4-Aminopyridine antagonizes the acute relaxant action of metformin on adrenergic contraction in the ventral tail artery of the rat

Peuler, Jacob D.; Lee, JiHun M.; Smith, Jacquelyn M.

doi:10.1016/s0024-3205(99)00522-6

Cited by 8 publications

(16 citation statements)

References 18 publications

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“…sulfonylureas) and some that mimic and/or improve insulin action (the biguanide metformin and the thiazolidinediones pioglitazone and rosiglitazone) (46,47,48,49,50). Only agents of the latter type are known to exert direct vasodilatory (vasorelaxant) effects on the arterial vessel wall (17,18,19,20,21,22,23, 49, 51,52,53,54,55,56,57,58); effects now recognized as largely responsible for their antihypertensive action (49, 54,55,56,57,58). Also, the full expression of their vasorelaxant effects (at least with low, therapeutically-relevant concentrations) is delayed for a number of hours (19, 21,22,23).…”

Section: Discussionmentioning

confidence: 99%

“…Evidence shows that thiazolidinediones do so largely directly (21, 51,52,53) while metformin does so only indirectly, i.e. by repolarizing arterial smooth muscle cell membranes (17) due to activation of voltage-dependent K channels (20). However, we found it difficult to appreciate how sildenafil, simply by coincidence, would interfere with these distinctly different mechanisms to produce essentially the same net effect.…”

Section: Discussionmentioning

confidence: 99%

“…However, we will employ rings from the ventral tail artery of the laboratory rat since all of our previous experiments with direct vasorelaxant properties of metformin and the thiazolidinediones were successfully performed with that particular preparation (18,19,20,21,22,23). In addition, while certainly much smaller, the rat tail artery is also more muscular and richer in adrenergic nerve endings and receptors than the aorta and, as such, more closely resembles systemic arterial resistance vessels (26,27,28).…”

Section: Methodsmentioning

confidence: 99%

“…[Eight was the largest number that our in vitro bath system and Grass recorder could accommodate on any given day]. Each ring was mounted between two tungsten wire stirrups which in our experience were strong enough not to bend during ring contractions yet thin enough not to damage the inner endothelial cell layer (18,19,20,21,22,23). Then, each ring was suspended in a 40 ml tissue bath and equilibrated for several minutes before experimentation at a resting (baseline) tension of 1000 mg in standard physiological (Krebs) buffer which was warmed to 37 °C and gassed to pH 7.4 with regulated delivery of O 2 /CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…At high concentrations, well above levels observed in plasma of diabetic patients (14,15,16), their relaxation of isolated arterial vascular tissues in vitro occurs rapidly (17,18,19,20,21). At lower, more therapeutically-relevant concentrations, the appearance of their relaxant action in vitro can be delayed for a number of hours (19, 21,22,23).…”

Section: Introductionmentioning

confidence: 93%

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Sildenafil does not enhance but rather attenuates vasorelaxant effects of antidiabetic agents

Peuler

Phelps

2015

J. Smooth Muscle Res.

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Type 2 diabetic men commonly experience erectile dysfunction for which phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) are often recommended. By preventing degradation of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle, these inhibitors also enhance arterial vasorelaxant effects of nitric oxide donors (which stimulate cGMP synthesis). In the present work, we confirmed this enhancing effect after co-administration of sildenafil with nitroprusside to freshly-isolated rat tail arterial tissues. However, in the same tissues we also observed that sildenafil does not enhance but rather attenuates vasorelaxant effects of three commonly-used antidiabetic drugs, i.e. the biguanide metformin and the thiazolidinediones pioglitazone and rosiglitazone. Indeed, sildenafil completely blocked vasorelaxant effects of low concentrations of these drugs. In addition, we found that this same novel anti-vasorelaxant interaction of sildenafil with these agents was abolished by either 1) omitting extracellular glucose or 2) inhibiting specific smooth muscle glycolytic pathways; pathways known to preferentially utilize extracellular glucose to fuel certain adenosine triphosphate (ATP)-dependent ion transporters: e.g. ATP-sensitive K channels, sarcoplasmic reticulum Ca-ATPase, plasma membrane Ca-ATPase and Na/K-ATPase. Accordingly, we suspect that altered activity of one or more of these ion transporters mediates the observed attenuating (anti-vasorelaxant) interaction of sildenafil with the antidiabetic drugs. The present results are relevant because hypertension is so common and difficult to control in Type 2 diabetes. The present data suggest that sildenafil might interfere with the known antihypertensive potential of metformin and the thiazolidinediones. However, they do not suggest that it will interact with them to cause life-threatening episodes of severe hypotension, as can occur when it is co-administered with nitrates.

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