Effect of calcium entry blocker nitrendipine on renal function after renal vascular occlusion

The ability of the Ca entry blocker nitrendipine to improve postischemic renal function was studied in nine groups (n = 70) of rats. After anesthesia, nitrendipine was administered for 15 min through the femoral vein. The dose administered depended on the group. Group 1 (n = 7), the control, received only 0.9% NaCl, group 2 (n = 12) 0.25 mg/kg; group 3 (n = 10) 0.50 mg/kg; group 4 (n = 8) 0.75 mg/kg; group 5 (n = 6) 1.00 mg/kg; group 6 (n = 7) 1.50 mg/kg; group 7 (n = 7) 2.00 mg/kg; group 8 (n = 6) 2.50 mg/kg; and group 9 (n = 7) 3.00 mg/kg. After the administration of nitrendipine, the kidneys were rendered ischemic for one hour by cross-clamping the renal vessels. Comparison of 24-h creatinine clearances for 72 h after reversal of ischemia demonstrated that nitrendipine was capable of providing a degree of protection against renal ischemia and the protective effect was dose dependent (p less than .05).     

Effects of intravesically administered verapamil HC1 (calcium entry blocker) on the bladder function in unanesthetized rats.

The effects of intravesically administered verapamil HCl (calcium entry blocker) on the bladder function were investigated using an experimental model for unanesthetized rats. Intravesical verapamil HCl caused a marked suppression of maximum intravesical pressure accompanied by an increase of residual urine in a dose-dependent manner. The effect almost disappeared 90 min after the elimination of verapamil HCl. It is tentatively suggested that the intravesical instillation of verapamil HCl could be a potent therapy for disorders of bladder function, such as uninhibited contraction.     

Effect of long-acting calcium entry blocker (anipamil) on blood pressure, renal function and survival of uremic rats.

To assess more completely the long-term effect of a long-acting calcium channel blocker, anipamil was given p.o. to rats with subtotal (five-sixths) nephrectomy. The mortality rates in anipamil-treated and control groups were 5% and 20%, respectively, at 6 weeks after separation (P less than .01) and 10% and 55%, respectively, at 10 weeks after separation (P less than .01). Mean arterial blood pressure was also more well controlled in the anipamil-treated group (144 +/- 36 vs. 192 +/- 35 mm Hg; n = 20; P less than .05 at week 5). In paired experiments, the degree of renal impairment in the placebo- and anipamil-treated groups, just before the onset of preterminal azotemia, was determined. Rats that were treated with anipamil had lower serum creatinine concentrations, compared with the placebo controls, at 4 to 6 weeks after separation (0.55 +/- 0.02 vs. 0.87 +/- 0.02 mg/100 ml; P less than .05). To dissociate this beneficial effect of anipamil from mean arterial blood pressure control, experiments were also performed to assess the effects of hydralazine on the remnant kidney model of chronic renal failure. Rats with remnant kidneys were divided into three groups and treated with anipamil (2 mg/kg/day), hydralazine (80 mg/liter in drinking water) or control. The anipamil-treated group exhibited significantly greater protection of renal function than did the hydralazine-treated group for the same level of blood pressure control. Thus, a long-acting calcium channel entry blocker such as anipamil may afford an additional cytoprotective effect in the prevention of progression of chronic renal failure beyond the antihypertensive effects of the agent.     

Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil

BACKGROUND: Overdoses of calcium channel blocker agents result in hyperglycemia, primarily due to the blockade of pancreatic L-type calcium channels and insulin resistance on the cellular level. The clinical significance of the hyperglycemia in this setting has not previously been described. METHODS: This study is a retrospective review of all adult (age, >or=15 yrs) patients with a discharge diagnosis of acute verapamil or diltiazem overdose at five university-affiliated teaching hospitals. The severity of overdose was assessed by determining whether a patient met the composite end points of in-hospital mortality, the necessity for a temporary pacemaker, or the need for vasopressors. We compared the initial and peak serum glucose concentrations with hemodynamic variables between patients who did and did not meet the composite end points. RESULTS: A total of 40 patients met inclusion criteria, with verapamil and diltiazem accounting for 27 of 40 (67.5%) and 13 of 40 (32.5%) of the ingestions, respectively. For those patients who did and did not meet the composite end points, the median initial serum glucose concentrations were 188 (interquartile range, 143.5-270.5) mg/dL and 129 (98.5-156.5) mg/dL, respectively (p = .0058). The median peak serum glucose concentrations for these two groups were 364 (267.5-408.5) mg/dL and 145 (107.5-160.5) mg/dL, respectively (p = .0001). The median increase in blood glucose was 71.2% for those who met composite end points vs. 0% for those who did not meet composite end points (p = .0067). Neither the change in the median heart rate nor the change in systolic blood pressure was significantly different in any group. CONCLUSION: Serum glucose concentrations correlate directly with the severity of the calcium channel blocker intoxication. The percentage increase of the peak glucose concentration is a better predictor of severity of illness than hemodynamic derangements. If validated prospectively, serum glucose concentration alone might be an indicator to begin hyperinsulinemia-euglycemia therapy.     

