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C A Muller

Publications and source records attributed to C A Muller.

At least 19 recordsLinked to original sources
PubMed2001

Angiotensin-converting enzyme inhibition enhances a subthreshold stimulus to elicit delayed preconditioning in pig myocardium.

OBJECTIVES: We assessed the effect of angiotensin-converting enzyme (ACE) inhibition in combination with a subthreshold preconditioning (PC) stimulus to elicit delayed preconditioning against infarction in pig myocardium. BACKGROUND: Bradykinin triggers early PC. Angiotensin-converting enzyme inhibitors increase local bradykinin levels via inhibition of kinin breakdown and have been shown in experimental studies to augment early protection afforded by PC. A role for bradykinin in eliciting delayed PC has not so far been identified. METHODS: We used a two-day protocol. On day 1 (closed chest), pigs were either sham-operated (group 1) or preconditioned, using balloon catheter inflation of the left anterior descending (LAD) coronary artery, with either a full (4 x 5 min PC, group 2) or subthreshold PC stimulus (2 x 2 min PC, group 3). Additional groups were pre-treated with perindoprilat (0.06 mg/kg i.v.) before sham (group 4) or subthreshold PC (group 5). On day 2 (open chest), all pigs were subjected to 40 min occlusion of the LAD followed by 3 h of reperfusion. Infarct size was determined by tetrazolium staining. RESULTS: Group 1 had a mean infarct size of 42.8+/-3.2% of the risk zone. Preconditioning with 4 x 5 min reduced the infarct size to 19.5+/-3.9% (p < 0.05). Groups 3 and 4 had infarct sizes not statistically different from group 1. However, combining perindoprilat with subthreshold PC resulted in a significant limitation of the infarction (18.4+/-3.1% p < 0.05), comparable with group 2. CONCLUSIONS: This is the first study to show that ACE inhibition can augment a mild ischemic stimulus to induce a protected state 24 h later.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Hydrocortisone treatment of early SIRS in acute experimental pancreatitis.

This work studied the effects of hydrocortisone treatment in experimental acute pancreatitis on cytokines, phospholipase A2, and breakdown products of arachidonic acid and survival. Edematous and necrotizing pancreatitis were induced in Wistar rats by cerulein hyperstimulation and retrograde intraductal infusion of sodium taurocholate, respectively. Hydrocortisone (10 mg/kg) was administered intravenously 10 minutes after induction of acute pancreatitis. Serum was assayed for phospholipase A2; interleukin (IL) 1beta, IL-6, IL-10, thromboxane B2; Prostaglandin E2; and leukotriene B4 at five different time points. A significant release of inflammatory mediators was seen only in the severe model. Hydrocortisone powerfully suppressed arachidonic acid breakdown products and only mildly attenuated the systemic increase of phospholipase A2 and pro- and antiinflammatory cytokines. The mortality rate after 72 hr in the severe model was 86%. Hydrocortisone treatment reduced mortality to 13% (P = 0.001; Fisher's exact test). Hydrocortisone seems to be effective in the treatment of the early systemic inflammatory response syndrome associated with severe acute pancreatitis.

Acute Disease↗
PubMed1999

Levosimendan: effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langendorff-perfused guinea pig heart.

The majority of clinically used inotropes act by increasing cytosolic calcium levels, which may hypothetically worsen reperfusion stunning and provoke arrhythmias. We tested the hypothesis that the calcium sensitizer levosimendan (levo) given during ischemia alone or ischemia and reperfusion would improve reperfusion function without promoting arrhythmias. The Langendorff-perfused guinea pig heart, subjected to 40-min low-flow ischemia (0.4 ml/min) with or without levo (10-300 nM) given during ischemia or ischemia/reperfusion was used. Left ventricular developed pressure (LVDP) was used as an index of mechanical function. The effect of levo (300 nM) or dobutamine (0.1 microM) on the incidence of ischemia/reperfusion arrhythmias was also investigated. Control hearts (vehicle-perfused) had LVDPs of 69.4 +/- 2.1 mm Hg whereas hearts treated with levo during ischemia and reperfusion (300 nM) had LVDPs of 104.5 +/- 2.7 mm Hg (p <.05). Hearts treated with levo during ischemia alone (10 nM) had reperfusion LVDPs of 95.8 +/- 4.2 mm Hg (p <.05) after 30-min reperfusion. Hearts treated with both levo and 10 microM glibenclamide (K(ATP) channel blocker) during ischemia had reperfusion LVDPs of 73.4 +/- 4.3 mm Hg after 30-min reperfusion. Of control hearts, 25% developed reperfusion ventricular tachycardia but not ventricular fibrillation. Levo-treated hearts had no ischemia/reperfusion arrhythmias whereas 83% (p <.05 versus control) of dobutamine-treated hearts developed ventricular tachycardia and 33% (p <.05 versus levo) developed reperfusion ventricular fibrillation. Levo improved reperfusion function without promoting arrhythmias in this model. This was possibly achieved by opening the K(ATP) channels during ischemia and sensitizing myocardial contractile apparatus instead of elevating cytosolic calcium levels in reperfused hearts.

