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Biomedical subjects

H T Yang

Publications and source records attributed to H T Yang.

At least 37 records · Page 2Linked to original sources
PubMed2000

Efficacy and specificity of bFGF increased collateral flow in experimental peripheral arterial insufficiency.

Angiogenic growth factors could prove to be useful in managing peripheral arterial insufficiency. The present study was designed to evaluate the dose response of basic fibroblast growth factor (bFGF), the efficacy of critical routes and dosing regimens, and the specificity of action in rats with peripheral arterial insufficiency. Bilateral ligation of femoral arteries greatly reduces blood flow capacity to the calf muscles but does not impair resting flow needs. Collateral blood flow to calf muscles was determined 16 days postocclusion, during treadmill running, with (85)Sr and (141)Ce microspheres, in blinded-randomized trials that included intra-arterial and intravenous infusions and subcutaneous injections of recombinant human bFGF. Peak blood flow of 75-80 ml. min(-1). 100 g(-1) for calf muscle was observed at a bFGF dose of 5 microg. kg(-1). day(-1) (ia for 14 days) compared with 50 ml. min(-1). 100 g(-1) for vehicle groups. Similar increases in collateral blood flow were observed with short-term or prolonged and continuous or intermittent delivery of bFGF by any route. Collateral blood flows were similar in corresponding muscles across both limbs. Vascular remodeling induced by bFGF required attendant vascular occlusion, inasmuch as vessels in the normal nonoccluded vascular tree were unresponsive to circulating bFGF. Improvement in collateral blood flow with exogenous bFGF is robust, amenable to short-term administration, and requires vascular occlusion to be effective.

Animals↗
PubMed2000

Prior exercise training increases collateral-dependent blood flow in rats after acute femoral artery occlusion.

We evaluated whether prior training would improve collateral blood flow (BF) to the calf muscles after acute-onset occlusion of the femoral artery. Exercise training was performed in the absence of any vascular occlusion. Adult male Sprague-Dawley rats ( approximately 325 g) were kept sedentary (n = 14), limited to cage activity, or exercise trained (n = 14) for 6 wk by treadmill running. Early in the day of measurement, animals were surgically prepared for BF determination, and the femoral arteries were occluded bilaterally. Four to five hours later, collateral BF was determined twice during treadmill running with the use of (141)Ce and (85)Sr microspheres: first, at a demanding speed and, second, after a brief rest and at a higher speed. The absence of any further increase in BF at the higher speed indicated that maximal collateral BF was measured. Prior training increased calf muscle BF by approximately 70% compared with sedentary animals; however, absolute BF remained below values previously observed in animals with a well-developed collateral vascular tree. Thus prior training appeared to optimize the use of the existing collateral circuit. This implies that altered vasoresponsiveness induced in normal nonoccluded vessels with exercise training serves to improve collateral BF to the periphery.

Acute Disease↗
PubMed1999

Identification of genes controlling collagen-induced arthritis in mice: striking homology with susceptibility loci previously identified in the rat.

The susceptibility to collagen-induced arthritis in the highly susceptible DBA/1 mouse has earlier been shown to be partly controlled by the MHC class II gene Aq. To identify susceptibility loci outside of MHC, we have made crosses between DBA/1 and the less susceptible B10.Q strain, both expressing the MHC class II gene Aq. Analysis of 224 F2 intercross mice with 170 microsatellite markers in a genome-wide scan suggested 4 quantitative trait loci controlling arthritis susceptibility located on chromosomes 6, 7, 8, and 10. The locus on chromosome 6 (Cia6), which was associated with arthritis onset, yielded a logarithm of odds score of 4.7 in the F2 intercross experiment and was reproduced in serial backcross experiments. Surprisingly, the DBA/1 allele had a recessive effect leading to a delay in arthritis onset. The suggestive loci on chromosomes 7 and 10 were associated with arthritis severity rather than onset, and another suggestive locus on chromosome 8 was most closely associated with arthritis incidence. The loci on chromosomes 7, 8, and 10 all appeared to contain disease-promoting alleles derived from the DBA/1 strain. Interestingly, most of the identified loci were situated in chromosomal regions that are homologous to regions in the rat genome containing susceptibility genes for arthritis; the mouse Cia6 locus is homologous with the rat Cia3, Pia5, Pia2, and Aia3; the locus on chromosome 7 (Cia7) is homologous with the rat Cia2; and the locus on chromosome 10 (Cia8) is homologous with the rat Cia4.

