Glucagon: Present status in cardiovascular disease

Kones, Richard; Phillips, John H.

doi:10.1002/cpt1971123427

Cited by 26 publications

(8 citation statements)

References 28 publications

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“…Besides its well known glycogenolytic and lipolytic activity, glucagon can stimulate the heart or reduce both systemic and regional vascular resistance in animals and in man (for a review, see Kones & Phillips, 1971). During the last decade, numerous studies have appeared describing the vasodilator effects of glucagon in the hepatic (Kock, Roding, Hahnloser, Richardson & Withrington, 1976 a,b;1977), mesenteric 1971;Ross, 1970;Ulano, Treat, Shanbour & Jacobson, 1972;MacFerran & Mailman, 1977) or renal (Stowe & Hook, 1970;Levy & Starr, 1972;Levy, 1975 a,b;Ueda, Nakanishi, Miyazaki & Abe, 1977) vascular beds of anaesthetized dogs or cats.…”

Section: Introductionmentioning

confidence: 99%

Studies on the Mechanism of Action of Glucagon in Strips of Rabbit Renal Artery

Gagnon

Regoli

Rioux

1980

British J Pharmacology

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The vasodilator effects of glucagon and adenosine cyclic 3′,5′‐monophosphate (cyclic AMP) were evaluated in strips of rabbit renal artery contracted with noradrenaline (NA) in the absence and presence of phosphodiesterase inhibitors or calcium (Ca2+) antagonists. The vascular relaxant effect of glucagon was markedly potentiated by various concentrations of four different phosphodiesterase inhibitors (papaverine, theophylline, 3‐isobutyl‐1‐methylxanthine (IBMX) and indomethacin), while that of cyclic AMP was potentiated by only two of them (papaverine and indomethacin) and inhibited by the others (theophylline and IBMX). Amongst the four phosphodiesterase inhibitors, IBMX (10 μg/ml) was found to produce the largest potentiation (e.g. the sensitivity increased by a factor of 10) of glucagon‐induced vascular relaxations (ED50 of glucagon in the presence of IBMX = 9.2 ± 1.0 ng/ml). Ca2+ antagonists such as verapamil and SKF 525A produced a dose‐dependent inhibition of the vasodilator action of glucagon. Verapamil (2.5 μg/ml) also antagonized cyclic AMP‐induced vascular relaxations. The vasodilator effect of verapamil was inhibited dose‐dependently by raising the concentration of extracellular Ca2+ from 0.05 to 0.2 g/l (or 1.25 to 5.0 mm) while those elicited by glucagon or cyclic AMP were not influenced, thus suggesting that the latter two drugs do not interfere with Ca2+ influx. Disodium edetate (Na2EDTA, 210 to 840 μg/l) produced a dose‐dependent vasodilator effect which was attributed to the facilitation of Ca2+ extrusion from the smooth muscle cells and/or Ca2+ binding to the cell membrane. The relaxation produced by Na2EDTA was significantly blocked by verapamil (10 μg/ml) or SKF 525A (10 μg/ml). The results were taken as an indication that glucagon produces at least a fraction of its vasodilator effect by promoting Ca2+ extrusion from the vascular smooth muscle cells and/or Ca2+ binding to or sequestration into intracellular sites, presumably via a cyclic AMP‐dependent mechanism.

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Section: Introductionmentioning

confidence: 99%

Studies on the Mechanism of Action of Glucagon in Strips of Rabbit Renal Artery

Gagnon

Regoli

Rioux

1980

British J Pharmacology

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“…Digitalis preparations have occasionally been found to aggravate cardiac failure in patients with myocardial infarction (4,6) or hypertensive cardiovascular disease (5), presumably because of their vasopressor effect and perhaps particularly because this effect may preceed the inotropic effect (6,9,11,17). Although the vasopressor response to the glycosides may be attenuated or reversed in the presence of cardiac failure, at least in some circumstances, (10,12,13 (20)(21)(22)(23)(24)(25), perhaps because of failure to stimulate the enzyme, adenyl cyclase, in the presence of cardiac failure (26), reports of its use in acute myocardial infarction are generally more optomistic (27)(28)(29)(30). In view of these points, the effects observed with glucagon suggest that it and other agents with similar hemodynamic effects, such as isoproterenol, could be useful in the emergency management of acute severe aortic regurgitation.…”

Section: Discussionmentioning

confidence: 99%

Digitalis-Induced Increase in Aortic Regurgitation and the Contrasting Effects of Glucagon in the Sedated Dog

