Calcium channel blockers and prostaglandin generation by gastric surface epithelial cells.

We investigated the effects of calcium channel blockers on generation of prostaglandin (PG) E2 and 6-keto PGF1 alpha by gastric mucosal surface epithelium. Surface epithelial cells (SEC) isolated from rat gastric mucosa were incubated with either verapamil (1 or 10 micrograms/ml), diltiazem (2.5 or 25 micrograms/ml) or nifedipine (2.5 or 25 micrograms/ml) for 30 min at 37 degrees C in calcium containing or calcium-free medium. Verapamil (both doses) significantly increased PGE2 and 6-keto PGF1 alpha generation by the surface epithelial cells but only in calcium containing medium. Diltiazem did not affect PG generation in calcium containing nor calcium-free medium. Nifedipine 25 micrograms/ml decreased PGE2 but increased 6-keto PGF1 alpha generation. The inhibitory effect of nifedipine on PGE2 generation was abolished in calcium-free medium, while the calmodulin antagonist did not affect verapamil-induced increase in PG generation.     

Toxic and teratologic effects of verapamil on early chick embryos: evidence for the involvement of calcium in neural tube closure

Toxic and teratologic effects of verapamil, a calcium antagonist, on chick embryos explanted at stage 8 (four-somite stage) and cultured for 6-8 hours were investigated. In general, embryos responded to verapamil in a dose-related manner. Concentrations lower than 2 micrograms/ml had no apparent effect on the development of embryos. A concentration of 15 micrograms/ml significantly increased the incidence of embryos (approximately 80% of viable embryos) with neural tube closure defects and less numerous somites. Higher concentrations (e.g., 30 micrograms/ml) were embryotoxic and over 90% of the embryos were either severely malformed or dead after 8 hours of incubation. Compared to controls, verapamil-treated neuroepithelial cells had smoother apical surfaces and less conspicuous microfilament bundles. The deleterious effects of verapamil (15 micrograms/ml) could be reversed by subculturing the affected embryos, within 3 hours of treatment, on nutrient medium alone or on nutrient medium containing 25 micrograms/ml chlorotetracycline (CTC), a calcium agonist, the latter being more effective provided that treatment did not exceed 4 hours. Exposure of the developing neuroepithelium to 15 micrograms/ml verapamil for 3-4 hours resulted in a significant reduction in free Ca2+ levels, as revealed by the pyroantimonate precipitation method, throughout neuroepithelial cells. Overall results suggest that verapamil causes neural tube closure defects by reducing intracellular free Ca2+ levels, thereby relaxing apical microfilament bundles of developing neuroepithelial cells.     

Comparison of verapamil and nifedipine in thrombosis models

Calcium blockers and calmodulin antagonists have been reported to inhibit the aggregation of blood platelets in vitro. In the present study, the effects of two calcium blockers, verapamil and nifedipine, were compared in several rodent thrombosis models. In rat and mouse platelet-rich plasma, preincubation with either verapamil or nifedipine had a dose-dependent inhibitory effect on collagen-induced aggregation (P less than 0.01). The concentration required for 50% inhibition of rat platelet aggregation was 0.91 X 10(-4) M for verapamil and 1.77 X 10(-4) M for nifedipine. In in vivo thrombosis models in mice, acute pretreatment with nifedipine had a significant, dose-dependent protective effect (P less than 0.05). At a dose of 500 micrograms/kg, nifedipine inhibited thrombotic sudden death provoked by arachidonic acid, a thromboxane agonist (U46619), or a combination of collagen and epinephrine. In vivo platelet depletion induced by U46619 was also inhibited by this calcium blocker. Thus, nifedipine is protective against a variety of thrombotic stimuli, and its antiplatelet aggregatory effect apparently extends to the in vivo situation. In contrast, no in vivo antithrombotic activity was observed for verapamil. Two additional calcium blockers, perhexilene and diltiazem, and three calmodulin antagonists, W-7, chlorpromazine, and trifluoperazine, were also tested in the U46619-induced thrombotic sudden death model. Of these, only diltiazem (5 and 10 mg/kg) had an acute protective effect.     