Adenosine Triphosphate↗
PubMed1998

Effects of mibefradil, a novel calcium channel blocking agent with T-type activity, in acute experimental myocardial ischemia: maintenance of ventricular fibrillation threshold without inotropic compromise.

OBJECTIVES: We tested whether mibefradil, a selective T-type calcium channel blocking agent, could differentially inhibit experimental ventricular arrhythmogenesis more than contractility during acute regional ischemia and reperfusion compared with that during L-channel blockade by verapamil. BACKGROUND: T-type calcium channels are found in nodal and conduction tissue and in vascular smooth muscle, but in much lower density in contractile myocardium. The potential role of mibefradil in ventricular arrhythmogenesis remains unclear. METHODS: Mibefradil (Ro 40-5967, 1 mg/kg body weight intravenously [i.v.]) was given as a bolus 30 min before anterior descending coronary artery ligation, followed by 2 mg/kg per h i.v. during 20 min of ischemia and 25 min of reperfusion in open chest pigs. In a second group, mibefradil was given in a dose twice as high. A third group received verapamil (0.3 mg/kg i.v.), followed by an infusion of 0.6 mg/kg per h. RESULTS: During the ischemic period, the low (clinically relevant) dose of mibefradil prevented the fall of the ventricular fibrillation threshold, without depressing the maximal rate of pressure development of the left ventricle (LVmax dP/dt). This low dose increased left ventricular blood flow, whereas peripheral arterial pressure remained unchanged. The higher dose of both mibefradil and verapamil was antiarrhythmic during ischemia, at the cost of depressed contractile activity. During reperfusion, only the higher dose of mibefradil and verapamil was antiarrhythmic but both depressed contractile activity. CONCLUSIONS: Mibefradil is antiarrhythmic, without inotropic compromise. Speculatively, both T-type and L-type calcium channel blockade are involved in these effects.

Animals↗
PubMed1998

Combination of a calcium antagonist, verapamil, with an angiotensin converting enzyme inhibitor, trandolapril, in experimental myocardial ischemia and reperfusion: antiarrhythmic and hemodynamic effects of chronic oral pretreatment.

The combination of a calcium antagonist with an angiotensin-converting enzyme (ACE) inhibitor is increasingly used in the therapy of hypertension, but there are no experimental data supporting the use of this combination in acute myocardial ischemia and reperfusion. We tested the effects of oral pretreatment in a pig model, paying special attention to arrhythmias and adverse hemodynamic effects. Pigs received verapamil 240 mg + trandolapril 4 mg, verapamil 240 mg, or placebo orally once daily for 10 days, after which a coronary artery was ligated for 20 minutes and then allowed to reperfuse. The ventricular fibrillation threshold (VFT) was measured during ischemia to assess the vulnerability of the heart to ventricular fibrillation, whereas spontaneous tachyarrhythmias were monitored during reperfusion. Regional left ventricular (LV) blood flow was measured with radioactive microspheres. During the ischemic period, both the combination of verapamil plus trandolapril, and verapamil alone, prevented a fall in the VFT, indicating antiarrhythmic activity. The combination maintained LV contractile activity and cardiac output (CO) at preligation levels, whereas verapamil alone decreased cardiac output. During reperfusion, verapamil plus trandolapril prevented spontaneous ventricular tachyarrhythmias and increased blood flow in the reperfused zone. In contrast, verapamil was not antiarrhythmic and decreased CO. Thus the addition of the ACE inhibitor trandolapril to the calcium antagonist verapamil resulted in antiarrhythmic activity during ischemia and reperfusion, and produced a better hemodynamic profile.

