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PubMed2003

Radiation and gene therapy: rays of hope for the new millennium?

Radiotherapy is, after surgery, the most widely used form of cancer treatment but the main limitation of radiation treatment is damage to normal tissues. This may be overcome by targeted radiotherapy - the selective delivery to malignant deposits of cytotoxic radionuclides bound to tumour-seeking agents. Several gene transfer techniques are being evaluated which combine gene therapy and targeted radiotherapy, rendering malignant cells more sensitive to radiation or causing them to take up radioactive drugs - providing tumour cell kill with reduced damage to normal tissues. This review examines several aspects of targeted radiotherapy/gene therapy strategies. As well as identification of suitable gene/radiopharmaceutical combinations, expression of the transgenes must be confined to tumour cells via tumour specific transcriptional regulation or via delivery vehicles which specifically target tumour cells. The inability of current delivery vehicles to target every cell within a tumour mass must be addressed by maximising collateral cell damage in targeted radiotherapy strategies via radiation mediated bystander effects and suitable in vitro models are described, which allow assessment of promising gene transfer strategies in scenarios where tumour heterogeneity of transgene expression and cell proliferative state are considered.

Animals↗

PubMed1975

[Coronary collateral vessels after long-term treatment with fendiline hydrochloride in a double-blind study (author's transl)].

After long-therapy with 5 mg/kg body-weight of N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)amine hydrochloride (fendiline hydrochloride, Sensit) in dogs the development of functioning coronary collateral vessels can be proven by filling the vessel system with synthetic resin. From earlier studies, it is known that coronary collateral vessels can protect the heart from the consequences of stenoses and tissue damage due to hypoxia.

Animals↗

PubMed1989

Electrophysiological characterization of putative C1 adrenergic neurons in the rat.

Recent studies in the rat have demonstrated that at least two populations of sympathoexcitatory reticulospinal neurons reside in the nucleus reticularis rostroventrolateralis. It appears that only one of these populations consists of C1 adrenergic neurons. The present study used both double-labeling (one retrograde tracer and immunohistochemistry) and triple-labeling (two retrograde tracers and immunohistochemistry) to determine if C1 adrenergic neurons, which are immunoreactive for phenylethanolamine N-methyltransferase, exhibit a projection pattern that is sufficiently unique to permit the electrophysiological discrimination between C1 adrenergic and non-adrenergic neurons in the nucleus reticularis rostroventrolateralis. Double-labeling experiments indicated that 71% (range: 53-80) of phenylethanolamine-N-methyltransferase-immunoreactive neurons in the nucleus reticularis rostroventrolateralis could be retrogradely labeled from the thoracic cord, as were 76% (range: 67-94) following tracer injection in the central tegmental tract at pontine levels. Triple-labeling experiments indicated that 88% (range: 82-93) of nucleus reticularis rostroventrolateralis neurons with projections to both spinal cord and central tegmental tract were phenylethanolamine-N-methyltransferase-immunoreactive. Single-unit recording, in nucleus reticularis rostroventrolateralis, was used to identify antidromic potentials elicted from stimulation sites in the spinal cord and/or central tegmental tract. Since clonidine is known to reduce central adrenaline turnover, sensitivity to this drug was used to identify putative adrenergic neurons. Twenty-six nucleus reticularis rostroventrolateralis neurons with axonal projections to both the ipsilateral spinal cord and the central tegmental tract were recorded in halothane-anesthetized rats. All these cells were barosensitive, pulse-modulated, and 16 of the 16 cells tested exhibited a 66 +/- 8% reduction in activity upon the intravenous administration of clonidine (20 micrograms/kg). Most (13 out of 16) exhibited a strong respiratory modulation. The conduction velocity of their spinal collateral was generally low (0.9 +/- 0.1 m/s) and their firing rate moderate (7.4 +/- 1.2 spikes/s). Forty-three nucleus reticularis rostroventrolateralis cells with axonal projections exclusively to the thoracic cord were studied for comparison. These cells were strongly barosensitive and pulse-synchronous, had a high discharge rate (25 +/- 3 spikes/s) and a moderate conduction velocity (3.4 +/- 0.3 m/s). Only one of the 15 cells tested was inhibited by clonidine and only two to these 15 cells exhibited a detectable respiratory modulation. Thus barosensitive nucleus reticularis rostroventrolateralis neurons with axonal projections to both the spinal cord and the central tegmental tract likely belong to the C1 adrenergic cell group. It is concluded that this subgroup of adrenergic neurons probably subserves a vasomotor function.

