Arterial hypertension, myocardial hypertrophy and disorders of cardiac rhythm induced by ligation of the left coronary artery in the rat

Cardiac hypertrophy and hypertension are major elements in sudden cardiac death in patients with coronary artery disease. To investigate in animals the hypothesis that left ventricular hypertrophy (LVH) and/or hypertension increase the incidence of severe ventricular arrhythmias, we have undertaken a 30 min period of coronary artery ligation in anaesthetized spontaneously hypertensive rats (SHR), normotensive (NT) Wistar Kyoto (WKY) and Wistar (W) rats. Mean systolic blood pressure (SBP) was 190 +/- 4 mmHg in SHR vs 123 +/- 5 mmHg in WKY and 116 +/- 4 mmHg in W (p less than 0.001). LVH index was 2.81 +/- 0.04 in SHR vs 196 +/- 0.03 in WKY and 1.65 +/- 0.05 in W (p less than 0.01). Incidence (IVF) and duration (DVF) of ventricular fibrillation were significantly more elevated in SHR than in NT rats. IVF was 100 p. 100 in SHR vs 36 p. 100 in WKY and 27 p. 100 in W (p less than 0.001); DVF was 61 +/- 17 s in SHR vs 6 +/- 6 s in WKY and W (p less than 0.001). In addition the calcium channel blocker nicardipine (N) has been administered orally to SHR either chronically during eight weeks (20 mg/kg-1 per os twice daily) or acutely as a single dose of 20 mg/kg. After long term treatment (LT) with N the LVH index and SBP were significantly reduced when compared to vehicle treated (VT) SHR; whereas a single administration of N (AT) only decreased SBP without affecting LVH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased susceptibility to arrhythmias in hypertrophied hearts of physically trained rats

Summary The aim of this study was to investigate the propensity to develop cardiac arrhythmias during an acute period of ischemia between normal and hypertrophied (by means of a swimming training regimen) rat hearts. We used the coronary artery ligation in vivo technique which induced the occurrence of cardiac arrhythmias in rats that was followed by the determination of the occluded zone size. This study was coupled to an in vitro study using a two-compartment tissue bath in which half of the ventricular preparation was exposed to normal conditions and the other to ischemic conditions (low pH, hypoxia, and hyperkalemia). We also measured the collagen content and the DNA/protein ratio of the hearts.Twenty-eight male Wistar rats submitted to an eight-week swimming training (SWT) and twenty-eight cage-confined matched rats were used for the studies. SWT resulted in a 14% decrease in mean body weight and an 8% increase in absolute heart weight. We also observed a resting bradycardia in the trained animals and blood pressure remained unchanged between the two groups. Collagen content was unchanged and DNA/protein ratio was lower in the left ventricle of trained animals. During a 30-min period of coronary artery ligation, SWT rats demonstrated fewer ischemia-induced arrhythmias as compared to controls. The size of the zone affected by the vasal occlusion was lower in trained animals. Electrophysiological data recorded in the two-compartment bath showed a marked prolongation of action potential duration and refractory period in the SWT rat hearts. During the 15-min period of in vitro ischemia there was a global alteration of all electrophysiological parameters which did not differ between the two groups. Our data support the hypothesis that resting bradycardia and decrease in ischemic zone size may be involved in the arrhythmogenic protection observed in hypertrophied hearts of swimming rats after an acute ligation of the left coronary artery. Our results also indicate that cardiac hypertrophy, as defined by quantitative changes in cardiac mass or by the electrophysiological alterations that are related to its development, is not necessarily associated with an increased risk for the occurrence of arrhythmias.     

Mortality after coronary artery occlusion in different models of cardiac hypertrophy in rats

