Microvascular ischemia in patients with successful percutaneous coronary intervention: effects of ranolazine and isosorbide-5-mononitrate.

OBJECTIVE: About one-third of patients undergoing percutaneous coronary interventions (PCIs) for flow-limiting coronary stenosis continue to develop signs of myocardial ischemia (MI) during exercise stress test [EST], despite successful coronary revascularization. Coronary microvascular dysfunction is a likely major cause of the persistence of EST-induced MI in these patients. PATIENTS AND METHODS: We studied 15 patients (14 men, age 67±5 years) fulfilling the following strict inclusion criteria: (1) recent PCI (<6 months), with drug-eluting stent, of coronary artery stenoses for stable angina, with evidence of full success (no residual stenosis >20% in any vessel); (2) persistence of ST-segment depression induction during EST. After a basal investigation, patients received either ranolazine (375 mg bid) or isosorbide-5-mononitrate (ISMN, 20 mg bid) for 3 weeks in a single-blind, randomized crossover study. Clinical assessment, symptom-limited EST, echocardiographic color-Doppler, with tissue-Doppler examination, and coronary microvascular dilator response to adenosine (CFR-ADO) and cold pressor test (CFR-CPT), assessed by transthoracic echo-Doppler, were obtained at baseline and the end of the 3-week therapy with each drug. RESULTS: Compared to both baseline and ISMN, ranolazine showed a longer time to 1 mm ST-segment depression (404±116 s vs. 317±98 and 322±70 s, respectively; p<0.01). No differences were observed in coronary microvascular function and diastolic left ventricular function between the 2 drugs and compared to baseline. CONCLUSIONS: Our data show that ranolazine, but not ISMN, improved time to ischemia during EST. This effect, however, was independent of any effects on coronary microvascular and diastolic function.

Influence of glucose load on cardiovascular and humoral responses to a cold pressure test.

To investigate the relationship between insulin and reactivity to the cold pressure test four groups of mildly obese patients (12 per group: normotensive, essential hypertensive, normotensive (N-NIDD) and hypertensive non-insulin-dependent diabetics (H-NIDD)) underwent a standardised oral glucose tolerance test. During the test, BP and heart rate were monitored and venous blood samples were obtained at 0, 60 and 120 minutes to determine serum levels of glucose, insulin (microU/ml), sodium, potassium (mEq/I), renin activity (ng/ml/hour), aldosterone, noradrenaline and adrenaline. The cold pressure tests were performed before glucose ingestion (I-CPT) and again at 60 minute after ingestion (II-CPT). As expected, glucose ingestion caused a significant increase in glycaemia and serum insulin; the latter rose significantly more at 60 minutes in normotensives (85 +/- 6) and essential hypertensives (83 +/- 5) than in N-NIDD (30 +/- 4) and H-NIDD (29 +/- 3). Plasma K significantly decreased in normotensives (4.4 +/- 0.1 vs. 3.6 +/- 0.1, P < 0.05) and essential hypertensives (4.3 +/- 0.1 vs. 3.5 +/- 0.1, P < 0.05) but did not change in either N-NIDD or H-NIDD. PRA significantly increased in normotensives (0.6 +/- 0.1 vs. 1.2 +/- 0.1, P < 0.01) and essential hypertensives (0.8 +/- 0.1 vs. 1.5 +/- 0.2, P < 0.05) but did not change in N-NIDD or H-NIDD. Plasma sodium and catecholamines did not change in any group. I-CPT induced similar reactivity in all the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Subunit requirements for Torpedo AChR channel expression: a specific role for the delta-subunit in voltage-dependent gating.

This study examines the subunit requirement for Torpedo acetylcholine receptor (AChR) channel expression and the influence of non-alpha-subunit deletions on single AChR-channel currents. Xenopus oocytes injected with subunit combinations deficient in single non-alpha-subunit mRNA transcripts display the following order of ACh sensitivity: beta-less > gamma-less > delta-less. Oocytes injected with only the alpha-subunit and one non-alpha-subunit display the order: alpha delta > alpha gamma > alpha beta. These sequences indicate the effectiveness of non-alpha-subunit substitution is delta > gamma > beta. Single AChR-channel currents measured in oocytes deficient in either beta or gamma display conductance and voltage-sensitive burst kinetics similar to the wild-type channel. In contrast, the delta-less combination express channels with burst kinetics that are relatively faster and voltage insensitive. These results indicate that either a specific structural domain in the delta-subunit or its specific interactions with the alpha-subunit contribute to the voltage-dependent gating of the Torpedo AChR channel.