Action Potentials↗

PubMed1989

Sequential amplification of dihydrofolate reductase and multidrug resistance genes in Chinese hamster ovary cells selected for stepwise resistance to the lipid-soluble antifolate trimetrexate.

We describe the development of resistance to trimetrexate and piritrexim (BW 301U) by a stepwise selection protocol in Chinese hamster ovary cells. Selection in trimetrexate resulted in initial resistance as a result of dihydrofolate reductase gene amplification. Several trimetrexate-resistant variants that display 250-340-fold and 25-50-fold resistance to lipophilic and hydrophilic antifolates, respectively, were established. Increased antifolate resistance was associated with a prominent overexpression of dihydrofolate reductase as determined from the elevated folate reductase activity, cellular labeling with fluorescein-methotrexate, and steady-state mRNA levels as a result of a consistent dihydrofolate reductase gene amplification. However, upon subsequent incremental increases in trimetrexate, further resistance was also associated with amplification of the multidrug resistance gene. This resulted in overexpression of P-glycoprotein and a subsequent 20-50-fold collateral resistance to pleiotropic drugs such as adriamycin, actinomycin D, vinca alkaloids, etoposide, and colchicine. In contrast, initial resistance following selection with low piritrexim concentrations resulted from an unknown mechanism(s) not involving overproduction of either dihydrofolate reductase or P-glycoprotein. This piritrexim resistance was shared with trimetrexate but not with methotrexate. Upon further selection with piritrexim, resistant variants emerge with amplified dihydrofolate reductase but not with multidrug resistance genes. These variants were subsequently resistant to both hydrophilic and lipophilic folate antagonists but retained sensitivity to pleiotropic drugs. The pattern of resistance with methotrexate, trimetrexate, and piritrexim shared a common mechanism, dihydrofolate reductase gene amplification, but differed regarding the additional amplification of the multidrug resistance gene in trimetrexate-resistant cells as well as the emergence of an additional unknown mechanism(s) of resistance to lipid-soluble antifolates upon initial selection in piritrexim.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1977

Collateral sensitivity between methylene dimethane sulfonate and halogenated methotrexate derivatives in the Yoshida sarcoma in vivo and in vitro.

A Yoshida lymphosarcoma line (YMDR8) resistant to methylene dimethane sulfonate (MDMS) showed collateral sensitivity against three halogenated methotrexates: 3'-bromomethotrexate (NSC-98580), 3'-bromo-5'-chloromethotrexate (NSC-98579), and 3',5'-dichloromethotrexate (NSC-29630); however, it was cross-resistant to methotrexate itself. Two other independently derived MDMS-resistant cell lines, YMDR7 and YMDR9, also demonstrated collateral sensitivity against 3'-bromomethotrexate, but with the latter, the origin of the "induced" sensitivity probably was not due to interference with antigenic or oncogenic properties of the cell line. When these agents were used in vivo (in Wistar rats) and in vitro, subpopulation changes within the tumor lines could be observed. The possible importance of this parameter in the development of such sensitivity is discussed.

Animals↗

PubMed1996

Collateral sensitivity to the bisdioxopiperazine dexrazoxane (ICRF-187) in etoposide (VP-16)-resistant human leukemia K562 cells.

Etoposide (VP-16)-resistant K562 cells (K/VP.5) were 26-fold resistant to VP-16, due in part to a reduction in DNA topoisomerase II (topoisomerase II) protein levels. Compared with parental K562 cells, VP-16-resistant K/VP.5 cells were found to be 3.4-fold more sensitive to the effects of dexrazoxane (ICRF-187), a topoisomerase II inhibitor that does not stabilize topoisomerase II-DNA covalent complexes. In contrast, K/VP.5 cells were 4.0-fold cross-resistant to merbarone and showed no cross-resistance to fostriecin, two other topoisomerase II inhibitors that do not stabilize topoisomerase II-DNA covalent complexes. Preincubation with ICRF-187 resulted in greater inhibition of subsequent VP-16-induced topoisomerase II-DNA covalent complexes in K/VP.5 cells than in K562 cells. Conversely, preincubation with merbarone resulted in less inhibition of VP-16-induced topoisomerase II-DNA covalent complexes in K/VP.5 cells than in parental K562 cells. Preincubation with forstriecin had little effect on VP-16-induced topoisomerase II-DNA covalent complex formation in either cell line. The onset rates for ICRF-187 inhibition of VP-16-induced topoisomerase II-DNA complex formation were similar in sensitive and resistant cells. In addition, ICRF-187 had a comparable concentration-dependent inhibitory effect on the topoisomerase II catalytic activities of K562 and K/VP.5 cells. Together, our results indicate that collateral sensitivity to ICRF-187 in K/VP.5 cells is due to decreased topoisomerase II protein levels rather than to an alteration in topoisomerase II activity. Furthermore, results suggest that ICRF-187, merbarone, and fostriecin have different mechanisms of action that can be studied effectively in K/VP.5 and K562 cells.