Effect of the calcium entry blocker NB-818 on cerebral blood flow after unilateral carotid occlusion in the Mongolian gerbil

The effect of NB-818 on regional cerebral cortical blood flow (rCBF) during normal and ischemic periods was studied in Mongolian gerbils by means of hydrogen clearance methods, and that effect was compared with that of nimodipine. In normal animals, the rCBF increased dose-dependently, when NB-818 was tested. The increased rCBF showed a slow onset and long duration of action. When comparing the potency of increase in rCBF, the action of NB-818 (0.01-0.1 mg/kg i.p.) was more potent and longer lasting than that of nimodipine (0.01-0.1 mg/kg i.p.). Thus, the cerebral ischemia, produced by unilateral common carotid artery (CCA) occlusion, was studied. Before the unilateral CCA occlusion, the rCBF value was 41.4 +/- 0.27 ml/100 g of brain per min. The rCBF after unilateral CCA occlusion in gerbils was divided into three types as follows: rCBF values of above 30 ml/100 g of brain per min (type I), between 20 to 29 ml/100 g of brain per min (type II) and below 19 ml/100 g of brain per min (type III). In type I and II, NB-818 (0.01-0.1 mg/kg i.p.) significantly improved the reduced rCBF after the occlusion, and its effects continued throughout the experiments. In type II and III, supratentorial brain edema was observed 4.5 hr after the occlusion. The brain edema was significantly inhibited by NB-818 in the type II but not in the type III because the increased rCBF in type III with NB-818 was slight.(ABSTRACT TRUNCATED AT 250 WORDS)     

The comparative effects of verapamil and a new dihydropyridine calcium channel blocker on digoxin pharmacokinetics

Conflicting conclusions have been reported about interaction of calcium channel blockers with digoxin. The effects of verapamil (240 mg/day) and a new dihydropyridine calcium channel blocker, isradipine (15 mg/day), on the pharmacokinetics of 1 mg intravenous digoxin were compared. All 24 volunteer subjects were healthy, male, nonobese, and aged 18 to 38 years. Groups of 12 subjects received each oral agent over 15 days, with collections of blood and urine for 72 hours after intravenous digoxin. Significant (P less than 0.05) reduction in nonrenal (7.01 +/- 1.97 to 4.00 +/- 1.86 L/hr) and total clearance (14.1 +/- 2.6 to 11.5 +/- 2.5 L/hr) were induced by verapamil, without change in renal clearance. A near-significant (P less than 0.1) increase in peripheral volume of distribution contributed to prolonged elimination half-life (23.1 +/- 4.4 to 34.3 +/- 9.7 hours). By contrast, isradipine caused only a 9% reduction in volume of distribution. Verapamil causes digoxin accumulation by reducing nonrenal elimination. No evidence of clinically relevant interaction of isradipine with digoxin was seen.     

Effect of chronic treatment with the calcium entry blocker, isradipine, on vascular calcium overload produced by vitamin D3 and nicotine in rats.