Effects of calcium channel antagonists on the vagally mediated cardiac chronotropic response in dogs

A brief electrical stimulation of the vagus nerve may elicit a triphasic response comprising (i) an initial prolongation of the same or the next cardiac cycle, (ii) a return of the subsequent cardiac cycle to about the level prior to vagal stimulation, and (iii) a secondary prolongation of cardiac cycle length that lasts several beats. We compared the effects of two calcium channel antagonists, verapamil and nifedipine, on this triphasic response to vagal stimulation in chloralose-anesthetized, open-chest dogs. In the absence of vagal stimulation, nifedipine (doses of 10, 40, and 50 micrograms/kg for a total dose of 100 micrograms/kg, i.v.) and verapamil (two doses of 100 micrograms/kg each, i.v.) increased the cardiac cycle length (A-A interval) by 16% (429 +/- 20 to 496 +/- 21 ms) and 29% (470 +/- 33 to 605 +/- 54 ms), respectively. Nifedipine (100 micrograms/kg total) attenuated the initial vagally mediated prolongation of the A-A interval, from 474 +/- 19 to 369 +/- 42 ms above the basal A-A interval. Following the initial prolongation of the vagal effect, other A-A intervals were not affected. In contrast, verapamil potentiated the vagally mediated initial prolongation in cardiac cycle length at the first dose administered (100 micrograms/kg) from 492 +/- 17 to 561 +/- 14 ms, but other increases in dosages had no further effect. Thus these two calcium channel antagonists have different effects on the sinoatrial chronotropic responses caused by brief vagal stimulation.     

Effect of chemically different calcium antagonists on lipid profile in rats fed on a high fat diet.

Different classes of calcium antagonists, viz. verapamil (diphenylalkylamine), diltiazem (benzothiazepine), nifedipine, felodipine and nimodipine (dihydropyridines), were examined for their effects on lipid profile in rats. Clofibrate was the reference standard. Clofibrate significantly prevented the rise of serum triglycerides and total cholesterol produced by high fat diet and raised antiatherogenic index to 1.6 times than that of high fat diet controls. Of the calcium antagonists studied, felodipine was most effective in preventing the rise of serum triglycerides and total cholesterol in high fat diet fed rats. Felodipine's antiatherogenic index was very high (886%)--much more than that of clofibrate (303%). Diltiazem and nimodipine which also significantly prevented the rise in triglycerides and total cholesterol produced by high fat diet had a moderately beneficial antiatherogenic index similar to that of clofibrate. Though verapamil and nifedipine slightly increased the triglyceride levels, total cholesterol levels were reduced only by verapamil and not by nifedipine. Despite this both these drugs moderately raised antiatherogenic index similar to clofibrate.     

Bay K 8644-like contractile effects of a peptide isolated from spontaneously hypertensive rats

The in vitro contractile effect of a peptide recently isolated from the blood of spontaneously hypertensive rats was assessed on rat aortic rings. Preincubation of aortic rings with the peptide had no effect on resting tension but significantly enhanced K+ or norepinephrine-induced contractile responses. Contractile effects were abolished by removal of extracellular calcium or by additions of the calcium channel antagonists, verapamil and nifedipine. The antagonism of peptide enhancement of contraction by verapamil was noncompetitive, whereas nifedipine blockade was competitive in nature. Moreover, preincubation of aortic rings with the peptide attenuated the contractile response to Bay K 8644, a newly described synthetic calcium channel agonist. We suggest that this peptide has similar effects to Bay K 8644 and may act as an endogenous modulator of voltage-dependent calcium channels.     

