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M S Finkel

Publications and source records attributed to M S Finkel.

49 records · Page 3Linked to original sources
PubMed1992

Inotropic effects of calcium antagonists in the cardiomyopathic Syrian hamster.

The inotropic responses of papillary muscles isolated from the BIO 14.6 cardiomyopathic Syrian hamster were compared with those of age-matched F1B controls. Length-tension curves revealed the preservation of contractile function at 1-2 months of age and significant loss of function at 4-6 months of age. Papillary muscles prepared from 4-6-month-old myopathic hamsters were significantly less sensitive to increasing frequency of stimulation than were controls (p less than 0.05). There were no differences in the responses to nifedipine, Bay K 8644, diltiazem, or gallopamil. Only verapamil demonstrated a biphasic inotropic response in the cardiomyopathic hamster with a low-dose positive inotropic effect (131 +/- 4% at 4 +/- 2 x 10(-7) M) and a 50-fold higher IC50 for negative inotropy compared with F1B controls (200 +/- 30 vs. 4.0 +/- 1.0 microM). Verapamil is also a less potent negative inotrope in 1-2-month-old myopathic papillary muscles compared with controls (IC50, 280 +/- 70 vs. 32 +/- 10 microM; p less than 0.05). These inotropic effects are not shared by the other calcium channel modulators studied (i.e., nifedipine, Bay K 8644, diltiazem, gallopamil). These findings do not support the presence of a functional defect in the sarcolemmal L-type calcium channel in the cardiomyopathic Syrian hamster. The mechanism of action of verapamil in the cardiomyopathic Syrian hamster remains to be elucidated.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Radioligand binding and inotropic effects of ryanodine in the cardiomyopathic Syrian hamster.

We compared the radioligand-binding and inotropic effects of ryanodine [known specific regulator of sarcoplasmic reticulum (SR) calcium release channel] on BIO 14.6 cardiomyopathic Syrian hamsters with those on age-matched F1B controls. Scatchard analyses of [3H]ryanodine binding to cardiac membranes prepared from 1-2-month-old BIO 14.6 and F1B Syrian hamsters revealed the presence of a significant increase in binding capacity (Bmax = 942 +/- 49 vs. 567 +/- 33 fmol/mg protein) with no difference in affinity (KD = 3.9 +/- 0.4 vs. 3.5 +/- 0.5 nM, p less than 0.01). Ryanodine is a significantly less potent negative inotrope in isolated papillary muscles prepared from 1-2-month-old BIO 14.6 hamsters than in muscles from F1B controls (IC50 = 4.3 +/- 1 vs. 0.5 +/- 0.4 microM, p less than 0.05). Ryanodine was 200-fold less potent in the 4-6-month-old myopathic muscles than in controls (IC50 = 20 +/- 5 vs. 0.1 +/- 0.01 microM, p less than 0.01). A paradoxic positive inotropic effect of ryanodine observed in 4-6-month-old myopathic muscles at low concentrations was not seen in controls (ECmax = 126 +/- 5% at 1 +/- 0.1 x 10(-8) M). These data support the presence of a defect both biochemical and physiologic in the ryanodine-sensitive SR calcium release channel in the BIO 14.6 cardiomyopathic Syrian hamster. Purification, cloning, sequencing, and expression studies will be required to distinguish among primary, secondary, intrinsic, and regulatory defects in the ryanodine-sensitive SR calcium release channel in the cardiomyopathic Syrian hamster.

Animals↗
PubMed1992

Bay K 8644 is a negative inotrope in the presence of arachidonic acid but not eicosapentaenoic acid.

