Electrocardiographic evidence for a cardioprotective effect of nifedipine during experimental hypercalcemia

Summary To investigate the effect of nifedipine on hypercalcemic electrocardiographical alterations, steadily increasing hypercalcemia was induced in guinea-pigs by continuous calcium gluconate infusion until cardiac arrest occurred. During the experimental time the electrocardiograms were continuously recorded and compared in animals with and without pretreatment by nifedipine (Adalat^®).The hypercalcemia-induced electrocardiographical alterations intensified during increasing serum calcium levels. Ascending serum potassium and magnesium levels indicated increasing cell damage with a leak of these mainly intracellular ions.Pretreatment by nifedipine did not significantly influence the hypercalcemia-induced bradycardia and augmentation of the P-Q interval except a small and transient effect during relatively low calcium levels. The drug, however, exerted a distinct normalizing effect on hypercalcemic reduction of the S-T segment and the Q-T interval despite of an unaltered development of hypercalcemia. Accordingly, the cellular potassium and magnesium leaks were markedly reduced and the survival time during calcium infusion was significantly prolonged after nifedipine pretreatment. These electrophysiological data are in agreement with our previous cytochemical studies, which showed a protective effect of nifedipine against hypercalcemia-induced overloading of the cellular calcium depots in myocardial cells. Whether this cardio-protective effect of nifedipine during hypercalcemia can be used therapeutically in hypercalcemic crisis, has to be examined in clinical studies.

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Zusammenfassung Um den Effekt von Nifedipin auf die hyperkalzämischen Veränderungen des Elektrokardiogramms zu untersuchen, wurde an Meerschweinchen eine stetig zunehmende Hyperkalzämie durch kontinuierliche Kalziumglukonat-Infusion erzeugt, welche bis zum Herzstillstand andauerte. Während der Versuchszeit wurde das Elektrokardiogramm (Ekg) kontinuierlich aufgenommen. Die Elektrokardiogramme von Tieren mit und ohne Vorbehandlung mit Nifedipin (Adalat^®) wurden miteinander verglichen.Die typischen hyperkalzämischen Veränderungen im Ekg verstärkten sich mit zunehmendem Serumkalziumspiegel. Steigende Kalium- und Magnesiumspiegel im Serum deuteten auf eine zunehmende Zellschädigung mit Ausstrom dieser vorwiegend intrazellulären Ionen hin.Eine Vorbehandlung mit Nifedipin beeinflußte die hyperkalzämiebedingte Bradykardie und -Verlängerung außer einem geringen und vorübergehenden Effekt während relativ niedriger Kalziumspiegel nicht signifikant. Auf die hyperkalzämische Verkürzung der -Strecke und des -Intervalls hingegen entfaltete Nifedipin eine ausgeprägt normalisierende Wirkung trotz der unveränderten Ausbildung einer Hyperkalzämie. Dementsprechend waren nach Vorbehandlung mit Nifedipin der zelluläre Kalium- und Magnesiumausstrom deutlich reduziert und die Überlebenszeit während der Kalziuminfusion deutlich verlängert. Diese elektrophysiologischen Befunde stehen im Einklang mit unseren früheren zytochemischen Untersuchungen, in denen ein protektiver Effekt von Nifedipin gegen eine hyperkalzämieinduzierte Überladung der intrazellulären Kalziumdepots in Myokardzellen nachgewiesen werden konnte. Ob dieser kardioprotektive Effekt von Nifedipin bei Hyperkalzämie therapeutisch bei einer hyperkalzämischen Krise genutzt werden kann, muß in klinischen Studien geklärt werden.