Calcium-dependent regulation of progesterone production by isolated rat granulosa cells: effects of the calcium ionophore A23187, prostaglandin E2, dl-isoproterenol and cholera toxin

The role of calcium in the regulation of ovarian steroidogenesis was investigated in granulosa cells from estradiol-treated immature rats. Incubation of granulosa cells with various calcium channel blockers (verapamil, cobalt or manganese) and a calcium chelator (EGTA) resulted in marked decreases in progesterone production in response to follicle-stimulating hormone (FSH), cholera toxin, prostaglandin E2, dl-isoproterenol and dibutyryl cyclic AMP (Bt2cAMP). Cyclic AMP production, however, was unaffected by treatment with EGTA and verapamil at concentrations which attenuated steroidogenesis (0.1-1.0 mM and 125 microM, respectively). Two inhibitors of the calcium-dependent regulatory protein, calmodulin [trifluoperazine, 40 microM and 1[bis-(p-chlorophenyl)methyl] 3-[2,4-dichloro-beta-(2,4- dichlorobenzyloxy )-phenethyl]imidazolium chloride, ( R24571 ) 20 microM] significantly inhibited both cyclic AMP and progesterone production elicited by these stimulatory agents. Over the concentration range of 62.5 ng/ml-1.0 micrograms/ml, the calcium ionophore A23187 increased basal progesterone production in a dose-dependent manner, with half-maximal stimulation at approximately 0.14 microgram/ml. Maximal steroidogenic response to the calcium ionophore (1 microgram/ml) however, was only 50% of that evoked by FSH (0.33 microgram/ml). A23187 (0.5 microgram/ml) significantly enhanced progesterone production stimulated by a low concentration of FSH (0.025 microgram/ml) but failed to potentiate the maximally stimulatory action of the gonadotropin (0.33 microgram/ml). These findings support our earlier suggestion that the calcium-calmodulin system plays a central role in the gonadotropic regulation of ovarian steroidogenesis and suggest that a transmembrane flux of extracellular calcium may be an important and common step in the mechanism of stimulation of granulosa cell progesterone production.     

Cardiovascular effects of prostaglandin I2 and prostaglandin F2 alpha in the unanesthetized bullfrog, Rana catesbeiana

The cardiovascular effects of prostaglandin (PG)I2 and PGF2 alpha were compared in the unanesthetized American bullfrog (Rana catesbeiana). Control mean arterial pressure (MAP) and heart rate (HR) were 25.7 +/- 1.1 mm Hg and 35.1 +/- 1.1 beats/min, respectively. Intravenous injections of PGI2 decreased MAP and increased HR in a dose-dependent fashion over the range of concentrations tested (0.03, 0.3, 3, and 10 micrograms/kg-body weight [bw]. Neither atropine (1 mg/kg-bw) nor verapamil (1 mg/kg-bw) treatment altered the MAP or HR responses to PGI2 (3 micrograms/kg-bw). However, propranolol (5 mg/kg-bw) significantly blunted the hypotensive effects without affecting the increase in HR. Prostaglandin F2 alpha (tested at 0.3, 3, 30, and 100 micrograms/kg-bw) increased both MAP and HR. Mean arterial pressure increased with concentrations greater than 0.3 microgram/kg-bw and reached peak effects at 30 micrograms/kg-bw. Prostaglandin F2 alpha increased HR at doses greater than 0.3 microgram/kg-bw. Neither the pressor nor positive chronotropic effects of PGF2 alpha (30 micrograms/kg-bw) were affected by atropine or propranolol. However, verapamil significantly attenuated the pressor effects without affecting the increase in HR. These results demonstrate that both prostaglandins have qualitatively similar effects on HR, but opposite effects on MAP. Prostaglandin I2 is a hypotensive prostaglandin, while PGF2 alpha is hypertensive. The pressor effects of PGF2 alpha are partially dependent on calcium influx. The positive chronotropic effects of both prostaglandins are independent of the autonomic nervous system, suggesting a different mechanism of action.     

