Nitrendipine Research Articles

Effects of dihydropyridine calcium channel modulators on cardiac sodium channels

To investigate whether cardiac sodium channels have dihydropyridine (DHP) receptors we studied the effects of the optically pure (greater than 95%) enantiomers of the DHPs PN200-110 and BAY-K 8644 and the racemic DHP nitrendipine (NTD). Whole cell and single-channel sodium currents were recorded from cultured ventricular cells of neonatal rats using the patch-clamp method. NTD reduced cardiac sodium currents in a voltage-dependent manner. Inhibitory effects were due to an increase in traces without activity. The unit conductance remained unchanged. At negative holding potentials, NTD transiently increased the probability of channel opening. Both (+) and (-) PN 200-110 blocked sodium channels, although the (-) isomer was about one order of magnitude less effective. The blocking effects were voltage dependent. (+) BAY-K 8644 had similar blocking effects. (-) BAY-K 8644 produced an increase in sodium currents due to an increased frequency of channel openings and a marked prolongation of open time without any significant change in unit conductance. The DHPs have effects on cardiac sodium whole cell and single-channel currents that appear identical to and are as stereospecific as their effects on cardiac calcium currents, although the concentrations required are larger. In contrast the inwardly rectifying potassium channel (IK1) is unaffected by these DHPs. We conclude that functionally equivalent DHP receptors are present in cardiac sodium and calcium channels but not potassium channels and take this as evidence of the homology between sodium and calcium channels.

Effects of a dihydropyridine calcium antagonist and agonist on human basophil histamine release.

Calcium influx is important to basophil histamine release, and even though a cromolyn-binding protein has been proposed to constitute a Ca2+ channel, the pathway of Ca2+ influx or involvement of a Ca2+ channel in this process has yet to be established. We evaluated the effects of a dihydropyridine antagonist, nitrendipine, and agonist, BAY k 8644, on human basophil histamine release. Nitrendipine inhibited ragweed antigen E-dependent basophil histamine release in a dose-dependent fashion with a 50% inhibitory dose of 3.7 (+/- 1.1) X 10(-6) mol/L, and maximal inhibition of histamine release (41.8% +/- 7.1%) was achieved with 1.0 X 10(-5) mol/L nitrendipine. Increased extracellular concentrations of Ca2+ reduced nitrendipine inhibition of histamine release. In contrast, the Ca2+ agonist, BAY k 8644, enhanced antigen E-dependent histamine release with an ED50 value of 5.0 (+/- 1.1) X 10(-6) mol/L. BAY k 8644 by itself, however, did not cause basophil histamine release nor did it enhance histamine release to the calcium ionophore A23187. Further, when the effects of BAY k 8644 on basophil histamine release were evaluated in the presence of nitrendipine, the enhancing action of BAY k 8644 was diminished in a competitive fashion. Therefore, even though these compounds act at specific Ca2+ channels in other tissues, our data do not establish either the presence of such channels in the IgE-dependent histamine release process of basophils or the mechanism of action for dihydropyridines in basophil histamine secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Nitrendipine in a Rat Model of Ischemic Acute Renal Failure

An increase in intracellular calcium has been identified as an etiologic factor in acute renal failure (ARF) and blockade of slow calcium channels has been successful in its amelioration. Diuretics may also prevent or mitigate the effects of renal ischemia. We examined the actions of a new calcium channel blocker, nitrendipine (NTR), given intravenously to rats prior to bilateral clamping of the renal pedicle for 45-60 min. Four groups of rats were studied. Group I: Rats given the vehicle only and subjected to sham surgery had a creatinine clearance (Ccr) of .93 +/- .05 ml/min (n = 20). Group II: Rats given NTR (1 or 3 mg/kg) and subjected to sham surgery had a Ccr of .65 +/- .03 ml/min (n = 17). Group III: The infusion of the vehicle alone 10-15 min before clamping resulted in a Ccr of .12 +/- .02 ml/min (n = 23, p less than .001 vs. group I). Group IV: Rats given NTR and then clamped had a Ccr of .30 +/- .04 ml/min (n = 31, p less than .001 vs. group III, p less than .001 vs. group II). Higher doses of NTR did not improve the results. We concluded that NTR partially protects against ARF, but NTR lowered Ccr compared to control rats (p less than .001, group I vs. group II).

Inhibitory effects of nitrendipine on myometrial and vascular smooth muscle in human pregnant uterus and placenta.

