Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Abstract

Fibrates are commonly employed to treat abnormal lipid metabolism via their unique ability to stimulate peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, they also decrease systemic arterial pressure, despite recent evidence that PPARα may contribute to expression of renin and related hypertension. Yet, mechanisms responsible for their potential antihypertensive activity remain unresolved. Rapid decreases in arterial pressure following bolus intravenous injections of bezafibrate strongly suggest they may relax arterial smooth muscle directly. But since bezafibrate is highly susceptible to photodegradation in aqueous media, it has never been critically tested for this possibility in vitro with isolated arterial smooth muscle preparations. Accordingly, we tested gemfibrozil which is resistant to photodegradation. We examined it over a therapeutically-relevant range (50-400 μM) for both acute and delayed relaxant effects on contractions of the isolated rat tail artery; contractions induced by either depolarizing its smooth muscle cell membranes with high potassium or stimulating its membrane-bound receptors with norepinephrine and arginine-vasopressin. We also examined these same gemfibrozil levels for effects on spontaneously-occurring phasic rhythmic contractile activity, typically not seen in arteries under in vitro conditions but commonly exhibited by smooth muscle of uterus, duodenum and bladder. We found that gemfibrozil significantly relaxed all induced forms of contraction in the rat tail artery, acutely at the higher test levels and after a delay of a few hours at the lower test levels. The highest test level of gemfibrozil (400 μM) also completely abolished spontaneously-occurring contractile activity of the isolated uterus and duodenum and markedly suppressed it in the bladder. This is the first evidence that a fibrate drug can directly relax smooth muscle contractions, either induced by various contractile agents or spontaneously-occurring. These findings are particularly relevant to both the recently renewed concern over the impact of fibrates on hypertension and a new understanding of their gastrointestinal side effects.

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.…”

Chronic social isolation in the prairie vole induces endothelial dysfunction: implications for depression and cardiovascular disease

“…Plasma was stored for later analysis of cholesterol as described below. Then the chest of each animal was opened, lungs and large veins discarded, residual blood in its cavity flushed out with cold physiological buffer, prepared as described previously [45], and the thoracic aorta removed with as much care as possible to minimize stretching. Unfortunately, some stretching was unavoidable as we found that the aorta in this animal was surrounded by considerably more connective and fat tissue than we have encountered in larger species [46].…”

“…Each cleaned aorta was then sectioned into a pair of 3-millimeter cylindrical rings, using a bound set of evenly-spaced scalpel blades to optimize length uniformity. Each of these rings was mounted between two tungsten wire stirrups, which are strong enough not to bend during ring contraction yet thin enough not to damage the inner monolayer of endothelial cells [45, 47]. For a select number of aortas, this inner endothelial cell layer was deliberately removed from one ring of each pair (before mounting on stirrups) by rubbing it off with a roughened hypodermic needle inserted through the lumen of the vessel as described previously [47].…”