Treatment of young rats with vitamin D3 and nicotine produced a 35-fold increase in the calcium content of the aorta and a 4-fold increase in the calcium content of the mesenteric arterial bed. Blood pressure was not modified. In vitro, aortic rings and mesenteric arterial bed preparations from such animals showed diminished vasoconstrictor responses to norepinephrine. After precontraction with norepinephrine, the endothelium-dependent vasodilator, carbachol, produced vasorelaxation. This latter effect was attenuated in aortic rings and mesenteric arterial bed preparations from animals previously treated with vitamin D3 and nicotine, but the vasodilator effect of sodium nitroprusside (which is independent of the endothelium) was unchanged. Prolonged treatment with the calcium entry blocker, isradipine, at a dose (1 mg/kg, i.p.) which had no effect on blood pressure, prevented calcium overload of the mesenteric arterial bed, but did not modify aortic calcium overload. Isradipine treatment had no effect on vasoconstrictor responses to norepinephrine in vitro. Such treatment did, however, restore the endothelium-dependent vasodilator effect of carbachol in the mesenteric arterial bed (but not in aortic rings). In conclusion, in a rat model of vascular calcium overload produced by administration of vitamin D3 plus nicotine, chronic treatment with a low dose of the calcium entry blocker, isradipine, restored the endothelium-dependent vasorelaxant effect of carbachol in the mesenteric arterial bed, but not in the aorta.     

钙通道阻滞剂对肾衰竭患者钙磷代谢影响的研究现状

钙通道阻滞剂（calcium channel blocker，CCB）被广泛用于肾衰竭患者的降压治疗，除了对心血管系统的作用外，有许多研究证明，CCB对PTH分泌、PTH／PTHrP及其受体、骨质代谢、转移性钙化等方面存在干预作用，由此可能对肾衰竭患者的钙磷代谢产生影响。     

Effect of the calcium antagonist verapamil on human leucocyte sodium transport in vitro

Sodium efflux rate constants and intracellular sodium were measured in leucocytes from healthy volunteers in the presence and absence of the calcium antagonist verapamil hydrochloride. Verapamil stimulated sodium pump activity and this effect was dependent on the presence of external calcium. Verapamil has been reported to reverse the abnormality of sodium transport seen in leucocytes from patients with essential hypertension and the present study demonstrates that sodium pump activity in leucocytes from control subjects is also stimulated by exposure to verapamil in vitro. This direct cellular effect appears to be due to the calcium antagonist properties of the drug.     

Effect of calcium channel blocker nifedipine on uterine artery flow velocity waveforms

Calcium channel blockers have been used successfully in the treatment of pregnancy hypertension and premature labor. Only limited information related to their effect on uterine blood flow during pregnancy is available. In this study we measured the ratio between peak systolic to end-diastolic flow velocity (S/D ratio) in the ascending branch of the uterine artery in nine pregnant patients prior to and following a 10-mg dose of sublingual nifedipine. Another group of seven matched patients who received a placebo served as a control group. All studies were performed between 17 and 22 weeks gestation. The S/D ratio decreased shortly after sublingual nifedipine, but the change was not significant. It increased gradually afterward so that by 60 minutes it returned to the control value. The mean systolic blood pressure decreased by 8.6% to its lowest value after 25 minutes (P less than 0.01). The mean diastolic blood pressure decreased by 15.7% to its lowest value after 35 minutes (P less than 0.002). Maternal heart rate did not change significantly. No significant changes were observed in any of the measured variables in the placebo group. In conclusion, nifedipine does not induce significant changes in uterine arterial resistance in midtrimester and may be considered during pregnancy, providing that large fluctuations in maternal blood pressure are avoided.     

钙预适应对缺血再灌注心肌细胞的保护作用

目的:从细胞水平研究钙预适应对培养心肌细胞的缺血再灌注损伤是否具有保护作用。方法:实验选用3日龄健康清洁级SD乳鼠15只,雌雄不限,体质量10～15g。体外分离培养SD乳鼠心肌细胞,以模拟缺血溶液和模拟再灌注溶液模拟体内缺血再灌注过程,将培养心肌细胞随机分别用正常对照组、缺血再灌注组、钙适应缺血再灌注组,实验结束后检测心肌细胞活性、培养基乳酸脱氢酶(lactatedehydrogenase,LDH)水平和心肌细胞凋亡。结果:模拟缺血再灌注可引起明显的心肌细胞损伤,无钙复钙可明显减少模拟缺血再灌注对心肌细胞的损伤,钙适应缺血再灌注组细胞的台盼蓝摄取率、LDH活性、凋亡指数犤(6.2±1.2)%,(1592.0±111.7)μkat/L,(6.2±0.4)%犦均明显低于缺血再灌注组犤(24.6±1.8)%,(2873.9±43.3)μkat/L,(10.6±0.6)%犦(t=19.02,23.92,13.64,P<0.01)。结论:在细胞水平上证实了无钙复钙预适应对缺血再灌注心肌细胞有明显的保护作用。     

