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M V Cohen

Publications and source records attributed to M V Cohen.

At least 19 recordsLinked to original sources
PubMed2004

Augmented taurine release is not the mechanism of ischemic preconditioning's cardioprotection.

In ischemic preconditioning (IPC) a brief ischemic period protects the heart from a subsequent ischemic insult by an unknown mechanism. Osmotic swelling has been proposed to be a major cause of cell death when ischemic tissue is reperfused. The present study tests whether the preconditioned heart during reperfusion might release more taurine, an important osmolyte in the cardiac myocytes, to decrease cellular osmolarity, oppose swelling, and preserve viability. We collected the coronary effluent from isolated rabbit hearts for 10 min before and 10 min after preconditioning with 5 min of global ischemia. The heart then experienced 15 min of global ischemia and effluent was collected during reperfusion for 40 min. A control group was studied similarly but without the preconditioning ischemia. Fifteen min of ischemia was chosen to avoid any taurine release caused by ischemic cell death. Taurine was measured with HPLC. In the IPC group there was a postischemic release over baseline of 5.09 +/- 1.51 micromol (approx 3.3% of the total taurine pool), whereas in the control group the release was not significantly different, 5.72 +/- 1.67 micromol. The percent of the taurine pool lost from each heart during reperfusion was calculated based on an assumption of a total content of 20 microM taurine/gm wet weight. Since the amount of taurine released by the isolated rabbit heart following ischemia was not different in preconditioned and non-preconditioned hearts, we conclude that reduced swelling through taurine release is not the mechanism of the cardioprotective effects of IPC.

Animals↗
PubMed2001

Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generating free radicals and opening mitochondrial K(ATP) channels.

It has been assumed that all G(i)-coupled receptors trigger the protective action of preconditioning by means of an identical intracellular signaling pathway. To test this assumption, rabbit hearts were isolated and perfused with Krebs buffer. All hearts were subjected to a 30-minute coronary artery occlusion followed by 120 minutes of reperfusion. Risk area was measured with fluorescent particles and infarct size with triphenyltetrazolium chloride staining. Control hearts showed 29.1+/-2.8% infarction of the risk zone. A 5-minute infusion of acetylcholine (0.55 mmol/L) beginning 15 minutes before the 30-minute occlusion resulted in significant protection (9.2+/-2.7% infarction). This protection could be blocked by administration of 300 micromol/L N-2-mercaptopropionyl glycine (MPG), a free radical scavenger, or by 200 micromol/L 5-hydroxydecanoate (5-HD), a mitochondrial K(ATP) antagonist, for 15 minutes beginning 5 minutes before the acetylcholine infusion (35.2+/-3.9% and 27.8+/-2.4% infarction, respectively). Similar protection was observed with other known triggers, ie, bradykinin (0.4 micromol/L), morphine (0.3 micromol/L), and phenylephrine (0.1 micromol/L), and in each case protection was completely abrogated by either MPG or 5-HD. In contrast, protection by adenosine or its analog N(6)-(2-phenylisopropyl) adenosine could not be blocked by either MPG or 5-HD. Therefore, whereas most of the tested agonists trigger protection by a pathway that requires opening of mitochondrial K(ATP) channels and production of free radicals, the protective action of adenosine is not dependent on either of these steps. Hence, it cannot be assumed that all G(i)-coupled receptors use the same signal transduction pathways to trigger preconditioning.

Acetylcholine↗
PubMed2001

Acute alcohol-induced protection against infarction in rabbit hearts: differences from and similarities to ischemic preconditioning.

Recent studies reveal that brief ethanol exposure induces cardioprotection against simulated ischemia in cardiomyocytes by the activation of protein kinase C- epsilon. The present study tests the ability of ethanol to induce protection in rabbit hearts in which infarct size was the end-point and explores the signal transduction pathways involved. In isolated rabbit hearts, 50 m m ethanol infused for 5 min with 10 min of washout prior to 30 min of regional ischemia reduced infarct size (triphenyltetrazolium chloride staining) by 49%. Neither adenosine receptor blockade with 8-(p -sulfophenyl) theophylline nor the free radical scavenger N-2-mercaptopropionyl glycine inhibited the protection triggered by ethanol. In contrast, protein kinase C inhibition with chelerythrine, protein tyrosine kinase inhibition with genistein, and blockade of ATP-sensitive potassium channels (K(ATP)) with either 5-hydroxydecanoate or glibenclamide did abolish protection. Thus, transient ethanol exposure followed by washout prior to ischemia elicits a preconditioning-like effect involving protein kinase C, at least one protein tyrosine kinase, and K(ATP)channels, but neither adenosine nor free radicals.