Chronic treatment with minoxidil induces cardiac trophic and sympathetic responses, which may increase the propensity for lethal arrhythmias. To test this hypothesis, acute coronary artery occlusion was performed in conscious normotensive rats treated for 2 or 5 weeks with minoxidil with the use of a 2-stage approach to cause a myocardial infarction. For comparison, rats with aortocaval (A-V) shunts and spontaneously hypertensive rats (SHR) were studied. Minoxidil increased left ventricular and right ventricular weights by 15% to 20%, and the A-V shunt increased these weights by 30% to 40%. In SHR, left ventricular weight was increased by 50%, and right ventricular weight was increased by 25%. In rats treated with minoxidil for 5 weeks, coronary artery occlusion caused a rapid and marked mortality, and 4 hours after myocardial infarction, only 18% of these rats were alive versus 61% of the control rats. In rats with the A-V shunt, coronary artery occlusion was also associated with increased mortality, and after 6 hours, 33% were still alive compared with 59% of the control rats. In contrast, SHR with marked hypertension and cardiac hypertrophy showed only a minor increase in mortality (survival rates were 53% versus 60% in SHR versus Wistar-Kyoto rats, respectively). Mortality was preceded by high arrhythmia scores, and ventricular fibrillation was the cause of death. Discontinuation of minoxidil for 1 week, sympathetic blockade with nadolol or clonidine, or blockade of the renin-angiotensin system with enalapril or losartan did not improve minoxidil-induced excess mortality. We conclude that ventricular stretch and other mechanisms (eg, cardiac vagal activity) in rats appear to be more potent than hypertension-induced left ventricular hypertrophy in predisposing for lethal arrhythmias in the setting of acute ischemia.     

Hypertensive myocardial hypertrophy and rhythm disorders: 2 possible origins

It has been suggested that complex ventricular arrhythmias commonly occur in hypertensive patients with left ventricular hypertrophy. We have previously demonstrated that coronary artery ligation in anesthetized spontaneously hypertensive rats (SHR) and their normotensive controls (WKY) resulted in a significantly increased incidence and duration of ventricular fibrillation in SHR compared with WKY. The object of the present study was to characterize the structural and electrophysiological abnormalities in hypertrophied hearts, associated with the occurrence of arrhythmias. We used a double tissue bath in which a ventricular strip was exposed simultaneously to normal and to altered conditions (low pH, hypoxia and high potassium). Electrical activity recorded using standard micro-electrode techniques showed the occurrence of arrhythmias in all preparations and the development of major alterations in conduction (a conduction block appeared at 11 +/- 1 mn in SHR vs 16 +/- 1 mn in WKY, p less than 0.05), and maximal upstroke velocity (Vmax values before and 3 mn after the beginning of ischemia were 229 +/- 12 to 46 +/- 7 v/s for the SHR and 227 +/- 10 to 106 +/- 12 v/s for the WKY; p less than 0.001). These changes were associated in hypertrophied ventricles with a marked sub-endocardial collagen fibrosis as estimated by the use of automated image analysis (subendocardial collagen density = 4.39 +/- 0.34 p. 100 in SHR vs 1.66 +/- 0.15 p. 100 in WKY; p less than 0.001). Action potential duration measured using conventional glass micro-electrodes in a single chamber tissue bath revealed a highly significant difference (p less than 0.001) in APD 90 p. 100 of papillary muscles between SHR (114.7 +/- 2.8 ms) and WKY (76.9 +/- 1.7 ms). The addition of tetra-ethylammonium to block potassium channels induced triggered activity arising from early afterdepolarizations only in muscles hypertrophied SHR hearts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-related increase in the incidence of ventricular arrhythmias in isolated hearts from spontaneously hypertensive rats

Summary In order to test the effect of arterial hypertension on cardiac electrical activity, isolated Langendorff perfused hearts from spontaneously hypertensive (SHR) and normotensive (WKY) rats were studied. The incidence of spontaneous ventricular arrhythmias occurring during the control perfusion was 0% (n=28) in WKY, 31% in SHR (n=29, p<0.01), 7% (n=14) in 3-month-old SHR, and 53% in 14-month-old SHR (n=15, p<0.05). The incidence of venticular arrhythmias induced by programmed electrical stimulation (PES=stimulus train+two extrastimuli) was 18% in WKY (n=28), 48% in SHR (n=27, p<0.05), 29% (n=14) in 3-month-old SHR, and 69% (n=13) in 14-month-old SHR (p<0.05). The incidence of PES-induced irreversible ventricular fibrillation was 0% in WKY and in 3-month-old SHR (n=42), whereas it was 38% (n=13) in 14-month-old SHR (p<0.001). Myocardial norepinephrine was significantly reduced in SHR with respect to WKY, but no significant difference was observed between 3-month-old SHR and 14-month-old SHR. Thus, no correlation between myocardial norepinephrine and ventricular arrhythmias could be found. It was concluded that the duration of hypertension was the most important factor in the development of severe ventricular arrhythmias.     

