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Biomedical subjects

R S Danziger

Publications and source records attributed to R S Danziger.

9 recordsLinked to original sources
PubMed1992

Contractile response of individual cardiac myocytes to norepinephrine declines with senescence.

The present study utilized individual isolated left ventricular cardiac myocytes from hearts of animals of a broad age range to evaluate the response to norepinephrine and to other stimuli that augment myocardial cell contractile performance. During electrical stimulation before drugs neither the amplitude nor the velocity of shortening normalized for resting cell length differed among cells isolated from 2-, 6- to 8-, or 24-mo-old animals. Norepinephrine augmented twitch amplitude and velocity about fourfold in cells from 2-mo-old hearts but only by 2.5-fold in cells from 24-mo-old hearts (age effect, P less than 0.001). In contrast, the contractile response to increases in bathing [Ca2+] or to the addition of the calcium channel agonist BAY K 8644 or of 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT cAMP) did not vary with age. These results indicate that the age-associated contractile deficit during beta-adrenergic stimulation is specific to the beta-adrenergic pathway and an age-associated deficit in the net production of cAMP. This can be attributed to a diminished cardiac myocyte response to beta-adrenergic agonists, in contrast to modulation of the beta-adrenergic response by other receptor agonists, which are present in intact tissue but absent under the conditions of the present study.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Ethanol acutely and reversibly suppresses excitation-contraction coupling in cardiac myocytes.

We used adult rat cardiac myocytes to examine the acute effects of 0.1-5.0% (vol/vol) ethanol (ETOH) on 1) the cytosolic [Ca2+] (Cai) transient measured as the change in indo 1 fluorescence at 410/490 nm and contraction elicited by electrical stimulation of single cells and 2) the sarcoplasmic reticulum (SR) Ca2+ content in cell suspensions. During stimulation at 1 Hz, clinically relevant ETOH correlations (0.1-0.15% [vol/vol]) caused a 10-15% decrease in the contraction amplitude, measured by myocyte edge tracking, without decreasing the Cai transient that initiates contraction. At higher ETOH concentrations (1-5% [vol/vol]), ETOH caused profound contractile depression and also reduced the magnitude of the Cai transient. These effects were reversed within minutes of ETOH washout. Addition of norepinephrine (10 microM) to the bathing solution or an increase in bathing [Ca2+] in the continued presence of ETOH could also reverse its effects. The relation of the amplitude of the Cai transient to the contraction amplitude measured across a range of bathing [Ca2+] was shifted by ETOH, such that for a given Cai transient a marked reduction in contraction amplitude occurred. In unstimulated myocyte suspensions, ETOH (1-5% [vol/vol]) caused a concentration-dependent depletion of SR Ca2+ content, manifested as a diminution in the Cai increase elicited by caffeine in the presence of extracellular EGTA and no added Ca2+. Thus, in rat cardiac myocytes a reduction in the myofilament Ca2+ response, possibly due to a decrease in myofilament Ca2+ sensitivity, is a mechanism for contractile depression due to clinically relevant ETOH concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade.

STUDY OBJECTIVE: To determine whether beta-adrenergic blockade augments cocaine-induced coronary artery vasoconstriction. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: A cardiac catheterization laboratory in an urban teaching hospital. PATIENTS: Thirty clinically stable patient volunteers referred for catheterization for evaluation of chest pain. INTERVENTIONS: Heart rate, arterial pressure, coronary sinus blood flow (by thermodilution), and epicardial left coronary arterial dimensions were measured before and 15 minutes after intranasal saline or cocaine administration (2 mg/kg body weight) and again after intracoronary propranolol administration (2 mg in 5 minutes). MEASUREMENTS AND MAIN RESULTS: No variables changed after saline administration. After cocaine administration, arterial pressure and rate-pressure product increased; coronary sinus blood flow fell (139 +/- 28 [mean +/- SE] to 120 +/- 20 mL/min); coronary vascular resistance (mean arterial pressure divided by coronary sinus blood flow) rose (0.87 +/- 0.10 to 1.05 +/- 0.10 mm Hg/mL.min); and coronary arterial diameters decreased by between 6% and 9% (P less than 0.05 for all variables). Subsequently, intracoronary propranolol administration caused no change in arterial pressure or rate-pressure product but further decreased coronary sinus blood flow (to 100 +/- 14 mL/min) and increased coronary vascular resistance (to 1.20 +/- 0.12 mm Hg/mL.min) (P less than 0.05 for both). CONCLUSIONS: Cocaine-induced coronary vasoconstriction is potentiated by beta-adrenergic blockade. Beta-adrenergic blocking agents probably should be avoided in patients with cocaine-associated myocardial ischemia or infarction.