Alkenes↗

PubMed1976

Pharmacoangiographic manipulation of renal collateral blood flow.

Vasodilatory or vasoconstrictive renal pharmacoangiography was applied in investigating the significance of 50 renal artery stenoses. The technique involves comparison of selective magnification renal arteriograms before and after intra-arterial injection of epinephrine or acetylcholine, seeking changes in direction of flow in potential collateral routes. The drug injected depended upon the hemodynamic conditions during control arteriography. Final determination of significance depended on response to surgery in most patients, and renin levels in a few. Vasoconstrictive angiography was determinate in 18/26 (69%) of significant stenoses and correctly identified hemodynamic significance in each. Other angiographic signs of collateral circulation were present in seven of the other eight significant stenoses studied with the vasoconstrictive method. Vasodilatory pharmacoangiography was determinate in 20 arteries, and correctly evaluated each of nine significant and 11 insignificant lesions. Pharmacoangiography is a moderately sensitive and completely specific angiographic method for evaluating the hemodynamic significance of renal artery stenoses.

Angiography↗

PubMed1973

The membrane effects, and sensitivity to strychnine, of neural inhibition of the Mauthner cell, and its inhibition by glycine and GABA.

1. Anionic conductance changes in Mauthner neurones of goldfish were measured during synaptically evoked inhibition and inhibition caused by iontophoretic application of the putative inhibitory transmitters glycine and gamma-aminobutyric acid (GABA).2. The effects of either amino acid were indistinguishable from those of the neural inhibitory transmitter(s). The membrane permeability during the neural or drug response was increased to Br(-), Cl(-), I(-), SCN(-), NO(3) (-), ClO(3) (-), and formate (HCOO(-)), but not to HCO(3) (-), BrO(3) (-), IO(3) (-), SO(4) (-), HPO(4) (-), H(2)PO(4) (-), acetate and citrate.3. Strychnine was injected intramuscularly, iontophoretically, or applied topically to the exposed brain in order to compare quantitatively its ability to prevent inhibition evoked by synaptic activation and by pharmacological means. Inhibitions were measured by the increase in membrane conductance.4. Strychnine, at concentrations just adequate to block completely the late collateral inhibition (LCI) and crossed VIII nerve inhibition, had little effect on the pharmacological inhibition caused by glycine, and sometimes there was no detectable effect at all. In one experiment even a local iontophoretic application of strychnine in a sufficient dose to diffuse over the cell and block the LCI almost completely, merely halved the effect of a small dose of glycine applied to the same localized region of the membrane.5. Higher concentrations of strychnine than those necessary to block synaptically evoked inhibition would reduce the effect of glycine but not that of GABA. The evidence indicated that any apparent effect of strychnine upon GABA could be explained by displacement of the GABA-containing iontophoretic pipette.6. The glycine-blocking action of iontophoretic pulses of strychnine was of relatively very slow onset and long duration compared to the effects of pulses of glycine and GABA.7. These findings can be interpreted as either (1) strychnine has a presynaptic action, preventing the release of inhibitory neurotransmitter, in addition to its less potent post-synaptic one in blocking pharmacological inhibition, or (2) strychnine acts entirely post-synaptically, but the physiological transmitter action differs from that of glycine and GABA in being considerably more sensitive to strychnine antagonism. In either case, the use of strychnine as evidence for the claim that glycine is an inhibitory neurotransmitter at the Mauthner cell is questionable.

Aminobutyrates↗

PubMed1989

Dry air-induced bronchoconstriction--a role for voltage-sensitive calcium channels?