Effects of captopril on left ventricular structure and function in SHR with established hypertension

Summary While antihypertensive therapy is considered to be an important clinical intervention in hypertensive patients, its effects on cardiac structure and function have not been intensely evaluated. In this study we tested the hypotheses that lowering blood pressure (BP) with the angiotensin I-converting enzyme inhibitor captopril, would: 1) normalize left ventricular mass and increase the cardiocyte mitochondria/myofibrils volume (V_mito/V_myo) ratio; and 2) not compromise peak ventricular performance. We treated 16-week-old SHR and WKY with captopril (40–80 mg/kg) and hydrochlorothiazide (500 mg/l) via their drinking water. After six weeks of treatment peak cardiac performance was measured during rapid volume overload. Tissue samples from the left ventricular wall were analyzed by electron microscopy and stereology. Captopril lowered BP in SHR and WKY but had no affect on the left ventricular/body weight ratio. The only intracellular change in treated SHR was an increase in sarcoplasmic volume density. Treated WKY exhibited decreased midmyocardial mitochondrial volume density. At peak cardiac output, acceleration of flow and cardiac index were not affected by treatment. Stroke work at peak cardiac output was decreased in the treated groups due to a decrease in mean arterial pressure. In addition, captopril treatment resulted in a shift of the cardiac output (CO)-left ventricular end diastolic pressure (LVEDP) curves, such that LVEDP at peak cardiac output was approximately 50% less in the treated groups compared to their respective control groups. Although captopril was efficacious in lowering BP, it is suggested that lowering BP with this agent does not, at least within six weeks, lead to a reversal of hypertrophy or to a significant alteration in the volume densities of myofibrils and mitochondria. However, an important effect of this antihypertensive drug which may be of clinical significance, is that it leads to a leftward shift of the CO-LVEDP curve in both hypertensive and normotensive rats.     

Attenuation of reperfusion-induced ventricular fibrillation in the rat isolated hypertrophied heart by preischemic diltiazem treatment

Summary The ability of the calcium antagonist diltiazem to protect against reperfusion-induced arrhythmias in hypertrophied myocardium was studied. Hearts from normotensive and DOCA-salt hypertensive rats were Langendorff perfused and subjected to 10 minutes of stabilization, 10 minutes of left coronary artery occlusion, and 5 minutes of reperfusion. The incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during reperfusion were determined and the effects of diltiazem or vehicle (given as a single bolus 3 minutes before coronary artery occlusion) were assessed in hypertrophied and normal hearts. In vehicle-treated (control) hypertrophied hearts, VF incidence was 91% compared with 67% in normal hearts, and the median duration of VF was 272 seconds (mean 207.4±32.3) compared with 27 seconds (mean 110.6±36.6; p<0.05), respectively, suggesting that reperfusion VF is more severe in hypertrophied hearts. In normal hearts, diltiazem 18 µg reduced VT incidence from 92% to 55%, reduced VF from 67% to 27%, and sustained VF from 42% to 9%. In hypertrophied hearts, 18 µg diltiazem reduced the VT incidence from 100% to 58%, reduced VF from 91% to 25% (p<0.01), and sustained VF from 82% to 8% (p<0.01). Median VF duration in this group was reduced to 0 seconds (p<0.05; mean 24.7±22.6). Diltiazem did not significantly affect heart rate or coronary flow rate decreases during ischemia. However, developed tension, at the onset of ischemia, was lower in diltiazem-treated groups than in the control groups. We suggest that the attenuation by diltiazem of reperfusion-induced arrhythmias observed in this model was related to an energy-sparing effect during ischemia. This study shows that diltiazem administered acutely before the onset of ischemia attenuates reperfusion-induced arrhythmias in the hypertrophied myocardium, despite its greater susceptibility to reperfusion-induced arrhythmias.     