Animals↗
PubMed1999

Role of Na+/Ca2+ exchange in endothelin-1-induced increases in Ca2+ transient and contractility in rabbit ventricular myocytes: pharmacological analysis with KB-R7943.

1. The effects of endothelin-1 (ET-1) on intracellular Ca2+ ion level and cell contraction were simultaneously investigated in rabbit ventricular cardiac myocytes loaded with indo-1/A1. The role of Na+/Ca2+ exchange in ET-1-induced positive inotropic effect (PIE) was examined by using KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulphonate), a selective inhibitor of reverse mode Na+/Ca2+ exchange. 2. ET-1 at 0.3 pM - 1 nM increased cell contraction and Ca2+ transient (CaT) with EC50 values of 2.9 pM and 1.2 pM, respectively, and the increase in amplitude of CaT was much smaller relative to the PIE: ET-1 at 1 nM increased peak cell shortening by 237%, while it increased peak CaT by 167%. For a given level of PIE, ET-1-induced increase in CaT was much smaller than that induced by elevation of [Ca2+]o and by isoprenaline. Therefore, ET-1 shifted the relationship between peak CaT and cell shortening to the left relative to the relationship for increase in [Ca2+]o, an indication that ET-1 increased myofibrillar Ca2+ sensitivity. 3. KB-R7943 at 0.1 microM and higher inhibited contraction and CaT induced by 0.1 nM ET-1 and at 0.3 microM it abolished the increase in CaT while inhibiting the PIE by 48.1%. Over concentration range of 0.1-0.3 microM, KB-R7943 neither inhibited baseline contraction and CaT nor the isoprenaline-induced response, although at 1 microM and higher it had a significant inhibitory action on these responses. 4. These results indicate that in rabbit ventricular myocytes both increases in CaT and myofibrillar Ca2+ sensitivity contribute to the ET-induced PIE, and the activation of reverse mode Na+/Ca2+ exchange may play a crucial role in increase in CaT induced by ET-1 in rabbit ventricular cardiac myocytes.

Animals↗
PubMed1999

Local control models of cardiac excitation-contraction coupling. A possible role for allosteric interactions between ryanodine receptors.

In cardiac muscle, release of activator calcium from the sarcoplasmic reticulum occurs by calcium- induced calcium release through ryanodine receptors (RyRs), which are clustered in a dense, regular, two-dimensional lattice array at the diad junction. We simulated numerically the stochastic dynamics of RyRs and L-type sarcolemmal calcium channels interacting via calcium nano-domains in the junctional cleft. Four putative RyR gating schemes based on single-channel measurements in lipid bilayers all failed to give stable excitation-contraction coupling, due either to insufficiently strong inactivation to terminate locally regenerative calcium-induced calcium release or insufficient cooperativity to discriminate against RyR activation by background calcium. If the ryanodine receptor was represented, instead, by a phenomenological four-state gating scheme, with channel opening resulting from simultaneous binding of two Ca2+ ions, and either calcium-dependent or activation-linked inactivation, the simulations gave a good semiquantitative accounting for the macroscopic features of excitation-contraction coupling. It was possible to restore stability to a model based on a bilayer-derived gating scheme, by introducing allosteric interactions between nearest-neighbor RyRs so as to stabilize the inactivated state and produce cooperativity among calcium binding sites on different RyRs. Such allosteric coupling between RyRs may be a function of the foot process and lattice array, explaining their conservation during evolution.

Algorithms↗
PubMed1998

European Multicentre Association Study of Schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms.

