scholarly journals Insulin-like stimulation of cardiac fuel metabolism by physiological levels of glucagon: involvement of PI3K but not cAMP

2008 ◽  
Vol 295 (1) ◽  
pp. E155-E161 ◽  
Author(s):  
Julie A. Harney ◽  
Robert L. Rodgers
Keyword(s):  
Left Ventricular Pressure ◽  
Adenosine Monophosphate ◽  
Left Ventricular ◽  
Glycolytic Flux ◽  
Blood Levels ◽  
Response Curves ◽  
Fuel Metabolism ◽  
Camp Levels ◽  
Stimulation Of

At concentrations around 10−9 M or higher, glucagon increases cardiac contractility by activating adenylate cyclase/cyclic adenosine monophosphate (AC/cAMP). However, blood levels in vivo, in rats or humans, rarely exceed 10−10 M. We investigated whether physiological concentrations of glucagon, not sufficient to increase contractility or ventricular cAMP levels, can influence fuel metabolism in perfused working rat hearts. Two distinct glucagon dose-response curves emerged. One was an expected increase in left ventricular pressure (LVP) occurring between 10−9.5 and 10−8 M. The elevations in both LVP and ventricular cAMP levels produced by the maximal concentration (10−8 M) were blocked by the AC inhibitor NKY80 (20 μM). The other curve, generated at much lower glucagon concentrations and overlapping normal blood levels (10−11 to 10−10 M), consisted of a dose-dependent and marked stimulation of glycolysis with no change in LVP. In addition to stimulating glycolysis, glucagon (10−10 M) also increased glucose oxidation and suppressed palmitate oxidation, mimicking known effects of insulin, without altering ventricular cAMP levels. Elevations in glycolytic flux produced by either glucagon (10−10 M) or insulin (4 × 10−10 M) were abolished by the phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 (10 μM) but not significantly affected by NKY80. Glucagon also, like insulin, enhanced the phosphorylation of Akt/PKB, a downstream target of PI3K, and these effects were also abolished by LY-294002. The results are consistent with the hypothesis that physiological levels of glucagon produce insulin-like increases in cardiac glucose utilization in vivo through activation of PI3K and not AC/cAMP.

Calcium-mediated activation of pyruvate dehydrogenase in severely injured postischemic myocardium

2001 ◽  
Vol 281 (2) ◽  
pp. H722-H730 ◽  
Author(s):  
Jerome Terrand ◽  
Irene Papageorgiou ◽  
Nathalie Rosenblatt-Velin ◽  
Rene Lerch
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Glucose Oxidation ◽  
Calcium Uptake ◽  
Indirect Evidence ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ruthenium Red ◽  
Glycolytic Flux ◽  
Pronounced Increase ◽  
Stimulation Of

Indirect evidence suggests that activity of pyruvate dehydrogenase (PDH) influences recovery of the myocardium after transient ischemia. The present study examined the relationship between postischemic injury and activity of PDH and the role of mitochondrial calcium uptake for observed changes in PDH activity. Isovolumically beating isolated rat hearts perfused with erythrocyte-enriched buffer containing glucose, palmitate, and insulin were submitted to either 20 or 35 min of no-flow ischemia. After 20 min of no-flow ischemia, hearts exhibited complete recovery of developed left ventricular pressure (DLVP). The proportion of myocardial PDH in the active state was modestly increased to 38% (compared with 13% in control hearts) without a change in glucose oxidation. In contrast, in hearts subjected to 35 min of no-flow ischemia (which exhibited poor recovery of DLVP), there was marked stimulation of glucose oxidation (+460%; P < 0.01) and pronounced increase in the active fraction of PDH to 72% ( P < 0.01). Glycolytic flux was not significantly altered. Ruthenium red (6 μM) completely abolished the activation of PDH and the increase in glucose oxidation. The results indicate that variable stimulation of glucose oxidation during reperfusion is related to different degrees of activation of PDH, which depends on the severity of the ischemic injury. Activation of PDH seems to be mediated by myocardial calcium uptake.