We examined the role played by voltage-sensitive calcium channels (VSCC) in airflow-induced bronchoconstriction (AIB). Collateral resistance (Rcs) in anesthetized male mongrel dogs was measured before and after periods of elevated airflow, or before and after hypocapnic challenge, using a wedged bronchoscope technique. A dihydropyridine calcium channel antagonist (nifedipine) was ineffective in preventing or even attenuating AIB in the canine lung periphery. Treatment with nifedipine did not affect the response of peripheral airways to aerosolized acetylcholine, indicating that receptor-operated calcium channels (ROCC) and/or release of calcium from intracellular stores were unaffected by this drug. Despite the ability of a calcium agonist (BAY K8644) to enhance responses to a hypocapnic challenge, it did not alter peripheral airway responses to dry air. Neither nifedipine nor BAY K8644 affected airway wall temperature at any time during the dry air experiments. We conclude that dihydropyridine receptors do not play a significant role in initiating AIB in the canine lung periphery.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMedDate not supplied

Effects of polyamines on synaptic transmission, with special attention to the glutamatergic system.

Effects of synthetic philanthotoxin-4.3.3 (PTX-4.3.3) and of its eleven structural analogues on glutamatergic transmission in the insect muscle, nicotinic transmission in the insect CNS and glutamatergic transmission in the mammalian CNS, are described. Compared with the insect muscle, the insect CNS is about 100 times less sensitive for most of these toxins and the mammalian CNS about 1000 times less reactive. In general, the relative activities of the analogues are comparable except for one toxin: dideaza-PTX-12, which is hardly active in insects and is the most active blocker of synaptic transmission from the Schaffer collaterals to pyramidal cells in the rat hippocampal slices. Dideaza-PTX-12 is also the most active inhibitor of glutamate uptake. It is concluded that the latter compound may be a prototype of a new class of neuroactive drugs affecting the glutamatergic transmission in the mammalian CNS.

Animals↗

PubMed1983

Patterns of cross-resistance to the antifolate drugs trimetrexate, metoprine, homofolate, and CB3717 in human lymphoma and osteosarcoma cells resistant to methotrexate.

Methotrexate (MTX)-resistant sublines of malignant human cells were selected in vitro by stepwise increase in drug concentration in the medium. By this procedure a subline of Burkitt's lymphoma cells (RAJI) was made 290-fold resistant (RAJI/MTX-R), T-cell leukemia cells (CCRF-CEM) were obtained 210-fold resistant (CEM/MTX-R), and 3 MTX-resistant human osteosarcoma lines were selected: TE-85/MTX-R (19-fold resistant; relative to wild-type); MG-63/MTX-R (8-fold resistant); and SAOS-2/MTX-R (200-fold resistant). We also studied a B-cell lymphoblastoid line, WI-L2/m4, that was 13,000-fold resistant. Assay of cellular dihydrofolate reductase (DHFR) showed the following pattern of activity in resistant cell lines, relative to parental cell activity: RAJI/MTX-R, 550-fold increased; CEM/MTX-R, unchanged; TE-85/MTX-R, 4-fold increased; MG-63/MTX-R, 6-fold increased; SAOS-2/MTX-R, unchanged; and WI-L2/m4, 110-fold increased. Measurement of MTX membrane transport showed decreased uptake in CEM/MTX-R and SAOS-2/MTX-R, relative to parental cell lines. The other DHFR-overproducing cells all gave normal initial MTX uptake rates but increased total uptake. The DHFR-overproducing lines all had significant cross-resistance to both metoprine and trimetrexate; the two lines with defective MTX transport were not cross-resistant, and the CEM/MTX-R cells showed collateral sensitivity to these agents. Only minor cross-resistance to homofolic acid was found in all MTX-resistant lines. The highly MTX-resistant RAJI/MTX-R and WI-L2/m4 cells showed minor cross-resistance to the dual inhibitor of thymidylate synthetase and DHFR, CB3717 (5- and 15-fold, respectively). These studies demonstrated that, depending upon the mechanism of resistance, MTX-resistant human tumor cells may be effectively killed by antifolates with different routes of uptake into cells, or with a different enzyme target. Thus, there are at least three functionally distinct classes of folate antagonist with antitumor activity.

Antineoplastic Agents↗

PubMed2003

Mu-opioid receptors facilitate the propagation of excitatory activity in rat hippocampal area CA1 by disinhibition of all anatomical layers.