As part of the European Multicentre Association Study of Schizophrenia (EMASS), we studied polymorphisms in the dopamine DRD2 and DRD3 receptor genes. The EMASS collaboration was established to create a large, statistically powerful sample of schizophrenic patients and controls from different European centres. Previous studies have suggested associations between schizophrenia and the Ser311Cys polymorphism in exon 7 of the dopamine DRD2 receptor gene [Arinami et al., (1994): Lancet 343:703-704] and a polymorphism Ser9gly in exon 1 of the dopamine DRD3 receptor gene [Crocq et al. (1992): J Med Genet 29:858-860]. We tested for these associations in samples of 373 and 413, and 311 and 306 patients and controls, respectively. We found no evidence for allelic association between schizophrenia and the Cys311 variant of the DRD2 receptor gene and no homozygotes for this variant were observed by any group. However, an excess of homozygotes for both alleles of the DRD3 polymorphism was observed in schizophrenic patients (chi2 = 8.54, P = 0.003, odds ratio = 1.64, 95% CI = 1.18-2.29). We also observed a significant excess of the 1-1 (Ser9Ser) genotype (chi2 = 8.13, P = 0.004, odds ratio = 1.7, 95% CI = 1.18-2.4). No evidence of heterogeneity between samples was detected and there was no evidence of an allelic association. These findings suggest that the rare Cys311 variant in exon 7 of the DRD2 receptor gene does not play a role in the pathogenesis of schizophrenia in European populations. Currently, our results do support the previous findings of an association between increased homozygosity of the Ser/Gly variant of the Dopamine D3 receptor gene and schizophrenia.

Alleles↗
PubMed1998

Endothelin: receptor subtypes, signal transduction, regulation of Ca2+ transients and contractility in rabbit ventricular myocardium.

Endothelin (ET) isopeptides, ET-1, ET-2 and ET-3, elicit a positive inotropic effect (PIE) in association with a negative lusitropic effect, essentially with identical efficacies and potencies in the isolated rabbit papillary muscle, but with different concentration-dependent properties. Pharmacological analysis indicates that the PIE of ET-1 is mediated by an ETA2 subtype that is less sensitive to BQ-123 and FR139317, whereas the PIE of ET-3 is mediated by an ETA1 subtype that is highly sensitive to these ETA antagonists. ETs increased the amplitude of intracellular Ca2+ transient (CaT) in indo-1 loaded rabbit ventricular myocytes, but the increase was much smaller than that produced by elevation of [Ca2+]o or isoproterenol for a given extent of PIE, an indication of increased myofibrillar Ca2+ sensitivity. ETs stimulate phosphoinositide (PI) hydrolysis, which leads to production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Evidence for the role of IP3-induced Ca2+ release in cardiac E-C coupling is tenuous. Generation of IP3 induced by ET-1 was transient and returned to the baseline level when the PIE reached an elevated steady level. Protein kinase C (PKC) that is activated by DAG and also via other pathways triggered by ETs stimulates Na+-H+ exchanger to lead to an increased [Na+]i and alkalinization. The former may contribute to an increase in the amplitude of CaT through Na+-Ca2+ exchanger, and the latter, to an increase in myofibrillar Ca2+ sensitivity. A number of PKC inhibitors, such as staurosporine, H-7, calphostin C and chelerythrine, consistently and selectively inhibited the PIE of ET-3 without affecting the PIE of isoproterenol and Bay k 8644. The maximum inhibition was 20-30% of the total response. A Na+-H+ exchange inhibitor, [5-(N-ethyl-N-isopropyl) amiloride (EIPA)] or a Ca2+ antagonist, verapamil, could not completely inhibit the PIE of ET-3, but the combination of both inhibitors totally abolished the PIE of ET-3. These findings indicate that activation of PKC and subsequent activation of Na+-H+ exchanger and/or L-type Ca2+ channels may play a crucial role in the cardiac action of ET isopeptides in the rabbit ventricular myocardium.

Animals↗
PubMed1998

Exercise training enhances basic fibroblast growth factor-induced collateral blood flow.

This study evaluated whether daily exercise would enhance the peripheral collateral vessel development found in response to exogenous basic fibroblast growth factor (bFGF) infusion. After bilateral femoral occlusion, male Sprague-Dawley rats (approximately 325 g) received intra-arterial infusions of either bFGF (1 microg/day; n = 15) or carrier solution (n = 13) via osmotic pumps for 2 wk. Subgroups of each treatment were kept sedentary (cage activity) or trained by walking at 20 m/min at 15% grade, two times a day, 5 days/wk for 4 wk. Training markedly increased citrate synthase activity in the active muscle (P < 0.001). Muscle function and blood flows (85Sr microsphere) were evaluated using an isolated hindquarter perfused at 100 mmHg via the abdominal aorta. The significant increase in blood flow to the entire hindlimb in the sedentary animals, caused by bFGF infusion (P < 0.05), was further increased (P < 0.01) in the bFGF-trained group. The quantitatively largest increases in blood flows were observed in the collateral-dependent tissues of the distal hindlimb. Blood flows to the entire calf muscle group increased approximately 140% in carrier-trained (P < 0.001), approximately 180% in bFGF sedentary (P < 0.001), and approximately 240% in the bFGF-trained (P < 0.001) groups compared with the carrier sedentary group. The increases in collateral blood flow were functionally important, as improvements in calf muscle performance correlated with measured blood flows. Our results demonstrate that exogenous bFGF administration in combination with a moderate-intensity exercise program greatly increases collateral-dependent blood flow and improves muscle performance. That physical activity enriched the bFGF response is consistent with the hypothesis that hemodynamic factors are important contributors to collateral vessel enlargement.