异搏定对肾综合征出血热急性肾功能衰竭的防治作用研究

目的：为了有效降低肾综合征出血热（ＨＦＲＳ）的病死率，探讨异搏定预防ＨＦＲＳ急性肾功能衰竭（急性肾衰）的疗效。方法：采用匹配比较方法，观察异搏定对ＨＦＲＳ患者急性肾衰的临床疗效。治疗组和对照组各８０例，两组患者年龄、性别、入院时病程、早期预定病情程度和肾损害情况均相似（Ｐ均＞０．０５）。两组均用以平衡盐液为主的综合液体疗法、对症、利尿等治疗；在此基础上治疗组加用异搏定注射液。连续观察尿量、血小板数和血尿素氮的变化；检测两组患者血浆内皮素（ＥＴ）和血清尿调蛋白（ＴＨＰ）值的变化。结果：治疗组治疗后第１天尿量即明显增加，迅速进入多尿期，越少尿期率高达９５％，明显优于对照组（Ｐ＜０．０５），且尿蛋白消失和尿素氮恢复正常早，并发症少，病死率低，与对照组比较均有显著性差异（Ｐ均＜０．０１）；血浆ＥＴ及血清ＴＨＰ在治疗后治疗组均低于对照组（Ｐ均＜０．０１）。结论：①异搏定有阻止ＨＦＲＳ肾脏病理改变进程，提高越少尿期率的作用。②治疗组治疗后ＥＴ值明显低于对照组，说明血浆ＥＴ可能参与了ＨＦＲＳ的发病过程；ＴＨＰ治疗后治疗组亦明显低于对照组，这也证实了异搏定对保护肾脏功能，缩短肾衰病程有重要作用。     

Inhibition of ischemia-induced subcellular redistribution of lysosomal enzymes in the perfused rat heart by the calcium entry blocker, diltiazem

Effect of diltiazem on subcellular distribution of lysosomal enzymes, high-energy phosphate metabolism and mechanical function in the ischemic heart was studied. Ischemia was induced by lowering the afterload pressure of the perfused working rat heart. The activities of cathepsin D, beta,N-acetylglucosaminidase and acid phosphatase were determined in the nonsedimentable and sedimentable fractions after centrifugation of the tissue extract to assess the subcellular distribution of lysosomal enzymes. After ischemia, decreases in the mechanical function and the tissue level of high-energy phosphates were observed. In addition, ischemia caused subcellular redistribution of lysosomal enzymes from the lysosomes to the cytoplasm. Reperfusion of the ischemic heart did not restore the mechanical function and the level of high-energy phosphates completely. Diltiazem (2.21 X 10(-6), 1.11 X 10(-5) and 2.21 X 10(-5) M) was provided for the heart 5 min before the onset of ischemia. Diltiazem preserved high-energy phosphates in the ischemic heart, and inhibited the subcellular redistribution of lysosomal enzymes being caused by ischemia, depending on its concentration. Reperfusion after ischemia with diltiazem recovered the mechanical function that had been decreased by ischemia. These results may indicate that diltiazem can protect the myocardium against ischemic damage.     

Effects of calcium entry blockers on coronary constriction and myocardial ischemia due to leukotriene D4

