You are here
- Home
- Archive
- Volume 90, Issue 4
- Pharmacological modulation of the ATP sensitive potassium channels during repeated coronary occlusions: no effect on myocardial ischaemia or function
Responses
PDF
Other responses
Jump to comment:
- Richard G Fiddian-GreenPublished on: 9 January 2022
- Richard G Fiddian-GreenPublished on: 9 January 2022
- Richard G Fiddian-GreenPublished on: 9 January 2022
- Published on: 9 January 2022The risk of shooting stressed myocytes with beta blockers, pinacidil and glibenclamide.
- Richard G Fiddian-Green, FRCS, FACS
Show MoreDear Editor,
It would seem that the K+(atp) channel opener pinacidil and closer glibenclamide might exert their effects by deceasing and increasing respecitively the rates of ATP resynthesis [1,2]. The implication is that the primary determinants of ATP resynthesis, pH, substrate availability for oxidative phosphorylation and body temperature, are important determinants of the degree of H+(atp) channel openess a...
Show LessDear Editor,
It would seem that the K+(atp) channel opener pinacidil and closer glibenclamide might exert their effects by deceasing and increasing respecitively the rates of ATP resynthesis [1,2]. The implication is that the primary determinants of ATP resynthesis, pH, substrate availability for oxidative phosphorylation and body temperature, are important determinants of the degree of H+(atp) channel openess and hence the effects of pinacidil and glibenclamide. Conceivably the drugs might even have opposing actions in different myocytes in the same myocardium. Consider the possibilities in terms of the myocyte buddy hypothesis.
"Dyslipidaema" is the plasma reflection of the heterogeneity of cellular metabolic needs and their collective mass action effect upon humoral, hepatic, adrenal and adipocyte modulators of fatty acid metabolism. In stressed myocardium substrate utilisation by each myocyte will be primarily determined but its own pH, [AMP], and exposure to humoral agents such as the "exercise factor" IL-6 and other cytokines[3].
A shift from dependence upon glucose for ATP resynthesis to fatty acids might be induced in stressed myocytes by inhibition of phosphofructokinase induced by the fall in pH and/or rise in [AMP] and/or by inhibiton of the pyruvate dehydrogenase complex by the release of cytokines. In terms of the myocyte buddy hypothesis that should mean that some myocytes are more dependent upon fatty acids than others, the greater the cellular demand the greater the mass action effect in determining the accompanying plasma lipid profile. The inference is that the avalaility of ATP, the degree of openess of K+(atp) channels and the potential for pinacidil and glibenclamide to either open or close them might vary from myocyte to myocyte especially in stressed myocardium.
Propranalol decrases myocardial uptake of fatty acid nd increases the uptake of glucose, the reverse of the ompensatory lipid shidt that occurs with exercise, and causes more myocardial depression in hearts perfused with fatty acids than in those perfused with glucose [4]. The inference is that propranalol decreases the efficiency of ATP resynthesis per unit volume of flowing blood and hence the avalaility of ATP to meet the needs of stressed myocytes at that moment [5].
The cardioprotective effects of propranalol might well be the product of an increase in the degree of openess of the K+(atp) channels. In which case support for the most stressed myocytes by trmsof the myocyte buddy hypothesis should also be compromised by the propranalol and the likelihood of developing apoptosis or even necrosis increaed in the most stressed myocytes, those dependent upon fatty acids for their ATP resyntheis by residual oxidative phosphorylation. In other words proprnalol might be cytoprotective in most of the myocardium but could precipitate the development of confluent areas of myocyte apoptosis and even necrosis in the most stresed regions of compromised myocardium. That is precisely what happened wit beta blockers in the ISIS-1 trial.
In this large randomised trial of early beta-blockade in acute myocardial infarction (ISIS-1), almost all the reduction in mortality associated with the use of atenolol occurred on the day of admission or on the subsequent day [6]. "Of 217 early deaths adequate records were available for 193 (79 allocated atenolol and 114 allocated control). In the atenolol group, necropsy had shown cardiac rupture in 5 patients, and a further 15 in whom necropsy had not been done had had electro-mechanical dissociation (total, 20 early deaths from these causes); among control patients the corresponding numbers were 17 and 37 (total, 54 such deaths). Electro-mechanical dissociation was probably a manifestation of acute rupture, and the observed difference in the numbers with this complication was responsible for much of the difference in early mortality. There was a slightly higher incidence of fatal ventricular fibrillation and aortic dissection in the control group, and of bradycardia/asystole in the atenolol group"[7].
