There is controversy over whether the cardioprotective effects of Na+/H+ exchanger inhibitors are exerted primarily during ischemia or during subsequent reperfusion, possibly because of interstudy differences in experimental conditions. We studied the impact of perfusate buffer composition on the relative degree of protection afforded by Na+/H+ exchanger inhibition during ischemia vs. reperfusion. Isolated rat hearts (n = 8/group) were perfused (37 degrees C, 75 mmHg) with bicarbonate- or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium and subjected to 20 min of global zero-flow ischemia and 45 min of reperfusion. One of two structurally distinct Na+/H+ exchanger inhibitors [5-(N,N-dimethyl)amiloride (DMA) or (3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate (HOE-694), 10 mumol/l] was transiently (5 min) infused 1) immediately before ischemia, 2) during initial reperfusion, or 3) during both of these periods. With bicarbonate-buffered medium, neither drug improved the postischemic recovery of left ventricular developed pressure (LVDP) when given only during reperfusion. In contrast, HOE-694 improved the postischemic recovery of LVDP from 39 +/- 5% in control to 66 +/- 6% (P < 0.05) when given before ischemia and from 33 +/- 4% in control to 65 +/- 4% (P < 0.05) when given before ischemia plus during reperfusion. With the latter protocol, the cardioprotective effect of HOE-694 occurred in a dose-dependent manner at 0.1-10 mumol/l. In contrast to the results with bicarbonate-buffered medium, in the presence of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium, DMA and HOE-694 significantly improved recovery of LVDP (from 34 +/- 5% in controls to 56 +/- 3 and 71 +/- 8%, both P < 0.05) when given only during reperfusion. They also provided significant protection when given before ischemia or before ischemia plus during reperfusion; with the latter protocol, HOE-694 produced an almost complete recovery of LVDP (88 +/- 9 vs. 30 +/- 7% in controls, P < 0.05). In conclusion, our results suggest that the influence of Na+/H+ exchanger activity during reperfusion on the extent of functional recovery is modulated significantly by perfusate buffer composition. As a consequence, the cardioprotective efficacy of Na+/H+ exchanger inhibitors may be overestimated under bicarbonate-free conditions.

We studied the effects of acidic reperfusion on 1) the incidence of ventricular fibrillation (VF) and 2) sarcolemmal Na(+)-K(+)-adenosinetriphosphatase (ATPase) activity. Isolated rat hearts (n = 12/group) were subjected to independent perfusion (15 min) of left and right coronary beds with pH 7.4 buffer followed by zero-flow ischemia (10 min) of the former bed. This was then reperfused for 5 min, with acidic (pH 6.6) buffer for the first 0 (control), 0.5,1,2, or 4 min and with pH 7.4 buffer thereafter. In the control group, 92% of hearts developed VF within 20 s of reperfusion and remained in VF. In the 0.5-, 1-, 2-, and 4-min acidic reperfusion groups, only 17, 17, 42, and 25% of hearts (P < 0.05 vs. control for all groups), respectively, exhibited VF during acidic reperfusion. However, on switching to pH 7.4, VF occurred in a further 50, 58, 0, and 0% of hearts, respectively; thus the overall incidences of VF were 67, 75, 42 (P < 0.05 vs. control), and 25% (P < 0.05 vs. control), respectively. Additional hearts (n = 8/group) were used for cytochemical determination of sarcolemmal Na(+)-K(+)-ATPase activity in both the ischemic/reperfused left ventricular (LV) and the nonischemic right ventricular (RV) free walls. Ischemia (10 min) reduced LV Na2(+)-K(+)-ATPase activity from 110 +/- 8 to 25 +/- 3% of the RV value. After 0.5, 1, 2, 3, and 4 min of acidic reperfusion, LV Na(+)-K(+)-ATPase activity was 24 +/- 3, 29 +/- 3, 37 +/- 5, 55 +/- 6, and 70 +/- 4, respectively (P < 0.05 vs. 10-min ischemia). No significant recovery of LV Na(+)-K(+)-ATPase activity occurred following up to 4 min of pH 7.4 reperfusion. In conclusion, 1) at least 2 min of acidic reperfusion is required to achieve sustained protection against VF and 2) the protective mechanism may involve enhanced recovery of Na(+)-K(+)-ATPase activity as well as inhibition of Na+ influx.

No abstract

1. Adrenomedullin is a recently discovered vasodilating and natriuretic peptide whose physiological and pathophysiological roles remain to be established. Like atrial natiuretic peptide adrenomedullin is expressed in the left ventricle. Ventricular expression of atrial natriuretic peptide is known to be markedly increased by volume or pressure overload. In this study we investigated whether ventricular expression of adrenomedullin is similarly stimulated under such conditions. 2. Ventricular adrenomedullin and atrial natriuretic peptide mRNA levels as well as those of a loading control mRNA (glyceraldehyde-3-phosphate dehydrogenase) were quantified by Northern blot analysis in (a) rats with severe post-infarction heart failure induced by left coronary ligation at 30 days post-surgery and (b) in rats with pressure-related cardiac hypertrophy induced by aortic banding at several time points (0.5, 1 and 4 h, and 1, 4, 7 and 28 days) after surgery. Levels were compared with those in matched sham-operated controls. 3. The mRNA level of atrial natriuretic peptide was markedly increased (8-10-fold) in the left ventricle of animals with post-infarction heart failure. In contrast, there was only a modest (40%) increase in the level of adrenomedullin mRNA. In rats with pressure-induced cardiac hypertrophy the ventricular level of atrial natriuretic peptide mRNA was again markedly increased (maximum 10-fold). The increase was first noticeable at 24 h post-banding and persisted until 28 days. In contrast, there was no change in adrenomedullin mRNA level compared with sham-operated rats at any time point. 4. Despite having similar systemic effects, the expression of adrenomedullin and atrial natriuretic peptide in the left ventricle is differently regulated. The findings imply distinct roles for the two peptides. The results do not support an important role for ventricular adrenomedullin expression in the remodelling process that occurs during the development of cardiac hypertrophy but suggest that ventricular adrenomedullin participates in the local and/or systemic response to heart failure.