Effects of intravenous anesthetic agents on left ventricular function in dogs

1977 ◽  
Vol 232 (1) ◽  
pp. H44-H48
Author(s):  
L. D. Horwitz
Keyword(s):  
Left Ventricular Pressure ◽  
Cardiovascular Effects ◽  
Sympathetic Nerves ◽  
Left Ventricular ◽  
Intravenous Anesthetic ◽  
First Derivative ◽  
Anesthetic Agents ◽  
Thiopental Sodium ◽  
Stimulation Of ◽  
Mean Heart Rate

The cardiovascular effects of ketamine hydrochloride and thiopental sodium were studied in 11 dogs. During anesthesia, mean heart rate rose to 185 beats/min with ketamine and 147 beats/min with thiopental. Cardiac output was increased with ketamine but unchanged by thiopental. The maximum first derivative of the left ventricular pressure (dP/dt max) fell by 14% with thiopental but did not change significantly with ketamine. Propranolol resulted in attenuation of the tachycardia and a fall of 10% in dP/dt max with ketamine but had little effect on the response to thiopental. Phentolamine had no consistent effects on either drug. With pentolinium both drugs decreased dP/dt max. Intracoronary injection of ketamine decreased dP/dt max. Adrenalectomy had little effect on the responses to either anesthetic. The results lead to the conclusion that both ketamine and thiopental have myocardial depressant effects, but, whereas thiopental does not alter sympathetic tone, the depressive effects of ketamine are obscured by stimulation of cardiac sympathetic nerves.

scholarly journals Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo

2018 ◽  
Vol 315 (3) ◽  
pp. H669-H680 ◽  
Author(s):  
Alessio Alogna ◽  
Michael Schwarzl ◽  
Martin Manninger ◽  
Nazha Hamdani ◽  
Birgit Zirngast ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Diastolic Pressure ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Concentric Hypertrophy ◽  
Ventricular Compliance ◽  
Left Ventricular Compliance ◽  
Stimulation Of

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 μg·kg−1·min−1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20–30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs ( n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated.

In vivo safety and accuracy of a clinically applicable telemetered left ventricular pressure module: intermediate-term results

2004 ◽  
Vol 10 (4) ◽  
pp. S67 ◽  
Author(s):  
Patrick I. McConnell ◽  
Daise de Cunha ◽  
Tanya Shipkowitz ◽  
Justin Van Hee ◽  
Phillip H. Long ◽  
...  
Keyword(s):  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure

Myocardial substrate metabolism influences left ventricular energetics in vivo

2000 ◽  
Vol 278 (4) ◽  
pp. H1345-H1351 ◽  
Author(s):  
Christian Korvald ◽  
Odd Petter Elvenes ◽  
Truls Myrmel
Keyword(s):  
Fatty Acid ◽  
Coronary Flow ◽  
Left Ventricular Pressure ◽  
Random Order ◽  
Left Ventricular ◽  
Acid Oxidation ◽  
Left Ventricular Volumes ◽  
Acid Consumption ◽  
Myocardial Substrate

The myocardial oxygen consumption (MV˙o 2) to left ventricular pressure-volume area (PVA) relationship is assumed unaltered by substrates, despite varying phosphate-to-oxygen ratios and possible excess MV˙o 2 associated with fatty acid consumption. The validity of this assumption was tested in vivo. Left ventricular volumes and pressures were assessed with a combined conductance-pressure catheter in eight anesthetized pigs. MV˙o 2 was calculated from coronary flow and arterial-coronary sinus O2 differences. Metabolism was altered by glucose-insulin-potassium (GIK) or Intralipid-heparin (IH) infusions in random order and monitored with [14C]glucose and [3H]oleate tracers. Profound shifts in glucose and fatty acid oxidation were observed. Contractility, coronary flow, and slope of the MV˙o 2-PVA relationship were unchanged during GIK and IH infusions. MV˙o 2 at zero PVA (unloaded MV˙o 2) was 0.16 ± 0.13 J ⋅ beat− 1 ⋅ 100 g− 1 higher during IH compared with GIK infusion ( P = 0.001), a 48% increase. The study demonstrates a marked energetic advantage of glucose oxidation in the myocardium, profoundly affecting the MV˙o 2-PVA relationship. This may in part explain the “oxygen-wasting” effect of lipid-enhancing interventions such as adrenergic drugs and ischemia.

scholarly journals Changes in the sensitivity to glucagon of lipolysis in adipocytes from pregnant and lactating rats

1988 ◽  
Vol 254 (3) ◽  
pp. 661-665 ◽  
Author(s):  
V A Zammit
Keyword(s):  
Adipose Tissue ◽  
The Other ◽  
High Concentration ◽  
Response Curves ◽  
Pregnant Rats ◽  
Adipose Tissue Lipolysis ◽  
The Right ◽  
Peak Lactation ◽  
Stimulation Of