Administration, Oral↗
PubMed1994

Chronic oral pretreatment with the angiotensin converting enzyme inhibitor, trandolapril decreases ventricular fibrillation in acute ischaemia and reperfusion.

The effect of chronic angiotensin converting enzyme (ACE) inhibition on the incidence of fatal ventricular fibrillation during regional myocardial ischaemia and reperfusion is not known. A reduction in cardiac angiotensin II and/or a vagomimetic response may result in antiarrhythmic activity. Pigs pre-treated with the ACE inhibitor trandolapril 0.3 mg.kg-1 or placebo orally for 10 days were subjected to thoracotomy. The left anterior descending coronary artery was ligated (CAL) for 20 min and reperfused for 45 min. Trandolapril decreased cardiac ACE activity and prevented the fall in the ventricular fibrillation threshold (VFT) during ischaemia: after 5 min of ischaemia the VFT in the trandolapril group was 25.5 +/- 4.6 mA (mean +/- SEM) vs 13.1 +/- 2.2 mA in the placebo group (P < 0.05). Trandolapril also decreased the incidence of spontaneous ventricular fibrillation during reperfusion to 1/6 vs 6/7 in the placebo group (P < 0.05). Heart rate in the trandolapril group fell. During ischaemia, trandolapril increased blood flow in the non-ischaemic zone, but decreased blood flow in the central ischaemic zone of the left ventricle. Similarly it decreased tissue levels of phosphocreatine in this zone. During reperfusion trandolapril increased blood flow both in non-ischaemic and central ischaemic zones. Chronic oral pre-treatment with trandolapril resulted in marked antifibrillatory effects which were associated with inhibition of cardiac ACE activity and a decreased heart rate.

Administration, Oral↗
PubMed1993

Self-peptides from four HLA-DR alleles share hydrophobic anchor residues near the NH2-terminal including proline as a stop signal for trimming.

Naturally processed MHC class II-associated peptides proved to be heterogeneous in size, varying from 13 to 25 amino acids. Truncation variants suggested sequence motifs that afford the amino termini to be shifted for obtaining an alignment: a 9- to 11-residue core region that is bordered by primary anchor residues is surrounded by extra sequences of variable lengths and hitherto unknown functions. Herein we present bulk sequencing analyses of self-peptides from four HLA-DR alleles and HLA-DQw7 clearly showing that the length of most of the NH2-terminal preanchor sequence is limited to 1 to 3 residues. Most strikingly, proline is the dominant residue reappearing at positions 2 and 3 in any allele. Proline revealed to function as a stop signal for NH2-terminal trimming as well as a secondary anchor: crude cytosolic and endosomal peptide fractions could be processed by aminopeptidases in vitro, whereupon DR1 binding peptides with increased affinity were generated. In addition, aminopeptidase treatment of DR1: self-peptide complexes implied that proline together with sterical constraints of the MHC molecule do protect the peptides' NH2-termini from further processing, whereas their COOH-termini were accessible to cathepsin B processing. Finally, bulk sequencing profiles contained signals from further putative anchor residues clustering in the NH2-terminal region:tyrosine, phenylalanine, leucine, isoleucine, and valine are enriched at positions 2 to 4 in DR1, DR5, and DR6, however, at positions 4 to 6 in DR3. Isotype-specificity is demonstrated by DQw7 displaying glutamine and asparagine at position 2. Obviously, the degenerate occurrence of aromatic or aliphatic side chains close to the NH2-terminal guarantees for essential interactions with a hydrophobic pocket of the investigated DR molecules. Most probably, this pocket is located in the nonpolymorphic DR alpha-chain rationalizing previous findings of promiscuous peptide binding to different DR alleles.

Alleles↗
PubMed1993

Synergistic effects of haemodynamic stabilisation and beta blockade on ventricular fibrillation threshold in coronary artery ligated pigs.