Adrenergic beta-Antagonists↗
PubMed1990

Assessment of the sensitivity of hydrogen inhalation in the detection of left-to-right shunting.

For the detection of left-to-right intracardiac shunting, the oximetric and standard indocyanine green techniques are relatively insensitive, in that neither can reliably detect a shunt with a ratio of pulmonary to systemic flow (Qp/Qs) less than 1.3 (percentage shunt, 23%). Although the hydrogen inhalation method is said to be much more sensitive in this regard, no previous study has measured its sensitivity. Accordingly, in 15 patients (4 men, 11 women, aged 38 to 67 years) without intracardiac shunting, hydrogen inhalation was performed 1) without and 2) with an artificially created femoral arteriovenous shunt of known size, and cardiac output was measured by thermodilution. For the 15 subjects with cardiac outputs of 3.64 to 8.10 liters/min, shunts of 22 to 248 ml/min were created, so that the shunts ranged from 0.5% to 3.3%. Hydrogen inhalation detected all shunts greater than or equal to 1.3% (Qp/Qs greater than or equal to 1.01). Of the 10 shunts less than 1.3%, it detected 5, with the smallest being 0.7%. Thus, the hydrogen inhalation technique is extremely sensitive in identifying the presence of left-to-right shunting, far more sensitive than the oximetric and standard indocyanine green methods.

Adult↗
PubMed1990

Interactive alpha- and beta-adrenergic actions of norepinephrine in rat cardiac myocytes.

We investigated the effects of the physiological neurotransmitter norepinephrine on the contractile properties and Ca2+ dynamics of isolated cardiac myocytes, with particular emphasis on possible interactions between alpha- and beta-adrenergic effects. Individual rat ventricular myocytes were electrically stimulated at a frequency of 1 Hz. Norepinephrine (10(-9) to 10(-5) M) increased extent and velocity of shortening and decreased the contraction duration. beta-Adrenergic activation gave a greater enhancement of extent and velocity of shortening than did norepinephrine alone (i.e. alpha plus beta). Neither alpha 1 nor alpha 2 adrenergic activation individually produced a significant impact upon contraction. Using suspensions of myocytes loaded with Quin-2, we also studied resting levels of cytosolic Ca2+ ([ Ca2+]c), the increase of [Ca2+]c due to caffeine-addition (as an index of sarcoplasmic reticulum Ca2+ content) and the subsequent increase in [Ca2+]c due to depolarization with 30 mM K+ (as an index of sarcolemmal voltage-dependent Ca2+ channel activity). Norepinephrine decreased resting [Ca2+]c, increased sarcoplasmic reticulum Ca2+ content and increased Ca2+ channel activity. beta-Adrenergic activation produced the same effect on resting [Ca2+]c and sarcoplasmic reticulum content, but gave significantly greater activation of sarcolemmal Ca2+ channel activity, than did norepinephrine (alpha plus beta). By contrast, alpha-adrenergic stimulation had no effect on resting [Ca2+]c or sarcoplasmic reticulum Ca2+ content. We conclude that beta-mediated effects predominate in the action of the physiological agonist norepinephrine on cardiac myocytes. However, alpha (specifically alpha 1)-adrenergic effects are significant in diminishing the potentiation of the extent and velocity of shortening, and of depolarization-induced entry of Ca2+ into the cell, which is seen on beta-stimulation alone. Thus, there may be an intrinsic feedback effect in the actions of norepinephrine on the cardiac myocyte.

Animals↗
PubMed1990

The age-associated decline in glomerular filtration in healthy normotensive volunteers. Lack of relationship to cardiovascular performance.

