Efficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice.

High-risk neuroblastoma (HR-NB) still remains the most dangerous tumor in early childhood. For this reason, the identification of new therapeutic approaches is of fundamental importance. Recently, we combined the conventional pharmacological approach to NB, represented by cisplatin, with fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells, which demonstrated an enhancement of the ability of cisplatin to induce apoptosis. In this work, we co-administrated acetazolamide, a carbonic anhydrase isoform IX (CAIX) inhibitor which was reported to increase chemotherapy efficacy in various cancer types, to the cisplatin/fendiline approach in SKNBE2 xenografts in NOD-SCID mice with the aim of identifying a novel and more effective treatment. We observed that the combination of the three drugs increases more than twelvefold the differences in the cytotoxic activity of cisplatin alone, leading to a remarkable decrease of the expression of malignancy markers. Our conclusion is that this approach, based on three FDA-approved drugs, may constitute an appropriate improvement of the pharmacological approach to HR-NB.

Scaffold repurposing of fendiline: Identification of potent KRAS plasma membrane localization inhibitors.

KRAS plays an essential role in regulating cell proliferation, differentiation, migration and survival. Mutated KRAS is a major driver of malignant transformation in multiple human cancers. We showed previously that fendiline (6) is an effective inhibitor of KRAS plasma membrane (PM) localization and function. In this study, we designed, synthesized and evaluated a series of new fendiline analogs to optimize its drug properties. Systemic structure-activity relationship studies by scaffold repurposing led to the discovery of several more active KRAS PM localization inhibitors such as compounds 12f (NY0244), 12h (NY0331) and 22 (NY0335) which exhibit nanomolar potencies. These compounds inhibited oncogenic KRAS-driven cancer cell proliferation at single-digit micromolar concentrations in vitro. In vivo studies in a xenograft model of pancreatic cancer revealed that 12h and 22 suppressed oncogenic KRAS-expressing MiaPaCa-2 tumor growth at a low dose range of 1-5 mg/kg with no vasodilatory effects, indicating their potential as chemical probes and anticancer therapeutics.

Fendiline Enhances the Cytotoxic Effects of Therapeutic Agents on PDAC Cells by Inhibiting Tumor-Promoting Signaling Events: A Potential Strategy to Combat PDAC.

The L-type calcium channel blocker fendiline has been shown to interfere with Ras-dependent signaling in K-Ras mutant cancer cells. Earlier studies from our lab had shown that treatment of pancreatic cancer cells with fendiline causes significant cytotoxicity and interferes with proliferation, survival, migration, invasion and anchorage independent growth. Currently there are no effective therapies to manage PDACs. As fendiline has been approved for treatment of patients with angina, we hypothesized that, if proven effective, combinatorial therapies using this agent would be easily translatable to clinic for testing in PDAC patients. Here we tested combinations of fendiline with gemcitabine, visudyne (a YAP1 inhibitor) or tivantinib (ARQ197, a c-Met inhibitor) for their effectiveness in overcoming growth and oncogenic characteristics of PDAC cells. The Hippo pathway component YAP1 has been shown to bypass K-Ras addiction, and allow tumor growth, in a Ras-null mouse model. Similarly, c-Met expression has been associated with poor prognosis and metastasis in PDAC patients. Our results presented here show that combinations of fendiline with these inhibitors show enhanced anti-tumor activity in Panc1, MiaPaCa2 and CD18/HPAF PDAC cells, as evident from the reduced viability, migration, anchorage-independent growth and self-renewal. Biochemical analysis shows that these agents interfere with various signaling cascades such as the activation of Akt and ERK, as well as the expression of c-Myc and CD44 that are altered in PDACs. These results imply that inclusion of fendiline may improve the efficacy of various chemotherapeutic agents that could potentially benefit PDAC patients.

Fendiline inhibits proliferation and invasion of pancreatic cancer cells by interfering with ADAM10 activation and ß-catenin signaling.