Adenosine Triphosphate↗
PubMed2001

Acute ethanol exposure fails to elicit preconditioning-like protection in in situ rabbit hearts because of its continued presence during ischemia.

OBJECTIVES: Is the timing of exposure critical for ethanol's ability to induce cardioprotection? BACKGROUND: Acute ethanol exposure has been reported to mimic ischemic preconditioning in vitro, but it failed to protect in situ. We hypothesized that these conflicting findings were related to ethanol's presence during ischemia in situ. METHODS: The effect on infarct size (triphenyltetrazolium chloride) of acute ethanol exposure (0.35, 0.7, and 1.4 g/kg IV) 10 min before ischemia was measured in open-chest rabbits after 30 min of regional ischemia and reperfusion and was compared to ethanol's ability to reduce infarct size in isolated hearts in which the timing of ethanol exposure could be varied. RESULTS: Ethanol exposure in situ shortly before ischemia did not reduce infarct size. Moreover, ethanol abolished protection from both ischemic preconditioning and mitochondrial KATP channel activation. In contrast, in buffer-perfused hearts exposed to 10 to 50 mmol/liter ethanol for 5 min followed by washout before ischemia, infarct size was significantly reduced. When ethanol exposure was prolonged until the end of ischemia in isolated hearts, protection was abolished. Conversely, protection was seen when ethanol was infused in situ followed by removal of the heart and perfusion with ethanol-free buffer prior to ischemia in a Langendorff preparation. When 50 min were allowed to metabolize the ethanol prior to ischemia, protection could also be shown in situ. CONCLUSIONS: Ethanol exposure followed by washout or sufficient time to metabolize the alcohol prior to ischemia induces preconditioning-like myocardial protection. However, if present throughout ischemia, ethanol actually blocks all preconditioning-related protection.

Animals↗
PubMed2001

Amp 579 reduces contracture and limits infarction in rabbit heart by activating adenosine A2 receptors.

To determine the mechanism by which AMP 579, an adenosine A1/A2 agonist, administered at reperfusion protects ischemic myocardium, buffer-perfused rabbit hearts were subjected to 30 min of global ischemia and 2 h of reperfusion. AMP 579 (500 nM) was included in the reperfusate for the first 70 min. Average left ventricular diastolic pressure during reperfusion in hearts receiving AMP 579 was lower than that in control hearts (17.9 +/- 2.4 vs. 39.0 +/- 6.5 mm Hg, p < 0.05), indicating attenuation of contracture. Left ventricular developed pressure and coronary flow during reperfusion were also significantly improved with AMP 579 treatment. AMP 579's anti-contracture effect was blocked by the adenosine A2-receptor antagonist 8-(3-chlorostyryl)caffeine (CSC), but not by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). CSC, but not DPCPX, also blocked AMP 579's ability to preserve developed pressure and coronary flow in these hearts. AMP 579 significantly reduced infarction in isolated hearts subjected to regional ischemia. The anti-infarct effect again was abolished by CSC but not by DPCPX. Finally, we tested whether 5'-(N-ethylcarboxamido)adenosine (NECA), another A1/A2 agonist, also administered for the initial 70 min of reperfusion, could duplicate the anti-infarct effect of AMP 579. One-hundred-nanomolar NECA duplicated the protection, but neither 50 nM CGS21680, a selective A2 agonist, nor 100 microM adenosine was protective. Therefore, AMP 579 given at reperfusion reduces contracture and infarction. Anti-contracture and anti-infarct effects require the adenosine A2, but not the A1, receptor suggesting that prevention of contracture and tissue salvage are mechanistically related. Not all A2 agonists were able to duplicate the anti-infarct effect, suggesting something unique about AMP579.