The effects of calcium channel blockers on isoproterenol induced cyclic adenosine 3',5'-monophosphate generation in intact human lymphocytes

We have investigated the effects of clinically available calcium channel blockers (nifedipine, verapamil and diltiazem) on isoproterenol stimulated cyclic adenosine 3',5'-monophosphate (cyclic AMP) generation in intact human lymphocytes. After preincubation of various calcium antagonists with intact lymphocytes at 37 degrees C for 15 minutes, 10 microM nifedipine or verapamil partially inhibited isoproterenol induced cyclic AMP generation in the presence of cyclic AMP phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) while they alone had no effect on cyclic AMP level at a concentration of up to 100 microM. In contrast, 10 nM-1.0 microM nifedipine, verapamil or diltiazem potentiated cyclic AMP generation induced by isoproterenol in a dose dependent manner. Similar results were observed in the time course studies of cyclic AMP generation. These effects are somewhat similar to the effect of phenothiazine, a calmodulin inhibitor, which, at 10 microM (close to IC50), also potentiated the effects of isoproterenol. In contrast, lanthanum chloride (LaCl3), an extracellular inorganic calcium antagonist, at 1.0 mM, inhibited isoproterenol induced cyclic AMP generation. The biochemical mechanisms underlying these potentiating effects are unknown. It may be partly related to the effect of calcium channel blockers (at least for nifedipine) on preventing beta 2 adrenergic receptor desensitization. This may provide a potential mechanism for the synergistic effect between calcium channel blockers and beta 2 adrenoceptor agonists on bronchial dilatation.     

The effect of calcium antagonists on histamine and leukotriene-induced tracheal microvascular permeability in the guinea pig

The effects of several calcium antagonists, i.e., nifedipine, verapamil and 8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8), were evaluated in situ on agonist-induced increases in permeability of the airway microvasculature in anesthetized guinea pigs. Vascular permeability was measured as tracheal extravascular albumin content by using 125I-bovine serum albumin and the utilization of 51Cr labelled-erythrocytes to correct for blood volume. Intratracheal injections of histamine (1, 10 and 100 micrograms) or leukotriene (LT) D4 (1, 10 and 100 ng) produced dose-dependent increases in extravasated radiolabelled albumin in the trachea. Although histamine produced a greater maximal response than LTD4, the latter provocation was ten times more potent than the former. Nifedipine, a dihydropyridine calcium slow channel blocker, exhibited dose-dependent (30, 100 and 300 micrograms/kg) inhibitory activity against histamine-induced increases in extravascular albumin, while another calcium slow channel blocker, verapamil (100, 300 and 1000 micrograms/kg), exhibited much less activity. TMB-8, a purported intracellular calcium antagonist (1 and 10 mg/kg), was observed to have some inhibitory activity versus histamine. Similar doses of all three calcium antagonists failed to significantly inhibit increases in tracheal microvascular permeability evoked by LTD4. These results suggest that differences in mediator-induced microvascular permeability in the guinea pig trachea are evident depending upon the agonist selected and the pool of calcium utilized.     

Effect of verapamil on CRF-induced abnormalities in phospholipid contents of brain synaptosomes

Chronic renal failure is associated with significant reductions in total phospholipids, phosphatidylinositol, phosphatidylserine, and phosphatidylethanolamine of brain synaptosomes. These derangements in synaptosomal phospholipid metabolism were attributed to the state of secondary hyperparathyroidism of chronic renal failure (CRF) and the parathyroid hormone-induced accumulation of calcium in synaptosomes. This study examined whether a calcium channel blocker, verapamil, would prevent this synaptosomal calcium accumulation and correct the abnormalities in synaptosomal phospholipids in CRF. Verapamil treatment of normal rats for 21 days did not affect synaptosomal content of calcium or phospholipids. CRF of 21 days' duration was associated with a significant (P less than 0.01) increase in synaptosomal calcium (10.2 +/- 0.5 vs 7.4 +/- 0.6 nmol/mg protein) and a significant reduction (P less than 0.01) in total phospholipids (397 +/- 12 vs 529 +/- 19 nmol phospholipid P/mg protein), phosphatidylinositol (2.7 +/- 0.22 vs 4.6 +/- 0.27 nmol phospholipid P/mg protein), and phosphatidylserine (37 +/- 1.9 vs 83 +/- 5.2 nmol phospholipid P/mg protein). Simultaneous treatment of CRF rats with verapamil for 21 days reversed the synaptosomal abnormalities in calcium and phospholipid contents. Our data support the notion that the effect of excess parathyroid hormone of CRF on synaptosomal phospholipids is mainly due to the parathyroid hormone-induced calcium accumulation.     