1. Rates of lipolysis were measured at different concentrations of glucagon in adipocytes prepared from parametrial adipose tissue of fed or starved rats in different reproductive states. All experiments were performed in the presence of a high concentration of adenosine deaminase (1 unit/ml). 2. Maximal rates of lipolysis (elicited by 25 nM-glucagon in each instance) were higher in adipocytes from peak-lactating rats than those from pregnant animals in both the fed and starved states. 3. Of adipocytes from fed animals, those from peak-lactating rats were the most sensitive to glucagon, whereas those from late-pregnant and early-lactating rats were 1-2 orders of magnitude less sensitive. 4. Adipocytes from 24 h-starved rats showed a much smaller stimulation of lipolysis by glucagon, making the assessment of sensitivity difficult. Therefore, rates of lipolysis were also measured in the presence of a maximally anti-lipolytic dose of insulin. The presence of insulin did not alter the relative sensitivities to glucagon of adipocytes from fed animals in different reproductive states, although all dose-response curves were shifted to the right. When lipolysis in adipocytes from starved animals was measured in the presence of insulin, it became evident that starvation for 24 h markedly increased the sensitivity of adipocytes from late-pregnant rats to glucagon, but did not affect that of cells from animals in the other reproductive states. 5. It is concluded that the large changes in sensitivity to glucagon that occurred during the reproductive cycle may enable the modulation of adipose-tissue lipolysis in vivo to satisfy the different metabolic requirements of the animal in the transition from pregnancy to peak lactation.

Role of spinal NK1 receptors in cardiovascular responses to chemical stimulation of the gallbladder

1995 ◽  
Vol 268 (2) ◽  
pp. H526-H534 ◽  
Author(s):  
H. L. Pan ◽  
A. C. Bonham ◽  
J. C. Longhurst
Keyword(s):  
Intrathecal Injection ◽  
Left Ventricular Pressure ◽  
Cardiovascular Responses ◽  
Pressure Change ◽  
Left Ventricular ◽  
Chemical Stimulation ◽  
Intrathecal Catheter ◽  
Nk1 Receptors ◽  
Stimulation Of

The present study examined the role of substance P (SP) as a sensory neurotransmitter in cardiovascular responses to bradykinin applied on the gallbladder. Experiments were performed in anesthetized cats in which sympathetic chains were transected at the T5-T6 level, and the tip of the intrathecal catheter was positioned at T6-T7 to limit the injectate between T6 and L2. Bradykinin (10 micrograms/ml) was applied onto the gallbladder before and after intrathecal injection of [D-Pro2,D-Phe7,D-Trp9]SP (100–200 micrograms, NK1/NK2-receptor antagonist), CP-99,994 (50–100 micrograms, selective NK1 antagonist), MEN-10,376 (100–500 micrograms, selective NK2 antagonist), or vehicle. Intrathecal injection of NK1 but not NK2 antagonist significantly reduced increases in mean arterial pressure, heart rate, and maximal rate of left ventricular pressure change by 28 +/- 2 mmHg (33 +/- 4%), 4 +/- 1 beats/min (42 +/- 5%), and 497 +/- 46 mmHg/s (36 +/- 4%), respectively. Intrathecal injection of NK1 or NK1/NK2 antagonist had no effect on cardiovascular responses evoked by electrical stimulation in the rostral ventral lateral medulla. These data suggest that endogenous SP, acting as a sensory neurotransmitter, is involved in the excitatory cardiovascular reflex caused by chemical stimulation of the gallbladder through its action on NK1 receptors in the spinal cord.

Effect of regional myocardial ischemia on cardiac pump performance during exercise

1978 ◽  
Vol 234 (2) ◽  
pp. H157-H162
Author(s):  
L. D. Horwitz ◽  
D. F. Peterson ◽  
V. S. Bishop
Keyword(s):  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Adrenergic Stimulation ◽  
Circumflex Coronary Artery ◽  
Pump Performance ◽  
Regional Myocardial Ischemia ◽  
Exercise Hemodynamics ◽  
Stimulation Of

