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Biomedical subjects

S B Freedman

Publications and source records attributed to S B Freedman.

At least 109 records · Page 6Linked to original sources
PubMed1987

Synthesis and characterization of all four isomers of the muscarinic agonist 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane].

The four separated isomers of the muscarinic agonist 1, previously known as AF30, have been synthesized by a route that has allowed the absolute stereochemistry of each isomer to be assigned. With the chirality of (-)-camphanic acid known, X-ray analysis of the more crystalline intermediate diastereomeric camphanate 5A allowed the absolute stereochemistry at the quinuclidine chiral center to be determined. Each diastereomer was separately transformed into the spirodioxolane with concomitant introduction of the second chiral center. Chromatographic separation followed by a second crystal structure determination revealed the absolute stereochemistry of all four isomers of 1. Detailed biological evaluation of each isomer indicated that while the 3(R),2'(S) isomer was the most active in binding studies, it was the 3(R),2'(R) isomer that displayed the largest functional selectivity between ganglion (M-1 site) and heart (M-2 site). With the same internal chiral standard, the absolute configuration of the more active enantiomer of 3 was shown to be S, confirming earlier literature reports.

Animals↗
PubMed1987

Antianginal efficacy of carvedilol, a new beta-blocker with vasodilating action.

To evaluate the antianginal efficacy of carvedilol, a beta-blocker with vasodilating activity, we performed a randomized double-blind placebo-controlled study of two single doses of carvedilol. Twelve patients (eight males, four females, mean age 57 years) with stable effort angina and a positive exercise ECG with angina underwent treadmill exercise testing 2 h after either placebo, or carvedilol 25 or 50 mg. Both doses of carvedilol reduced resting heart rate but only the 50 mg dose reduced resting blood pressure. Exercise time and time to angina increased by 24% and 35%, respectively, after carvedilol, and ST depression at both maximal and submaximal work levels was reduced. The time to 1 mm ST depression was increased by carvedilol but the heart rate at 1 mm ST depression and maximum ST/heart rate slope were unchanged. Maximum heart rate, systolic pressure, and rate-pressure product were significantly reduced by carvedilol. The 50 mg dose was significantly better than 25 mg in prolonging exercise time and reducing subjective and objective measurements of ischemia, and this was related to significantly greater hemodynamic effects. Carvedilol appears to be effective in preventing or reducing effort angina due to reduced myocardial oxygen demand, and it exhibits an important dose-response effect.

Adrenergic beta-Antagonists↗
PubMed1986

Prediction of multivessel coronary artery disease and prognosis early after acute myocardial infarction by exercise electrocardiography and thallium-201 myocardial perfusion scanning.

Exercise electrocardiography and thallium scanning were performed a mean of 24 days after uncomplicated acute myocardial infarction in 103 patients, aged 36 to 60 years, who also underwent coronary angiography. The purpose of the study was to determine the ability of the noninvasive tests to predict multivessel coronary artery disease (CAD) and prognosis. Patients were followed up to document medical complications (incidence 12%: 3 deaths, 1 resuscitated cardiac arrest, 4 recurrent infarctions, 4 admissions with unstable angina) and combined events (medical events or bypass surgery, incidence 23%). The sensitivity, specificity and predictive accuracy for predicting multivessel CAD were 64%, 77% and 64% for a positive exercise electrocardiographic (ECG) response, 64%, 88% and 80% for a remote thallium defect, and 42%, 96% and 88% for a combination of the 2 tests. With 2 tests yielding negative findings the probability of multivessel CAD was 13%. No variable (positive exercise ECG response, remote thallium defect and presence of multivessel CAD) predicted medical events, although there were nonsignificant trends to more events in patients with any of those findings. The relative risk of combined events was 2.5 (p less than 0.05) for a positive exercise ECG response; 1.8 (NS) for a remote thallium defect; 2.6 (p less than 0.05) for multivessel CAD; and 3.1 (p less than 0.025) for both positive ECG response and remote defect. A combination of exercise electrocardiography and thallium scanning early after acute myocardial infarction helps to identify subsets of patients with high and low probabilities of multivessel CAD and combined medical or surgical events.

Adult↗
PubMed1986

Late follow-up (41 to 102 months) of medically treated patients with coronary artery spasm and minor atherosclerotic coronary obstructions.