The inotropic and radioligand binding characteristics of arachidonic acid (AA) and the fish oil derivative, eicosapentaenoic acid (EPA), were studied. AA alone was a concentration-dependent negative inotrope in isolated hamster papillary muscles. The negative inotropic effect of AA was enhanced 500-fold by the coadministration of indomethacin (cyclo-oxygenase inhibitor) and caffeic acid (lipoxygenase inhibitor). The dihydropyridine calcium channel agonist Bay K 8644 (BK) was a concentration-dependent positive inotrope. BK in the presence of AA was a concentration-dependent negative inotrope. The negative inotropic effect of BK in the presence of AA was blocked by caffeic acid but not indomethacin. EPA alone was a concentration-dependent negative inotrope. EPA had no effect on the positive inotropic effect of BK. Scatchard analyses of [3H]nitrendipine (dihydropyridine) binding to cardiac membranes in the presence of AA or EPA resulted in a decrease in the KD (-1/slope) with no effect on Bmax (x intercept). Kinetic studies further revealed that both AA and EPA enhanced the off rate of [3H]nitrendipine binding. These data suggest that both AA and EPA mediate similar direct negative inotropic effects through cardiac sarcolemmal calcium channels. A unique effect on E-C coupling by AA, not shared by EPA, is mediated through the lipoxygenase pathway (leukotrienes). AA and its eicosanoid products may play critically important roles in regulating myocardial contractility during acute and chronic myocardial ischemia. Differences between AA and EPA may contribute to the beneficial effects of dietary fish oils enriched in EPA.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Physiologic regulation and distribution of the renal vasopressin receptor.

Previous studies suggest that circulating levels of vasopressin (AVP) influence the responsiveness of the kidney to AVP. To determine how changes in renal AVP receptors and adenylate cyclase (AC) contribute to such altered responsiveness, we analyzed AVP receptors and AVP-sensitive AC in kidneys from Sprague-Dawley, Long-Evans and homozygous Brattleboro rats. In autoradiographic studies, the distribution of [3H]AVP binding sites was similar in all groups, corresponding to the location of AVP-sensitive AC: collecting ducts greater than outer medullary collecting ducts greater than medullary thick ascending limb greater than cortical collecting ducts. No differences in AVP receptor affinity or content were observed in kidney medullary membranes from Sprague-Dawley, Long-Evans or Brattleboro rats (KD = 0.8, 0.9, and 0.7 nM; Bmax = 116 +/- 9, 95 +/- 11 and 98 +/- 6 fmol/mg). Basal and AVP-stimulated AC activities were lower in kidney membranes from Brattleboro rats compared with Sprague-Dawley and Long-Evans animals (basal = 28 +/- 4, 40 +/- 4 and 38 +/- 3 pmol cAMP/mg/min; EDmax = 57 +/- 5, 80 +/- 7 and 71 +/- 2 pmol cAMP/mg/min) with no change in ED50. In 48-hour water-deprived Sprague-Dawley rats, AVP receptors were decreased from 116 +/- 9 to 58 +/- 2 fmol/mg, suggesting that AVP receptors are down-regulated by elevated AVP blood levels. The absence of changes in basal or AVP-stimulated AC in dehydrated rats indicates that receptor-AC coupling is normal and that maximum AC activation can occur with partial receptor occupancy. The data also indicate that impaired renal responsiveness to AVP in Brattleboro rats is not due to down-regulation of AVP receptors.

Adenylyl Cyclases↗
PubMed1988

Calcium channel binding characteristics in the human heart.

The number, affinity, pharmacologic specificity and regional distribution of calcium channel binding sites in human hearts obtained at autopsy and open heart surgery were characterized using the radioligand [3H]nitrendipine. Scatchard analyses of saturation data from 6 autopsy hearts revealed a homogeneous distribution of high affinity binding sites (affinity-1 [KD] = 0.44 +/- 0.06, 0.52 +/- 0.07, 0.32 +/- 0.02, 0.30 +/- 0.03, and 0.45 +/- 0.01 nM; binding capacity [Bmax] = 30 +/- 4, 27 +/- 6, 25 +/- 7, 33 +/- 3, and 28 +/- 4 fmol/mg protein in right atrium, right ventricle, left atrium, left ventricle and ventricular septum, respectively). In ligand competition experiments, nifedipine and nitrendipine completely displaced binding with partial displacement by verapamil and 35% enhancement of binding by 10(-5) M diltiazem at 37 degrees. Analyses of right atrial appendages obtained at open heart surgery from 5 coronary artery bypass patients provided similar results (KD = 0.2 +/- 0.03 nM, Bmax = 42 +/- 2 fmol/mg protein). In addition, no significant differences in KD or Bmax were found in 3 hamster hearts assayed at the time of death or up to 18 hours postmortem at either 4 or 25 degrees. In contrast, there was a significant increase in Bmax (110 fmol/mg protein) with no change in KD (0.3 nM) in a myomectomy specimen from a patient with obstructive hypertrophic cardiomyopathy compared with either autopsy or surgical specimens. These studies illustrate the feasibility and potential advantages of studying calcium channels directly in human hearts.