1,2-Diacylglycerol content in myocardium from spontaneously hypertensive rats during the development of hypertension

Summary 1,2-Diacylglycerol (DAG) has been considered to play an important role as an activator of protein kinase C in the signal transduction of inositol phospholipid metabolism. To examine the relation of 1,2-DAG in heart tissues to cardiac hypertrophy associated with hypertension, we measured the amount of 1,2-DAG in spontaneously hypertensive rat (SHR) hearts at 4,10 and 20 weeks of age, and in age-matched normotensive Wistar-Kyoto (WKY) rat hearts using thin-layer chromatography with flame ionization detection (TLC-FID). Significant cardiac hypertrophy was found in 4-week-old SHR, while SHR did not yet have significant hypertension. Major phospholipids such as phosphatidylcholine and phosphatidylethanolamine increased from 4 to 20 weeks in the myocardium, but there was no difference between the two strains. The cholesterol levels of 4- and 20-week-old SHR were significantly higher than WKY rats. The 1,2-DAG contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA content was also observed in 4-week-old SHR hearts. However, analysis of the fatty acid composition of 1,2-DAG revealed no difference between the two strains. However, there was no significant difference in the 1,2-DAG content or in its fatty acid composition between SHR and WKY rat hearts at 10 and 20 weeks of age. It is suggested that an increase in the 1,2-DAG content of SHR hearts during the early stages appears related to the initiation of cardiac hypertrophy in SHR hearts before developed hypertension.     

Halothane anesthesia reduces inducibility of ventricular tachyarrhythmias in chronic canine myocardial infarction

Summary This study examined the effects of 2% halothane general anesthesia on ventricular electrophysiological properties and inducibility of sustained ventricular tachycardia (VT) and ventricular fibrillation (VF). Dogs with chronic anterior infarction and control dogs (no infarction) were studied before and after anesthesia using chronically implanted ventricular epicardial electrodes. PQ interval was increased by 15% with halothane, but QRS duration, QT interval, QTc, and sinus rhythm cycle length were unaffected by anesthesia. Diastolic threshold was unchanged by halothane. Halothane caused significant increases of 10–30% in ventricular effective refractory period (ERP) both in control and in infarct animals. VT and VF were not inducible in any of the nine control animals either before or after anesthesia. In infarct animals 34 of 75 (45%) had inducible VT or VF prior to halothane, but the incidence of inducible arrhythmias was significantly lower at 29% (22 of 75 animals) after halothane (p<0.01). In 75% of animals in which halothane suppressed inducibility of tachyarrhythmias, halothane-induced increases in ERP prevented achievement of the short extrastimulus coupling intervals at which the arrhythmias were induced before anesthesia. In conclusion: halothane anesthesia reduces the incidence of inducible sustained ventricular tachyarrhythmias in chronic canine myocardial infarction.A preliminary report of this study was given to the American Heart Association, Dallas, Texas, USA, November 1986.     

Ouabain arrhythmogenicity in hypertrophied right and left ventricle of the rat

Summary Susceptibility to the arrhythmogenic action of ouabain was tested in rats with right ventricular hypertrophy, due to experimental chronic hypoxic pulmonary hypertension, and in spontaneously hypertensive (SH) rats with left ventricular hypertrophy. As parameters of arrhythmogenicity the time-duration of infusion of a solution of ouabain (1 g/100 ml), at a rate of 0.7 mg/kg per minute, was measured until the appearance on the ECG of the first premature ventricular contraction, ventricular tachycardia and cardiac arrest. All three effects of digitalis toxicity (premature ventricular contraction, ventricular tachycardia and cardiac arrest) appeared significantly earlier both in rats with right ventricular hypertrophy, due to chronic experimental hypoxic pulmonary hypertension, and in SH rats with hypertrophy of the left ventricle, as compared to the infusion time of the same solution of ouabain needed to elicit the mentioned toxic effects in control rats without ventricular hypertrophy.This work was supported by a grant from the Serbian Research Foundation     

Effect of the blood supply to the normal noninfarcted myocardium on the incidence and severity of early postocclusion arrhythmias in dogs