     

Temperature dependence of nifedipine action

Recently, the use of calcium antagonists has been proposed as a new cardioplegic principle. At high doses (e.g. 10(-6)M nifedipine [3]) these drugs can be used for induction of reversible cardiac arrest. Apart from their effect on coronary flow, calcium antagonists seem to be beneficial to ischemic tissue because of their negative inotropic effect at high doses [6, 9]. Ionic cardioplegic solutions are commonly used in an advantageous combination with hypothermia. In the case of calcium antagonists, there is an indication that the specific cardioprotective effect is lessened at low temperatures [3]. Nifedipine is known to reduce contraction force without abolishing the generation of action potentials even at excessive doses [2]. To quantify the suppressing effect of nifedipine on the generation of contractions, we determined the maximal possible contraction frequency (Fm) under electrical stimulation at different temperatures. In isolated myocardial cells, Fm can be determined from the cell contour movements even with an almost complete force reduction and therefore it represents a measure for effective contractile refractoriness.     

Mildronate: cardioprotective action through carnitine-lowering effect

Mildronate [3-(2,2,2-trimethylhydrazinium)propionate dihydrate] ameliorates cardiac function during ischemia by modulating myocardial energy metabolism. Biochemical and pharmacological evidence supports the hypothesis that the mechanism of action of mildronate is based on its regulatory effect on carnitine concentration, whereby mildronate treatment shifts the myocardial energy metabolism from fatty acid oxidation to the more favorable glucose oxidation under ischemic conditions. Because mildronate treatment prepares cellular metabolism and membrane structures to survive ischemic stress conditions, it is possible that mildronate could be regarded as an agent of pharmacological preconditioning.     

Effect of intracoronary nifedipine on coronary bloodflow and myocardial metabolism during pacing-induced ischemia

The effects of intracoronary nifedipine on coronary bloodflow, its regional distribution, myocardial oxygen consumption and lactate metabolism during pacing-induced angina were evaluated in 15 subjects. These responses were directly compared to 10 subjects who received an alcohol-based control solvent. Myocardial bloodflow was measured by thermodilution, with changes in regional coronary flow assessed using a dual radiolabelled (technetium-99m and indium-111) intracoronary microsphere technique and single photon emission tomography. Neither intracoronary nifedipine (100 micrograms) or the control solvent produced changes in systemic arterial pressure (nifedipine -2 mmHg and control +2 mmHg, both not significant). Intracoronary nifedipine markedly increased left ventricular end diastolic pressure (pre-nifedipine 13.0 mmHg versus post nifedipine 20.1, P less than 0.05), while increasing total coronary sinus bloodflow (pre-nifedipine 134 mL/min versus post nifedipine 189, P less than 0.05): Regional coronary bloodflow increased in all myocardial segments, regardless of the severity of coronary stenosis (64 to 132% baseline, all P less than 0.05). In addition, intracoronary nifedipine increased myocardial oxygen consumption (pre-nifedipine 12.3 mL/min versus post nifedipine 15.7, P less than 0.05), with a trend towards improved lactate extraction (pre-nifedipine 0.24 mg/mL versus post nifedipine 0.12, not significant). Although decreased ventricular afterload (left ventricular systolic wall stress) may contribute to nifedipine's antianginal properties, a primary increase in regional coronary bloodflow also appears to be an important factor in the alleviation of myocardial ischemia.     

Usefulness of nifedipine for myocardial ischemia and the nifedipine gastrointestinal therapeutic system

Although conventional treatment of angina pectoris with nifedipine capsules involves frequent daily dosing, a new vehicle for the once-daily delivery of this potent but insoluble calcium channel blocking agent has been developed. With the gastrointestinal therapeutic system (GITS) formulation, constant effective drug levels of nifedipine are delivered for a full 24-hour period. When nifedipine GITS 30, 60 or 90 mg was administered once daily to patients with stable angina pectoris taking beta blockers, clinical effectiveness was demonstrated both by an increase in time to angina and by exercise time compared with placebo. Improvement was noted to be more significant with the higher doses of nifedipine administered once daily. This study indicates that nifedipine GITS provides additional antianginal protection in patients with exercise-induced angina secondary to coronary artery disease who are receiving a fixed dose of beta blocker.     