Protein synthesis in the hippocampus associated with memory facilitation by corticotropin-releasing factor in rats.

The present study used pharmacological, biochemical, and behavioral methods to examine the role of protein synthesis in the hippocampus in memory processes of a passive avoidance learning in rats. Results indicated that corticotropin-releasing factor (CRF) significantly improved memory retention in rats. Both cycloheximide (CHX) and actinomycin-D (ACT-D) impaired memory at high doses. At doses of CHX and ACT-D that did not affect memory alone, they both antagonized the memory-enhancing effect of CRF. Biochemically, there were specific increases in the optical density of three protein bands in the cytosolic fraction of hippocampal cells in rats showing good memory. There were also marked increases in the optical density of two protein bands in the nucleus fraction of the same animals. Similar results were observed in animals injected with CRF. However, no significant protein alteration was observed in animals receiving stress. These results together suggest that there are new protein syntheses in the hippocampus that are specifically associated with passive avoidance learning in rats.     

Effects of nifedipine and verapamil on body temperature in cats

Nifedipine and verapamil injected into the cerebral ventricles of unanaesthetized cats produced a longlasting rise in the body temperature. The hyperthermic effect of nifedipine and verapamil were not dose-dependent. The hyperthermic effect of verapamil was preceded by a shortlasting fall in the body temperature, which was not dose-dependent. Calcium antagonists, nifedipine and verapamil also produced mydriasis, tachypnoea, dyspnoea, ataxia, tremor and muscular weakness. These symptoms were inconsistent and of slight intensity. In agreement with the theory of ionic set point controlling the body temperature, the most probable explanation is that calcium antagonists, nifedipine and verapamil produced changes in the body temperature by acting on sodium and calcium fluxes in the posterior hypothalamus.     

Verapamil attenuates lung vascular responses to endotoxin in sheep

Experiments were conducted on five chronically instrumented unanesthetized sheep to determine the effects of verapamil, a calcium channel inhibitor, on the pulmonary hemodynamic and microvascular permeability responses to endotoxemia. Paired control endotoxemia experiments (E) and endotoxemia with verapamil treatment (30-60 micrograms.kg-1.min-1) experiments (V + E) were conducted on each sheep in random order. In the V + E experiments sheep were pretreated with a continuous intravenous infusion of verapamil 1.5-2.0 h before endotoxin infusion (1.0 microgram/kg, given over 15 min). Verapamil significantly increased base-line pulmonary arterial pressure, left atrial pressure, lung lymph flow rate, and circulating blood leukocyte levels and significantly decreased base-line cardiac output. During the endotoxin response, verapamil significantly attenuated both phase I pulmonary arterial hypertension and phase II lung lymph flow rate compared with control endotoxin experiments. The results indicate that verapamil attenuates both the pulmonary hemodynamic and increased lung microvascular permeability response to endotoxin in sheep. In a series of in vitro experiments, verapamil was found to be a potent inhibitor of phorbol myristate acetate-induced superoxide production in isolated sheep granulocytes. These data suggest that the beneficial in vivo effects of verapamil during endotoxemia may in part be due to its inhibition of increased free cytosol calcium concentration and/or inhibition of toxic O2 metabolite production.     