ADAM10 (A Disintegrin and Metalloprotease Domain 10) affects the pathophysiology of various cancers, and we had shown that inhibition of ADAM10 sensitizes pancreatic cancer cells to gemcitabine. ADAM10 is activated in response to calcium influx, and here we examined if calcium channel blockers (CCB) would impede ADAM10 activation and affect biology of pancreatic cancer cells. We find that the CCB, fendiline, significantly reduces proliferation, migration, invasion, and anchorage independent growth of pancreatic cancer cells. This was associated with ADAM10 inhibition and its localization at the actin-rich membrane protrusions. Further, fendiline-treated cells formed cadherin-catenin positive tight adherens junctions and elicited defective protein trafficking and recycling. Furthermore, the expression of ß-catenin target genes, cyclinD1, c-Myc and CD44, were significantly decreased, suggesting that fendiline might prevent cell proliferation and migration by inhibiting ADAM10 function, cadherin proteolysis and stabilization of cadherin-catenin interaction at the plasma membrane. This will subsequently diminish ß-catenin intracellular signaling and repress TCF/LEF target gene expression. Supporting this notion, RNAi-directed downregulation of ADAM10 in cancer cells decreased the expression of cyclinD1, c-Myc and CD44. Furthermore, analysis of human pancreatic tumor tissue microarrays and lysates showed elevated levels of ADAM10, suggesting that aberrant activation of ADAM10 plays a fundamental role in growth and metastasis of PDACs and inhibiting this pathway might be a viable strategy to combat PDACs.

Fendiline inhibits K-Ras plasma membrane localization and blocks K-Ras signal transmission.

Ras proteins regulate signaling pathways important for cell growth, differentiation, and survival. Oncogenic mutant Ras proteins are commonly expressed in human tumors, with mutations of the K-Ras isoform being most prevalent. To be active, K-Ras must undergo posttranslational processing and associate with the plasma membrane. We therefore devised a high-content screening assay to search for inhibitors of K-Ras plasma membrane association. Using this assay, we identified fendiline, an L-type calcium channel blocker, as a specific inhibitor of K-Ras plasma membrane targeting with no detectable effect on the localization of H- and N-Ras. Other classes of L-type calcium channel blockers did not mislocalize K-Ras, suggesting a mechanism that is unrelated to calcium channel blockade. Fendiline did not inhibit K-Ras posttranslational processing but significantly reduced nanoclustering of K-Ras and redistributed K-Ras from the plasma membrane to the endoplasmic reticulum (ER), Golgi apparatus, endosomes, and cytosol. Fendiline significantly inhibited signaling downstream of constitutively active K-Ras and endogenous K-Ras signaling in cells transformed by oncogenic H-Ras. Consistent with these effects, fendiline blocked the proliferation of pancreatic, colon, lung, and endometrial cancer cell lines expressing oncogenic mutant K-Ras. Taken together, these results suggest that inhibitors of K-Ras plasma membrane localization may have utility as novel K-Ras-specific anticancer therapeutics.

Fendiline-evoked [Ca2+]i rises and non-Ca2+-triggered cell death in human oral cancer cells.

The effect of fendiline on cytosolic free Ca(2+) concentrations ([Ca(2+)](i)) and proliferation has not been explored in human oral cancer cells. This study examined whether fendiline altered Ca(2+) levels and caused cell death in OC2 human oral cancer cells. [Ca(2+)](i) and cell viability were measured using the fluorescent dyes fura-2 and WST-1, respectively. Fendiline at concentrations above 10 microM increased [Ca(2+)](i) in a concentration-dependent manner. The Ca(2+) signal was reduced partly by removing extracellular Ca(2+). The fendiline-induced Ca(2+) influx was sensitive to blockade of L-type Ca(2+) channel blockers. In Ca(2+)-free medium, after pretreatment with 50 microM fendiline, 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor)-induced [Ca(2+)](i) rises were inhibited; and conversely, thapsigargin pretreatment nearly abolished fendiline-induced [Ca(2+)](i) rises. Inhibition of phospholipase C with 2 microM U73122 did not change fendiline-induced [Ca(2+)](i) rises. At concentrations between 5 and 25 microM, fendiline killed cells in a concentration-dependent manner. The cytotoxic effect of 15 microM fendiline was not reversed by prechelating cytosolic Ca(2+) with BAPTA/AM. Collectively, in OC2 cells, fendiline induced [Ca(2+)](i) rises by causing Ca(2+) release from the endoplasmic reticulum and Ca(2+) influx from L-type Ca(2+) channels. Furthermore, fendiline-caused cytotoxicity was not via a preceding [Ca(2+)](i) rise.