Animals↗
PubMed1997

Does nitric oxide contribute to the negative chronotropic and inotropic effects of endothelin-1 in the heart?

N omega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, was used to examine whether nitric oxide was involved in the negative chronotropic and inotropic effects of endothelin-1 in the presence of isoprenaline in mammalian heart. In isolated rabbit right atria, endothelin-1 elicited a negative chronotropic effect in the presence of isoprenaline, which was associated with a decrease in the isoprenaline-induced accumulation of cyclic AMP. On the other hand, in the dog ventricular trabeculae, the negative inotropic effect of endothelin-1 was not accompanied by a significant reduction in the isoprenaline-induced accumulation of cyclic AMP. N omega-nitro-L-arginine methyl ester affected neither the negative chronotropic effect nor the negative inotropic effect of endothelin-1. The effects of endothelin-1 on the isoprenaline-induced cyclic AMP accumulation were not influenced by N omega-nitro-L-arginine methyl ester either. These results indicate that the negative chronotropic and inotropic effects of endothelin-1 in the presence of isoprenaline in mammalian cardiac muscle do not involve the nitric oxide-mediated signaling pathway.

Adrenergic beta-Agonists↗
PubMed1997

Arsenic methylation capacity, body retention, and null genotypes of glutathione S-transferase M1 and T1 among current arsenic-exposed residents in Taiwan.

In order to elucidate the relationships among arsenic methylation capacity, body retention, and genetic polymorphisms of glutathione S-transferase (GST) M1 and T1, a total of 115 study subjects were recruited from Lanyang Basin located on the northeast coast of Taiwan. Specimens of drinking water, blood, urine, hair and toenail were collected from each study subject. Urinary inorganic and methylated arsenic were speciated by high performance liquid chromatography combined with hydride-generation atomic absorption spectrometry. Arsenic concentration in hair and toenail were quantitated by atomic absorption spectrophotometry. The polymerase chain reaction was used to determine genetic polymorphisms of GST M1 and T1. Arsenic concentrations in urine, hair, and toenail of study subjects were positively correlated with arsenic levels in their drinking water. Percentages of various arsenic species in urine (mean +/- standard error (SE) were 11.8 +/- 1.0, 26.9 +/- 1.2 and 61.3 +/- 1.4, respectively, for inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Men and women had similar arsenic methylation capability. No associations were observed between arsenic methylation capability and arsenic content in either drinking water or urine. Ratios of arsenic contents in hair and toenail to urinary arsenic content (mean +/- standard error) were 6.2 +/- 0.7 and 16.5 +/- 1.7, respectively. Genetic polymorphisms of GST M1 and T1 were significantly associated with arsenic methylation. Subjects having the null genotype of GST M1 had an increased percentage of inorganic arsenic in urine, while those with null genotype of GST T1 had an elevated percentage of DMA in urine. Arsenic contents in hair and toenail were significantly correlated with the increase in arsenic concentrations of drinking water and urine, while no significant associations were observed between arsenic contents in hair and toenail and polymorphisms of GST M1 and T1. The relationship between arsenic methylation capability and body retention was modified by genetic polymorphisms of GST M1 and T1. Arsenic contents in hair and toenail were negatively associated with MMA percentage and positively associated with DMA percentage among subjects having null genotypes of GST M1 and T1, but not among those with non-null genotypes.

Arsenic↗
PubMed1997

Species-dependent differences in inotropic effects and phosphoinositide hydrolysis induced by endothelin-3 in mammalian ventricular myocardium.