Hippocampal mu-opioid receptors (MORs) have been implicated in memory formation associated with opiate drug abuse. MORs modulate hippocampal synaptic plasticity acutely, when chronically activated, and during drug withdrawal. At the network level, MORs increase excitability in area CA1 by disinhibiting pyramidal cells. The precise inhibitory interneuron subtypes affected by MOR activation are unknown; however, not all subtypes are inhibited, and specific interneuron subtypes have been shown to preferentially express MORs. Here we investigate, using voltage-sensitive dye imaging in brain slices, the effect of MOR activation on the patterns of inhibition and on the propagation of excitatory activity in rat hippocampal CA1. MOR activation augments excitatory activity evoked by stimulating inputs in stratum oriens [i.e., Schaffer collateral and commissural pathway (SCC) and antidromic], stratum radiatum (i.e., SCC), and stratum lacunosum-moleculare (SLM; i.e., perforant path and thalamus). The augmented excitatory activity is further facilitated as it propagates through the CA1 network. This was observed as a proportionately larger increase in amplitudes of excitatory activity at sites distal from where the activity was evoked. This facilitation was observed for excitatory activity propagating from all three stimulation sites. The augmentation and facilitation were prevented by GABAA receptor antagonists (bicuculline, 30 microM), but not by GABAB receptor antagonists (CGP 55845, 10 microM). Furthermore, MOR activation inhibited IPSPs in all layers of area CA1. These findings suggest that MOR-induced suppression of GABA release onto GABAA receptors augments all inputs to CA1 pyramidal cells and facilitates the propagation of excitatory activity through the network of area CA1.

Animals↗

PubMed2004

Gene knockout of glycine transporter 1: characterization of the behavioral phenotype.

N-methyl-d-aspartate receptor (NMDAR) activation requires both the binding of glutamate to its recognition site and occupancy of the strychnine insensitive glycine modulatory site (GMS). Pharmacological studies suggest that the glycine transporter, GlyT1, maintains subsaturating concentrations of glycine at synaptic NMDARs. To characterize further the role of GlyT1, we generated mice in which the gene encoding GlyT1 was inactivated by homologous recombination through insertion of a PGK-Neo cassette in place of exons 2 and 3. Real-time quantitative PCR revealed no transcripts in newborn homozygous [GlyT1(-/-)] mice and a 50% reduction in heterozygous (HZ) [GlyT1(+/-)] mice as compared with WT littermates. The activity of Na(+)-dependent glycine transport in forebrain homogenates was similarly affected. Homozygous mice died within 12 h of birth. In acute hippocampal slices, exogenous glycine or d-serine (10 microM) enhanced NMDAR currents with Schaffer collateral stimulation in WT mice but not HZ mice, suggesting that the GMS was more occupied in the latter. The NMDAR/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ratio of the excitatory postsynaptic currents was significantly increased in the HZ mice. In the water maze, the HZ mice exhibited better spatial retention. Furthermore, HZ mice were less sensitive to an amphetamine disruption of prepulse inhibition than WT mice but were more sensitive to the effects of MK-801. Thus, reduced expression of GlyT1 enhances hippocampal NMDAR function and memory retention and protects against an amphetamine disruption of sensory gating, suggesting that drugs which inhibit GlyT1 might have both cognitive enhancing and antipsychotic effects.

Amino Acid Transport Systems, Neutral↗

PubMed1995

Gain and loss of hypersensitivity to resistance modifiers in multidrug resistant Chinese hamster ovary cells.

Some, but not all, multidrug resistant cell lines exhibit collateral hypersensitivity to resistance modifiers. We have examined the relationship between levels of P-glycoprotein expression and resistance modifier hypersensitivity in Chinese hamster ovary cell lines. We have defined a model system for the gain and loss of such sensitivity which indicates that its presence is not simply proportional to P-glycoprotein levels, but is acquired only above a certain level of P-glycoprotein expression. We also show that previously reported differences in such sensitivity between lines is not attributable to differences in genetic background of the cell lines used for selection of drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Response to ICRF-159 in cell lines resistant to cleavable complex-forming topoisomerase II inhibitors.

We have studied the relationship between expression of genes implicated in mediating resistance to cleavable complex-forming topoisomerase II (topo II) inhibitors and cellular sensitivity to ICRF-159, a 'catalytic' inhibitor of topo II. Overexpression of the membrane transporters, P-glycoprotein and multidrug resistance-related protein (MRP), or down-regulation of topo IIalpha and/or -beta, did not confer ICRF-159 resistance. Indeed, marked topo IIalpha down-regulation appeared to be associated with collateral sensitivity to ICRF-159. Our results indicate that the resistance mechanisms that pertain to cleavable complex-forming topo II inhibitors and ICRF-159 are distinct. The evidence presented here suggests that topo IIalpha, not topo IIbeta, is more likely to be the major in vivo target for ICRF-159.

