ATP-sensitive potassium channel is essential to maintain basal coronary vascular tone in vivo

1992 ◽  
Vol 262 (5) ◽  
pp. C1220-C1227 ◽  
Author(s):  
F. F. Samaha ◽  
F. W. Heineman ◽  
C. Ince ◽  
J. Fleming ◽  
R. S. Balaban
Keyword(s):  
Competitive Inhibitor ◽  
K Channel ◽  
Resonance Spectroscopy ◽  
Coronary Resistance ◽  
Tissue Ischemia ◽  
Isolated Hearts ◽  
Anesthetized Dogs ◽  
State Increase

Glibenclamide, a known selective inhibitor of ATP-sensitive potassium channels, was infused into the coronary vasculature of anesthetized dogs and of isolated perfused rabbit hearts to assess the role of this channel in the maintenance of basal coronary resistance. Infusion of glibenclamide at a concentration of 55-80 microM in the dogs resulted in a twofold steady-state increase in coronary resistance with resultant tissue ischemia. Infusion of 1 microM glibenclamide in the isolated hearts resulted in a 67% increase in coronary resistance with resultant tissue ischemia. The ischemic changes were reversible upon removal of the drug. These findings indicate that the ATP-sensitive K+ channel plays a significant role in the maintenance of basal coronary resistance in vivo. Higher concentrations of glibenclamide (80-100 microM) in the in vivo dog heart consistently gave rise to an oscillating pattern of coronary flow. These oscillations were either eliminated or decreased in amplitude and frequency by the infusion of 8-phenyltheophylline, a specific competitive inhibitor of adenosine receptors. 31P-nuclear magnetic resonance spectroscopy performed at the peaks and troughs of these oscillations revealed oscillation of the phosphorylation potential at the same frequency. Thus adenosine release caused by tissue ischemia appears to play a major role in creating the oscillating pattern of coronary blood flow, that occurs during the inhibition of ATP-sensitive K+ channels by glibenclamide.

Endothelium-derived relaxing factor in regulation of basal cardiopulmonary and renal function

1991 ◽  
Vol 261 (2) ◽  
pp. R323-R328 ◽  
Author(s):  
M. A. Perrella ◽  
F. L. Hildebrand ◽  
K. B. Margulies ◽  
J. C. Burnett
Keyword(s):  
Renal Function ◽  
Competitive Inhibitor ◽  
Vehicle Group ◽  
Relaxing Factor ◽  
Anesthetized Dogs ◽  
Endothelium Derived Relaxing Factor ◽  
Renal Vascular ◽  
Renal Responses

The endothelium has emerged as an important modulator of vascular tone by producing both vasodilating and vasoconstricting substances. In vitro studies have demonstrated that endothelial cells produce endothelium-derived relaxing factor (EDRF), which promotes vasodilation via the stimulation of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). However, the role of EDRF in the basal regulation of cardiopulmonary and renal function is not well defined. The present study was therefore designed to assess the function of EDRF by studying two groups of normal anesthetized dogs, of which one received a competitive inhibitor to EDRF generation, NG-monomethyl-L-arginine (L-NMMA; 50 micrograms.kg-1.min-1 iv), and the other received a vehicle. The L-NMMA infusion produced no significant increase in mean arterial pressure but marked increases in systemic, pulmonary, and renal vascular resistances compared with the vehicle group. Although renal blood flow decreased with L-NMMA, no changes were observed in glomerular filtration rate or sodium excretion. Associated with the cardiopulmonary and renal responses with L-NMMA was a modest increase in plasma endothelin (7.9 +/- 1.3 to 10.2 +/- 1.8 pg/ml, P less than 0.05), an endothelium-derived vasoconstrictor. No alteration was observed in plasma or urinary cGMP with EDRF inhibition. These cardiopulmonary and renal responses with L-NMMA may be attributed not only to EDRF inhibition but to an imbalance between endothelium-derived relaxing and contracting factors.