If beta blockers can cause myocardial rupture by precipitating confluent areas of myocyte apoptosis and necrosis might they might also cause myocardial fibrosis, ventricular aneurysms and chronic heart failure as previously proposed [8]. If thy do pinacidil or glibenclamide could have similar effects.
references
(1). Lembert N, Idahl LA, Ammon HP. K-ATP channel independent effects of pinacidil on ATP production in isolated cardiomyocyte or pancreatic beta-cell mitochondria. Biochem Pharmacol. 2003 Jun 1;65(11):1835-41.
(2). Muller G, Wied S, Wetekam EM, Crecelius A, Unkelbach A, Punter J. Stimulation of glucose utilization in 3T3 adipocytes and rat diaphragm in vitro by the sulphonylureas, glimepiride and , is correlated with modulations of the cAMP regulatory cascade. Biochem Pharmacol. 1994 Aug 30;48(5):985-96.
(3). Oxygen supply dependency: has it any clinical relevance? Richard G Fiddian-Green (8 September 2004) eLetter re: HJ Silverman, J Abrams, and LJ Rubin Effects of interleukin-2 on oxygen delivery and consumption in patients with advanced malignancy Chest 1988; 94: 816-821
(4). Opie LH, Thomas M. Propranolol and experimental myocardial infarction: substrate effects. Postgrad Med J. 1976;52 Suppl 4:124-32.
(5). The need for a moratorium on use of beta blockers? Richard G Fiddian-Green (7 September 2004) eLetter re: P.J. Devereaux, Salim Yusuf, Homer Yang, Peter T.-L. Choi, and Gordon H. Guyatt Are the recommendations to use perioperative ß-blocker therapy in patients undergoing noncardiac surgery based on reliable evidence? CMAJ 2004; 171: 245-247
(6). Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet. 1986 Jul 12;2(8498):57-66.
(7). Mechanisms for the early mortality reduction produced by beta- blockade started early in acute myocardial infarction: ISIS-1. ISIS-1 (First International Study of Infarct Survival) Collaborative Group. Lancet. 1988 Apr 23;1(8591):921-3. Erratum in: Lancet 1988 Jul 30;2
(8). The need to manage heart failure from an early age Richard G Fiddian-Green bmj.com, 6 Nov 2002 eLettr re: Martin R Cowie and Alex Zaphiriou Recent developments: Management of chronic heart failure BMJ 2002; 325: 422-425
Conflict of Interest:
None declared. - Published on: 9 January 2022A myocyte buddy system in stressed myocardium?
- Richard G Fiddian-Green, FRCS, FACS
Show MoreDear Editor,
It would seem, from Boron's [1,2] and our [3,4] data, that the ATP - dependent sodium pump located on the baso-lateral border of most cells might be exquisitely sensitive to the appearance of protons in interstitial fluid coming from contiguous cells under reductive stress. They might even respond by pumping protons into their cytosol and increasing their protonmotive force driving ATP resynthesis by...
Show LessDear Editor,
It would seem, from Boron's [1,2] and our [3,4] data, that the ATP - dependent sodium pump located on the baso-lateral border of most cells might be exquisitely sensitive to the appearance of protons in interstitial fluid coming from contiguous cells under reductive stress. They might even respond by pumping protons into their cytosol and increasing their protonmotive force driving ATP resynthesis by oxidative phosphorylation. In so doing the rate at which protons are removed from their cytosol and ATP is resynthesised will also be increased. Any excess of ATP produced might then become available for diffusion into contiguous myocytes whose capacity to replenish ATP stores might have been compromised.
As the severity of the reductive stress increases the cytoslic, acidois might then increase until a point at which the cells are near maximally stressed. At this point ATP synthase might reverse itself using the energy released by ATP hydrolysis in the mitochondria to increase the degree of cytoslic acidosis further by pumping mitochondrial protons into the cytosol. Temperature may also be increased increasing the rate of ATP resynthesis by increasing the rate of glycolytic turnover, the proportion being resynthesised by anaerobic glycolysis increasing progressively as the degree of dysoxia increases. At some stage a point will be reached with increasing reductive stress further begins to generate free radicals. These may cause myocyte death [5].