Antineoplastic Agents↗

PubMed1991

Retention of activity by selected anthracyclines in a multidrug resistant human large cell lung carcinoma line without P-glycoprotein hyperexpression.

A subline (COR-L23/R) of the human large cell lung line [corrected] COR-L23, derived by in vivo exposure to doxorubicin, exhibits an unusual multidrug resistant (MDR) phenotype. This subline shows cross-resistance to daunorubicin, vincristine, colchicine and etoposide but does not express P-glycoprotein. Interestingly, COR-L23/R [corrected] shows little or no resistance to a range of structurally-modified analogues of doxorubicin comprising 9-alkyl and/or sugar modified anthracyclines. We have previously identified these same compounds as effective agents against P-glycoprotein-positive MDR cell lines. In contrast to typical MDR cell lines, COR-L23/R [corrected] shows only minimal chemosensitisation by verapamil and no collateral sensitivity to verapamil. Compared to the parental cell line, COR-L23/R [corrected] displays reduced accumulation of doxorubicin and daunorubicin. Accumulation defects were apparent only after 0.5-1 h of incubation of cells with these agents. The rate of daunorubicin efflux was shown to be enhanced by COR-L23/R [corrected] and this efflux was demonstrated to be energy-dependent. The use of anthracyclines which retain activity in MDR cells thus appears to be a valid approach for the circumvention of MDR, not only in cells which express P-glycoprotein, but also where defective drug accumulation is due to other mechanisms possibly involving an alternative multidrug transporter.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1988

Isolation and characterization of Saccharomyces cerevisiae mutants resistant to T-2 toxin.

T-2 toxin, a trichothecene mycotoxin, inhibits the growth of Saccharomyces cerevisiae. We have isolated nine spontaneous S. cerevisiae mutants resistant to this toxin. The mutants were distinguished from the wild type according to their degree of resistance to T-2 toxin on media with dextrose or glycerol as the carbon source. Generation time, mutation stability and level of cross-resistance to roridin A, another trichothecene, were determined for each mutant. The T-2 toxin resistant mutants were further characterized by subsequent tests involving cross-resistance and collateral sensitivity to chlorampenicol, neomycin, paromomycin, ethidium bromide and thiolutin. Mutants have been placed into three subgroups and the mechanism of T-2 toxin resistance in each group has been postulated. Mutant HK1 is the first S. cerevisiae isolate resistant to roridin A. One particular isolate, mutant HK11, carries a single recessive nuclear mutation. This mutation was termed ttt (for T-2 toxin resistant).

Antifungal Agents↗

PubMed2000

Coronary microcirculation: physiology and pharmacology.

Coronary microvessels play a pivotal role in determining the supply of oxygen and nutrients to the myocardium by regulating the coronary flow conductance and substance transport. Direct approaches analyzing the coronary microvessels have provided a large body of knowledge concerning the physiological and pharmacological characteristics of the coronary circulation, as has the rapid accumulation of biochemical findings about the substances that mediate vascular functions. Myogenic and flow-induced intrinsic vascular controls that determine basal tone have been observed in coronary microvessels in vitro. Coronary microvascular responses during metabolic stimulation, autoregulation, and reactive hyperemia have been analyzed in vivo, and are known to be largely mediated by metabolic factors, although the involvement of other factors should also be taken into account. The importance of ATP-sensitive K(+) channels in the metabolic control has been increasingly recognized. Furthermore, many neurohumoral mediators significantly affect coronary microvascular control in endothelium-dependent and -independent manners. The striking size-dependent heterogeneity of microvascular responses to all of these intrinsic, metabolic, and neurohumoral factors is orchestrated for optimal perfusion of the myocardium by synergistic and competitive interactions. The regulation of coronary microvascular permeability is another important factor for the nutrient supply and for edema formation. Analyses of collateral microvessels and subendocardial microvessels are important for understanding the pathophysiology of ischemic hearts and hypertrophied hearts. Studies of the microvascular responses to drugs and of the impairment of coronary microvessels in diseased conditions provide useful information for treating microvascular dysfunctions. In this article, the endogenous regulatory system and pharmacological responses of the coronary circulation are reviewed from the microvascular point of view.

Animals↗