Summary This work was initiated by the discrepancy existing between the traditional experimental infarction model with occlusion of one single major coronary artery in the otherwise healthy myocardium and the clinical situation in which two or more major coronary arteries are stenosed at the same time. A model mimicking this latter clinical situation was elaborated as follows:In anaesthetized, open-chest dogs the haemodynamic, electrophysiological and blood flow changes due to 5 min occlusion of the left anterior descending coronary artery (LAD) were studied in the absence and presence of a critical constriction of the left circumflex coronary artery (LCX). Control LAD occlusion resulted in enhanced ST-segment elevation and inhomogeneity of electrical activation, depressed left ventricular contractility (LVdP/dt) and local myocardial contractility, as well as in a decline of myocardial blood flow (MBF) in the ischaemic area supplied by LAD. These changes were accompanied by no or slight extrasystolic activity.In the presence of critical stenosis of LCX, occlusion of the LAD aggravated myocardial ischaemia, i.e. ST-segment elevation and diminution of MBF were more marked, mainly in the subepicardium of the ischaemic area. The incidence and severity of arrhythmias significantly increased. Even ventricular fibrillation occurred in one third of the animals, both during LAD occlusion and after its release.Thus, acute LAD occlusion in the presence of a stenosed LCX produced a more severe myocardial ischaemia associated with more severe arrhythmias than occlusion of LAD alone. This model is more relevant to the clinical situation in which multivessel coronary artery disease is common.     

Increase in G(i alpha) protein accompanies progression of post-infarction remodeling in hypertensive cardiomyopathy

Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in beta-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to beta-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G(s alpha) protein and beta-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G(i alpha) was increased (1.5-fold) in the noninfarcted left ventricle of the SHR in which infarction had been induced when compared with that in SHR that underwent sham operation. This increase was observed especially in rats with a high plasma ANP level. Furthermore, there was a positive correlation between G(i alpha) and the extent of post-MI remodeling in WKY. A similar correlation between G(i alpha) and the extent of hypertensive hypertrophy was observed in SHR. In conclusion, the vulnerability of hypertrophied hearts to ischemic damage is greater than that of normotensive hearts. An increase in G(i alpha) could be one mechanism involved in the transition from cardiac hypertrophy to cardiac failure when chronic pressure overload and loss of contractile mass from ischemic heart disease coexist.     

Effects of riboflavin analogues and diuretics on the spontaneously hypertensive rat heart

Summary The chronic treatment of spontaneously hypertensive rats (SHR) with 7,8-dimethyl-10-(3-chlorobenzyl) isoalloxazine [CBI], 7,8-diethyl-10-aminol isoalloxazine [DEAI], enduron (methyclothiazide) and amiloride were studied for their effects on blood pressure and cardiac contractile protein ATPasc activities. After 35 weeks of treatment all the above antihypertensive agents showed a decrease in blood pressure in the SHR (p<0.01). Chronic treatment with CBI, DEAI, enduron, and amiloride significantly improved the myofibrillar ATPasc activity at all pCa²⁺ concentrations (p<0.01). Furthermore, CBI, DEAI, enduron, and amiloride drug treatments enhanced actin-activated myosin ATPase activity (p<0.01). The Ca²⁺-activated myosin ATPase activity was significantly elevated after treating with CBI and DEAI (p<0.01). These results suggest that the antihypertensive agents used in this study helped in reducing the blood pressure with a subsequent increase in myocardial contractile protein ATPase activity.     

Pulmonary vascular reactivity in the spontaneously hypertensive rat.

We examined the pulmonary vascular reactivity of normotensive rats (NR) and spontaneously hypertensive rats (SHR) to acute and chronic pressor stimuli. In rats kept at low altitude (1,520 m), SHR had a slight degree of right ventricular hypertrophy, but there was no difference between SHR and NR in either right ventricular systolic pressure or pulmonary artery wall thickness. When compared to blood-perfused lungs from low altitude NR, lungs from low altitude SHR were normoresponsive to acute airway hypoxia, hyporesponsive to intra-arterial angiotensin II, and hyperresponsive to intra-arterial prostaglandin F2alpha. After exposing rats to simulated high altitude (4--6 weeks at 4,270 m) to induce hypoxic pulmonary hypertension, SHR had a higher right ventricular systolic pressure, a greater degree of right ventricular hypertrophy, and more pulmonary artery medial thickening than did NR. The results indicate that although the pulmonary vasculature of SHR does not become hypertensive spontaneously, it might have an increased tendency to develop hypertension when exposed to an appropriate stimulus, i.e., chronic airway hypoxia.     