The anti-anginal drug fendiline elevates cytosolic Ca(2+) in rabbit corneal epithelial cells.

The effect of the anti-anginal drug fendiline on intracellular free Ca(2+) levels ([Ca(2+)](i)) in a rabbit corneal epithelial cell line (SIRC) was explored using fura-2 as a fluorescent Ca(2+) indicator. At a concentration above 1 microM, fendiline increased [Ca(2+)](i) in a concentration-dependent manner with an EC(50) value of 7 microM. The [Ca(2+)](i) response consisted of an immediate rise and an elevated phase. Extracellular Ca(2+) removal decreased half of the [Ca(2+)](i )signal. Fendiline induced quench of fura-2 fluorescence by Mn(2+) (50 microM), suggesting the presence of Ca(2+) influx across the plasma membrane. This Ca(2+) influx was abolished by La(3+) (50 microM), but was insensitive to dihydropyridines, verapamil and diltiazem. Fendiline (10 microM)-induced store Ca(2+) release was largely reduced by pretreatment with thapsigargin (1 microM) (an endoplasmic reticulum Ca(2+) pump inhibitor) to deplete the endoplasmic reticulum Ca(2+). Conversely, pretreatment with 10 microM fendiline abolished thapsigargin-induced Ca(2+) release. Fendiline (10 microM)-induced Ca(2+) release was not altered by inhibiting phospholipase C with 2 microM 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122). Cumulatively, this study shows that fendiline induced concentration-dependent [Ca(2+)](i )increases in corneal epithelial cells by releasing the endoplasmic reticulum Ca(2+) in a phospholipase C-independent manner, and by causing Ca(2+) influx.

Effects of the antianginal drug fendiline on Ca2+ movement in hepatoma cells.

This study investigated the effect of the anti-anginal drug, fendiline, on intracellular free Ca2+ levels ([Ca2+]i) in HA/ 22 human hepatoma cells by using fura-2 as a fluorescent Ca2+ dye. Fendiline (1-100 microM) increased [Ca2+]i with an EC50 of 25 microM. Removal of extracellular Ca2+ reduced the [Ca2+]i signals by 51 +/- 5%. Fendiline (10 microM)-induced Ca2+ release was abolished by pretreatment with 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor). Inhibition of phospholipase C with 2 microM 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122) did not alter 10 microM fendiline-induced Ca2+ release. Several other calmodulin antagonists, such as phenoxybenzamine (100-200 microM), trifluoperazine (5-50 microM), and fluphenazine-N-chloroethane (2-100 microM), had no effect on [Ca2+]i. Together, it was found that fendiline increased [Ca2+]i in human hepatoma cells by discharging Ca2+ from the endoplasmic reticulum in an inositol 1,4,5-trisphosphate-independent manner and by inducing Ca2+ entry. This effect of fendiline does not appear to be via antagonism of calmodulin.

Fendiline, an anti-anginal drug, increases intracellular Ca2+ in PC3 human prostate cancer cells.

BACKGROUND: The effects of the anti-anginal drug fendiline on intracellular Ca2+ concentrations ([Ca2+]i) in human PC3 prostate cancer cells were examined. METHODS: [Ca2+]i was measured using the fluorescent dye fura-2. RESULTS: Fendiline (0.5-100 microM) increased [Ca2+]i in a concentration-dependent manner. Ca2+ removal partly inhibited the Ca2+ signals. In Ca2+-free medium, pretreatment with 100 microM fendiline inhibited most of the [Ca2+]i increase induced by 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor), and pretreatment with thapsigargin abolished the fendiline-induced [Ca2+]i increases. Adding 3 mM Ca2+ increased [Ca2+]i in cells pretreated with 0.5-200 microM fendiline in Ca2+-free medium. Pretreatment with 1 microM U73122 to block the formation of inositol-1.4.5-trisphosphate (IP3) did not alter fendiline-induced internal Ca2+ release. CONCLUSIONS: The anti-anginal drug fendiline induced internal Ca2+ release and external Ca2+ entry. Because prolonged increases in [Ca2+]i may lead to cell injury and death, the long-term effect of fendiline on the function of prostate cancer cells should be investigated.

Dual effect of the antianginal drug fendiline on bladder female transitional carcinoma cells: mobilization of intracellular CA2+ and induction of cell death.