Role of adenosine in coronary autoregulation

1986 ◽  
Vol 250 (4) ◽  
pp. H558-H566 ◽  
Author(s):  
F. L. Hanley ◽  
M. T. Grattan ◽  
M. B. Stevens ◽  
J. I. Hoffman
Keyword(s):  
Steady State ◽  
Adenosine Deaminase ◽  
Low Pressure ◽  
Catalytic Subunit ◽  
Coronary Resistance ◽  
Pressure Flow ◽  
Intracoronary Infusion ◽  
Adenosine Concentration ◽  
Anesthetized Dogs

The role of cardiac interstitial adenosine as an important metabolite in coronary autoregulation has not been established. We therefore measured steady-state cardiac interstitial adenosine concentration at a high and a low coronary inflow pressure using an epicardial diffusion well in anesthetized dogs. Although coronary resistance for the high and low pressure points showed highly significant differences (P less than 0.001), adenosine averaged 302 +/- 98 and 286 +/- 91 (SD) pmol/ml for the high and low pressure points, respectively (P greater than 0.20). Cardiac interstitial adenosine concentration was then measured with and without an intracoronary infusion of adenosine deaminase catalytic subunit. Adenosine averaged 28 +/- 21 (SD) pmol/ml during the infusion compared with 281 +/- 68 during control conditions (P less than 0.001). Finally, pressure-flow relations were obtained with and without the adenosine deaminase infusion, and there was no loss of autoregulation in the pressure of adenosine deaminase. These findings indicate that intracoronary adenosine deaminase markedly reduces interstitial adenosine concentration, that cardiac interstitial adenosine concentration remains constant during autoregulation, and that the coronary bed autoregulates normally when interstitial adenosine is reduced to levels close to zero. We conclude that cardiac interstitial adenosine concentration is not an important component in coronary autoregulation.

Role of EDRF/NO in parasympathetic coronary vasodilation following carotid chemoreflex activation in conscious dogs

1994 ◽  
Vol 267 (2) ◽  
pp. H605-H613 ◽  
Author(s):  
W. Shen ◽  
M. Ochoa ◽  
X. Xu ◽  
J. Wang ◽  
T. H. Hintze
Keyword(s):  
Vagus Nerve ◽  
Conscious Dogs ◽  
Coronary Resistance ◽  
Vascular Response ◽  
Coronary Vasodilation ◽  
Relaxing Factor ◽  
Anesthetized Dogs ◽  
Endothelium Derived Relaxing Factor ◽  
Stimulation Of

The role of endothelium-derived relaxing factor (EDRF) in parasympathetic coronary vasodilation following carotid chemoreflex activation induced by nicotine in conscious dogs and stimulation of the vagus nerve in anesthetized dogs was studied. Injection of nicotine (11 +/- 4 micrograms) into the carotid artery increased coronary blood flow (CBF) by 126 +/- 16% from 28 +/- 3 ml/min and reduced late diastolic coronary resistance (LDCR) by 43 +/- 4% from 3.58 +/- 0.52 mmHg.ml-1.min, accompanied by a significant increase in mean arterial pressure and a decrease in heart rate (all P < 0.01). Pacing and propranolol did not change the coronary vascular response to chemoreflex activation. There were still increases in CBF by 113 +/- 17% from 29 +/- 3 ml/min and decreases in LDCR by 41 +/- 5% from 3.13 +/- 0.52 mmHg.ml-1.min (all P < 0.01). After infusion of N omega-nitro-L-arginine (L-NNA) (30 mg/kg), the increase in CBF following chemoreflex activation was only 23 +/- 3% from 37 +/- 3 ml/min, and the fall in LDCR was 19 +/- 3% from 3.09 +/- 0.51 mmHg.ml-1.min. Stimulation of the vagus nerve showed a relationship between stimulation frequency and coronary vasodilation that was significantly inhibited by L-NNA. Thus EDRF plays an important role in mediating parasympathetic coronary vasodilation during chemoreflex activation and perhaps during many reflexes that cause vagal cholinergic vasodilation in the heart.

scholarly journals Archives of General Psychiatry, June 1991

1991 ◽  
Vol 15 (12) ◽  
pp. 738-739 ◽  
Author(s):  
Robert Kerwin ◽  
Paul Bailey
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Second Messenger ◽  
Resonance Spectroscopy ◽  
General Psychiatry ◽  
Second Messenger Systems ◽  
Neurobiological Research ◽  
High Standards

We were recently asked by one of the editors of the Psychiatric Bulletin to comment on the June 1991 issue of the Archives of General Psychiatry because of its exclusive neurobiological approach that month. Having thus been given our brief and now having carefully read the issue, we feel obliged to warmly congratulate the Archives for a superb issue and a superb Journal that has consistently set high standards for the reporting of neurobiological research as applied to psychiatry. The June issue this year was the first to report the use of magnetic resonance spectroscopy (as opposed to imaging) in vivo (more of this later) and had many more excellent contributions on the action of lithium on neurotransmiter and second messenger systems and papers on the role of serotonin and endorphins in a variety of conditions.

scholarly journals Crustacean cardioexcitatory peptides may inhibit the heart in vivo.