Animals↗
PubMed2001

Menadione mimics the infarct-limiting effect of preconditioning in isolated rat hearts.

The role of mitochondrial free radicals in the cardioprotective effect of ischemic preconditioning was examined in isolated buffer-perfused rat hearts. Infarct size in control rat hearts subjected to 30 min of regional ischemia and 120 min of reperfusion was 32.6 +/- 3.4% of the risk zone. Ischemic preconditioning (3 cycles of 5-min global ischemia/5-min reperfusion) before the same regional ischemia and reperfusion protocol significantly reduced infarct size to 2.6 +/- 0.8% of the risk zone. Perfusion with menadione (3.0 microM), a generator of mitochondrial free radicals, in lieu of preconditioning ischemia significantly reduced infarction to 10.9 +/- 2.7%. N-2-mercaptopropionylglycine (1.0 mM), a free radical scavenger, blocked the protection of menadione, significantly increasing infarction to 23.5 +/- 1.1%. Myxothiazol (0.6 microM), a site III mitochondrial inhibitor, blocked the protection of menadione and significantly increased infarction to 25.2 +/- 3.8%. The infarct-limiting effect of menadione was attenuated to 19.7 +/- 1.5% of the risk zone by 10 microM SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Furthermore, menadione significantly increased p38 MAPK phosphorylation to a level 5.6-fold over basal. These results indicate that free radicals that originate within mitochondria can activate p38 MAPK and protect hearts against infarction.

Animals↗
PubMed2001

Attenuation of oxidant stress during reoxygenation by AMP 579 in cardiomyocytes.

AMP 579, an adenosine A(1)/A(2) receptor agonist, has a strong anti-infarct effect when administered just before reperfusion. Because oxidative stress has been proposed to contribute to myocardial reperfusion injury, we tested whether AMP 579 can reduce the production of reactive oxidant species (ROS) during reoxygenation in cultured chick embryonic cardiomyocytes. The intracellular fluorescent probe 2',7'-dichlorofluorescin diacetate (DCFH) was used to detect ROS. The cells were subjected to 60 min of simulated ischemia, followed by either 15 min or 3 h of reoxygenation. AMP 579 (0.5 and 1 microM), when started 10 min before reoxygenation, significantly reduced ROS generation from 4.86 +/- 0.30 (arbitrary units) in untreated cells to 2.72 +/- 0.31 and 1.85 +/- 0.14, respectively (P < 0.05). Cell death that was assessed by propidium iodide uptake was markedly reduced by AMP 579 (49.6 +/- 4.7% of control cells vs. 25.4 +/- 2.4%, P < 0.05). In contrast, adenosine did not alter ROS generation or cell death. Attenuation of ROS production by AMP 579 was completely prevented by simultaneous exposure of cells to the selective adenosine A(2) antagonist 8-(13-chlorostyryl) caffeine. These results indicate that AMP 579 directly protects cardiomyocytes from reperfusion injury by a mechanism that attenuates intracellular oxidant stress. Furthermore, adenosine could not duplicate these effects.

Adenosine↗
PubMed2001

Effect of weight loss on the ECG of normotensive morbidly obese patients.

BACKGROUND: Morbid obesity produces a variety of ECG alterations, including leftward shifts of the P-wave, QRS, and T-wave axes; disproportionately high frequencies of low QRS voltage; left ventricular hypertrophy and left atrial abnormality; and a high frequency of T-wave flattening in the inferior and lateral leads. This study was designed to assess the effects of substantial weight loss on the ECG in morbid obesity. METHODS: We performed a resting 12-lead ECG on 60 normotensive patients (48 women and 12 men; mean +/- SD age, 37 +/- 7 years), whose body weight was twice their ideal body weight prior to and at the time of maximum weight loss after bariatric surgery. RESULTS: Mean weight decreased from 136 +/- 7 to 85 +/- 3 kg. Weight loss produced significant decreases in the frequencies of low QRS voltage; Romhilt-Estes point score > or = 5 points; SV(1) + RV(5) or V(6) > 35 mm; RV(5) or V(6) > 26 mm; RaVL > 11 mm; RaVL > or = 7.5 mm; SaVR > 14 mm; P-terminal force more negative than - 0.04 mm.s in lead V(1); and T-wave flattening in the inferior, lateral, and inferolateral leads. Weight loss significantly shifted the mean P-wave, QRS, T-wave axes rightward, and significantly reduced mean RaVL and mean SaVR voltage. CONCLUSION: Substantial weight loss is capable of reversing many of the ECG alterations associated with morbid obesity.