Perhaps it is simply the rate and degree of the development of the reductive stress induced by a coronary artery occlusion that precipitates myocyte death. Perhaps its the amount of free radicals produced or both. With increasing degrees of reductive stress survival of the myocytes should become increasingly dependent upon nutrient delivery and uptake as the degree of dysoxia increases until a point is reached at which it can no longer be met by the vasodilated vasculature in amounts that satisfy myocyte needs.
At this point a myocyte buddy system, as in scuba diving, might become operative. In the first instance the more healthy myocytes might assist the less healthy myocytes by providing them with supplementary supplies of ATP or even mopping up the lactate they are producing as their preferred substrate for ATP resyntheisis by oxidative phosphorylation. The healthy cells might also mop up some of the protons and free radicals being produced by the myocytes under stress. If tissue lactate does not accumulate in myocytes under reductive stress anaerobic glycolysis should continue to repleenish ATP stores. Should however, the removal of lactate cease ATP resynthesis in the stressed myocytes should also cease because of a mass action effect. With the apoptosis of myocytes under maximal stress the reverse might occur surving cells cannibalising the apoptotic cells for nutrient that can no longer be delivred in sufficient quantities by blood.
In this manner the onset of apoptosis might first be delayed and then retricted to isolated cells limiting the likelihood of developing dysfunction from large contiguous areas of apoptosis. Isolated apoptotic cells might even be replaced with healthy cells if the blood flow returns to normal levels. Should instead the process proceed too rapidly and be too extensive and/or be irreverible large areas of apoptosis, necrosis and an inflammatory response might develop setting the stage for irreversible myocyte damage and healing by fibrosis.
This is clearly an hyothesis but a credible one based upon accumulated facts addressed in earlier communications to Heart.
References
(1). Boron WF, Waisbren SJ, Modlin IM, Geibel JP Unique permeability barrier of the apical surface of parietal and chief cells in isolated perfused gastric glands. J Exp Biol. 1994 Nov;196:347-60.
(2). Waisbren SJ, Geibel JP, Modlin IM, Boron WF. Unusual permeability properties of gastric gland cells. Nature. 1994 Mar 24;368(6469):332-5.
(3). Dorricott NJ, Fiddian-Green RG, Silen W Mechanisms of acid disposal in canine duodenum. Am J Physiol. 1975 Jan;228(1):269-75.
(4). Fiddian-Green RG, Silen W Mechanisms of disposal of acid and alkali in rabbit duodenum. Am J Physiol. 1975 Dec;229(6):1641-8.
(5). Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ. Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol. 1993 Apr;264(4 Pt 1):C961-7.
Conflict of Interest:
None declared. - Published on: 9 January 2022Might myocardial protection be achieved by advanced perfusion with an anoxic acidic buffer?
- Richard G Fiddian-Green, FRCS, FACS
Show MoreDear Editor,
These studies do not exclude the possibility that myocardial protection might be induced independently of K+(atp) changes by priming the protonmotive force needed to drive ATP resynthesis by oxidative phosphorylation [1]. It could be an important consideration for the protonmotive force might be more easily and reliably primed in advance of angioplasty by perfusing the occluded vessel being targeted...
Show LessDear Editor,
These studies do not exclude the possibility that myocardial protection might be induced independently of K+(atp) changes by priming the protonmotive force needed to drive ATP resynthesis by oxidative phosphorylation [1]. It could be an important consideration for the protonmotive force might be more easily and reliably primed in advance of angioplasty by perfusing the occluded vessel being targeted with an acidic buffer than by occluding the coronary artery for a limited period. Indeed the failure to have demonstrated myocardial protection in this study might have been due to the failure of coronary artery occlusion to have had a consisent and even an appreciable effect upon the intramyocardial pH and the K+(atp) channel opening with which a fall in pH may be associated.
Functional recovery was better in neonatal rabbit hearts perfused with an acidic buffered cardioplegic solution than those perfused with a basic buffered cardioplegic solution [2]. Furthermore there was a significant inverse relationship between functional recovery and intramyocardial pH achieved by the three buffers examined in this study.
Coronary artery occlusion in dogs reduces the ability of the myocardium to produce H+ and CO2 and accordingly the magnitude of the protonmotive force needed to replenish ATP stores upon reperfusion [3]. The accumulation of H+ and CO2 diminishes with repeated occlusions. Furthermore the decrement in H+ accumulation between the first and second occlusions correlates with the duration of occlusion and is related to the impairment of anterior wall systolic shortening present after the first reperfusion period [4]. These studies are consistent with the hypothesis [2] that the ability to replenish ATP stores upon reperfusion is a function of the ability to generate a protonmotive force and that during ischaemia this is an active process, possibly one catalysed by reversal of ATP synthase.