OBJECTIVE: The aim was (1) to test the hypothesis that the prevention of haemodynamic deterioration decreases arrhythmia formation in the infarcting heart and augments the antiarrhythmic effects of beta blockade; and (2) to assess the ventricular fibrillation threshold as an index of innate arrhythmogenic propensity. METHODS: Changes in ventricular fibrillation threshold as an index of innate arrhythmogenic propensity. METHODS: Changes in ventricular fibrillation threshold were determined for 50 min after anterior descending coronary artery occlusion in open chest pigs (group 1, n = 5). In group 2 (n = 9), ventricular fibrillation threshold was studied in the same way but cardiac output was maintained at 100 ml.min-1.kg-1 body weight and mean aortic pressure at 60(SEM 3) mm Hg by means of right heart and arterio-arterial bypass. In both groups intravenous propranolol 1.2 mg.kg-1 was injected 35-40 min after coronary artery occlusion. In group 3 (n = 6) spontaneous arrhythmias following coronary artery occlusion were recorded to test how well the ventricular fibrillation threshold reflected the incidence and time course of these arrhythmias. RESULTS: In group 1, there was a deep trough in ventricular fibrillation threshold--from 11.3(0.3) mA to 6.0(0.3) mA--within 10 min of coronary artery occlusion (47% decrease, p < 0.001). There was a shallower trough between 10 and 30 min. In group 2, preocclusion ventricular fibrillation threshold increased from 13.9(1.2) mA to 32.1(5.6) mA (p < 0.05) because of stabilised haemodynamics. After coronary occlusion, fibrillation threshold remained high throughout, being 22.7(1.3) mA and 20.4(1.1) mA at the times of the expected troughs (p < 0.005 v group 1 for both values). Propranolol increased ventricular fibrillation threshold by 24(7)% in group 1 (p < 0.05) and by 53(8)% in group 2 (p < 0.0005). In group 3 spontaneous arrhythmias followed a biphasic pattern, similar to group 1. There was a positive correlation between ventricular fibrillation threshold and arrhythmia score (r = 0.84). CONCLUSIONS: (1) Haemodynamic stabilisation increased ventricular fibrillation threshold during ischaemia and enhanced the antiarrhythmic effects of beta blockade. (2) The ventricular fibrillation threshold accurately reflects the incidence and time course of spontaneous arrhythmias in this model.

Adrenergic beta-Antagonists↗
PubMed1992

Bucindolol, a beta blocker, decreased ventricular fibrillation and maintained mechanical function in a pig model of acute myocardial ischemia.

Bucindolol is a new beta blocker with marked vasodilatory properties and intrinsic sympathomimetic activity. We tested its potential effect against ventricular fibrillation (VF), in a pig model of acute myocardial ischemia. Bucindolol 6 mg/kg IV was administered in two equally divided doses, the first 30 minutes prior to, and the second 10 minutes after, ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Bucindolol decreased the incidence of VF to 1/11 versus 14/16 in the control group (p less than 0.005). Bucindolol also decreased the duration of ventricular tachycardia, 15 +/- 8 seconds versus 104 +/- 32 seconds in the control group (p less than 0.01). Bucindolol maintained LVmaxdP/dt at predrug and pre-CAL values, whereas LVmaxdP/dt was decreased by CAL in the control group. Bucindolol decreased arterial pressure and heart rate. Bucindolol increased blood flow in the peripheral ischemic zone (24.6 +/- 1.8% versus 16.2 +/- 1.7% (percent of pre-CAL value) in controls, p less than 0.002), as well as in the nonischemic zones (periischemic zone: 126.4 +/- 6.1% versus 96.7 +/- 4.8% in the control group, p less than 0.0005; remote nonischemic zone: 126.6 +/- 7.1% versus 87.1 +/- 4.3% of pre-CAL value in the control group, p less than 0.0001). Bucindolol had marked antiarrhythmic effects that were associated with beneficial effects on the mechanical function of the left ventricle and on blood flow to the ischemic myocardium.

Adrenergic beta-Antagonists↗
PubMed1992

Antiarrhythmic effects of the angiotensin converting enzyme inhibitor perindoprilat in a pig model of acute regional myocardial ischemia.