1. Species-dependent variations in the positive inotropic effect (PIE) of endothelin-3 (ET-3), and the relationships between the PIE and specific binding sites for [125I]-ET-3 and the PIE and the acceleration of phosphoinositide hydrolysis by ET-3, were studied in ventricular muscles from the rat, guinea-pig, rabbit, ferret and dog. 2. ET-3 in the presence of (+/-)-bupranolol (0.3 microM) and prazosin (0.3 microM) elicited a concentration-dependent PIE in the ventricular muscle from the rat, guinea-pig, rabbit and ferret. The potency of ET-3 and its efficacy in inducing a PIE were highest in the rabbit, intermediate in the rat and guinea-pig and lowest in the ferret. ET-3 did not have any inotropic effect on ventricular muscle from the dog. 3. Specific high-affinity binding of [125I]-ET-3 was observed with membrane fractions derived from the ventricular muscle of the five species. The maximal specific binding (Bmax) of ET-3 was highest in the rat and guinea-pig, intermediate in the rabbit and ferret and lowest in the dog. The values of KD in the rabbit and dog (33 and 52 pM) were lower than those in the rat, guinea-pig and ferret (141-221 pM). 4. In slices of ventricular muscle from all five species, ET-3 increased the accumulation of [3H]-inositol monophosphate (IP1) in a concentration-dependent manner. The extent of accumulation of IP1 was highest in the rat, intermediate in the guinea-pig and rabbit and lowest in the ferret and dog. 5. The results demonstrate the wide range of variations in the PIE of ET-3 on mammalian ventricular muscles. The variations in the coupling processes subsequent to the acceleration of the hydrolysis of PI, triggered by the binding of ET-3 to its receptor, might be important in these species-dependent differences in the PIE of ET-3.

Animals↗
PubMed1997

Pharmacological evidence for alpha(1D)-adrenoceptors in the rabbit ventricular myocardium: analysis with BMY 7378.

1. It was examined by means of BMY 7378, a selective antagonist of alpha 1D-adrenoceptors, whether alpha 1D-adrenoceptors contribute to the regulation of myocardial contractility and hydrolysis of phosphoinositide (PI) in rabbit ventricular muscle. 2. BMY 7378 had a biphasic antagonistic action on the positive inotropic effect (PIE) of phenylephrine depending on the concentration. BMY 7378 at 1-10 nM shifted the concentration-response curve (CRC) for the PIE of phenylephrine to the right and downward and at 100 nM to 1 microM it antagonized the PIE in a competitive manner, the slope of Schild plot being 0.93 and the pA2 being 7.17 +/- 0.09. 3. The inhibitory action of BMY 7378 at 1-10 nM is ascribed to the selective action on alpha 1-adrenoceptors because the PIE of neither isoprenaline nor endothelin-3 and angiotensin II was affected by this compound over this concentration range. 4. In the presence of 100 nM WB 4101, the antagonistic action of BMY 7378 at 1-10 nM remained unchanged but the antagonistic action of BMY 7378 at 100-300 nM disappeared. The antagonistic action of BMY 7378 at 1 nM was unaffected by 100 nM (+)-niguldipine. 5. Following pretreatment with chloroethyldonidine, BMY 7378 at 1 nM inhibited the maximal response to phenylephrine but the pD2 value for phenylephrine was increased in the presence of BMY 7378. The CRC for phenylephrine was shifted to the left in the presence of 10-100 nM BMY 7378 but it was shifted to the right by BMY 7378 at 300 nM. 6. Stimulation of PI hydrolysis induced by phenylephrine was not affected by BMY 7378 up to 10 nM but it was reduced significantly by BMY 7378 at higher concentrations (100 nM to 1 microM). 7. BMY 7378 inhibited the [3H]prazosin specific binding to the rabbit ventricular membrane fraction in a monophasic manner with a pKi value of 7.53 +/- 0.09. 8 The results indicate that in rabbit ventricular muscle, BMY 7378 at 1-10 nM suppressed the maximal response to phenylephrine (probably mediated by alpha 1D-adrenoceptors) and at 10-100 nM it inhibited the negative inotropic effect of phenylephrine, the mechanisms of which remain to be characterized. At higher concentrations (100 nM to 1 microM) BMY 7378 antagonized the functional and biochemical response via a presumed interaction mainly with the alpha 1D-adrenoceptor and partially with the alpha 1A-adrenoceptor.

Adrenergic alpha-Antagonists↗
PubMed1997

Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle.