Gastric erosions induced by intracisternal thyrotropin-releasing hormone (TRH) in rats

Intracisternal injection of TRH (1 microgram) under light ether anesthesia induced within 4 hr gastric lesions in 24-hr fasted rats maintained unrestrained at room temperature. Saline, ovine corticotropin-releasing factor (oCRF, 10 micrograms), or human pancreatic growth hormone-releasing factor [hpGRF(1-40), 10 micrograms] tested under the same conditions did not modify the integrity of the gastric mucosa. TRH injected intravenously (100 micrograms/kg) proved to be ineffective. The production of gastric erosions elicited by intracisternal TRH (0.1-1 microgram) or by a stabilized TRH analog, RX 77368 [pGlu-His-(3,3'-dimethyl)-ProNH2, (0.01-0.1 microgram)] was dose-dependent. RX 77368 shows an enhanced potency over TRH. TRH action on gastric mucosa was reversed by atropine, omeprazole and cimetidine. These results demonstrate that TRH, unlike the other hypothalamic releasing factors CRF or GRF, is able to act within the brain to cause the formation of gastric erosions probably through mechanisms involving changes in gastric acid secretion. Intracisternal injection of TRH or its potent analog RX 77368 appears also as a new, simple method to produce centrally mediated experimental gastric erosions in 24 hr-fasted rats.     

Role of calcium ion in acth-induced steroidogenesis in humans

In order to examine the role of calcium ion in ACTH-induced steroidogenesis in humans, we carried out infusion of a pharmacological dose of ACTH (4.2 micrograms/kg) and a physiological dose of ACTH (0.0084 microgram/kg) for 120 min, and infusion of dibutyryl cyclic AMP (DBcAMP) [0.33 mg/kg/min] for 20 min, in 22 normal subjects with or without verapamil treatment (360 mg/day, orally) for 5 days. The subjects were pretreated with 1.0 mg of dexamethasone and 5.0 mg of enalapril daily for 2 days before each infusion test to inhibit endogenous ACTH and angiotensin II. Following infusion of 0.0084 microgram/kg of ACTH, plasma levels of corticosterone (P less than 0.02) and cortisol (P less than 0.01) were significantly increased; with chronic verapamil treatment plasma levels of corticosterone (P less than 0.05) and cortisol (P less than 0.02) were significantly lower than those without verapamil. On the other hand, 4.2 micrograms/kg of ACTH for 120 min significantly increased the plasma levels of several steroid hormones, although there were no differences between the infusion with and without verapamil. Infusion of DBcAMP for 20 min significantly increased plasma levels of corticosterone (P less than 0.02) and cortisol (P less than 0.01), but verapamil did not affect the steroidogenic response to the DBcAMP infusion. The present results suggest that steroidogenesis induced by a physiological dose of ACTH differs from that after a pharmacological dose of ACTH or DBcAMP, and is mediated mainly by calcium ion as an intracellular messenger in man.     

Verapamil enhances high-density lipoprotein processing in Hep G2 cells preloaded with cholesterol

The effects of the calcium channel blocker of the arylalkylamine series verapamil have been investigated on high-density lipoprotein (HDL3) catabolism in the human hepatoma cell line Hep G2. It was found that verapamil markedly enhanced HDL3 binding, uptake and degradation in Hep G2 cells preloaded with nonlipoprotein cholesterol. This effect was dose-dependent, and a 1.5-2-fold increase of the three studied parameters was observed in cells pretreated 24 h with 100 microM verapamil. No significant effect of the drug was found in cells not preincubated with cholesterol. Verapamil induced an increase in the cellular cholesterol content in preloaded cells. Other calcium antagonists such as diltiazem, nifedipine, nitrendipine or amphiphilic drugs such as phenothiazines and propranolol also enhanced HDL3 uptake by Hep G2 cells. These effects of verapamil on HDL3 metabolism could be related to its amphiphilic characteristics, and to its calcium antagonist properties.     