Previous studies on the possible antiarrhythmic effects of angiotensin converting enzyme (ACE) inhibitors during early ischemia in pigs have been inconclusive or negative; however, proof of adequate ACE inhibition was not provided. Perindoprilat, 0.06 mg/kg, i.v., was administered 30 min prior to ligation of the anterior descending coronary artery (CAL) in anesthetised open-chest pigs. Plasma ACE activity was decreased by 95.0 +/- 1.9% when measured 5 min before CAL. Within 5 min of CAL, the ventricular fibrillation threshold (VFT) in the control group was decreased from 11.8 +/- 1.9 to 7.2 +/- 1.2 mA (p less than 0.01). Perindoprilat prevented the fall in the VFT and the increase in left ventricular end-diastolic pressure caused by CAL. Perindoprilat decreased arterial pressure. Cardiac output (thermodilution) was decreased by 23 +/- 3% after CAL in the control group and by only 10 +/- 5% (p less than 0.05) in the perindoprilat group (both versus pre-CAL values). In the control group cyclic AMP was increased from 0.97 +/- 0.04 (pre-CAL) to 1.16 +/- 0.04 nmol/g (p less than 0.05) in the central ischemic zone 20 min after CAL. Perindoprilat prevented this increase in cyclic AMP. Twenty minutes after CAL blood flow (microsphere method) in the nonischemic zone of the perindoprilat group was increased, whereas blood flow in the central ischemic zone was decreased compared to the control group. However, levels of tissue metabolites (ATP, phosphocreatine, lactate) measured in drill biopsies in the same zones of the two groups were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1990

Antiarrhythmic and metabolic effects of indoramin during acute regional ischemia and reperfusion in isolated rat heart.

The antiarrhythmic effect of alpha 1-adrenoceptor antagonists during myocardial ischemia and reperfusion remains controversial. The potential antiarrhythmic properties of indoramin, an alpha 1-antagonist, were assessed in the isolated perfused rat heart during regional ischemia and during sustained reperfusion. Coronary artery ligation (CAL) decreased the ventricular fibrillation threshold (VFT) of control hearts from 9.1 +/- 1.3 (pre-CAL, mean +/- SEM) to 2.1 +/- 0.5 mA 15 min post-CAL (p less than 0.0001). Perfusion with indoramin 10(-8) M (alpha 1-receptor antagonistic concentration) started 5 min prior to CAL did not prevent the fall in VFT after CAL. Indoramin 10(-6) M prevented the fall in VFT after CAL relative to the control group. Indoramin 10(-5) M markedly increased the VFT before CAL from 9.9 +/- 1.0 to 28.6 +/- 2.9 mA (p less than 0.0001) and prevented the fall in VFT after CAL. During reperfusion, indoramin 10(-5) M decreased the incidence of spontaneous ventricular fibrillation (VF) to 1 of 6 vs. 6 of 6 in the control group (p less than 0.02). Indoramin 10(-5) M preserved adenosine triphosphate in the reperfused myocardium: 2.82 +/- 0.06 vs. 2.16 +/- 0.21 mumol/g in the control group (p less than 0.05). Specific alpha 1-antagonist properties of indoramin did not appear to be involved in the antiarrhythmic effects.

Animals↗
PubMed1990

Studies in search of a suitable experimental insect model for xenodiagnosis of hosts with Chagas' disease. 4--The reflection of parasite stock in the responsiveness of different vector species to chronic infection with different Trypanosoma cruzi stocks.

Previous studies (1982, 1987) have emphasized the superiority of sylvatic vector species over domestic species as xenodiagnostic agents in testing hosts with acute or chronic infections by T. cruzi "Y" stock. The present study, which is unique in that it contains data on both infectivity rates produced by the same stock in 11 different vector species and also the reaction of the same vector species to seven different parasite stocks, establishes the general validity of linking efficiency of xenodiagnosis to the biotope of its agent. For example, infectivity rates produced by "São Felipe" stock varied from 82.5% to 98.3% in sylvatic vectors but decreased to 42.5% to 71.3% in domestic species. "Colombiana"stock produced in the same sylvatic vectors infectivity rates ranging from 12.5% to 45%. These shrank to 5%-22.5% in domestic bugs. The functional role of the biotope in the vector-parasite interaction has not been elucidated. But since this phenomenon has been observed to be stable and easy to reproduce, it leads us to believe that the results obtained are valid. Data presented also provide increasing evidence that the infectivity rates exhibited by bugs from xenodiagnosis in chronic hosts, are parasite stock specific. For example, infectivity rates produced by "Berenice", "Y", "FL" and "CL" varied in R. neglectus from 26.3% to 75%; in P. megistus from 56.3% to 83.8%; in T. sordida from 28.8% to 58.8% in T. pseudomaculata from 41.3% to 66.3% and in T. rubrovaria from 48.8% to 85%. Data from xenodiagnosis in the same hosts, carrying acute infections by the same parasite stocks, gave the five sylvatic vectors a positive rating of approximately 100%, thus suggesting that the heavy loads of parasites circulating in the acute hosts obscured the characteristic interspecific differences for the parasite stock. Nonetheless these latter were revealed in the same hosts with chronic infections stimulated by very low numbers of the same parasite stocks. Certain observations here described lead us to speculate as to the possibility of further results from other parasite stocks, allowing the association of the infectivity rates produced in bugs by different parasite stocks with the isoenzymic patterns revealed by these stocks.