In isolated rabbit right atria, endothelin (ET) isopeptides ET-1 and ET-3 elicited a concentration-dependent negative chronotropic effect (NCE) in the presence of isoproterenol (Iso): ET-1 was approximately 10 times more potent than ET-3. The NCE of ET-1 was abolished by the ETA- and ETB-receptor antagonist TAK-044 (1 microM) or the ETA-receptor antagonist BQ-123 (10 microM), but it was not affected by the ETB-receptor antagonist RES-701-1 or BQ-788. ET-1 decreased the adenosine 3',5'-cyclic monophosphate (cAMP) level in the presence of Iso in rabbit atria. Pretreatment with pertussis toxin (PTX) markedly attenuated the NCE of ET-1 and abolished the decrease in the cAMP level induced by ET-1. In isolated dog ventricular trabeculae, ET-1 elicited a pronounced negative inotropic effect (NIE), whereas ET-3 induced a small but significant positive inotropic effect in the presence of Iso. The NIE was abolished by the ETA-receptor antagonist BQ-123 (1 microM) and partially attenuated by the ETB-receptor antagonist RES-701-1. The positive inotropic effect of ET-3 was abolished by RES-701-1. Although pretreatment with PTX markedly attenuated the NIE of ET-1, cAMP levels in dog ventricular muscle were not decreased by ET-1. These results indicate that activation of an ETA receptor that is coupled to the PTX-sensitive G protein plays a dominant role in the NCE and NIE of ET-1. The NCE of ET-1 may, in part, be due to a decrease in cAMP level. By contrast, the NIE of ET-1 does not involve an alteration of cAMP accumulation. The present findings imply that ET isopeptides might antagonize the cardiostimulatory action of catecholamines mediated by beta-adrenoceptors when the blood level of both endogenous regulators are increased under cardiovascular pathophysiological situations.

Animals↗
PubMed1996

(+/-)-tamsulosin, an alpha 1A-adrenoceptor antagonist, inhibits the positive inotropic effect but not the accumulation of inositol phosphates in rabbit heart.

The influence of (+/-)-tamsulosin, a selective alpha 1A-adrenoceptor antagonist, on the positive inotropic effect and the accumulation of inositol phosphates that are induced via alpha 1-adrenoceptors was studied in comparison with that of another alpha 1A-adrenoceptor ligand oxymetazoline in the rabbit ventricular myocardium. Phenylephrine elicited a concentration-dependent positive inotropic effect via alpha 1-adrenoceptors in the presence of either (+/-)-bupranolol or S(-)-timolol. The mode of antagonism induced by (+/-)-tamsulosin on the effect of phenylephrine was dependent or the concentration applied: (+/-)-tamsulosin at 1 and 3 nM acted in a competitive manner, the slope of the regression line of the Schild plot being unity and the pA2 value being 9.12; at 10 nM, it shifted further the concentration-response curve to the right without affecting the maximal response but the slope became less than unity. At 100 nM and higher, it suppressed the maximal response to phenylephrine. (+/-)-Tamsulosin effectively antagonized the positive inotropic effect of phenylephrine even after inactivation of alpha 1B-adrenoceptors by treatment with chlorethylclonidine, which is an indication that the (+/-)-tamsulosin-sensitive subtype belongs to a class resistant to chlorethylclonidine. (+/-)-Tamsulosin, over the range of concentrations at which it antagonized the positive inotropic effect mediated by alpha 1-adrenoceptors, did not affect the accumulation of [3H]inositol phosphates that was induced by 10 microM phenylephrine. Oxymetazoline antagonized the positive inotropic effect of phenylephrine in a competitive manner without affecting the accumulation of inositol monophosphate induced by phenylephrine. These results indicate that the positive inotropic effect, mediated via (+/-)-tamsulosin- and oxymetazoline-sensitive subtype of alpha 1-adrenoceptors, is exerted by a subcellular mechanism that is independent of the accumulation of inositol phosphates.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1996

Methoxamine-induced inhibition of the positive inotropic effect of endothelin via alpha1-adrenoceptors in the rabbit heart.