From a series of 37 patients with coronary artery spasm and less than 70% diameter narrowing treated initially with verapamil and nitrates, 33 were followed up 41 to 102 months (mean 62). One patient died from carcinoma of the lung and 3 could not be traced. Before diagnosis, 3 had nontransmural myocardial infarction and 10 had either ventricular tachycardia and fibrillation or atrioventricular block. During follow-up there were no cardiac deaths or myocardial infarctions. Asymptomatic periods of more than 3 months occurred in 23 patients during follow-up: 18 with asymptomatic periods of more than 1 year were pain free at the time of study and 5 with asymptomatic periods of 3 to 6 months had infrequent pain. Ten patients had no asymptomatic periods. Symptomatic status at last review was related to initial response to therapy: 13 of 18 patients (72%) currently asymptomatic became asymptomatic with initial therapy compared with 5 of 15 patients (33%) currently experiencing pain (p = 0.06). Twenty-six patients were currently receiving therapy: 22 verapamil, 80 to 640 mg/day (mean 280), 2 nifedipine, 1 diltiazem and amiodarone and 1 isosorbide (15 were receiving additional isosorbide). Twelve patients were not receiving therapy or were receiving very low dosage therapy, including 8 with asymptomatic periods of more than 1 year. Patients with coronary spasm and less than 70% diameter narrowing treated medically have low mortality and morbidity rates over 5-year follow-up. Many have long asymptomatic periods and some may be able to stop therapy indefinitely.

Coronary Disease↗
PubMed1985

Interaction of steroidal alkaloid toxins with calcium channels in neuronal cell lines.

Depolarization with 50 mM K+ increased 45Ca2+ uptake into neuronal clonal cell lines NG108-15, N1E-115 and NH15-CA2. In each cell line this depolarization-induced uptake was blocked by inorganic and organic blockers of voltage sensitive calcium channels. However, tetrodotoxin (10(-6) M) was ineffective. Moreover, in the presence of tetrodotoxin, neither batrachotoxin nor veratridine inhibited the depolarization-induced uptake. The novel dihydropyridine BAY K8644 enhanced depolarization-induced 45Ca2+ uptake into each cell line in a nitrendipine reversible fashion. In the presence of tetrodotoxin, the BAY K8644/50 mM K+ stimulated uptake could be partially inhibited by batrachotoxin (10(-6) M) and veratridine (5 X 10(-5) M). These effects were not altered by the presence of scorpion venom (1 microgram/ml). The results indicate that both batrachotoxin and veratridine can modulate the effects of dihydropyridines on the gating properties of voltage sensitive calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Dihydropyridine sensitive calcium channels in a smooth muscle cell line.

The pharmacological properties of voltage sensitive calcium channels (VSCC) were examined in a rat aortic smooth muscle cell line (A10). The inorganic VSCC blockers Co2+ and Cd2+ blocked 45Ca2+ uptake into these cells in both 5 mM K+ and 50 mM K+ (depolarizing) conditions. The organic VSCC antagonists nitrendipine, nimodipine, D-600 and diltiazem also blocked 45Ca2+ uptake at low concentrations. The relative potencies of blockade were similar to those found in intact vascular smooth muscle. The VSCC "agonist" BAY K8644 enhanced 45Ca2+ uptake and this effect could be reversed by nitrendipine. These results indicate that A10 cells possess VSCC and that these VSCC behave similarly to those in authentic smooth muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Influence of coronary collateral blood flow on the development of exertional ischemia and Q wave infarction in patients with severe single-vessel disease.

The functional significance of coronary collateral flow from a nonobstructed supply artery was studied in 121 patients with severe (greater than or equal to 80%) single-vessel disease, 64 with and 57 without Q wave infarction. All patients underwent exercise thallium imaging and coronary angiography. On angiography, collateral flow was present in 85% of 74 occluded arteries compared with only 17% of 47 arteries with subtotal obstruction (p less than .001). Collateral flow was not seen in arteries with lesions of less than 90% obstruction. Collateral flow was present in 100% of 29 occluded arteries in patients without Q wave infarction compared with only 76% of 45 occluded arteries with Q wave infarction (p less than .005). Clinical variables did not correlate with collateral flow. Collateral flow did not prevent ischemia on exercise thallium imaging in patients without Q wave infarction: 30 of 33 (91%) with collateral flow had reversible thallium defects compared with 24 of 24 (100%) without collateral flow (p = NS). In patients with Q wave infarction, partially reversible exercise thallium defects (peri-infarctional ischemia) were more common with flow to the area from either subtotal obstruction (73%) or collateral flow (45%) than with no flow from total occlusion (27%; p = .05). In patients with severe single-vessel disease the presence of collateral flow is principally determined by coronary occlusion. Collateral flow may protect from Q wave infarction but does not prevent exercise ischemia on thallium imaging.