At the Mayo Clinic optimal metabolic protection of the heart in cardiac surgery, defined in terms of improved postoperative outcome in patients, is said to occur when the temperature-corrected integrated mean pH is maintained at 6.8 or higher [5]. This implies that there may be a limit to the cardioprotective benefits likely to be conferred by priming the protonmotive force.
Within 30 minutes of storing human atrial samples in low pH (pH<_7 buffers="buffers" apoptosis="apoptosis" was="was" detected="detected" with="with" proapoptotic="proapoptotic" markers="markers" including="including" exposure="exposure" to="to" phosphatidyl="phosphatidyl" serine="serine" cytochrome="cytochrome" c="c" apoptotic="apoptotic" protease-="protease-" activating="activating" factor-1="factor-1" and="and" caspase-3="caspase-3" _6.="_6." the="the" degree="degree" of="of" present="present" correlated="correlated" intramyocardial="intramyocardial" acidosis="acidosis" present.="present." in="in" a="a" complementary="complementary" study="study" pigs="pigs" having="having" open="open" heart="heart" surgery="surgery" postacidotic="postacidotic" reperfused="reperfused" cardiac="cardiac" tissue="tissue" also="also" ph="ph" dependent="dependent" approximately="approximately" threefold="threefold" greater="greater" than="than" precross-clamp="precross-clamp" levels.="levels." this="this" suggests="suggests" that="that" not="not" only="only" might="might" there="there" be="be" limit="limit" cardioprotective="cardioprotective" benefits="benefits" priming="priming" protonmotive="protonmotive" force="force" but="but" risk="risk" inducing="inducing" permanant="permanant" damage="damage" if="if" exceeded.="exceeded." p="p"/> pH 6.90 is close to the pH 6.86 we found to distiinguish sigmoid mucosa that developed severe ischaemic colitis after aortic surgery from that which did not [7,8]. Importantly in our study we found little correlation between the intramucosal pH and the vascular anatomy and stump pressures present. The inference is that it would be impossible to determine how low the intramyocardial pH might have fallen even with complete occlusion of the LAD as in this study. The failure to have demonstrated any myocardial protection in the present study might, therefore, simply be a reflection of the unpredictable effects of coronary artery occlusion upon intramyocardial pH. Our experience with acute and chronic ischaemia suggests that in some instances the pH might not have fallen at all even with complete occlusion [9].
In hepatocytes in which ATP resynthesis was inhibited some 95% with iodoacetate and KCN the formation of plasma membrane blebs accompanied all types of injury [10]. Cell death was a rapid event initiated by rupture of a plasma membrane bleb coincident with the onset of irreversible injury. An increase of cytosolic free Ca2+ was not the stimulus for bleb formation or the final common pathway leading to cell death. The cytosolic pH fell by more than 1 pH unit during this reductive stress and the acidosis was cytoprotective even though the pH fell well below 6.90. Cell death was more likely to occur in the presence than in the absence of oxygen and mitochondrial oxygen radical formation by complex III was involved in the cell killing [11].
How might the apparently beneficial effects of even a pH less than pH 6.86 be reconciled with the risks of apoptosis and free radical damage? Might it be that apoptosis, an ATP-dependent process, is an altruistic sacrifice intended to protect adjacent cells from the harmful effects of the inflammatory response induced by free radical release and cellular necrosis should it occur? [The absence of an inflammatory response in apoptosis is a striking feature distinguishing it from necrosis]. Might apoptosis even be a physiological stimulus for myocyte renewal [12]?
In other words might the beneficial effects of a progressive increase in the magnitude of the protonmotive force be succeeded by apoptosis when the beneficial effects are exceeded and an unacceptable energy demand/supply imbalance develops? Furthermore might the apoptotic cells then be replaced just as they are in the very dynamic process present in the gut mucosa, the development of a inflammatory response possibly compromising cell renewal? [The answer to this question might lie in a comparison between the scarless healing of wounds in utero and the scarred healing of wounds in adults].
Troponin T cross-linking occurs in human cardiac myocytes concomitantly with both apoptosis and autopsy autolysis [13]. This sugests that the troponin T release, used amongst other things to demonstrate the myocardial protection of ischaemia preconditioning in patients having coronary artery surgery [1], is incapable of distinguishing myocyte apoptosis from necrosis. It is conceivable that troponin T release might even be a passive reflection of the increase in cellular permeability that may occur independently of morphological evidence of cellular injury when the pH falls to abnormally low levels(14).