Assessment of autonomic control of the heart during transient myocardial ischemia

IntroductionIn the presence of coronary artery obstruction, complex cardiovascular reflexes may lead to changes in heart rate and even to the precipitation of malignant arrhythmias. The autonomic nervous system (ANS) has traditionally been considered to be “balanced” between continuously interacting sympathetic and parasympathetic outflows. The purpose of this study was to assess ANS control of the heart during prolonged coronary balloon occlusion procedures of one of the major coronary arteries.MethodsR-R intervals were obtained from continuous electrocardiographic data of 90 patients undergoing selective percutaneous coronary interventions (PCI) with balloon inflation periods ranging from 3 to 10 minutes (4.7 ± 1.1 minutes). Three 3-minute stages were chosen: (1) preinflation (baseline), (2) from the start of occlusion (PCI), and (3) immediately post deflation. The dynamics of the ANS was evaluated by heart rate variability analysis using standard time and frequency domain indices and the short-term fractal-like index (α₁).ResultsDuring PCI, time and frequency domain measures related to vagal control decreased significantly with respect to baseline (significantly in left anterior descending [LAD] artery occlusions). During the postdeflation stage, heart rate variability and high-frequency power increased (P < .01) in the group with right coronary artery occlusions, whereas a marked sympathetic increase, as assessed by an increase (P < .01) of normalized low-frequency power and the low/high-frequency ratio was observed in the LAD group after balloon deflation. Fractal index α₁ decreased during the PCI period but increased significantly after balloon deflation.ConclusionsSignificant changes in autonomic control of heart rate that were a function of the affected artery occurred during and after coronary artery occlusions. Occlusion of the LAD resulted in a significant reduction of vagal activity and a decrease of the short-term fractal index during PCI and a marked sympathetic response after postdeflation. However, a marked increment of vagal activity between the occlusion stage and postdeflation period was found in the right coronary artery group. These results may relate the site of the occlusion and lack of blood supply to different parts of the left ventricle.     

The effect of intravenous nifedipine administration on coronary occlusion during coronary angioplasty on ischemia tolerance and collateral function

In 29 consecutive patients (pts) coronary wedge pressure (CWP) was determined as an indicator of coronary collateral function during coronary angioplasty. Collaterals to the target vessel were angiographically detectable in 21 pts. CPW, aortic pressure (AOP), pulmonary wedge pressure (PCP), intervals to appearance of angina pectoris, surface and intracoronary ECG-changes were registered during two (n = 10) or three (n = 19) consecutive balloon dilatations. A total of 21 pts received 0.8-1.0 mg nifedipine intravenously before a second or third dilatation was performed; a control group (n = 8) received placebo. Hemodynamic parameters were reproducible for all dilatations without nifedipine. After administration of nifedipine significant changes occurred: decreases of CPW (from 34 to 29 mm Hg), AOP (from 121 to 110 mmHg), and PCP (from 12.4 to 9.4 mm Hg), and increase of ischemic tolerance time (angina pectoris) (from 35 to 56 s) (p less than 0.01). Changes in CWP and AOP showed a statistical tendency to correlate (p = 10). Thus, intravenous administration of nifedipine can improve ischemic tolerance during coronary angioplasty. Simultaneous measurement of coronary wedge pressure could not prove enhancement of collateral function as being responsible for these antiischemic effects.     

Effects of nitroglycerin and nifedipine on coronary and systemic hemodynamics during transient coronary artery occlusion

Nitroglycerin (NTG) and nifedipine (NIF) have the potential to augment coronary blood flow in addition to reducing peripheral determinants of myocardial oxygen demand as a synergistic protective mechanism during ischemia. To examine these effects, systemic and coronary hemodynamic responses were measured continuously before and during brief periods of myocardial ischemia induced by left anterior descending coronary balloon occlusion in 26 patients undergoing angioplasty (PTCA). Data were compared for two matched occlusion periods, one control and one "drug" occlusion. In 17 patients (NTG group), 200 micrograms of intracoronary NTG was given immediately before coronary occlusion. In nine patients (NIF group), 10 mg of sublingual NIF was given 15 minutes before the "drug" occlusion. NTG significantly but transiently reduced mean arterial pressure (91 +/- 11 to 82 +/- 15 mm Hg, p less than 0.05) and augmented basal coronary blood flow (95 +/- 38 to 127 +/- 54 ml/min, p less than 0.05) but did not alter great vein blood flow (59 +/- 29 vs 61 +/- 29 ml/min) or coronary occlusion pressure (25 +/- 7 to 24 +/- 7 mm Hg) during ischemia. NIF significantly reduced systolic, diastolic, and mean arterial pressure (119 +/- 21 to 95 +/- 8 mm Hg, p less than 0.001) and heart rate-pressure product from control. NIF maintained basal great vein blood flow (125 +/- 41 to 106 +/- 57 ml/min) during reduced myocardial oxygen demand, but did not affect great vein blood flow (73 +/- 29 to 79 +/- 37 ml/min) or coronary occlusion pressures during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Unique cardioprotective action of the new calcium antagonist mibefradil