Recent studies show that leukotrienes (LTs) produce profound coronary artery constriction. Although calcium entry blockers are commonly used to remedy coronary vasospasm, their capacity to interfere with LT-mediated coronary constriction is unknown. Therefore, we compared effects of intracoronary LTD4 before and during treatment with calcium entry blockers in the in situ, blood-perfused hearts of domestic pigs. Intravenous administration of verapamil (0.1-1.6 mg/kg), nifedipine (10 or 100 micrograms/kg) or diltiazem (0.6-2.0 mg/kg) sufficient to increase base-line coronary blood flow (CBF) and decrease mean arterial pressure did not change decrement in CBF after LTD4. Infusion of verapamil (0.01-0.04 mg/min) into the left anterior descending coronary artery raised pre-LTD4 CBF almost 2-fold without alteration in mean arterial pressure, heart rate or left ventricular end-diastolic pressure. Intracoronary boluses of LTD4 (0.3, 1.0 and 3.0 micrograms) during verapamil infusion into the same vessel caused dose-dependent decreases in CBF identical to those observed when LTD4 was injected during control infusion. ECGs showed myocardial ischemia during severe flow reduction after high dose intracoronary LTD4 (3.0 or 10.0 micrograms). When the same LTD4 doses were injected during intracoronary verapamil, electrocardiographic changes did not occur despite similar decreases in CBF. The capacity of verapamil to prevent LTD4-induced ischemia may be caused by higher residual CBF after LTD4 even though the magnitude of LTD4-induced CBF decrement was unaltered. LTD4-induced coronary constriction seems to be mediated by a mechanism unrelated to calcium entry channels blocked by verapamil, nifedipine or diltiazem.     

Effect of the calcium channel blocker nitrendipine on left ventricular mass in patients with hypertension

Reductions in left ventricular (LV) mass have been reported after antihypertensive therapy with certain sympatholytic agents and converting enzyme inhibitors, but little or no improvement has been noted after vasodilator therapy. In this study we evaluated the effect of the calcium channel blocker nitrendipine on echocardiographic LV mass. During a 12-month period, nitrendipine was used as monotherapy in 30 patients and in combination with propranolol or a diuretic in an additional 28 patients. Nitrendipine monotherapy lowered supine blood pressure from 148/97 to 136/83 mm Hg, but LV mass did not change significantly. Supine blood pressure decreased from 155/103 to 134/86 mm Hg in patients receiving combination therapy but, again, changes in LV mass were not significant. These data suggest that nitrendipine is effective in lowering blood pressure, but this is not associated with a significant decrease in LV mass in patients with mild hypertension.     

SR 33557, a novel calcium entry blocker. I. In vitro isolated tissue studies.

The effects of SR 33557 on isolated cardiovascular preparations were compared to those of nifedipine, verapamil and diltiazem. In rat aortic strips, SR 33557, like nifedipine, verapamil and diltiazem, caused a significant and simultaneous inhibition of potassium-induced 45Ca++ influx and contractile responses (nifedipine greater than SR 33557 greater than verapamil greater than diltiazem). SR 33557 also antagonized Ca(++)-induced contractions in K(+)-depolarized aorta preparations (pA2:9.08 +/- 0.03) and is the first calcium channel antagonist, structurally not related to 1,4-dihydropyridines, to inhibit competitively contractions induced by BAY K8644. In spike-generating vascular smooth muscle (rat portal vein), contractures evoked by noradrenaline (4 microM) or KCl (100 mM) were reduced by all four antagonists, the pharmacological potency being nifedipine greater than SR 33557 greater than verapamil greater than diltiazem. Unlike SR 33557, nifedipine, verapamil and diltiazem showed a parallel enhancement of frequency of spontaneous contractions in rat portal vein in spite of a concentration-related reduction in amplitude. By using rabbit atrial preparations, spontaneous right atrial rate and electrically stimulated (120/min) basal contractions of left atria were used as indices of chronotropy and inotropy. The potency series for negative chronotropic effects was nifedipine greater than SR 33557 greater than verapamil greater than diltiazem. For negative inotropic effects the potency order was verapamil greater than nifedipine greater than SR 33557 greater than diltiazem, respectively. Thus, SR 33557 should depress heart rate to a greater extent than ventricular contractility. These results suggest that SR 33557 is a potent calcium entry blocker that (unlike verapamil and diltiazem) is particularly selective for vascular smooth muscle and devoid of any potent negative inotropic actions.     