Animals↗
PubMed1989

Critical role of dose in protection by propranolol against ventricular fibrillation in a pig model of acute myocardial ischemia.

We hypothesized that the antiarrhythmic efficacy of propranolol during acute myocardial ischemia could be dose related. Propranolol was administered in two equally divided doses 30 min before and 10 min after ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Only the lowest dose of propranolol, i.e., 0.1 mg/kg intravenously (i.v.) (plasma level 22 +/- 2 ng/ml) decreased the incidence of ventricular fibrillation (VF), i.e. 3 of 12 versus 16 of 20 in control group (p less than 0.01). VF incidence with propranolol 0.5 or 3 mg/kg was 4 of 6 and 8 of 9, respectively (both NS vs. control group). Propranolol 0.1 mg/kg did not change left ventricular (LV) blood flow. Propranolol 3 mg/kg reduced blood flow in the peripheral ischemic myocardium to 13.2 +/- 1.2 versus 19.2 +/- 1.4 ml/100 g/min in control group (p less than 0.01), and in the midischemic zone to 4.4 +/- 0.5 versus 7.0 +/- 0.9 ml/100 g/min in control group (p less than 0.001). Propranolol 0.1 mg/kg prevented a disparity of levels of cyclic AMP from arising between ischemic and non-ischemic myocardium, whereas propranolol 3.0 mg/kg did not. Furthermore, LV mechanical function was suppressed by propranolol 3 mg/kg. Only the lowest dose of propranolol (i.e., 0.1 mg/kg) decreased the incidence of VF in this model.

Adenosine Triphosphate↗
PubMed1988

Verapamil and tiapamil in prevention of ventricular fibrillation in pigs with coronary ligation. Comparative effects on left ventricular function.

Antiarrhythmic and hemodynamic effects of the calcium channel antagonist verapamil were compared with those of tiapamil, a congener, in open-chest pigs with anterior descending coronary artery ligation. Tiapamil (6 mg/kg i.v.) decreased the incidence of ventricular fibrillation to 4 of 10 versus 22 of 25 in controls (p less than 0.05) and maintained left ventricular dP/dtmax after ligation (predrug value: 2,312 +/- 112 mm Hg/sec; 20 minutes after ligation: 2,139 +/- 229 mm Hg/sec). Tiapamil increased blood flow in the peripheral ischemic zone (24 +/- 3.2% vs. 16.9 +/- 1.6% of preligation value in controls, p less than 0.05) as well as in the peri-ischemic and nonischemic zones (153.9 +/- 12.7% and 186.3 +/- 17.1%, respectively; both p less than 0.0001 vs. 97.9 +/- 5% and 91.3 +/- 4.7% in controls). Verapamil (0.6 mg/kg i.v.) decreased the incidence of ventricular fibrillation to 0 of 7 versus 22 of 25 in controls (p less than 0.005); left ventricular dP/dtmax decreased from 2,062 +/- 144 to 1,060 +/- 168 mm Hg/sec (p less than 0.0001). Verapamil did not change blood flow in the peripheral, peri-ischemic, or nonischemic zones. Thus, tiapamil, and not verapamil, decreased ischemic ventricular fibrillation while maintaining left ventricular mechanical function. Verapamil congeners warrant further evaluation as antiarrhythmic agents in acute myocardial ischemia.