Adult↗
PubMed1984

The effects of dihydropyridines on neurotransmitter release from cultured neuronal cells.

Depolarizing stimuli increase the release of transmitter substances from cultured PC12 pheochromocytoma cells and reaggregate cultures of mouse mesencephalic dopamine neurones. We measured the stimulated release of (3H) norepinephrine and (3H) dopamine from these systems respectively. In the cultured mouse dopaminergic neurones, several organic calcium channel blockers including nitrendipine, D-600, verapamil and diltiazem were unable to inhibit potassium-evoked transmitter release. However, release was blocked by 3 mM cobalt. The novel dihydropyridine calcium channel agonist BAY K8644 also had no effect on basal or evoked dopamine release. In contrast, BAY K8644 greatly stimulated the potassium-evoked release of (3H) norepinephrine from PC12 cells. The BAY K8644 enhanced release could be blocked by the dihydropyridine antagonist nitrendipine. These results indicate that while stimulus-secretion coupling in the PC12 cell line involves dihydropyridine sensitive calcium channels, this is not the case in primary cultured neurones.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Interactions of maitotoxin with voltage-sensitive calcium channels in cultured neuronal cells.

The dinoflagellate toxin maitotoxin (MTX) stimulated 45Ca2+ uptake in cultured NG108-15 neuroblastoma X glioma cells. Depolarizing stimuli (e.g., 50 mM K+) produced an immediate stimulation in Ca2+ uptake, whereas that produced by MTX occurred only after a lag period of about 2 min. MTX did not stimulate Ca2+ uptake into fibroblasts. Both 50 mM K+- and MTX-stimulated Ca2+ uptake was blocked by organic calcium channel antagonists (nitrendipine, D-600, diltiazem) at very low concentrations. Cd2+ was also a potent blocker. The novel dihydropyridine BAY K8644 enhanced Ca2+ uptake in the presence of 50 mM K+ but had no effect in 5 mM Ca2+. However, in the presence of MTX, BAY K8644 stimulated Ca2+ uptake in 5 mM K+. The effects of MTX were not blocked by tetrodotoxin but were decreased in Na+-free medium. MTX did not stimulate Na+ uptake into NG108-15 cells and did not alter [3H]nitrendipine binding to rat brain cortical synaptosomes. It is concluded that MTX may alter the voltage dependence of calcium-channel activation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Calcium channel activation: a different type of drug action.

Depolarization of NG108-15 (neuroblastoma-glioma) cells causes an increase in 45Ca2+ influx. This effect is blocked by low concentrations of dihydropyridines such as nitrendipine and by other blockers of voltage-sensitive calcium channels such as D-600, diltiazem, and Cd2+. Two other dihydropyridines, BAY K8644 and CGP 28392, have the opposite effect. Low concentrations of these compounds enhance depolarization-induced 45Ca2+ influxes. BAY K8644 is more effective than CGP 28392. Both agents have no effect on fluxes measured under nondepolarizing conditions. The effects of BAY K8644 and CGP 28392 can be inhibited by nitrendipine, D-600, diltiazem, or Cd2+. Whereas the interaction between nitrendipine and BAY K8644 is shown to be competitive in nature, that between BAY K8644 and D-600 is shown to be noncompetitive. These results indicate that dihydropyridines show a variety of effects on calcium channels, ranging from agonistic through partially agonistic to antagonistic. Moreover, the results also indicate that dihydropyridines and D-600 exert their effects on calcium channels at different sites.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Specific receptor-mediated inhibition of cyclic AMP synthesis by dopamine in a neuroblastoma X brain hybrid cell line NCB-20.

