists, on the development of NEC in asphyxiated newborn piglets. Animals (3 groups, n = 8 in each) were pretreated 1 h prior to the experiments with (1) BN 50727, (2) BN 50730, or (3) vehicle only (doses were 50 ng/kg for both drugs in 5 ml/kg vehicle, in gastric tube). 1 h after the induction of bilateral pneumothorax, in the critical phase (arterial hypotension, bradycardia, hypoxaemia, and combined acidosis), the piglets were resuscitated and a 24 h-recovery period was allowed to them. BN 50727 administration resulted in moderate decreases n postasphyxial tachycardia and hypertension, increased superior mesenteric artery flow, and improved oxygen saturation in the first hour of reperfusion. There were no similar changes in clinical parameters after BN 50730 treatment. Both PAF-antagonist significantly (p < 0.001) reduced the degree of histological injuries, determined by the modified method of Schneider et al (1987; Pedialr Res 21:422), in the crypts and villi of small intestine (duodenum, jejunum, ileum) of piglets 24 h after the asphyxia. In conclusion, BN 50727 and BN 50730 have a protective effect during neonatal NEC.