Adolescent↗
PubMed2000

Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals.

The critical time for opening mitochondrial (mito) K(ATP) channels, putative end effectors of ischemic preconditioning (PC), was examined. In isolated rabbit hearts 29+/-3% of risk zone infarcted after 30 minutes of regional ischemia. Ischemic PC or 5-minute exposure to 10 micromol/L diazoxide, a mito K(ATP) channel opener, reduced infarction to 3+/-1% and 8+/-1%, respectively. The mito K(ATP) channel closer 5-hydroxydecanoate (200 micromol/L), bracketing either 5-minute PC ischemia or diazoxide infusion, blocked protection (24+/-3 and 28+/-6% infarction, respectively). However, 5-hydroxydecanoate starting 5 minutes before long ischemia did not affect protection. Glibenclamide (5 micromol/L), another K(ATP) channel closer, blocked the protection by PC only when administered early. These data suggest that K(ATP) channel opening triggers protection but is not the final step. Five minutes of diazoxide followed by a 30-minute washout still reduced infarct size (8+/-3%), implying memory as seen with other PC triggers. The protection by diazoxide was not blocked by 5 micromol/L chelerythrine, a protein kinase C antagonist, given either to bracket diazoxide infusion or just before the index ischemia. Bracketing preischemic exposure to diazoxide with 50 micromol/L genistein, a tyrosine kinase antagonist, did not affect infarction, but genistein blocked the protection by diazoxide when administered shortly before the index ischemia. Thus, although it is not protein kinase C-dependent, the protection by diazoxide involves tyrosine kinase. Bracketing diazoxide perfusion with N:-(2-mercaptopropionyl) glycine (300 micromol/L) or Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (7 micromol/L), each of which is a free radical scavenger, blocked protection, indicating that diazoxide triggers protection through free radicals. Therefore, mito K(ATP) channels are not the end effectors of protection, but rather their opening before ischemia generates free radicals that trigger entrance into a preconditioned state and activation of kinases.

Adenosine Triphosphate↗
PubMed2000

Favorable remodeling enhances recovery of regional myocardial function in the weeks after infarction in ischemically preconditioned hearts.

BACKGROUND: In a previous study, we found that recovery of segment shortening in the ischemic zone of conscious, chronically instrumented rabbits was significantly better in ischemically preconditioned than control animals after 72 hours of reperfusion. However, although this period of reperfusion was felt to be sufficient to allow recovery from stunning, regional function was disproportionately low for the size of the infarcts. METHODS AND RESULTS: To further characterize the recovery of left ventricular regional function, rabbits were chronically instrumented with a balloon occluder around a branch of the left coronary artery and a pair of ultrasonic crystals to monitor segment shortening in the ischemic zone. The preconditioned group had 1 cycle of 5-minute occlusion/10-minute reperfusion before a 30-minute occlusion, whereas control rabbits experienced only the 30-minute occlusion. All monitored segments were either dyskinetic or akinetic during the 30-minute occlusion. There was no difference in function between the 2 groups until 24 hours of reperfusion. At 72 hours, systolic shortening in control hearts averaged only 5% of the preischemic value, whereas shortening was 29% of baseline in preconditioned hearts. By day 21, systolic shortening averaged 26% in control hearts and 65% in preconditioned hearts (P<0.02) and appeared to have reached a plateau. Infarct size was 31.4+/-2.8% and 15.5+/-2.1% in control and preconditioned hearts, respectively. Moreover, in ischemically preconditioned hearts, the recovery of regional function was better than in controls for any given amount of microinfarction in the myocardial segment between crystals (P=0.02). CONCLUSIONS: The progressive improvement in preconditioned hearts is most consistent with favorable remodeling in the ischemic zone, which the preconditioning process seems to accentuate.