The effect of fendiline, an antianginal drug, on cytosolic free Ca2+ levels ([Ca2+]i) in populations of bladder female transitional carcinoma (BFTC) cells was explored using fura-2 as a Ca2+ indicator. Fendiline at concentrations between 3 and 200 micromol/l increased [Ca2+]i in a concentration-dependent manner and the signal saturated at 100 micromol/l. The [Ca2+]i signal was biphasic, with an initial rise and a slow decay. Ca2+ removal inhibited the Ca2+ signal by about half in peak amplitude. Adding 3 mmol/l Ca2+ increased [Ca2+]i in cells pretreated with 100 micromol/l fendiline in Ca2+ -free medium, suggesting that fendiline induced Ca2+ influx via capacitative Ca2+ entry. In Ca2+ -free medium, pretreatment with 1 micromol/l thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) to deplete the endoplasmic reticulum Ca2+ store inhibited most of the 100 micromol/l fendiline-induced internal Ca2+ release; and conversely, pretreatment with 100 micromol/l fendiline partly inhibited 1 micromol/l thapsigargin-induced Ca2+ release. This indicates that the major internal Ca2+ store of fendiline-induced [Ca2+]i increases is located in the endoplasmic reticulum. The Ca2+ release induced by 100 micromol/l fendiline may be partly mediated by inositol 1,4,5-trisphosphate, because the [Ca2+]i increase was inhibited by 50% by inhibiting phospholipase C with 2 micromol/l U73122. Fendiline (100 micromol/l) decreased cell viability by 12-44% after being added to cells for 2- 30 min. Together, the findings indicate that in BFTC cells, fendiline exerts a dual effect: mobilization of intracellular Ca2+ and induction of cell death.

The anti-anginal drug fendiline increases intracellular Ca(2+) levels in MG63 human osteosarcoma cells.

The effect of fendiline, an anti-anginal drug, on cytosolic free Ca(2+) levels ([Ca(2+)](i)) in MG63 human osteosarcoma cells was explored by using fura-2 as a Ca(2+) indicator. Fendiline at concentrations between 1 and 200 microM increased [Ca(2+)](i) in a concentration-dependent manner and the signal saturated at 100 microM. The Ca(2+) signal was inhibited by 65+/-5% by Ca(2+) removal and by 38+/-5% by 10 microM nifedipine, but was unchanged by 10 microM La(3+) or verapamil. In Ca(2+)-free medium, pre-treatment with 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor) to deplete the endoplasmic reticulum Ca(2+) store inhibited fendiline-induced intracellular Ca(2+) release. The Ca(2+) release induced by 50 microM fendiline appeared to be independent of IP(3) because the [Ca(2+)](i) increase was unaltered by inhibiting phospholipase C with 2 microM U73122. Collectively, the results suggest that in MG63 cells fendiline caused an increase in [Ca(2+)](i) by inducing Ca(2+) influx and Ca(2+) release in an IP(3)-independent manner.

Enhancement of the mutagenicity of anticancer drugs by the calcium antagonists verapamil and fendiline.

The enhancement of the mutagenicity of anticancer drugs by the calcium antagonists verapamil (CAS 52-53-9) and fendiline (CAS 13042-18-7) is reviewed. Both calcium antagonists enhance synergistically the induction of chromosome aberrations (dicentric and ring chromosomes) in cultured human lymphocytes by the antitumor agent bleomycin. Since two other calcium antagonists, nifedipine and diltiazem, when tested with the same system, did not show this effect, the comutagenicity of verapamil and fendiline does not seem to be related with calcium antagonism per se. Verapamil furthermore potentiates the induction of various chromosome and chromatid aberrations in Chinese hamster ovary (CHO) cells in vitro by the antitumor agent mitomycin C. In bacteria (Salmonella typhimurium) verapamil enhances synergistically the induction of gene mutations (frameshifts) by several anticancer drugs, including various anilinoacridine derivatives. When applied alone, neither verapamil which was tested in each of the three studies (human lymphocytes, CHO-cells, and bacteria) nor fendiline, which was tested only in human lymphocytes, proved to be mutagenic. To explain the comutagenicity of verapamil and fendiline, it is assumed that they prevent the mutagen (e.g., bleomycin) to be extruded from the cell. Consequently, the mutagen would be accumulated intracellularly and this would enhance its efficiency.