BACKGROUND: Mibefradil is a calcium antagonist with few negative inotropic effects at therapeutic concentrations. METHODS AND RESULTS: The effect of mibefradil on infarct size (IS) was compared with those of placebo, amlodipine, and verapamil in 64 anesthetized pigs. In placebo pigs, after 90 minutes of ischemia and 120 minutes of reperfusion, IS (by triphenyl tetrazolium chloride staining) was 15.3+/-10.8% (SD) of the area at risk. Mibefradil (0.60 mg/kg IV) reduced heart rate and left ventricular (LV) pressure, and IS was 1. 9+/-3.9% (P<0.05 versus placebo). Verapamil (0.15 mg/kg IV) also decreased heart rate, LV pressure, and IS (6.1+/-4.2%, P<0.05 versus placebo). Amlodipine (0.20 mg/kg IV) did not alter heart rate, LV pressure, or IS (9.9+/-5.4%, P=NS versus placebo). When heart rate was maintained constant by left atrial pacing and LV pressure was adjusted to that of the placebo group by an intra-aortic balloon, mibefradil still decreased IS (3.8+/-3.0%, P<0.05 versus placebo), but verapamil did not (11.6+/-8.3%, P=NS versus placebo). With glibenclamide infusion, mibefradil no longer reduced IS (13.1+/-4.3% versus 17.8+/-5.6% with glibenclamide alone, P=NS). CONCLUSIONS: The IS-limiting effect of mibefradil, in contrast to that of verapamil, was not dependent on favorable hemodynamics but was abolished by glibenclamide, suggesting a direct cardioprotective action of mibefradil.     

Mechanisms of regional ischemia and antianginal drug action during exercise

Several mechanisms involved in the production of regional exercise-induced ischemia are described. Each offers the potential for modification using different types of antianginal drugs operating to alter regional O₂ demands, improve regional perfusion, or both, leading to reduced ischemia and increased contractile function in the ischemic zone.

Evidence is presented for matching of regional subendocardial myocardial blood flow and flow per beat with regional myocardial contraction at various levels of ischemia at rest, during steady-state exercise, and after antianginal drugs, signifying a particularly important role for heart rate control. In addition to reducing myocardial O₂ demand per minute, β-blockers and bradycardic drugs cause improvement of absolute subendocardial blood flow and particularly flow per beat by producing vasoconstriction in the epicardial region of the ischemic zone, with improvement of transmural blood flow distribution.

Vasodilator drugs can act at several locations to increase regional blood flow and also to decrease O₂ demands. A recruitable vasodilator reserve has been shown to exist during exercise-induced ischemia either in native resistence vessels, collateral channels, or both, which appears to be due at least in part to reduction of increased -adrenergic constrictor tone to the coronary vessels during exercise, even in the presence of severe ischemia.

The potential for additive effects using combinations of bradycardic and vasodilating agents are described within a framework relating regional subendocardial blood flow to regional systolic contraction. The experimental findings described suggest some potential new directions for antianginal therapy and, along with recent clinical observations, support the use of combinations of antianginal agents that act by different mechanisms.     