Hopkins¹,

Taylor²

1974

J. Clin. Invest.

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A B S T R A C T The hemodynamic and phasic ascending aortic flow changes induced by acetylstrophanthidin and glucagon were studied in closed-chest sedated dogs with aortic regurgitation. While the positive inotropic effect of both agents was reflected in an increase in peak rate of rise of left ventricular pressure, acetylstrophanthidin increased aortic regurgitation, while glucagon decreased it. With the former, left ventricular end-diastolic pressure rose from 20±6 to 27+6 mm Hg (P < 0.005), but fell from 18+4 to 11±3 mm Hg (P < 0.001) with glucagon. Acetylstrophanthidin increased systemic vascular resistance, aortic diastolic pressure, and diastolic regurgitant flow rate, and, heart rate and the duration of regurgitation per beat and per minute being unchanged, regurgitant flow per beat increased 32±15% (P <0.001). Glucagon decreased regurgitant flow per beat 27±14% (P < 0.001) because of abbreviation of diastole associated with tachycardia, and because of reduction in regurgitant flow rate. Despite tachycardia, the duration of regurgitation per minute was unchanged, and the small fall in regurgitant blood flow per minute was not significant, but this pertained in the face of 47% increase in effective cardiac output (P < 0.001). In contrast, acetylstrophanthidin increased regurgitant flow per minute 28±14% (P < 0.001) without change in effective cardiac output. The increase in cardiac contractility, tachycardia, and systemic vasodilatation induced by glucagon preferentially enhanced forward blood flow, which led to reduction in left ventricular volume overload, while it increased cardiac output. Contrarily, acetylstrophanthidin increased aortic regurgitation and, despite its inotropic effect, increased left ventricular volume overload without an increase in cardiac output.

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“…Agents which may elevate RBF, but do not alter systemic blood pressure, when infused into the renal artery include dopamine (McDonald et a!., 1964) and glucagon (Kones and Phillips, 1971). Not only does RBF increase with these agents, but GFR also increases.…”

Section: Vasodilator Agentsmentioning

confidence: 97%

Interrelationship Between Renal Haemodynamics, Drug Kinetics and Drug Action

Duchin

Schrier²

1978

Clinical Pharmacokinetics

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The renal haemodynamics of a particular patient may affect the pharmacological and pharmacokinetic properties of various drugs. For example, diminution in renal haemodynamics may lead to fluid retention and an increase in the volume of distribution fif the drug. A Iso, fluid retention causes a decrease in plasma protein concentration which for certain drugs can result in altered protein binding and consequent~v increased proportion of unbound drug and a more marked pharmacological response.The clearance fif many drugs and/or metabolites also in influenced by the state fif renal haemodynamics. In states of poor renal perfusion, drugs which are mainly eliminated through renal mechanisms have a reduced rate of clearance. The resultant prolongation fif the elimination half-life of the drug may increase its toxicity. Knowledge of the renal haemodynamic state, therefore, should be considered in determining the dose and/requency fif drug administration.Studies in man have shown that both renal blood flow and glomerular filtration rate are reduced below normaf'in siates of congestive head failure, liver disorders such as cirrhosis, and, fif course, acute and chronic renal failure. In these pathological states, severe cortical vasoconstriction may be present and primarily account for the impairment in renal haemodynamics and alterations in drug kinetics and action. Not on£v can (he renal haemodynamic state affect Ihe actions fif drugs, but also exogenous administration (if certain drugs can alter renal haemodynamics. The kidney's response to these agents is influenced by pathological and physiological factors, including sodium balance and the ability (if the kidney to allloregulate its blood flow. In general, however, renal haemod,vnamics are diminished by renal vasoconstriCtors and improved by renal vasodilators. The altered slate of renal haemod,vnamics in turn may modify the pharmacological and pharmacokinetic properties (if other drugs present in the body.Renal blood flow (RBF) constitutes about 25 % of the cardiac output and in relation to their size, the kidneys are among the most highly perfused organs in the body. Normal renal function which includes maintenance of normal salt and water balance, regulation of acid-base status, and removal of endogenous and foreign substances is dependent, in part, upon RBF. The blood supply to the kidney not only provides nutrients for the kidney's metabolic needs, but also is responsible for the delivery of endogenous and exogenous compounds which must be excreted. Since many drugs and their metabolites are

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Glucagon: Present status in cardiovascular disease

Cited by 26 publications

References 28 publications

Studies on the Mechanism of Action of Glucagon in Strips of Rabbit Renal Artery

Studies on the Mechanism of Action of Glucagon in Strips of Rabbit Renal Artery

Digitalis-Induced Increase in Aortic Regurgitation and the Contrasting Effects of Glucagon in the Sedated Dog

Interrelationship Between Renal Haemodynamics, Drug Kinetics and Drug Action

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