Effects of the calmodulin antagonists fendiline and calmidazolium on aggregation, secretion of ATP, and internal calcium in washed human platelets.

Ca2(+)-calmodulin dependent phosphorylation of myosin is essential for the induction of platelet shape change and subsequent reactions. Therefore, we studied the effects of the calmodulin antagonists fendiline and calmidazolium on the thrombin-induced aggregation, secretion of ATP, and increases in the intracellular free calcium concentration ([Ca2+]i) in washed human platelets in the absence and presence of extracellular Ca2+. In Ca2+ free medium, fendiline (10-100 microM) and calmidazolium (3-30 microM) concentration-dependently inhibited aggregation. The effect of fendiline could be partly reversed by extracellular Ca2+ and higher thrombin concentrations. Furthermore, aggregations induced by the calcium ionophore ionomycin and by the protein kinase C-activator 4-beta-phorbol 12-myristate 13-acetate were inhibited by fendiline, although to a smaller degree than the thrombin-induced aggregation. Thrombin-induced secretion of ATP was attenuated by low concentrations of fendiline (1-3 microM) and calmidazolium (1 microM) but enhanced by higher concentrations (10-30 and 3-10 microM, respectively), independently of extracellular Ca2+. Fendiline (1-10 microM) did not affect [Ca2+]i in resting and thrombin-stimulated platelets. At higher concentrations (30-100 microM), it induced increases in [Ca2+]i in unstimulated platelets and attenuated the response to thrombin in Ca2+ free medium, whereas thrombin-induced Ca2+ influx was markedly enhanced. Similar results were obtained with calmidazolium (1-3 microM). These stimulating effects on ATP secretion and on [Ca2+]i of fendiline and calmidazolium may be attributed to interactions with platelet membranes by which the permeability of small cations is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Fendiline and calmidazolium enhance the release of endothelium-derived relaxant factor and of prostacyclin from cultured endothelial cells.

We investigated the effects of fendiline, calmidazolium and trifluoperazine, compounds described as calmodulin antagonists, on the release of the endothelial autacoids prostacyclin (PGI2) and endothelium-derived relaxant factor (EDRF). Cultured bovine aortic endothelial cells were grown on microcarrier beads and continuously superfused with Tyrode's solution. Samples collected from the superfusate were assayed for PGI2 concentration (6-keto PGF1 alpha radioimmunoassay) and for EDRF activity (stimulation of soluble guanylate cyclase in vitro). Stimulation of endothelial cells by ATP (3 microM) resulted in a 6.9 +/- 1.4-fold increase of PGI2 concentration in the superfusate (p less than 0.01) and an 8.6 +/- 3.4-fold enhanced guanylate cyclase activity (p less than 0.01). In the presence of calmidazolium (10 microM), the basal values of PGI2 concentration increased 28-fold (p less than 0.01) and the guanylate cyclase activity 10-fold (p less than 0.01). Further enhancement of both was observed after additional administration of ATP. Fendiline (30 microM) did not affect autacoid release by non-stimulated cells. However, the ATP-induced release of PGI2 and EDRF was more than doubled (p less than 0.01) in the presence of this drug compared to ATP-stimulation alone. Trifluoperazine (10 microM) had no enhancing effect on EDRF release, and the ATP-induced release of PGI2 was even significantly attenuated by 84 +/- 12% (p less than 0.01). Calmidazolium and fendiline were also applied to endothelial cells loaded with the fluorescent indicator of free calcium concentration (Ca2i+), indo-1. However, effects of calmidazolium on Ca2i+ could not be quantified since calmidazolium caused some leakage of indo-1 out of the cells. A smaller leakage was observed during the combined application of fendiline and ATP.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of fendiline on cAMP metabolism and activity of the isolated uterus of the rat.