Animals↗
PubMed2000

The electrocardiogram in morbid obesity.

Electrocardiographic variables that occurred with significantly higher frequency in morbidly obese patients than in lean controls were low QRS voltage, leftward shift of the P, QRS, and T axes and multiple electrocardiographic criteria for left ventricular hypertrophy and left atrial enlargement. P-terminal force, RaVL, SaVR, and R/S ratio in lead V1 values were significantly higher in morbidly obese than in lean subjects.

Adult↗
PubMed2000

Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart: evidence for involvement of p38 MAPK.

Recent studies suggest that p38 mitogen-activated protein kinase (MAPK) may be involved in ischemic preconditioning (PC). To further test this possibility, the regulation of MAPK-activated protein kinase 2 (MAPKAPK2), a kinase immediately downstream from p38 MAPK, and the activity of c-Jun NH(2)-terminal kinase (JNK), a second MAPK, were examined in preconditioned hearts. Isolated, perfused rabbit hearts were subjected to 20 to 30 minutes of global ischemia. Ventricular biopsies before treatment and after 20 minutes of ischemia were homogenized, and the activities of MAPKAPK2 and JNK were evaluated. For the MAPKAPK2 experiments, 7 groups were studied, as follows: control hearts; preconditioned hearts; hearts treated with 500 nmol/L R(-) N(6)-(2-phenylisopropyl) adenosine (PIA), an A(1)-adenosine receptor agonist; preconditioned hearts pretreated with 100 micromol/L 8-(p-sulfophenyl) theophylline (SPT), an adenosine receptor antagonist; preconditioned hearts also treated with SB 203580, a potent inhibitor of p38 MAPK activation; hearts treated with 50 ng/mL anisomycin (a p38 MAPK/JNK activator); and hearts treated with both anisomycin (50 ng/mL) and the tyrosine kinase inhibitor genistein (50 micromol/L). MAPKAPK2 activity was not altered in control hearts after 20 minutes of global ischemia. By contrast, there was a 3.8-fold increase in activity during ischemia in preconditioned hearts. Activation of MAPKAPK2 in preconditioned hearts was blocked by both SPT and SB 203580. MAPKAPK2 activity during ischemia increased 3.5-fold and 3.3-fold in hearts pretreated with PIA or anisomycin, respectively. MAPKAPK2 activation during ischemia in hearts pretreated with anisomycin was blocked by genistein. In separate hearts, anisomycin mimicked the anti-infarct effect of PC, and that protection was abolished by genistein. JNK activity was measured in control and preconditioned hearts. There was a comparable, modest decline in activity during 30 minutes of global ischemia in both groups. As a positive control, a third group of hearts was treated with anisomycin before global ischemia, and in these, JNK activity increased by 290% above baseline. These results confirm that the p38 MAPK/MAPKAPK2 pathway is activated during ischemia only if the heart is in a preconditioned state. These data further support p38 MAPK as an important signaling component in ischemic PC.

Animals↗
PubMed2000

Exogenous nitric oxide can trigger a preconditioned state through a free radical mechanism, but endogenous nitric oxide is not a trigger of classical ischemic preconditioning.

Nitric oxide (NO) has been reported to play an important role in the late phase of ischemic preconditioning (PC) in the rabbit heart. However, the role of NO in the early phase of ischemic PC ("classical PC") is controversial. Accordingly, the present study was designed to determine whether NO contributes to the cardioprotective effect of classical PC in rabbits. Isolated hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.2+/-3.3% of the risk zone. PC with 5 min of global ischemia and 10 min of reperfusion reduced infarct size to 10.2+/-2.4% (P<0.05). Perfusion with 2 microm S-nitroso-N-acetylpenicillamine (SNAP), a NO donor, in lieu of ischemia mimicked PC (4.4+/-1.9% infarction, P<0.01 v control). To determine whether this protection was dependent on either protein kinase C (PKC) as has previously been demonstrated for classical PC or free radicals known to be produced during exogenous NO administration, chelerythrine (5 microm), a PKC inhibitor, or N-(2-mercaptopropionyl)-glycine (300 microm), a free radical scavenger, was administered with or shortly after SNAP. Neither drug had any independent effect on infarct size, and each blocked SNAP's cardioprotection (31.0+/-5.1 and 25.7+/-5.2% infarction, resp.). N(omega)-nitro- L -arginine methyl ester (L -NAME, 100 microm), a NO synthase inhibitor, failed to block the cardioprotection from the above ischemic PC protocol (9.5+/-2.8% infarction, P<0.05 v control). L -NAME alone had no effect on infarct size (30.6+/-2.7%). These results suggest that the beneficial effect of exogenous NO production during SNAP pretreatment is mediated by a protein kinase C-dependent pathway via MPG-sensitive oxidants. However, we were unable to show any contribution of endogenous NO to classical PC's protection in isolated rabbit hearts.