1995 ◽  
Vol 198 (12) ◽  
pp. 2547-2550 ◽  
Author(s):  
I J McGaw ◽  
J L Wilkens ◽  
B R McMahon ◽  
C N Airriess
Keyword(s):  
Stroke Volume ◽  
Isolated Heart ◽  
Cancer Magister ◽  
Isolated Hearts ◽  
Cardiovascular Performance ◽  
Cast Doubt ◽  
Cardiac Stroke Volume

Peptide neurohormones exist as functionally similar analogues in a wide variety of invertebrate and vertebrate phyla, and many have been implicated as cardiovascular regulators. In decapod crustaceans, these include the pentapeptide proctolin, crustacean cardioactive peptide (CCAP) and the FMRF amide-related peptides F1 and F2, all of which are found in the pericardial organs located immediately upstream of the heart. Cardioexcitatory activity has been demonstrated by these four peptides in both isolated and semi-isolated arthropod hearts; CCAP, however, has minimal effects on the heart of Cancer magister. In the present study, we determined the effects of proctolin, F1 and F2 on the heart of the crab C. magister in both in vitro (semi-isolated heart) and in vivo (whole animal) preparations. In semi-isolated hearts, infusion of each peptide caused cardioexcitation, increasing the rate and stroke volume of the heart. In whole crabs, the peptides were cardioinhibitory; the strongest effects were observed with F1 and F2, which dramatically decreased heart rate, cardiac stroke volume and cardiac output. These results cast doubt on current perceptions of the functional role of cardioactive peptides in the regulation of invertebrate cardiovascular performance in vivo.

Regulation of cardiac AMP-specific 5′-nucleotidase during ischemia mediates ATP resynthesis on reflow

1998 ◽  
Vol 274 (4) ◽  
pp. C992-C1001 ◽  
Author(s):  
Marianna I. Bak ◽  
Joanne S. Ingwall
Keyword(s):  
Adenine Nucleotides ◽  
Fold Increase ◽  
Resonance Spectroscopy ◽  
Intracellular Acidosis ◽  
Chemical Assay ◽  
Ischemic Tissue ◽  
Salutary Effect ◽  
Decreasing Ph

The ability to resynthesize ATP during recovery from ischemia is limited to the size of endogenous pool of adenine nucleotides. Cytosolic AMP-specific 5′-nucleotidase (5′-NT) plays a key role in ATP degradation and hence the capacity for ATP resynthesis. We have suggested ( J. Clin. Invest. 93: 40–49, 1994) that intracellular acidosis [intracellular pH (pHi)] is a potent inhibitor of 5′-NT under in vivo conditions. To test this hypothesis further, we used the hyperthyroid rat heart because we could alter pHiduring ischemia and determine the consequences of lower pHion AMP accumulation (by chemical assay) and ATP resynthesis (by31P nuclear magnetic resonance spectroscopy) during reperfusion. Global no-flow ischemia caused pHito decrease from 7.1 under well-oxygenated control perfusion to 6.7. We found that decreasing pHifurther from pH 6.7 to 6.4 leads to increased accumulation (30%) of AMP during ischemia and to a 2.5-fold increase in ATP resynthesis during reperfusion. Analysis of all known substrates, products, activators, and inhibitors of the 5′-NT suggests that 5′-NT is activated primarily by Mg2+and ADP and is inhibited by H+. Thus these observations provide evidence for a salutary effect of intracellular acidosis on preserving the AMP pool due to inhibition of 5′-NT and suggest a novel role of H+in protecting ischemic tissue.