Increasing concentrations of fendiline inhibit various types of muscle activation (KCl, oxytocin and electrical stimulation), as well as spontaneous rhythmic activity of the isolated uterus of the rat. Contrary to verapamil and nifedipine, fendiline in micromolar concentrations (from 1.5 to 15.5 mumol) affects various types of muscle activation almost to the same degree. Fendiline probably influences a common pathway in calcium metabolism in all types of muscle activation. The relaxant effect of fendiline does not depend on cAMP, being even associated with a significant decrease of the level of this nucleotide during electrical stimulation of the isolated uterus of the rat. Fendiline may have its place in the therapy of premature delivery and abortion, particularly because it exhibits lower selectivity in relation to the type of activation of the smooth muscle. Fendiline induces a stronger inhibition of the tonic than of the phasic component of contraction produced by oxytocin and KCl. Fendiline is more active against the oxytocin-induced contraction, probably due to an additional action on the fast Na+ channels. These findings indicate that KCl and oxytocin act through different calcium channels (voltage and receptor calcium channels). Our experiments in which fendiline inhibited more strongly the tonic than the phasic component of KCl-produced contraction also confirm the hypothesis on the existence of voltage calcium channels (or subtypes of one voltage calcium channel) in the isolated uterus of the rat. By adding calcium to the medium, almost all types of muscle activation are established, after the inhibitory action of fendiline, except its depressive action on the electrical stimulation of the isolated rat uterus. Calcium most effectively antagonizes the inhibitory effect of fendiline on spontaneous rhythmic activity. The finding that certain types of activation, after the inhibitory action of fendiline, occur to a different degree by addition of calcium to the medium, are also indirect confirmation of the existence of different calcium channels. Halothane, in a concentration of 1 vol %, did not change the relaxant action of fendiline during electrical stimulation and during spontaneous rhythmic activity.

Temperature dependence of calcium antagonist action.

Calcium-tolerant ventricular myocytes from adult rats were electrically stimulated. The maximal contraction frequency (fm) was determined at different temperatures. In drug-free Tyrode solution, fm follows the Arrhenius equation from 7 to 39.5 degrees C. However, all investigated calcium antagonist drugs (verapamil, nifedipine, diltiazem, fendiline) introduce a discontinuity between 27 and 30 degrees C into the Arrhenius plots of fm. Above this transition temperature calcium antagonists lower fm more pronouncedly than below. Below, 10- or 100 fold higher concentrations are needed for the same relative effect as at 37 degrees C. It is argued that these findings might be important in cardiac surgery when calcium antagonists are used for cardioplegia at deep hypothermia.

Skinned coronary smooth muscle: calmodulin, calcium antagonists, and cAMP influence contractility.

The effects of Ca2+, calmodulin, cAMP, the catalytic subunit of cAMP-dependent protein kinase (CSU) and some Ca2+ antagonists were studied in chemically (Triton X-100) skinned coronary smooth muscle. Calmodulin increased the Ca2+ responsiveness of the muscle fiber as indicated by the reduction in the threshold as well as the half-maximal activating Ca2+ concentration. Trifluoroperazine, a calmodulin antagonist, inhibited Ca2+-calmodulin-induced contraction. Both cAMP and CSU were effective inhibitors of contraction induced at an intermediate Ca2+ concentration. Fendiline, a Ca2+-antagonist, at 2 x 10(-4) M produced a significant inhibitory effect, which was reduced by increasing the Ca2+ concentration. From other Ca2+ antagonists tested, W-7, but not D600 and verapamil, produced some inhibitory effect. The data indicate that the response of skinned coronary smooth muscle to Ca2+, calmodulin and cAMP are similar to those obtained with other skinned smooth muscles. Furthermore, skinned fiber preparation can serve as a useful tool to investigate possible direct effects of drugs on the activating and regulatory systems in smooth muscle.

Physiological tone regulation and drug susceptibility of coronary smooth musculature of extramural stem arteries.

The great extramural coronary stem arteries (as well as extramural collaterals and anastomoses) deserve particular interest with respect to their peculiar susceptibility to autonomic neurotransmitters and drugs. Obviously these arteries, preferentially affected by atherosclerotic processes, are most responsive to such vasodilators which block vascular tone and contractility by interference with Ca-dependent excitation-contraction coupling. This applies first of all to the new pharmacological family of Ca-antagonists but also to the classical nitrites. As we have emphasized in 1971. Ca-antagonism is a new principle of coronary vascular dilation with profound clinical implications (5). In fact, the Ca-antagonists have become, within a few years, the drugs of choice for the treatment of all spastic forms of angina. By contrast adenosine, dipyridamole, chromonar and theophylline preferably dilate the small intramural resistance vessels, but do not significantly reflex the extramural stem arteries. Therefore, in coronary heart disease, the latter drugs do usually not produce major circulatory improvement.