The effect of transient intestinal ischemia on inflammatory parameters

BACKGROUND AND AIMS: To determine the early biological changes occurring in intestinal ischemia in vivo. PATIENTS AND METHODS: We studied the effects of acute transient intestinal ischemia in 15 patients undergoing elective open surgery for the treatment of abdominal subrenal aortic aneurysm induced by clamping of the aorta at subrenal level and above the branching of the inferior mesenteric artery. Blocking the blood flow results in hypoperfusion of the inferior mesenteric artery and then to rectal mucosal ischemia. RESULTS: With the introduction of a mucosal ischemic period the basal intestinal mucosal pH decreased during ischemia, and showed a rapid increase during reperfusion to the level preceding ischemia. Parameters were evaluated in blood taken from inferior mesenteric vein. A rectal dialysis was put into the rectum to evaluate eicosanoid concentrations in rectal fluid collected before and during clamping and after declamping. Significant enhancement in plasma level of xanthine, a marker for tissue damage, was observed during reperfusion. Interleukin-6 levels were significantly elevated from 11.28+/-3.4 pg/ml (preischemic) to 109+/-85.9 pg/ml (ischemic) and to 189.33+/-120.24 pg/ml (reperfusion); and tromboxane B(2) levels from 141.57+/-51.20 pg/ml preoperation to 473.01+/-319.01 pg/ml during the surgical procedure. CONCLUSION: These observations indicate that even transient ischemia modifies the inflammatory pattern.     

Effects of nifedipine on diastolic function during brief periods of flow-limiting ischemia in the conscious dog

To determine the contribution of transsarcolemmal calcium flux to abnormal diastolic function produced by brief periods of flow-limiting ischemia and reperfusion, we evaluated early and late diastolic function during transient coronary occlusion and reperfusion before and during administration of intravenous nifedipine (NIF) (10 +/- 1 microgram/kg/min) in nine preinstrumented conscious dogs. We also assessed the effects of nitroprusside (NTP) (2 +/- 0.2 micrograms/kg/min) during an identical period of ischemia and reperfusion to independently assess the consequences of altered loading alone on diastolic function. To minimize the effects of temporal dysynchrony and altered ventricular loading conditions on isovolumetric relaxation, we developed a conscious dog preparation of reversible transient (30 to 60 sec) bilateral coronary occlusion (BCO). BCO was characterized by significant systolic depression: maximum (+)dP/dt decreased (from 2617 +/- 600 to 1981 +/- 565 mm Hg/sec, p less than .05), left ventricular transverse dimension shortening diminished (from 20 +/- 5 to 9 +/- 5%, p less than .05), and the left ventricle dilated (42.4 +/- 6.4 to 43.8 +/- 6.3 mm, p less than .05). Concomitantly the time constants of isovolumetric relaxation prolonged (from 22 +/- 3 to 28 +/- 4 msec, p less than .05) and minimal diastolic left ventricular pressure increased (from -3 +/- 6 to 6 +/-6 mm Hg, p less than .05). The passive diastolic pressure-dimension relationship shifted upward and to the right and was associated with increased chamber stiffness (from 0.50 +/- 0.26 to 1.03 +/- 0.53 mm Hg/mm, p less than .05) and increased left ventricular end-diastolic pressure (from 7 +/- 7 to 19 +/- 7 mm Hg, p less than .05). Reperfusion immediately after BCO was characterized by prompt restoration of systolic contractile performance [maximum (+)dP/dt 3220 +/- 530 mm Hg/sec] but persistently abnormal early and late diastolic function (time constant of isovolumetric relaxation 30 +/- 6 msec, left ventricular end-diastolic pressure 20 +/- 7 mm Hg). The effects of drug administration on ventricular function during BCO were then evaluated under matched loading conditions. NTP improved time constant of isovolumetric relaxation (20 +/- 8 vs 28 +/- 4 msec, p less than .05) and minimal diastolic left ventricular pressure (2 +/- 5 vs 6 +/- mm Hg, p less than .05) during BCO, but NIF did not (time constant of isovolumetric relaxation 27 +/- 6 msec, minimal diastolic left ventricular pressure 7 +/- 5 mm Hg).(ABSTRACT TRUNCATED AT 400 WORDS)