Potentiation of reperfusion-associated ventricular fibrillation by left ventricular hypertrophy

Important electrophysiological alterations that may predispose hearts to arrhythmias have been described for hypertrophied myocytes, and hypertrophy coupled with ischemia has been associated with an increased incidence of sudden death; however, an influence of hypertrophy on reperfusion arrhythmias has not been previously described. We hypothesized that reperfusion-associated arrhythmias would be potentiated by left ventricular hypertrophy. After induction of renovascular hypertension, 37 awake, unsedated dogs (17 with left ventricular hypertrophy and 20 without hypertrophy) underwent 15 minutes of coronary artery occlusion and reperfusion. All dogs were pretreated with lidocaine bolus injections and with lidocaine by continuous infusion during coronary occlusion and reperfusion. Reperfusion-associated ventricular fibrillation occurred in seven of 17 dogs with left ventricular hypertrophy versus one of 18 dogs without hypertrophy (p less than or equal to 0.05). The presence of hypertension was not significantly associated with an increased incidence of reflow ventricular arrhythmias. Neither QT interval nor area-at-risk was different between the dogs with and without reperfusion ventricular fibrillation; however, increased heart rate just before reperfusion did correlate with an increased incidence of ventricular fibrillation at reperfusion. Thus, 1) left ventricular hypertrophy was associated with a significantly increased incidence of reperfusion-induced ventricular fibrillation after 15 minutes of ischemia, 2) this increased incidence was independent of the presence of hypertension, and 3) lidocaine protected control and hypertrophied hearts against ventricular fibrillation during ischemia but was ineffective in protecting hypertrophied hearts against reperfusion-induced ventricular fibrillation.     

高血压大鼠左室肥厚消退后的心电活动变化

用尼群地平、卡托普利治疗自发性高血压大鼠，逆转其左室肥厚，比较左室肥厚消退前后心电活动变化。结果发现，两药均可使左室肥厚消退，与同周龄自发性高血压大鼠相比，两药物治疗组单相动作电位复极化９０％时程（ｍｓ）缩短（分别为８７±９ＶＳ１０４±１４；９０±９ＶＳ１０４±１４，Ｐ均＜０．０５），室颤阈值（ｍＡ）提高（分别为１６．７５±４．４３ＶＳ８．７５±３．８８；２０．００±５．４０ＶＳ８．７５±３．８８，Ｐ均＜０．０５），氯化铯诱发心律失常的发生率降低，各指标值与同周龄ＷＫｙ鼠相近。表明随着左室肥厚消退，心电活动异常也得到改善。     

Different ratio of myosin heavy chain isoforms in arterial smooth muscle of spontaneously hypertensive rats

Summary The relative proportion of the two putative heavy chains of smooth muscle myosin (MHC1 and MHC2) was determined in the caudal and femoral arteries of spontaneously hypertensive rats (SHR) and normotensive (WKY) rats at 16 weeks of age. The heavy chain polypeptides with M_r 204000 and 200000 were resolved electrophoretically under denaturing conditions in porous polyacrylamide gels. Both proteins reacted strongly with a monoclonal antibody (2C4) to smooth muscle MHC. In caudal arteries the ratio of MHC1/MHC2 was 3.11 in SHR rats compared with 1.81 in WKY rats (p<0.005) and similarly in femoral arteries, 2.81 vs 1.51 (p<0.001). In the portal vein there was no significant difference, 1.71 vs 1.51. The possibility that the higher MHC ratio in the SHR is the genetically mediated defect in arterial smooth muscle cells leading to the hypertension is discussed as an alternative to the elevated systemic blood pressure causing the altered MHC ratio.     

Reperfusion-induced arrhythmias and myocardial ion shifts: A pharmacologic interaction between pinacidil and cicletanine in isolated rat hearts