Human myometrial visceral and vascular preparations and placental chorionic and stem villous vessels were dissected from myometrial and placental specimens obtained at term Caesarean section and after vaginal delivery. Vascular ring preparations and myometrial strips were mounted in organ bath and isometric tension recorded. Only myometrial preparations developed spontaneous contractile activity, which was effectively blocked by the calcium channel blocker nitrendipine (NTD) 10(-7) M. Pretreatment with calcium-depleted medium for 30 min. almost abolished myometrial responses to high K+ (124 mmol), oxytocin (OX) and prostaglandin F2 alpha (PGF2 alpha). Vascular responses to high K+ (124 mmol) were also nearly abolished by such treatment. However, noradrenaline (NA), vasopressin (VP) and PGF2 alpha in myometrial arteries and PGF2 alpha in chorionic vessels and stem villous arteries induced significant, but reduced contractions after calcium depletion. In all vascular preparations, exposed to calcium-depleted medium, NTD (10(-8) M) almost abolished contractions induced by calcium (0.1-4.0 mM) in the presence of K+ (124 mmol) and depressed responses to calcium in the presence of the other agonists tested. NTD (10(-10)-10(-7) M) depressed myometrial contractions induced by K+, OX and PGF2 alpha more effective than vascular responses to K+, NA, VP and PGF2 alpha in the myometrial arteries and K+ and PGF2 alpha in the placental arteries. It is concluded that activation of contraction in vessels from the human utero-placental unit implies multiple cellular sources of calcium, while in myometrial smooth muscle, influx of superficially bound calcium may be an important initial step in contractile activation. Treatment with calcium channel blockers during late human pregnancy might involve relaxation of the myometrium together with vasodilatation of the myometrial and foetal placental vascular beds.

Separation of cardiac plasmalemma into cell surface and T-tubular components. Distribution of saxitoxin- and nitrendipine-binding sites.

To compare surface sarcolemmal with T-tubular distributions of [3H]saxitoxin (STX)- and [3H]nitrendipine (NTD)-binding sites, we centrifuged membrane vesicles from sheep and bovine ventricles on a 10-40% linear sucrose gradient from which fractions were assayed for STX and NTD binding; for markers of surface sarcolemma (ouabain-sensitive Na,K-ATPase activity, [3H]quinuclidinyl benzilate binding); and for markers of junctional sarcoplasmic reticulum known to be preferentially associated with T-tubules (ryanodine-sensitive Ca2+ uptake, calsequestrin, an Mr 300,000 putative phosphorylatable "foot" protein, and electron microscopically visible junctional sarcoplasmic reticulum-plasmalemma complexes). We identified three distinct peaks in the sucrose gradient, each characterized by significant high and low affinity STX- and high affinity NTD-binding: Peak I (approximately 19% sucrose), highly enriched in surface sarcolemma; Peak III (approximately 36% sucrose), enriched in junctional sarcoplasmic reticulum markers and hence in junctional sarcoplasmic reticulum complexes with T-tubule; and Peak II (approximately 27% sucrose), showing greatest specific STX binding and only moderate NTD binding, enriched in T-tubular membrane, unassociated with junctional sarcoplasmic reticulum. For ventricular myocytes, the ratio NTD sites/STX sites was 2.5 for surface sarcolemma, but only approximately 1.0 for T-tubules. Unlike data published for mammalian skeletal muscle, sheep and beef cardiac NTD receptors were not significantly more concentrated in T-tubular than in surface plasmalemma.

Nitrendipine attenuates the pulmonary vascular remodeling and right ventricular hypertrophy caused by intermittent hypoxia in rats.

We designed experiments to determine whether intermittent hypoxia would produce significant pathologic and physiologic changes in rats and whether pretreatment with a calcium channel blocker, nitrendipine, would reduce the pulmonary vascular remodeling and right ventricular hypertrophy caused by intermittent hypoxia. Intermittent exposure to hypobaric hypoxia (0.5 atmospheres) 10 h a day for 30 days increased the hematocrit (65 +/- 1 versus 42 +/- 1%, mean +/- SEM), right ventricular systolic pressure (33 +/- 1 versus 20 +/- 1 mmHg), and right ventricular weight adjusted for body weight (RV/BW) (126 +/- 6 versus 60 +/- 2 mg/100 g) in male Sprague-Dawley rats. Intermittent hypoxia also increased the percentage of small pulmonary vessels with muscle (76 +/- 3 versus 19 +/- 5%) and the thickness of the vessel wall as a percentage of the total vessel diameter (34 +/- 1 versus 22 +/- 1%). Nitrendipine (10 mg/kg) prevented the acute increase in right ventricular systolic pressure caused by hypoxia. Chronic treatment with nitrendipine (10 mg/kg given twice a day by gavage for 30 days) significantly reduced the increase in hematocrit (61 +/- 1 versus 65 +/- 1%), right ventricular systolic pressure (29 +/- 1 versus 33 +/- 1 mmHg), and RV/BW (108 +/- 4 versus 126 +/- 6 mg/100 g) caused by hypoxia. Chronic treatment with nitrendipine also reduced the percentage of small pulmonary vessels with muscle (38 +/- 8 versus 76 +/- 3%) and prevented the increase in vessel wall thickness (20 +/- 2 versus 34 +/- 1%). Thus, nitrendipine treatment significantly reduces the right ventricular hypertrophy and pulmonary vascular changes caused by intermittent hypoxia.