Third-chromosome mutagen-sensitive mutants of Drosophila melanogaster.

A total of 34 third chromosomes of Drosophila melanogaster that render homozygous larvae hypersensitive to killing by chemical mutagens have been isolated. Genetic analyses have placed responsible mutations in more than eleven complementation groups. Mutants in three complementation groups are strongly sensitive to methyl methanesulfonate, those in one are sensitive to nitrogen mustard, and mutants in six groups are hypersensitive to both mutagens. Eight of the ten loci mapped fall within 15% of the genetic map that encompasses the centromere of chromosome 3. Mutants from four of the complementation groups are associated with moderate to strong meiotic effects in females. Preliminary biochemical analyses have implicated seven of these loci in DNA metabolism.

The mei-9 alpha mutant of Drosophila melanogaster increases mutagen sensitivity and decreases excision repair.

The mei-9(a) mutant of Drosophila melanogaster , which reduces meiotic recombination in females (Baker and Carpenter 1972), is deficient in the excision of UV-induced pyrimidine dimers in both sexes. Assays were performed in primary cultures and established cell lines derived from embryos. An endonuclease preparation from M. luteus , which is specific for pyrimidine dimers, was employed to monitor UV-induced dimers in cellular DNA. The rate of disappearance of endonuclease-sensitive sites from DNA of control cells is 10-20 times faster than that from mei-9(a) cells. The mutant mei-218, which is also deficient in meiotic recombination, removes nuclease-sensitive sites at control rates. The mei-9(a) cells exhibit control levels of photorepair, postreplication repair and repair of single strand breaks. In mei-9 cells DNA synthesis and possibly postreplication repair are weakly sensitive to caffeine. Larvae which are hemizygous for either of the two mutants that define the mei-9 locus are hypersensitive to killing by the mutagens methyl methanesulfonate, nitrogen mustard and 2-acetylaminofluorene. Larvae hemizygous for the mei-218 mutant are insensitive to each of these reagents. These data demonstrate that the mei-9 locus is active in DNA repair of somatic cells. Thus functions involved in meiotic recombination are also active in DNA repair in this higher eukaryote. The results are consistent with the earlier suggestions (Baker and Carpenter 1972; Carpenter and Sandler 1974) that the mei-9 locus functions in the exchange events of meiosis. The mei-218 mutation behaves differently in genetic tests and our data suggest its function may be restricted to meiosis. These studies demonstrate that currently recognized modes of DNA repair can be efficiently detected in primary cell cultures derived from Drosophila embryos.

Isolation and characterization of X-linked mutants of Drosophila melanogaster which are sensitive to mutagens.

Thirteen X-linked mutants have been isolated in Drosophila melanogaster which render male and homozygous female larvae sensitive to the mutagen methyl methanesulfonate. Their characterization and preliminary assignment to functional groups is described. Four of these mutants are alleles of mei-41 (Baker and Carpenter 1972). Like previously isolated alleles of this locus, these mutants reduce fertility and increase loss and nondisjunction of the X-chromosome in homozygous females. The remaining mutants have been tentatively assigned to six functional groups (two mutants to the mus(1)101 locus, two to mus(1)102 , two to mus(1)103, and one each to mus(1)104, mus(1)105 , and mus(1)106). Several of the complementation groups can be distinguished on the basis of nondisjunction and cross sensitivity to mutagens. Females homozygous for the mei-41, mus(1)101 and mus(1)102 mutants exhibit elevated levels of nondisjunction. Mutants belonging to complementation groups mei-41, mus(1)101, and mus(1)104 are sensitive to nitrogen mustard (HN2) in addition to their MMS sensitivity. Among these mutants there is currently a direct correlation between sensitivity to HN2, sensitivity to 2-acetylaminofluorene and a deficiency in post-replication repair ( Boyd and Setlow 1976). Only the mei-41 mutants are hypersensitive to UV radiation, although several of the mutants exhibit sensitivity to gamma-rays. Semidominance is observed in female larvae of the mei-41, mus(1)104, and mus(1)103 mutants after exposure to high concentrations of MMS. The properties of the mutants generally conform to a pattern which has been established for related mutants in yeast. Additional properties of these mutants are summarized in Table 9.