Adult↗
PubMed1987

Correlation of changes in cardiac calcium channels with hemodynamics in Syrian hamster cardiomyopathy and heart failure.

We compared hemodynamics with [3H]nitrendipine (calcium channel) binding to cardiac membranes from Bio 14.6 cardiomyopathic Syrian hamsters at 4 and 10 months with their F1B controls. A 50% increase in the number (Bmax) of nitrendipine binding sites (calcium channels) was seen only in the 4 month old myopathic vs controls (Bmax = 468 +/- 11 vs 309 +/- 10 fmol/mg prot with no change in affinity (KD) (KD = .65 +/- .12 vs .75 +/- .14 nM), while no differences in Bmax or KD were seen at 10 months (Bmax = 375 +/- 9 vs 362 +/- 7 fmol/mg prot/KD = .82 +/- .18 vs .89 +/- .17 nM) myopathic vs control respectively. Hemodynamic studies revealed no significant differences in cardiac output, cardiac index, stroke volume, heart rate, mean arterial pressure, peripheral resistance, body weight, heart weight at 4 months, but a significant decrease in peripheral resistance (1120 +/- 360 vs 2080 +/- 240) increase in body weight (118 +/- 2 vs 94 +/- 2 grams) and heart weight (97 +/- 5 vs 78 +/- 2 gms/100 gms body weight) in 10 month myopathic vs control animals. We conclude that the onset of cardiomyopathy at 4 months is associated with a selective increase in calcium channel binding sites and heart failure at 10 months is associated with a relative decrease in these sites.

Animals↗
PubMed1987

Solubilization of calcium channel antagonist binding sites from rat brain.

Calcium antagonist binding sites were solubilized from rat brain membranes using the detergent 3-[(3-cholamidopropyl)dimethylammonio] 1-propanesulfonate (CHAPS). CHAPS-solubilized [3H]nitrendipine binding sites are saturable over a range of 0.05-4 nM and Scatchard analysis reveals a single, high-affinity (KD = 0.49 +/- 0.10 nM), low-capacity (Bmax = 56 +/- 4 fmol/mg of protein) binding site. Reversible ligand competition experiments using solubilized binding sites demonstrated appropriate pharmacologic specificity, with dihydropyridines (nifedipine = nitrendipine greater than Bay K 8644) completely displacing binding, verapamil partially displacing binding, and diltiazem enhancing binding, as previously described in membrane preparations. Lyophilized Crotalus atrox venom was purified by ion exchange chromatography followed by gel filtration to a single peptide band on sodium dodecyl sulfatepolyacrylamide gel electrophoresis. This fraction of molecular weight 60,000 competitively inhibits [3H]nitrendipine binding to both membrane and soluble preparations with an IC50 of 5 micrograms/ml. This polypeptide should serve as a useful ligand for future efforts in purifying the dihydropyridine calcium channel binding site in brain.

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

Adenosine uptake sites in dog heart and brain; interaction with calcium antagonists.

[3H] Nitrobenzylthioinosine (NBI) binding is characterized in dog heart and brain. Evidence is presented suggesting that [3H]NBI is binding to the adenosine uptake site in both tissues. Physiologic studies in open-chested dogs clearly demonstrate that NBI acts as a coronary vasodilator, consistent with an action at the adenosine uptake site. The binding is reversible, saturable and of high affinity (KD = 0.78 +/- .06 nM for heart and 0.52 +/- .05 nM for brain). Both dipyridamole and hexobendine are high potency inhibitors of [3H]NBI binding in heart and brain while other antihypertensives and vasodilators such as propranolol and nitroglycerin have no effect. The inhibition of [3H]NBI binding observed with dipyridamole was competitive indicating that both agents are acting at the same site. The dihydropyridine calcium antagonists also inhibited binding with a lower potency than the adenosine uptake blockers. Non-dihydropyridine calcium antagonists were much less potent in this regard. The inhibition of [3H]NBI binding observed with the dihydropyridine calcium antagonists was non-competitive suggesting that the calcium channel and adenosine uptake site may be coupled to each other.

Adenosine↗
PubMed1984

[3H]nitrendipine binding to adrenal capsular membranes.