异搏定对大鼠缺血再灌注损伤后视网膜内 caspase-3表达的影响

目的:在大鼠视网膜缺血再灌注损伤的模型上,研究异搏定对再灌注视网膜组织内caspase-3表达的影响。方法:60只大鼠随机分为对照组及异搏定组,每组30只。结扎大鼠左颈总动脉1h,然后再灌注。异搏定组腹腔注射异搏定1mg/kg,对照组腹腔注射生理盐水1mL/kg,分别检测再灌注后1、6、12、24、48、72h大鼠视网膜内caspase-3的光密度变化及视网膜平均凋亡发生率,每时段大鼠各5只。结果:再灌注后视网膜内caspase-3的表达位于光感受器细胞层。再灌注后1、6、12、24、48、72h对照组视网膜光感受器细胞层的平均光密度分别为0.067±0.004、0.923±0.045、1.962±0.377、3.793±0.860、2.039±0.427、1.332±0.109,而在异博定组分别为0.046±0.003、0.721±0.024、1.023±0.109、2.094±0.473、1.669±0.193、0.827±0.013。异博定对caspase-3的平均抑制率为33.6%;对照组细胞凋亡平均发生率分别为(1.8±0.1)%、(7.1±0.2)%、(18.2±1.4)%、(34.7±2.1)%、(22.6±0.9)%、(16.3±0.4)%,而异博定组分别为(1.5±0.3)%、(3.9±0.4)%、(11.9±1.1)%、(19.6±2.1)%、(12.3±1.3)%、(7.1±0.5)%,异搏定对细胞凋亡的保护率平均为42.3%。结论:异搏定可以下调再灌注后视网膜内caspase-3的水平,从而减少视网膜细胞凋亡的发生。     

Tissue protection by verapamil in the calcium paradox

The effect of verapamil (+/- 2 mumol/l verapamil) on calcium paradox injuries, as well as on hearts subjected to calcium-free perfusion alone, was studied in isolated perfused rat hearts. Three different protocols for calcium depletion (5 min) were followed: 5 or 45 ml of nominally calcium-free solution (1 or 9 ml/min), or 45 ml of nominally calcium-free solution to which 20 mumol/l CaCl2 was added. Ultrastructural analyses showed that verapamil protects against cellular injuries upon readmission of calcium to hearts subjected to partial calcium depletion (5 ml calcium-free solution, or 45 ml to which 20 mumol/l CaCl2 was added) by reducing the number of affected cells. No protection was found after more extensive calcium washout. However, in all groups examined, we found an inverse relationship between the number of injured cells and ATP content. Verapamil protected against contracture development and reduced the increase in tissue calcium content observed after readmission of calcium to hearts perfused with 5 ml calcium free solution, whereas no significant effect of verapamil on tissue calcium content was found in hearts perfused with 45 ml nominally calcium-free solution. In hearts studied after calcium-free perfusion no effect of verapamil treatment on the separation of the intercalated disc was found. The protective effect of verapamil could not be explained by differences in calcium or cAMP levels after calcium-free perfusion.     

Differential effects of the calcium entry blocker D 600 on contractions of rat and guinea-pig aortas, elicited by various alpha-1 adrenoceptor agonists

Contractions of rat and guinea-pig aortas to the alpha-adrenoceptor agonists I-norepinephrine, cirazoline , St 587, clonidine and Sgd 101/75 and the effect of calcium entry blockade by D 600 on the responses were evaluated. In rat aorta, D-600 (10(-8) to 10(-5) M) effectively and concentration-dependently reduced the maximal responses to St 587, clonidine and Sgd 101/75 (maximal percentage inhibition 84 +/- 2.1, 86 +/- 4.1 and 65 +/- 2.8, n = 5-6, respectively) in contrast to those of I-norepinephrine and cirazoline (maximal percentage inhibition 23 +/- 2.1 and 21 +/- 4.1, n = 6, respectively). Reducing the receptor number on rat aorta by approximately 85% by means of the irreversible blocker dibenamine did not result in a greater sensitivity of norepinephrine-induced contractions toward D 600. Prazosin was found 800 to 1000 times more potent than yohimbine in antagonizing the contractile effects of St 587, clonidine and cirazoline on rat and guinea-pig aortas. No difference existed between the pA2 values of prazosin and yohimbine against the different agonists; the pA2 values of prazosin and yohimbine were significantly higher in rat aorta than those in guinea-pig aorta. The results can be explained by assuming the existence of two different agonist recognition sites on the alpha-1 adrenoceptor on rat aorta, whereas the alpha-1 adrenoceptor on guinea-pig aorta contains one agonist recognition site only. The architecture of the alpha-1 adrenoceptor on rat aorta must therefore be different from that in guinea-pig aorta.