Solubilization and affinity labeling of a dihydropyridine binding site from skeletal muscle: Effects of temperature and diltiazem on [ 3H]dihydropyridine binding to transverse tubules

Effects of temperature and d-cis-diltiazem (DTZ) on [ 3H]nitrendipine (NTD) and [ 3H]nimodipine (NIM) binding to skeletal muscle t-tubular membranes were studied. A decrease in temperature from 37°C to 10°C decreased K D and increased B max slightly. DTZ increased binding by increasing B max under all conditions and also decreased K D for NTD at 37°C. The binding protein labeled with [ 3H]isothiocyanate dihydropyridine revealed a molecular weight of 36,000. The binding site for NTD was solubilized by deoxycholate and dihydropyridine binding was still stimulated by DTZ in the solubilized form.

Comparison of Nitrendipine Combined with Low-Dose Hydrochlorothiazide to Hydrochlorothiazide Alone in Mild to Moderate Essential Hypertension

Patients with mild to moderate essential hypertension were treated in four centers with hydrochlorothiazide (HCTZ) 25 mg daily for 4 weeks. Those patients failing to achieve control (supine diastolic blood pressure (DBP) 90 mm Hg or lower) were randomly assigned to nitrendipine (NTP) 5 mg or placebo (PLA) b.i.d. NTP or PLA was increased stepwise to 20 mg b.i.d. as needed to achieve control. Treatment with HCTZ was maintained at 25 mg daily. Eighty-six patients completed the study: 41 in NTP + HCTZ and 45 in PLA + HCTZ groups. Both groups were comparable in baseline characteristics. Supine systolic blood pressure (SBP) was 148.6 +/- 14.4 and DBP was 96.0 +/- 5.4 mm Hg in the NTP + HCTZ group. SBP was 147.4 +/- 16.6 and DBP was 96.4 +/- 5.6 mm Hg in the PLA + HCTZ group. At the end of 7 weeks of titration and treatment with NTP or PLA combined with HCTZ, SBP had fallen to 133.4 +/- 15.1 and DBP to 85.4 +/- 5.9 mm Hg in the NTP + HCTZ group. SBP fell to 138.8 +/- 16.2 and DBP to 90.7 +/- 6.3 mm Hg in the PLA + HCTZ group. The increment in lowering of both SBP and DBP was significantly greater (p = 0.002 and p = 0.0007, respectively) in the NTP + HCTZ group compared to the PLA + HCTZ group.

Calcium antagonist binding sites in the rat central nervous system

Some of the calcium antagonists with diverse structures are considered to specifically block voltage dependant calcium ion channels of excitatory membranes. Each drug acts on a specific site of the calcium ion channel. Receptor binding experiments with use of tritiated Ca antagonist make it possible to examine the functional sites of these drugs. In this paper, we performed binding experiments and autoradiographic studies Ca ion channel antagonist binding sites using tritiated nitrendipine(NTD) in the rat brain. Brain P2 fraction was prepared, and saturation analysis and kinetic studies at the temperature of 0°C, 25°C and 37°C were performed. In addition, competitive studies by various Ca antagonists were done. The in vitro autoradiographic study was done as follows: After cryostat sections of the rat brain were incubated with 2nM 3H-NTD, a tritium sensitive film was apposed on the slides in the dark and stored for 4 weeks at 4°C. As control, experiments were done with sections to which 10#x2212;5 M nifedipine was added at the same time. As preliminary experiments of autoradiography, saturation analysis on cryostat sections at 0°C was done, with results showing a Kd value of 60pM. Autoradiographic studies of 3H-NTD revealed that specific binding sites were diffusely distributed in the neuronal elements with dominancy in the superior colliculus, hippocampus and interpeduncular nucleus.

The Siege of Pensacola, 1781, in Maps with Data on Troop Strength, Military Units, Ships, Casualties, and Related Statistics. By William S. and Hazel P. Coker. (Pensacola: The Perdido Bay Press, 1981. Pp. viii, 132. Maps. Appendices. Bibliography. Index. Paper: $12.00.)

The Siege of Pensacola, 1781, in Maps with Data on Troop Strength, Military Units, Ships, Casualties, and Related Statistics. By William S. and Hazel P. Coker. (Pensacola: The Perdido Bay Press, 1981. Pp. viii, 132. Maps. Appendices. Bibliography. Index. Paper: $12.00.)

The Siege of Pensacola, 1781, in Maps with Data on Troop Strength, Military Units, Ships, Casualties, and Related Statistics. By William S. and Hazel P. Coker. (Pensacola: The Perdido Bay Press, 1981. Pp. viii, 132. Maps. Appendices. Bibliography. Index. Paper: $12.00.)

The Siege of Pensacola, 1781, in Maps with Data on Troop Strength, Military Units, Ships, Casualties, and Related Statistics. By William S. and Hazel P. Coker. (Pensacola: The Perdido Bay Press, 1981. Pp. viii, 132. Maps. Appendices. Bibliography. Index. Paper: $12.00.) - Volume 38 Issue 4