Digoxin induced intestinal vasoconstriction. The effects of proximal arterial stenosis and glucagon administration.

Levinsky, R A; Lewis, Robert M.; Bynum, T. E.; Hanley, Henry G.

doi:10.1161/01.cir.52.1.130

Cited by 50 publications

(9 citation statements)

References 24 publications

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“…Both ouabain and digoxin, when administered acutely in vivo , and often in high doses, induce vasoconstriction [95, 159-164]. Nanomolar ouabain, however, augments myogenic constriction in rodent isolated arteries [36, 42, 65, 165, 166].…”

Section: Cardiotonic Steroid Structure-activity Relationships: Hypmentioning

confidence: 99%

Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins

Blaustein

Hamlyn

2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Salt retention as a result of chronic, excessive dietary salt intake, is widely accepted as one of the most common causes of hypertension. In a small minority of cases, enhanced Na+ reabsorption by the kidney can be traced to specific genetic defects of salt transport, or pathological conditions of the kidney, adrenal cortex, or pituitary. Far more frequently, however, the salt retention may be the result of minor renal injury or small genetic variation in renal salt transport mechanisms. How the salt retention actually leads to the increase in peripheral vascular resistance (the hallmark of hypertension) and the elevation of blood pressure remain an enigma. Here we review the evidence that endogenous ouabain (an adrenocortical hormone), arterial smooth muscle α2 Na+ pumps, type-1 Na/Ca exchangers, and receptor- and store-operated Ca2+ channels play key roles in the pathway that links salt to hypertension. We discuss cardenolide structure-function relationships in an effort to understand why prolonged administration of ouabain, but not digoxin, induces hypertension, and why digoxin is actually anti-hypertensive. Finally, we summarize recent observations which indicate that ouabain upregulates arterial myocyte Ca2+ signaling mechanisms that promote vasoconstriction, while simultaneously downregulating endothelial vasodilator mechanisms. In sum, the reports reviewed here provide novel insight into the molecular mechanisms by which salt retention leads to hypertension.

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Section: Cardiotonic Steroid Structure-activity Relationships: Hypmentioning

confidence: 99%

Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins

Blaustein

Hamlyn

2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…The cardiac glycosides are known to produce vasoconstriction directly and possibly through activation of the adrenergic nervous system (Ross et al, 1960;Stark et al, 1972;Levinsky et al, 1975;Treat et al, 1971). This effect is not specific for any vascular bed.…”

Section: Discussionmentioning

confidence: 99%

“…This extracardiac effect of the cardiac glycosides results in an increase in vascular resistance of several regional vascular beds in humans and in experimental animals. Although usually of no clinical consequence, a digitalis-induced increase in mesenteric vascular resistance has been postulated to be important in the pathogenesis of non-occlusive intestinal ischemia seen in debilitated patients with congestive heart failure (Shanbour and Jacobsen, 1972;Levinsky et al 1975;Lanciault and Jacobsen, 1976).…”

mentioning

confidence: 99%

Non-steroidal anti-inflammatory drugs potentiate the vasoconstrictor effects of ouabain in the dog.

Nies¹,

Gerber²

1981

Circulation Research

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The purpose of this study was to determine whether inhibitors of prostaglandin synthesis alter the peripheral vascular effects of the cardiac glycoside, ouabain. Ouabain (35 /»g/kg) was given to 12 mongrel dogs, six of which had been pretreated 1 hour previously with the non-steroidal antiinflammatory drugs (NSAID), indomethacin or meclofenamate (6 mg/kg, iv, bolus followed by 1 mg/ min infusion). Hemodynamic variables were monitored for 30 minutes before and for 3 hours after ouabain administration. Mean arterial pressure was significantly increased in all dogs for 45 minutes after ouabain, and cardiac output was unchanged. In the animals that did not receive non-steroidal anti-inflammatory drugs, ouabain transiently (15 min) decreased renal blood flow and increased renal vascular resistance. Mesenteric blood flow was not altered by ouabain until 90 minutes, after which time it was significantly increased. In the dogs pretreated with NSAID, renal blood flow was reduced for 60 minutes after administration of ouabain. In addition, 30 minutes after ouabain, the mesenteric blood flow was reduced by 43 ± 17 ml/min from a baseline value of 192 ± 42 ml/min (P < 0.05), and this reduction persisted for the entire 3-hour observation period. Control animals that did not receive ouabain showed neither an increase in arterial pressure nor a decrease in renal or mesenteric blood flow over the period of the experiment. Thus, pretreatment with NSAID enhanced the duration of the renal vasoconstrictor effects of ouabain in the dog and converted late mesenteric vasodilation to early and persistent vasoconstriction. These data imply a potentially important role for vasodilating prostaglandins in modulating the mesenteric as well as the renal circulatory responses to ouabain.

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“…Both the cardiotonic steroids ouabain and digoxin induce vasoconstriction when administered in vivo, but only ouabain raises the blood pressure after prolonged administration in rats. Digoxin and the related cardiotonic steroid digitoxin are actually very effective in lowering blood pressure in rats with ouabaininduced hypertension (Levinsky et al 1975, Hulthen et al 1984, Kimura et al 2000. This suggests a more complex relationship between the various effects observed for cardiotonic steroids than inhibition of the pump alone can account for.…”

Section: Introductionmentioning

confidence: 99%

The C-terminal cavity of the Na,K-ATPase analyzed by docking and electrophysiology

Paulsen

Jurkowski

Apostolov

et al. 2012

Molecular Membrane Biology

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The Na,K-ATPase is essential to all animals, since it maintains the electrochemical gradients that energize the plasma membrane. Naturally occurring inhibitors of the pump from plants have been used pharmaceutically in cardiac treatment for centuries. The inhibitors block the pump by binding on its extracellular side and thereby locking it. To explore the possibilities for designing an alternative way of targeting the pump function, we have examined the structural requirements for binding to a pocket that accommodates the two C-terminal residues, YY, in the crystal structures of the pump. To cover the sample space of two residues, we first performed docking studies with the 400 possible dipeptides. For validation of the in silico predictions, pumps with 13 dipeptide sequences replacing the C-terminal YY were expressed in Xenopus laevis oocytes and examined with electrophysiology. Our data show a significant correlation between the docking scores from two different methods and the experimentally determined sodium affinities, which strengthens the previous hypothesis that sodium binding is coupled to docking of the C-terminus. From the dipeptides that dock the best and better than wild-type YY, it may therefore be possible to develop specific drugs targeting a previously unexplored binding pocket in the sodium pump.

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Digoxin induced intestinal vasoconstriction. The effects of proximal arterial stenosis and glucagon administration.

Abstract: SUMMARYPrevious studies have shown that intravenous cardiac glycosides produce mesenteric vasoconstriction (MVC)

Cited by 50 publications

References 24 publications

Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins

Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins

Non-steroidal anti-inflammatory drugs potentiate the vasoconstrictor effects of ouabain in the dog.

The C-terminal cavity of the Na,K-ATPase analyzed by docking and electrophysiology

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