The influence of methoxamine on the positive inotropic effect of endothelin was assessed in the isolated rabbit ventricular myocardium. Methoxamine by itself elicited a positive inotropic effect and it simultaneously inhibited the positive inotropic effects of endothelin-1 and endothelin-3 without affecting the acceleration of the hydrolysis of phosphoinositide that was induced by the endothelin isopeptides. By contrast, the positive inotropic effects induced by elevation of concentration of external Ca2+ ions, by Bay k 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate), by dihydroouabain and by forskolin were unaffected by methoxamine. The inhibitory action of methoxamine was abolished by alpha1-adrenoceptor antagonists, such as prazosin, WB 4101 (2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride) and (+/-)-tamsulosin; and it was inhibited to a lesser extent by chlorethylclonidine. In addition, methoxamine did not modify the specific binding of [125I]endothelin-3 to ventricular membrane fraction. These results indicate that methoxamine antagonizes the positive inotropic effect of endothelin isopeptides at the level of the signal-transduction process, subsequent to acceleration of the hydrolysis of phosphoinositide, via activation of alpha1-adrenoceptors in the rabbit ventricular myocardium.

Adrenergic alpha-Agonists↗
PubMed1996

Basic fibroblast growth factor increases collateral blood flow in rats with femoral arterial ligation.

The potential for exogenous infusion of basic fibroblast growth factor (bFGF) to increase collateral blood flow to dependent tissue was quantified in adult male rats with peripheral arterial insufficiency. Occlusion of the femoral artery at a proximal site did not infringe on resting blood flow to the distal hindlimb muscle, but did remove the blood flow reserve. Blood flow to the hindlimb muscles was measured with radiolabeled microspheres using an isolated hindlimb preparation perfused in the descending aorta (Krebs-Henseleit bicarbonate, 5% albumin medium containing red blood cells [40% hematocrit]) at 100 mm Hg. Calf muscle blood flow changed modestly (approximately equal to 50%) with infusion of only the carrier (heparin/saline), increased markedly over the first 2 weeks of bFGF infusion (1 microgram/d into the femoral artery), but did not change further with infusion for 4 weeks. Waiting 2 weeks after 1 week of bFGF infusion did not further increase the intermediate improvement in blood flow. The improved collateral blood flow and increased muscle capillary density likely contributed to the enhanced muscle performance observed during nerve stimulation in situ. X-ray films of arterial casts identified an expansion of upper thigh vessels that likely served as collaterals. In animals with peripheral arterial insufficiency, short-term exogenous infusion of bFGF is effective at inducing vascular expansion that is sufficient to improve the flow reserve of dependent distal tissue and enhance muscle function. This raises the expectation that a similar response in patients with peripheral arterial insufficiency would significantly improve morbidity, including the symptoms of intermittent claudication.

Animals↗
PubMed1996

The positive inotropic effect and the hydrolysis of phosphoinositide induced by endothelin-3 in rabbit ventricular myocardium: inhibition by a selective antagonist of ET(A) receptors, FR139317.

Endothelin-3 (ET-3), an isopeptide of ET, had a concentration-dependent positive inotropic effect (PIE) on rabbit papillary muscle. The maximal inotropic response to ET-3 was 65% of the maximal response to isoproterenol. ET-1 elicited a PIE below 10(-9) M, namely, over a concentration range at which ET-3 did not elicit a PIE. The selective ET(A) antagonist FR139317 effectively antagonized the PIE of ET-3. FR139317 abolished the PIE induced by ET-1 (<10(-9)M) but did not inhibit the PIE induced by high concentrations of ET-1. FR139317 also antagonized the PIE of sarafotoxin S6c. ET-3 caused a time- and concentration-dependent increase in [3H]inositol phosphates (inositol monophosphate, inositol bisphosphate and inositol trisphosphate). FR139317 at 10(-5) M decreased the ET-3-induced increase in inositol phosphates by about 60%, whereas it attenuated the increase in [3H]IP1 induced by ET-1 (3 x 10(-8)M) by only 20%. Thus, in the presence of FR139317, the PIEs of ET-3 and ET-1 were partially dissociated from the PI hydrolysis that was induced by these isopeptides. FR139317 inhibited the specific binding of [125I]ET-1 and of [125I]ET-3, and it was apparent that FR139317 had a high-affinity and a low-affinity site for competing for specific binding with each ligand. These findings indicate that different subtypes of the ET receptor are involved in the induction of the PIEs of ET-3 and ET-1. The PIE of ET-3 may be mediated predominantly by ET(A1) receptors that are susceptible to FR139317 and BQ-123 and partially by ET(B) receptor that are inhibited by RES-701-1. Both ET(A1) and ET(A2) receptors may be responsible for the PIE of ET-1, depending on the concentration in rabbit ventricular myocardium.

Animals↗