Whether the well-documented age-associated decline in the glomerular filtration rate, manifest as a decline in creatinine clearance, is secondary to an age-related change in cardiovascular performance is at present unknown. To answer this question, we measured arterial blood pressure, 24-hour creatinine clearance, and cardiac output determined from gated cardiac blood pool scans in the sitting position in healthy normotensive men (n = 75) and women (n = 42) (ages 25 to 82 years), from the Baltimore Longitudinal Study on Aging. These subjects were selected for the absence of cardiovascular disease, renal disease, and confounding medications. By linear regression analysis, creatinine clearance, expressed in mL/min/m2, declined cross-sectionally with age (creatinine clearance = 90 -0.33[age], r = .31, P less than .001), whereas systolic blood pressure in mm Hg increased with age (systolic blood pressure = 111 + 0.27[age], r = .30, P less than .001); cardiac output in L/min/m2 did not vary with age (r = .03, P = .74). In stepwise multiple regression analysis with age, cardiac index, and systolic blood pressure as independent variables and creatinine clearance as the dependent variable, only age was a significant predictor of creatinine clearance. (F = 11.31, DF + 116, r = .30, P less than .001). Thus, the age-associated decline in creatinine clearance is not modulated by changes in cardiac index or systolic blood pressure in healthy normotensive subjects.

Adult↗
PubMed1989

Decrease with senescence in the norepinephrine-induced phosphorylation of myofilament proteins in isolated rat cardiac myocytes.

(1) The effects of norepinephrine on protein phosphorylation in isolated rat cardiac ventricular myocytes were determined by autoradiography on 32P-labelled proteins separated by electrophoresis; (2) In cells from young adult rats (6 months old) there was a marked increase due to norepinephrine (10(-8) to 10(-4) M) in the incorporation of 32P into proteins identified on the grounds of molecular weight as troponin I and C-protein: in cells from senescent rats (24 months old) this increase was much attenuated. (3) Age-associated decrements in protein phosphorylation were much diminished when maximally effective concentrations of the adenylate cyclase-activator forskolin and the cyclic AMP analog 8(4-chlorophenylthio) cyclic AMP were used instead of norepinephrine. Moreover, age-associated differences were abolished if the phosphodiesterase inhibitor isobutylmethylxanthine was present in addition to norepinephrine, or alone. (4) Study of the rates of dephosphorylation of troponin I, as initiated with the beta-adrenergic antagonist propranolol, showed no change in half-time as a function of age: this indicates no change in protein phosphatase activity. (5) These results suggest that there is less active net formation of cyclic-AMP in senescent heart cells in response to the neurotransmitter norepinephrine, giving a lesser activation of c-AMP-dependent protein kinase and less phosphorylation of these target proteins.

Actin Cytoskeleton↗
PubMed1988

Extracellular ATP has a potent effect to enhance cytosolic calcium and contractility in single ventricular myocytes.

The effect of extracellular ATP on the contraction of single rat cardiac myocytes was investigated, together with the effect on the transient change in cytosolic Ca2+ (Cai) elicited by excitation and on the relationship between these two parameters. In unstimulated single myocytes, ATP caused a small increase in Cai (measured as the ratio of fluorescence of Indo-1 at 410 to that at 490 nm. In myocytes bathed in a medium containing 1.0 mM [Ca2+] at 23 degrees C and stimulated at 1 Hz, ATP (1 microM) resulted in a two-threefold increase in amplitude of contraction, as measured by video cinemicrographic techniques. The duration of the Cai-transient was not altered but its amplitude was markedly enhanced, as was the amplitude of contraction. The relation between Cai and contraction-amplitude was not altered by ATP, when measured over a range of extracellular [Ca2+], suggesting that ATP does not affect the myofilament-Ca2+ interaction. The primary site of action of ATP in increasing Cai is at the sarcolemma since the addition to suspensions of myocytes of caffeine (10 mM), which depletes the sarcoplasmic reticulum Ca2+ load, does not prevent the subsequent increase of Cai due to ATP. Further, lowering of the extracellular [Ca2+] to less than 1 microM with EGTA abolishes the response of Cai to ATP, though not the response to caffeine. Thus in rat cardiac myocytes ATP stimulates trans-sarcolemmal influx of Ca2+: ADP, AMP and adenosine are ineffective. ATP markedly augments the amplitude of the Cai transient elicited by electrical stimulation thus rendering it a potent inotropic agent.

Adenosine Triphosphate↗