We studied the effects of angiotensin-converting enzyme (ACE)/kininase II inhibition selectively in the ischemic zone on reperfusion arrhythmias, and the role of bradykinin versus angiotensin II (produced locally in this zone) in modulating the severity of such arrhythmias. Isolated rat hearts (n = 12 per group) were subjected to independent perfusion of left and right coronary beds. The left coronary bed received the ACE/kininase II inhibitor ramiprilat, alone or in combination with either HOE140 (bradykinin B2 receptor antagonist) or angiotensin II, before induction of regional ischemia (10 min) by discontinuation of flow to the bed. Ramiprilat (1, 10, or 100 nM) did not significantly alter the incidence of reperfusion-induced ventricular tachycardia (VT) or fibrillation (VF), but reduced the incidence of sustained VF from 83% in controls to 75, 50, and 25% (p < 0.05). The protective effects of 100 nM ramiprilat were abolished by coinfusion of HOE140 (10 or 100 nM) but not affected by coinfusion of angiotensin II (1 nM). HOE140 (10 nM), when infused alone into the left coronary bed before 7-min ischemia, increased the incidence of sustained VF from 42 to 100% (p < 0.05). Although HOE140 caused vasoconstriction in the left coronary bed when given alone or in combination with ramiprilat, its proarrhythmic effects were not due to a reduction of flow to the bed. We conclude that selective inhibition of ACE/kininase II in the ischemic zone moderately attenuates reperfusion arrhythmias and that enhanced bradykinin availability rather than reduced angiotensin II in synthesis contributes to such an effect.

Objective: To reduce the length of hospital stay for patients undergoing pacemaker surgery. Patient and Methods:We prevented the leads from dislodging by anchoring a screw-in type pacing lead in the right atrium/ventricle through a cephalic vein that was cut down. We retrospectively compared the cost and duration of the hospital stay for the subpectoral technique ( Results:The mean (± SD) duration of hospital stay was 5.1 ± 2.1 days for the subpectoral technique group and 22.2 ± 15.2 days for the conventional technique group (P < 0.001), and the cost was 2,167,883 ± 147,549 yen in the subpectoral technique group and 2,528,053 ± 217,810 yen in the conventional technique group (P < 0.001). We noted no major complications such as bleeding, lead dislodgement, or wound infection. Conclusion: Our novel subpectoral technique helped reduce the length and cost of the hospital stay associated with pacemaker surgery.

Angiotensin-converting enzyme (ACE) inhibitors have cardioprotective effects in animals, but whether that occurs in humans is still controversial. The effect of myocardial ACE activity on coronary vascular resistance during coronary artery bypass surgery and on serum brain natriuretic peptide (BNP) concentration after surgery was studied in myocardial tissue sampled from the right atrium of patients during cardiac surgery (n=20). Tissue enzyme activity (nmol/min per mg protein) was measured using a photometric technique, and the flow rate and pressure upon antegrade infusion of a crystalloid cardioplegic solution was measured for calculating the coronary vascular resistance (mmHg. ml(-1). min(-1)). Serum BNP concentration (pg/ml) was measured on days 0 and 5 after the surgery. Linear regression between tissue ACE activity and coronary vascular resistance (y = 0.46x + 0.56, r=0.85) as well as serum BNP concentration on days 0 (y = 129x + 30, r=0.59) and 5 (y = 347x + 180, r=0.73) after the surgery was significant (x: ACE activity; y: coronary vascular resistance/serum BNP concentration). The results indicate that inhibition of myocardial ACE activity might improve coronary circulation during surgery and hence, cardiac function after surgery.

SUMMARYLeft ventricle (LV) hypertrophy is associated with an increased risk of sudden death, which may be due in part to a greater vulnerability to severe ventricular arrhythmias. Our objectives were to determine (i) whether pressure overload-induced LV hypertrophy increases susceptibility to ischemia-and/or reperfusion-induced ventricular fibrillation (VF), and (ii) whether any increased susceptibility is mediated by changes intrinsic to the hypertrophied myocardium. LV pressure overload was induced in rats by abdominal aortic constriction (AC), while controls received sham-operations (SH). Three weeks after the operation, LV weight was 44 ± 3% greater in AC rats than in SH rats although right ventricle (RV) weights were similar. At this time, isolated hearts (n = 12/group) were subjected to dual coronary perfusion. After 15 minutes of aerobic perfusion, either the left or right coronary bed (supplying predominantly LV or RV tissue, respectively) was subjected to 7 minutes of zero-flow ischemia and either 5 minutes of reperfusion (reperfusion study) or 40 minutes of sustained ischemia (ischemia study). AC rats exhibited greater susceptibility than SH rats to both ischemia-and reperfusion-induced ventricular fibrillation, but only when the hypertrophied LV was subjected to ischemia. The increased susceptibility to arrhythmias was not entirely due to a larger ischemic zone, indicating that intrinsic changes within hypertrophied myocardium played a role in arrhythmogenesis. (Jpn Heart J 2003; 44: 989-1004)