Summary Pinacidil is a member of the new antihypertensive drug family possessing an action that involves an increased, potassium efflux in vascular and cardiac muscle. We investigated the contribution of opening of ATP-sensitive potassium channel to the development of reperfusion-induced arrhythmias and myocardial ion shifts, particularly that of Na⁺, K⁺, Ca²⁺ and Mg²⁺ in isolated rat hearts. After 30 min of normothermic global ischemia, pinacidil with 1 to 60 mol/l failed to reduce the incidence of reperfusion-induced arrhythmias, even on the postischemic/reperfused myocardium in a subset of hearts unresponsive to reperfusion-induced arrhythmias (the duration of ischemia was reduced to 25 min), pinacidil treatment was associated with a greater incidence of reperfusion-induced arrhythmias (100%) as compared to the control value (50%). These proarrhythmic effects of pinacidil were also reflected in a maldistribution of myocardial ion contents both in nonischemic and ischemic/reperfused hearts. Cicletanine, a furopyridine antihypertensive agent that has no effect on coronary resistance, reduced the incidence of reperfusion arrhythmias, and its antiarrhythmic effect was antagonized by pinacidil. The same observation was made in relation to myocardial ion content, e.g., pinacidil-induced K⁺ loss and Ca²⁺ gain were antagonized by cicletanine, both in nonischemic and ischemic/reperfused hearts. It is hypothesized that the increased tendency to develop reperfusion-induced ventricular fibrillation is associated with the pinacidil-induced K⁺ efflux. The present study does not attempt to address the question of specific ionic currents; however, it has been suggested that proarrhythmic and antiarrhythmic effects of pinacidil and cicletanine, respectively, may relate to same receptor sites in which the latter may reflect a specific blockade of the outward K⁺ ion current via ATP-sensitive K⁺ channels. If this is so, the use of K⁺ channel openers as antihypertensive agents may be of particular concern in that population of postinfarction patients who are known to be at high risk of sudden coronary death.     

Determinants of infarct size in non-human primates

Summary To achieve a better understanding of the major factors that determine infarct size in non-human primates, a mathematical model was constructed using stepwise regression analysis. The model was developed on the basis of infarct size measurements, including the anatomical area at risk, regional myocardial blood flow measurements and hemodynamic determinants obtained in 23 control baboons undergoing up to 2 h of coronary artery thrombosis followed by thrombolysis.In this model, the size of the perfusion bed of the occluded coronary artery and the duration of coronary artery occlusion were found to be the only important predictors of infarct size (expressed as a percentage of left ventricular mass). R² (square or the multiple correlation coefficient) was 70% in this model. Collateral blood flow and rate-pressure product were not identified as important predictors of infarct size.In a second group of eight baboons, atenolol (0.1 mg·kg^–1) was administered intravenously 15 min after the onset of coronary artery thrombosis. Predicted infarct size (based on the mathematical model obtained in the control group) was larger than the observed infarct size in seven out of eight cases. In four instances observed infarct size was smaller than the 95% lower limit of the predicted value.It is concluded that the determinants of infarct size in non-human primates differ from those in canine models with respect to collateral flow and estimates of myocardial oxygen consumption (rate pressure product). The developed mathematical model of infarct size prediction allows the detection of cardioprotective drug effects with an acceptable efficacy.Supported by grants from the Nationaal Fonds voor Wetenschappelijk Onderzoek and Onderzocksfonds K. U. Leuven.     

Regional oxygen supply and consumption balance in experimental left ventricular hypertrophy

Summary The aim of the present study was to determine if the relationship between myocardial O₂ supply and O₂ consumption was preserved after prolonged pressure overload due to aortic valve stenosis. This was examined in anesthetized open-chest dogs in which the aortic valve was plicated 6 months previously. We measured coronary blood flow with radioactive microspheres and regional small vessel O₂ saturation with microspectrophotometry, to obtain O₂ supply, and O₂ consumption. Regional O₂ consumption was calculated as the product of flow and O₂ extraction. The left ventricular weight/body weight ratio was 81% greater in the dogs with aortic valve stenosis. There were no hemodynamic differences between the groups except that left ventricular systolic pressure was 38±22 mm Hg greater than aortic in the hypertrophied group. Coronary blood flow did not differ between the control and hypertrophied groups nor were there subepicardial vs subendocardial differences. When maximal coronary flow was determined with chromonar (10 mg/kg), the flow increase was significantly attenuated in the hypertrophied subendocardium (242.1±82.3 (hypertrophy) vs 512.4±204.1 ml·min^–1·100 g^–1 (control)). There were no significant differences in O₂ extraction or O₂ consumption/g between control and hypertrophied animals. There was a significantly lower O₂ supply/consumption ratio in the subendocardium compared to the subepicardium of both groups. However, the O₂ supply/consumption ratio was not decreased by hypertrophy. Thus, despite significant hypertrophy, a loss of flow reserve and a high left ventricular pressure, O₂ supply/consumption balance is preserved in valvular aortic stenosis at rest.