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

Abstract

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.

Resveratrol can both enhance and relax adrenergic contractions of the rat tail artery

“…Accordingly, proximal and distal segments of each vessel were isolated (Fig. 1), cleaned and carefully sectioned into multiple 3-mm cylindrical rings using a bound set of evenly-spaced scalpel blades as we have successfully employed previously (20,21,22,23). As described in Fig.…”

“…1, a maximum of eight rings were selected at random from the middle portion of each segment for experimental treatments during each experimental period. Each ring was mounted between two tungsten wire stirrups, which in our experience (20,21,22,23, 25) are strong enough not to bend during ring contractions yet thin enough not to damage the inner endothelial cell layer [presence of intact endothelium was confirmed by relaxation responses to acetylcholine in a representative number of precontracted rings in preliminary and follow-up experiments]. Each ring was then suspended in a 40 ml tissue bath and allowed to equilibrate for several minutes before experimentation at a passive loading (resting) tension of 1,500 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 .…”

“…One vessel not yet studied is the long ventral tail artery of the laboratory rat, despite being widely recognized as a convenient, inexpensive and yet valid model for many other arteries throughout the body (17,18,19). Our lab has successfully used the rat tail artery as a model for studying mechanisms of direct relaxant effects of other agents also known for lowering arterial pressure chronically (20,21,22,23). Therefore, the purpose of our studies was to further investigate resveratrol's arterial relaxant effect using the rat tail artery model.…”

Obesity and Erectile Dysfunction: From Bench to Clinical Implication

“…However, an animal study demonstrated that sildenafil blocked metformin's vasodilatory effect in freshly-isolated rat tail arteries [88]. Another combination treatment with anti-hypertensive drugs was shown to not significantly affect the efficacy of udenafil [89].…”

Role of Glucose-Lowering Medications in Erectile Dysfunction

“…Conversely, in vivo studies reported that sildenafil abolished the vasorelaxant effects of both pioglitazone and rosiglitazone, interfering with potential beneficial effects of these antidiabetic drugs on ED and probably exerting an aberrant activity on certain ATP-dependent ion transporters through the enhancement of glucose-/glycolysis-dependent contraction-facilitating processes [ 127 ].…”