Dopamine and dopamine receptor agonists were found to inhibit adenylate cyclase activity dose-dependently in a neuroblastoma X Chinese hamster brain explant hybrid cell line NCB-20. Apomorphine (with an IC50 value of 10 nM) was the most effective inhibitor, followed by 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthaline (ADTN), dopamine, and N-dipropyldopamine. The inhibition was potently reversed by sulpiride, butaclamol, and flupenthixol in a stereospecific manner, but was unaffected by yohimbine, except at high concentrations. Clonidine also inhibited adenylate cyclase activity in these cells and this was reversed by the alpha 2-adrenoreceptor antagonist yohimbine, but not by sulpiride. [D-Ala2, D-Leu5] Enkephalin inhibited adenylate cyclase activity in NCB-20 cells at nanomolar concentrations; this was reversed by naloxone. All three inhibitory neurotransmitters were able to reverse the stimulation of cyclic AMP synthesis by serotonin or prostaglandin E1. The dopamine receptor that modulates cyclic AMP synthesis in NCB-20 cells is pharmacologically quite distinct from a high-affinity spiperone binding site identified in these cells, but shows the pharmacologic specificity of the "D2" receptor previously described in mammalian brain.

Alprostadil↗
PubMed1984

Ergonovine-induced myocardial ischemia: no role for serotonergic receptors?

Because ergonovine appears to produce coronary contractions by a serotonergic (5-HT) mechanism, we attempted to prevent ergonovine-induced ischemia in patients with vasospastic angina by pretreatment with ketanserin, a new selective 5-HT blocker. We studied seven patients with consistently positive results of ergonovine testing (ST segment elevation in three and ST segment depression in four). Ergonovine testing was performed before and after a bolus of 10 mg of ketanserin (all patients) and infusion of 2 to 4 mg/hr for 8 hr (six patients). To assess 5-HT blockade during ketanserin infusion, the constrictor response of hand veins to 5-HT was tested before and after ketanserin. Despite evidence of 5-HT blockade in hand veins, ergonovine-induced ischemia was not prevented by ketanserin in any patient, and there was no significant change in the dose of ergonovine required to provoke ischemia. In one patient, four spontaneous episodes of ST segment elevation occurred during infusion of ketanserin. The plasma concentrations of ketanserin at the time of ergonovine testing ranged from 61 to 127 ng/ml (mean 102) and were well above those that completely inhibit canine coronary 5-HT contractions in vitro. Although human coronary arteries may differ in their responsiveness to 5-HT or ketanserin, these data suggest that ischemia from ergonovine-induced coronary vasospasm is not mediated by 5-HT receptors.

Aged↗
PubMed1984

Identification and characterization of voltage-sensitive calcium channels in neuronal clonal cell lines.

Voltage-sensitive calcium channels ( VSCCs ) have been identified in three clonal cells. These are the neuroblastoma X Chinese hamster brain hybrid ( NCB -20), the neuroblastoma X glioma hybrid (NG108-15), and the neuroblastoma ( N4TG1 ). Depolarization of NCB -20 cells with 50 mM KCl or 50 microM veratridine (VE) produced a 2- to 3-fold increase in net 45Ca2+ uptake. In NCB -20 cells, this voltage-sensitive 45Ca2+ uptake was inhibited selectively by organic calcium antagonists such as nitrendipine, cinnarizine, verapamil, and diltiazem (IC50 values = 6.4, 750, 1800, and 4500 nM, respectively). High K+-induced uptake was unaffected by 4-aminopyridine, tetraethylammonium, and tetrodotoxin (TTX), whereas VE-induced 45Ca2+ uptake was completely blocked by 3 microM TTX. In contrast to NCB -20 cells, NG108-15 cells showed a much smaller response to depolarizing stimuli. Following differentiation of NG108-15 cells by chronic treatment with 10 microM prostaglandin E1 and 50 microM 3-isobutyl-1-methylxanthine, depolarization induced a large increase in voltage-sensitive 45Ca2+ uptake. This induction was apparent after 24 hr and increased linearly for 96 hr. VSCC activity was also induced by 1.5% dimethyl sulfoxide and by other agents that increase intracellular cAMP, such as forskolin (1 microM) and cholera toxin (1 microgram/ml). Voltage-sensitive 45Ca2+ uptake in differentiated NG108-15 cells was inhibited by nitrendipine, D-600, and diltiazem (IC50 values = 7, 690, and 1600 nM). Our results suggest that VSCCs in neuronal clonal cell lines can be altered by cellular differentiation. In contrast to those VSCCs involved in neurotransmitter release, the VSCCs described here appear to be blocked by organic calcium channel antagonists at very low concentrations.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Clinical studies of patients with coronary spasm.