急性低氧下钙阻断剂对左,右心泵功能的影响

在20条麻醉开胸狗上,用RM-6000多道仪同步记录左心室内峰压(LVP)、左室压力变化率(L+dP/dt_(max))、右心室内峰压(RVP)、右室压力变化率(R±dp/dt_(max))、肺动脉压力(P_(Pa))、主动脉血流每搏峰值(Fa)、心率(HR)等各项生理指标,观察钙通道阻断剂Nife-dipine,Diltiazem和Verapamil对左、右心室功能影响。在钙通道阻断剂处理后,左室的LVP,L±dp/dt_(max)下降,而Fa增加;右室的RVF,R±dp/dt_(max)和P_(Pa)均有升高趋势,显示钙通道阻断剂对左、右心泵功能的影响不同。这可能提示左、右心室功能对钙离子的依赖程度不同。在急性低氧状态下,此三种钙阻断剂均使急性低氧引起LVP的增加反应消失,Fa增加明显,Verapamil和Diltiazem有减轻急性低氧引起的RVP和P_(Pa)的增压作用。从这些钙通道阻断剂对左右心泵功能影响的比较来看,Diltiazem比Verapamil和Nifedipine对急性低氧状态下的心泵功能有较好的作用。     

Increased vasodilator responsiveness to BRL 34915 in spontaneously hypertensive versus normotensive rats: contrast with nifedipine

The blood pressure-lowering potency and activity of BRL 34915, a new vasodilator and putative stimulator of potassium efflux from vascular smooth muscle, was investigated in conscious spontaneously hypertensive rats (SHR) and normotensive rats (NTR) after intravenous administration and compared with that of the calcium channel blocker, nifedipine. In SHR, BRL 34915 (3-100 micrograms/kg) or nifedipine (10-3000 micrograms/kg) produced similar reductions in mean arterial pressure of 58 +/- 3% and 55 +/- 3%, respectively. BRL 34915 (ED30% = 13.8 micrograms/kg) was 15.3 times more potent than nifedipine (ED30% = 207 micrograms/kg) in SHR. In contrast, only a 1.7-fold difference in potency was observed in NTR between BRL 34915 (ED30% = 123 micrograms/kg) and nifedipine (ED30% = 182 micrograms/kg). The potency ratio (ED30% NTR/ED30% SHR) for BRL 34915 was 8.83 whereas nifedipine had a ratio of 0.88, reflecting the greater responsiveness of the SHR to BRL 34915. Systemic hemodynamics were monitored in anesthetized SHR and NTR to determine the basis for the reductions in blood pressure. BRL 34915 (3-100 micrograms/kg iv) lowered mean arterial pressure in both groups solely by decreasing total peripheral vascular resistance, since no changes in cardiac output were observed. Relaxation responses were also obtained in phenylephrine-contracted isolated aortic strips from both strains of rat to ascertain whether differences in responsiveness existed at this level of the vasculature. No significant difference in the potency of BRL 34915 (3-10 microM) as a vasodilator was found in aortas from SHR or NTR. These results indicate that, unlike nifedipine, BRL 34915 is a more potent vasodepressor agent in SHR than in NTR and suggests that the potassium efflux stimulator may preferentially relax resistance vessels in the hypertensive rat.     

Inhibition of Na+-Ca2+ exchange by calcium antagonists in rat brain microsomal membranes

Na+-Ca2+ exchange rates were studied in native and/or pronase pretreated rat brain microsomal membranes in the presence of calcium channel antagonists verapamil, nimodipine and nifedipine. In native membranes all the substances used inhibited Na+-Ca2+ exchange. A relatively stronger inhibition was observed in membranes pretreated with pronase. The values of Ki for nimodipine and nifedipine did not change and it fell to about one half for verapamil. Lineweaver-Burk's plots have revealed that the verapamil inhibition in native membranes as well as in pronase pretreated ones was of a non-competitive type; Km for calcium oscillated around 15 mumol.l-1. It is suggested that the inhibition strength depends on the access of inhibitors to the membrane binding sites as well as on the solubility of inhibitors in membrane lipids.