The effect of brief periods of regional ischemia upon left ventricular pump performance was studied in nine dogs standing quietly at rest and during running exercise on a treadmill. Transient occlusions of the left circumflex coronary artery resulted in increase in heart rate at rest (+30 beats/min) but not during exercise. Other changes due to occlusion were similar at rest and during exercise and included decreases in stroke volume (-25% standing, -23% running); in dP/dt max, the maximum first derivative of the left ventricular pressure (-20% standing or running); and in left ventricular peak systolic pressure (-13% standing, -21% running); and rises in left ventricular end-diastolic pressure (+4.5 mmHg standing, +6.3 mmHg running). Cardiac output was unchanged by occlusions at rest but fell (-18%) during occlusions while the dogs were running. Propranolol reduced absolute levels of cardiac performance during exercise occlusions but had no effect at rest. Inotropic agents with ischemia had some effects at rest but did not alter exercise hemodynamics. It is concluded that integrated left ventricular function during ischemia is not impaired by exercise, probably because of beta-adrenergic stimulation of nonischemic myocardium.

Altered sensitivity of chronic diabetic rat heart to calcium

1983 ◽  
Vol 245 (6) ◽  
pp. E560-E567 ◽  
Author(s):  
D. R. Bielefeld ◽  
C. S. Pace ◽  
B. R. Boshell
Keyword(s):  
Rat Heart ◽  
Calcium Metabolism ◽  
Left Ventricular Pressure ◽  
Calcium Sensitivity ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Isolated Hearts ◽  
Pressure Development

An alteration in calcium metabolism in cardiac muscle was observed in diabetic rats 3 mo after streptozotocin treatment. Depression of cardiac output and left ventricular pressure development were more sensitive to decreased extra-cellular calcium in hearts from diabetic than from control animals and occurred within the normal physiological range of freely ionized serum calcium. This decrease in calcium sensitivity was not present after 2 wk of diabetes. In vivo treatment with insulin for 1 mo completely reversed the effect. Addition of octanoate (0.3 mM) to the perfusate of isolated hearts completely reversed the defect, whereas epinephrine (25 nM) only partially reversed it. When the glucose concentration of the perfusate was decreased, the function of diabetic hearts declined and was further diminished at decreasing calcium levels. Hearts from normal rats were unaffected. These results suggest that there is a defect in calcium metabolism or flux in the chronic diabetic rat heart.

Hypotensive mechanism of [Leu13]motilin in dogs in vivo and in vitro

1998 ◽  
Vol 76 (12) ◽  
pp. 1103-1109 ◽  
Author(s):  
Takeshi Iwai ◽  
Hiroyuki Nakamura ◽  
Hisanori Takanashi ◽  
Kenji Yogo ◽  
Ken-Ichi Ozaki ◽  
...  
Keyword(s):  
Mesenteric Artery ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Gastric Antrum ◽  
Ventricular Pressure ◽  
High Dose ◽  
Aortic Blood Flow ◽  
Arterial Blood

The effects of [Leu13]motilin were examined in vivo after its intravenous administration into anesthetized dogs and in vitro with isolated preparations of canine mesenteric artery. [Leu13]Motilin (0.1-10 nmol·kg-1, i.v.) induced both strong and clustered phasic contractions in the gastric antrum and duodenum. At doses of over 1 nmol·kg-1, [Leu13]motilin also produced transient decreases in arterial blood pressure, left ventricular pressure, maximum rate of rise of left ventricular pressure, and total peripheral resistance, and an increase in aortic blood flow and heart rate. A selective motilin antagonist, GM-109 (Phe-cyclo[Lys-Tyr(3-tBu)-betaAla]betatrifluoroacetate), completely abolished the gastric antrum and duodenal motor responses induced by [Leu13]motilin. In contrast, hypotension induced by [Leu13]motilin (1 nmol·kg-1) was unchanged in the presence of GM-109. In isolated mesenteric artery preparations precontracted with U-46619 (10-7 M), [Leu13]motilin (10-8-10-5 M) induced an endothelium-dependent relaxation, and this was inhibited by a pretreatment with Nomega-nitro-L-arginine, a competitive inhibitor of NO synthase (10-4 M). A high dose (10-4 M) of GM-109 slightly decreased [Leu13]motilin-induced relaxation, and shifted the concentration-response curve of [Leu13]motilin to the right. However, the pA2 value (4.09) of GM-109 for [Leu13]motilin in the present study was conspicuously lower than that previously demonstrated in the rabbit duodenum (7.37). These results suggest that [Leu13]motilin induces hypotension via the endothelial NO-dependent relaxation mechanism and not through the receptor type that causes upper gastrointestinal contractions.Key words: motilin, gastrointestinal motility, hypotension, hemodynamics, anesthetized dog, mesenteric artery, endothelium, nitric oxide.

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