In conclusion,
1. The effects of coronary artery occlusion on intramyocardial pH are unpredictable
2. It would be easier to control the degree of acidosis induced in preconditoning by using an acidic buffer than by using coronary artery occlusion.
3. Perfusing a stenotic coronary artery being targeted for angioplasty with a very acidotic anoxic buffer might be a better way of limiting the risk of developing ischaemia/reperfusion injury in the myocardium than ischaemic preconditioning.
4. The degree of benefit obtained by priming the protonmotive force can be expected to be inversely related to the degree of dysfunction and apoptosis caused.
5. The dysfunction and apoptosis might be benign and even completely reversible events.
6. Troponin T release might not be a reliable measure of irreversible myocardial damage.References
(1). Fiddian-Green RG. eLetters re: DP Jenkins, WB Pugsley, AM Alkhulaifi, M Kemp, J Hooper, and DM Yellon Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery Heart 1997; 77: 314-318
(2). Iannettoni MD, Bove EL, Fox MH, Groh MA, Bolling SF, Gallagher KP. The effect of intramyocardial pH on functional recovery in neonatal hearts receiving St. Thomas' Hospital cardioplegic solution during global ischemia. J Thorac Cardiovasc Surg. 1992 Aug;104(2):333-43.
(3). Khuri SF, Axford TC, Garcia JP, Khabbaz KR, Dearani JA, Khait I, Zolkewitz M, Healey NA. Metabolic correlates of myocardial stunning and the effect of cardiopulmonary bypass. J Card Surg. 1993 Mar;8(2 Suppl):262-70.
(4). Warner KG, Khuri SF, Marston W, Sharma S, Butler MD, Assousa SN, Saad AJ, Siouffi SY, Lavin PT. Significance of the transmural diminution in regional hydrogen ion production after repeated coronary artery occlusions. Circ Res. 1989 Mar;64(3):616-28.
(5). Dearani JA, Axford TC, Patel MA, Healey NA, Lavin PT, Khuri SF. Role of myocardial temperature measurement in monitoring the adequacy of myocardial protection during cardiac surgery. Ann Thorac Surg. 2001 Dec;72(6):S2235-43;
(6).Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V, Crittenden MD, Khuri SF. Acidosis-induced apoptosis in human and porcine heart. Ann Thorac Surg. 2004 Apr;77(4):1376-83.
(7). Fiddian-Green RG, Amelin PM, Herrmann JB, Arous E, Cutler BS, Schiedler M, Wheeler HB, Baker S. Prediction of the development of sigmoid ischemia on the day of aortic operations. Indirect measurements of intramural pH in the colon. Arch Surg. 1986 Jun;121(6):654-60.
(8). Schiedler MG, Cutler BS, Fiddian-Green RG. Sigmoid intramural pH for prediction of ischemic colitis during aortic surgery. A comparison with risk factors and inferior mesenteric artery stump pressures. Arch Surg. 1987 Aug;122(8):881-6.
(9). Fiddian-Green RG, Stanley JC, Nostrant T, Phillips D Chronic gastric ischemia. A cause of abdominal pain or bleeding identified from the presence of gastric mucosal acidosis. J Cardiovasc Surg (Torino). 1989 Sep-Oct;30(5):852-9.
(10). Herman B, Gores GJ, Nieminen AL, Kawanishi T, Harman A, Lemasters JJ. Calcium and pH in anoxic and toxic injury. Crit Rev Toxicol. 1990;21(2):127-48.
(11). Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ. Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol. 1993 Apr;264(4 Pt 1):C961-7
(12). Swynghedauw B Are adult cardiocytes still able to proliferate? Arch Mal Coeur Vaiss. 2003 Dec;96(12):1225-30.
(13). Gorza L, Menabo R, Di Lisa F, Vitadello M. Troponin T cross- linking in human apoptotic cardiomyocytes. Am J Pathol. 1997 Jun;150(6):2087-97.
(14). A. L. Salzman, H. Wang, P. S. Wollert, T. J. Vandermeer, C. C. Compton, A. G. Denenberg and M. P. Fink Endotoxin-induced ileal mucosal hyperpermeability in pigs: role of tissue acidosis. Am J Physiol Gastrointest Liver Physiol 266: G633-G646, 1994;
Conflict of Interest:
None declared.