Coronary artery spasm may cause myocardial ischemia in patients without severe coronary atherosclerotic obstruction. Spontaneous rest angina, particularly at night, is the predominant symptom; most patients are smokers. Ergonovine tests have high sensitivity and specificity for the diagnosis of coronary spasm, but should be used when vasospasm is suspected but no electrocardiogram was recorded during spontaneous angina. Arterial constriction measured during ergonovine testing suggests that the arterial hypersensitivity to vasoconstrictors at sites of atherosclerotic lesions is independent of the severity of the lesion. Coronary vasospasm may also be provoked by exercise, possibly through an alpha-adrenergic mechanism. Both spontaneous and exercise-induced attacks of vasospasm are prevented by calcium-antagonist drugs that remain effective during longer-term treatment. The cyclic nature of the condition is demonstrated when successful therapy is discontinued without recurrence of symptoms and may be due to alteration of arterial hypersensitivity.

Angina Pectoris↗
PubMed1982

Verapamil in stable effort angina: effects on left ventricular function evaluated with exercise radionuclide ventriculography.

A double blind placebo-controlled study was performed in 12 patients with stable angina pectoris to evaluate the effects of oral verapamil (320 mg/day) on left ventricular function, as measured at rest and during exercise with gated equilibrium radionuclide ventriculography. On verapamil, patients had a lower heart rate-blood pressure product at each work load than with placebo. Anginal threshold increased by 28 +/- 19 watts (p less than 0.005), and maximal exercise capacity increased by 20 +/- 14 watts (p less than 0.001) with verapamil, but the rate-pressure product at the onset of angina and at maximal exercise was unchanged. Left ventricular ejection fraction at rest during verapamil therapy was the same as with placebo therapy. On exercise during placebo therapy, the ejection fraction decreased from 40 +/- 9 to 35 +/- 11 percent (p less than 0.025) because end-systolic volume increased disproportionately compared with end-diastolic volume. On exercise during verapamil therapy, the ejection fraction did not decrease (44 +/- 8 versus 45 +/- 12 percent) and was significantly higher at identical work loads than on placebo because of a smaller increase in end-systolic volume. Oral verapamil is effective treatment for effort angina and may prevent the decrease in left ventricular ejection fraction due to exercise-induced ischemia.

Aged↗
PubMed1982

Long-term follow-up of verapamil and nitrate treatment for coronary artery spasm.

Thirty-seven patients with coronary artery spasm and minor coronary atherosclerosis (34) or normal coronary arteries (3) were followed up long-term. All had angina at rest, 32 had nocturnal angina, and 13 had a positive exercise test with S-T elevation. Three had a previous subendocardial infarction; 10 had had serious arrhythmias, which caused syncope in 7. At last review, 21 months (range 1 to 61) after starting therapy, 27 patients continued on verapamil, 314 (120 to 600) mg/day; 4 who did not respond to verapamil were taking nifedipine, 58 (30 to 80) mg/day; and 16 were also taking isosorbide dinitrate, 41 (20 to 80) mg/day. Of the 31 patients on therapy, 21 were asymptomatic, 9 were improved (1 to 4 attacks/month), and 1 had an average of 8 anginal attacks/month; the remaining 6 had stopped therapy and 5 were asymptomatic a mean of 10 (3 to 18) months after stopping. The exercise test became negative in all 12 patients tested on therapy, although 3 required nitrates in addition to verapamil or nifedipine. In 26 supervised treatment withdrawals in the hospital, a mean of 15 (1 to 55) months on therapy, 10 developed angina in less than 48 hours. Angina recurred in all 6 unsupervised, patient-initiated withdrawals. Failure to stop smoking was positively associated with recurrence of angina on treatment withdrawal (p less than 0.02). Long-term treatment of coronary artery spasm with verapamil or nifedipine together with isosorbide dinitrate was well tolerated and effectively relieved angina. No documented serious arrhythmias, syncopal episodes, myocardial infarction, or death occurred during follow-up.

Coronary Angiography↗