Animals↗
PubMed2000

No confirmation for a causal role of volume-regulated chloride channels in ischemic preconditioning in rabbits.

Volume-regulated chloride channels have recently been proposed to be end-effectors in ischemic preconditioning. The present study attempted to confirm this hypothesis by looking both at cardioprotection and channel activity. In isolated rabbit cardiomyocytes, hypo-osmotic stress (167 mosm/l) induced a current with a magnitude of 2-5 pA/pF at 60 mV. That current could be blocked by the selective chloride channel blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) or indanyloxyacetic acid 94 (IAA-94), but only at 100 microM and 1 m M respectively. Lower concentrations were not effective. Because the channel-blocking concentrations were toxic in isolated perfused rabbit hearts, as evidenced by cessation of cardiac contraction and massive infarction, neither agent could be tested against preconditioning's anti-infarct effect. NPPB and IAA-94 at 1 microM and 10 microM, respectively (the doses used in a previous report), did not affect coronary flow, heart rate and developed pressure, and also did not prevent the infarct size reduction of ischemic preconditioning with 5 min global ischemia/10 min reperfusion preceding 30 min of regional ischemia and 120 min of reperfusion [11. 4(+/-3.6) and (11.1(+/-3.7)% infarction of risk area, respectively]. The volume-regulated chloride and organic osmolyte channel blocker 4, 4;-diisothiocyanostilbene-2,2;-disulfonic acid (DIDS) at 100 microM blocked the hypo-osmotically induced current in myocytes, but again could not be used, since it induced total cessation of cardiac contraction and reduced infarct size in non-preconditioned hearts. Our data do not confirm a prior study on a causal role for volume-regulated chloride channels in the protection of ischemic preconditioning. This hypothesis remains to be adequately tested.

Animals↗
PubMed2000

Limitation of infarct size in rabbit hearts by the novel adenosine receptor agonist AMP 579 administered at reperfusion.

The novel A(1)/A(2)adenosine receptor agonist AMP 579 has been reported to reduce myocardial infarct size in pig and dog. The present study tested the effect of AMP 579 in two rabbit models. In open-chest rabbits undergoing 30 min of regional ischemia and 3 h of reperfusion AMP 579 (3 microg/min/kg) reduced infarct size when treatment was started either 10 min before ischemia or 10 min prior to reperfusion from 36.4+/-3.1% of the risk zone in untreated hearts to 11.8+/-4.4 and 12.3+/-1.0%, respectively. To determine whether protection observed when the drug was administered shortly before reperfusion represented a long-lasting effect rather than merely a transient delay of necrosis, the chest wound was closed in layers and the rabbits permitted to recover. After 3 days the hearts were removed to evaluate infarct size. Continued limitation of infarct size after 3 days of reperfusion (8.2+/-2.8% of the risk zone) confirmed that sustained tissue salvage had been conferred by the drug. In isolated, buffer-perfused rabbit hearts undergoing 30 min of regional ischemia and 2 h of reperfusion, AMP 579 again limited infarct size (8.6+/-2.9% of the risk zone) when treatment started 10 min prior to reperfusion, arguing against an anti-leukocyte mechanism of protection. AMP 579's protective effect in this in vitro model was abrogated by 8-(p-sulfophenyl)theophylline, indicating that it was mediated through adenosine receptors. We conclude that AMP 579 given just prior to reperfusion may be an effective anti-infarct intervention.

Animals↗