The physiologic regulation of aldosterone secretion is dependent on extracellular calcium and appears to be mediated by increases in cytosolic free calcium concentration in the zona glomerulosa cell. A specific role for voltage-dependent calcium channels was suggested by previous studies with the calcium channel antagonist verapamil. We therefore studied the [3H]nitrendipine calcium channel binding site in adrenal capsules. These studies revealed a single class of saturable, high affinity sites with KD = .26 +/- .04 nM and Bmax = 105 +/- 5.7 fmol/mg protein. Specific binding of [3H]nitrendipine was inhibited by calcium channel antagonists with potencies nitrendipine = nifedipine much greater than verapamil, while diltiazem had no inhibitory effect. In the rat, binding sites for [3H]nitrendipine were located in the adrenal capsule and medulla and were undetectable in the zona fasciculata. Physiologic studies with collagenase-dispersed adrenal glomerulosa cells demonstrated that nifedipine selectively inhibited angiotensin-II and potassium-stimulated steroidogenesis. These observations suggest both a pharmacologic and physiologic role for the nitrendipine binding site in aldosterone production.

Adrenal Medulla↗
PubMed1984

Characterization and autoradiographic distribution of the beta-adrenergic receptor in the rat lung.

An unexpected distribution of the beta-adrenergic receptor in the rat lung was revealed by an autoradiographic technique. [3H]-Dihydroalprenolol binding was stereoselective. L-propranolol was 300 times more potent than D-propranolol in competition experiments. Scatchard analysis revealed a Kd of 1.1 nM and Bmax of 14 fmol/mg wet weight. Relative potencies of beta-adrenergic ligands were: propranolol greater than alprenolol greater than timolol greater than pindolol greater than isoproterenol greater than epinephrine greater than soterenol greater than metoprolol greater than terbutaline greater than norepinephrine. The autoradiograms generated revealed a diffuse pattern with binding always associated with tissue structures. We conclude that beta-adrenergic receptors are extensively distributed in the lung, being present in large and small airways and blood vessels.

Animals↗
PubMed1983

Localization of opiate binding sites in kidney and adrenal gland of the rat.

[3H]ethylketocyclazocine (EKC) and [3H]etorphine bind to an apparent single class of sites in the rat kidney (kd = 7.3 and 5.2 nM; Bmax = 33.2 and 59.6 fmol/mg protein, respectively). No detectable binding was observed for [3H]dihydromorphine and [3H]D-Ala2,D-Leu5 enkephalin. Ligand selectivity pattern strongly suggests that both [3H]EKC and [3H]etorphine label a kappa opiate binding site since (-)bremazocine greater than EKC greater than etorphine greater than naloxone greater than dynorphin A much greater than beta-endorphin. In the adrenal gland, [3H]EKC also labels a single class of sites (Kd = 20.1 nM; Bmax = 74.7 fmol/mg protein) while no specific binding was seen with mu and delta ligands. Autoradiographically, [3H]EKC and [3H]etorphine binding sites are highly localized in kidney cortex compared to outer and inner medulla. Rather surprisingly, [3H]EKC binding sites in the adrenal are highly localized in the cortex with only low densities in the medulla. We are currently investigating the possible physiological roles of kappa agonists in kidney and adrenal gland functions.

Adrenal Glands↗
PubMedDate not supplied

Secretin receptors in the rat kidney: adenylate cyclase activation and renal effects.

In previous studies it has been demonstrated that pharmacological administration of secretin can alter urine output. Whether the effect is due to a direct action on kidney was investigated by examining the effect of secretin on renal output, and determining whether there were secretin receptors and a secretin sensitive adenylate cyclase in the kidney. Secretin had an antidiuretic action on kidney when administered intravenously to anesthetized hydrated rats. In addition, binding sites for (125I)-secretin, and a secretin sensitive adenylate cyclase were identified in rat kidney. Binding was saturable and reversable and was half maximally inhibited by 1 X 10(-7) M synthetic porcine secretin. Autoradiographic studies revealed a high density of secretin binding sites in the outer medulla of the kidney, a region that is composed mainly of the thick ascending limb of the loop of Henle, and is also the major site of action for the antidiuretic hormone, vasopressin. The data indicate that a functional secretin receptor system exists in kidney which may have a physiological role in regulating urine output.

Adenylyl Cyclases↗