In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog

1997 ◽  
Vol 272 (5) ◽  
pp. C1567-C1577 ◽  
Author(s):  
D. Holtzman ◽  
R. Meyers ◽  
E. O'Gorman ◽  
I. Khait ◽  
T. Wallimann ◽  
...  
Keyword(s):  
Reaction Rate ◽  
Ex Vivo ◽  
Competitive Inhibitor ◽  
High Energy ◽  
Energy Deficit ◽  
Resonance Spectroscopy ◽  
Atp Metabolism ◽  
Creatine Transport ◽  
Atp Regulation

Mitochondrial and cytosolic creatine kinase (CK) isozymes are active in cells with high and variable ATP metabolic rates. beta-Guanidinopropionic acid (GPA), a competitive inhibitor of creatine transport, was used to study the hypothesis that the creatine-CK-phosphocreatine (PCr) system is important in regulating brain ATP metabolism. The CK-catalyzed reaction rate and reactant concentrations were measured in vivo with 31P nuclear magnetic resonance spectroscopy during energy deficit (hypoxia) or high-energy turnover (seizures) states in urethane-anesthetized mice fed GPA, creatine, or standard chow (controls). Brain phosphagen (i.e., cellular energy reserves) or PCr plus phosphorylated GPA (GPAP) concentrations were equal. The phosphagen-to-NTP ratio was lower than in controls. In vivo CK reaction rate decreased fourfold, whereas ex vivo CK activity that was biochemically measured was doubled. During seizures, CK-catalyzed fluxes increased only in GPA-fed mice. Phosphagen increased in GPA-fed mice, whereas PCr decreased in controls. Survival was higher and brain phosphagen and ATP losses were less for hypoxic GPA-fed mice than for controls. In contrast to mice fed GPA, hypoxic survival and CK reactant concentrations during hypoxia and seizures were the same in creatine-fed mice and controls. Thus GPA, GPAP, or adaptive changes in ATP metabolism stabilize brain ATP and enhance survival during hypoxia in mice.

Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETBreceptors

1996 ◽  
Vol 81 (4) ◽  
pp. 1510-1515 ◽  
Author(s):  
Jocelyn Dupuis ◽  
Carl A. Goresky ◽  
Alain Fournier
Keyword(s):  
Pulmonary Hypertension ◽  
Cell Function ◽  
Systemic Circulation ◽  
Protective Role ◽  
Endothelial Cell Function ◽  
Endothelin 1 ◽  
Pulmonary Clearance ◽  
Anesthetized Dogs

Dupuis, Jocelyn, Carl A. Goresky, and Alain Fournier.Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB receptors. J. Appl. Physiol. 81(4): 1510–1515, 1996.—The pulmonary circulation plays an important role in the removal of circulating endothelin-1 (ET-1). Plasma ET-1 levels are increased in pulmonary hypertensive states of various etiologies (e.g., idiopathic, heart failure, and congenital anomalies) in proportion to the severity of pulmonary hypertension. It is possible that reduced pulmonary clearance of this peptide contributes to the hyperendothelinemia of those pathologies. The ETA and ETB receptors are abundant in lung tissues: on the vascular endothelium, the ETB receptor is predominant and may contribute to ET-1 extraction through receptor-mediated endocytosis. We designed experiments to determine and quantify the importance of the ETA and ETB receptors in the pulmonary extraction of circulating ET-1 in anesthetized dogs. The single-pass cumulative tracer ET-1 extraction by the lung was measured with the indicator-dilution technique before and 5 min after intrapulmonary injection of the specific ETAantagonist BQ-123 ( n = 5, 120–960 nmol) and the specific ETBantagonist BQ-788 ( n = 6, 1,000 nmol). The inhibitors had no significant effect on pulmonary and systemic hemodynamics. Mean cumulative pulmonary ET-1 extraction was not modified by BQ-123 [control (C): 36 ± 4%, antagonist (A): 34 ± 6%] but was completely abolished by BQ-788 (C: 34 ± 6%, A: 0 ± 2%, P < 0.001). The pulmonary rate constant ( K) for ET-1 removal was also unaffected by BQ-123 (C: 0.050 ± 0.0085 s−1, A: 0.047 ± 0.012 s−1) but significantly decreased and became close to zero after BQ-788 (C: 0.058 ± 0.014 s−1, A: 0.009 ± 0.007 s−1, P < 0.001). We conclude that the ETB receptor is completely and exclusively responsible for pulmonary ET-1 removal in vivo. Future studies are needed to show whether desensitization or downregulation of the ETB receptor may contribute to the increase in circulating ET-1 levels in conditions associated with pulmonary hypertension. This novel pulmonary endothelial cell function may play a protective role by modulating circulating ET-1 levels in the systemic circulation.

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