Animals↗
PubMed1987

Calcium channel blockers and early ischemic ventricular arrhythmias: electrophysiological versus anti-ischemic effects.

Calcium antagonists are able to reduce the incidence of early ischemic arrhythmias when given as pretreatment in a variety of models of acute myocardial regional ischemia. Two possible modes of action are electrophysiologic and anti-ischemic. First, a direct electrophysiologic effect of the calcium antagonist agents on the inward calcium current could inhibit four calcium-dependent phenomena, each of which has been linked to the development of ischemic arrhythmias: the slow response, delayed afterdepolarizations (DADs) and calcium-dependent automaticity, enhanced membrane depolarization and conduction slowing. The special circumstances in which each of these could occur are delineated. An anti-ischemic effect of calcium antagonists must also be considered in some models, because of the negative inotropic, negative chronotropic and coronary and peripheral vasodilator properties. Thus far a specific role for the calcium current in early ischemic arrhythmias has only been shown in a few models and not tested in man.

Animals↗
PubMed1986

Prevention of ventricular fibrillation by metoprolol in a pig model of acute myocardial ischaemia: absence of a major arrhythmogenic role for cyclic AMP.

Absence of a Major Arrhythmogenic Role for Cyclic AMP. Journal of Molecular and Cellular Cardiology (1986) 18, 375-387. We examined the mechanism whereby beta-adrenoceptor antagonism exerts an antiarrhythmic effect in early myocardial ischaemia. Ligation of the anterior descending coronary artery in the anaesthetized open-chest pig resulted in severe transmural anteroseptal ischaemia. Blood flow in the mid-ischaemic zone 20 min after ligation was decreased to 5.7 +/- 0.7% of the preligation control value. Epicardial ST-segment deflections of 6.7 +/- 0.4 mV were recorded over this zone. A distinct phase of ventricular arrhythmias was evident about 10 to 30 min after ligation. A high incidence of ventricular fibrillation (14/16 pigs) was associated with a circumstantial increase in levels of cyclic AMP in ischaemic tissue. Twenty minute values were: 1.10 +/- 0.06, P less than 0.05 v. the non-ischaemic tissue level of 0.86 +/- 0.05 nmol/g. Propranolol 3 mg/kg IV, metoprolol 20 mg/kg IV or sotalol 10 mg/kg IV were given between 30 min prior to and 10 min after ligation. Adequate beta-adrenoceptor antagonism by each agent could be proven. Metoprolol decreased the incidence of ventricular fibrillation (2/13, P less than 0.0005 v. control group), while propranolol or sotalol did not. All three beta-antagonists decreased tissue levels of cyclic AMP prior to ligation. However, the temporary increase in ischaemic tissue after ligation could not be prevented. Furthermore, cyclic AMP in ischaemic tissue 20 min after ligation was higher in the metoprolol group than in the propranolol or sotalol group (0.94 +/- 0.04 v. 0.81 +/- 0.02 P less than 0.05, and 0.79 +/- 0.03 nmol/g P less than 0.01, respectively). Blood flow in the mid-ischaemic zone of the metoprolol group was increased to 8.6 +/- 0.6% of preligation control value (P less than 0.0001 v. control group). In contrast, blood flow in the mid-ischaemic zone of the propranolol or sotalol group was decreased. Metoprolol also reduced epicardial ST-segment deflections over the mid-ischaemic zone to 3.5 +/- 0.2 mV (P less than 0.0001 v. control group). ST-segment deflections in the propranolol group were increased. The mechanism whereby metoprolol prevented ventricular fibrillation may be explained by a decrease in the severity of ischaemia but not in terms of changes of tissue levels of cyclic AMP.

Acute Disease↗
PubMed1985

Tiapamil--a new calcium antagonist.

Calcium antagonists are an important new modality in cardiovascular therapy. Tiapamil, a congener of verapamil, is undergoing clinical and laboratory evaluation. We have undertaken experimental studies on the anti-arrhythmic properties of tiapamil, and on the intravenous use of this agent in patients with acute myocardial infarction. Reasons are given for suggesting that tiapamil warrants further clinical evaluation, after which it may join the more established calcium antagonists as a valuable therapeutic agent.

Acute Disease↗