Depolarization-Stimulated Contractility of Gastrointestinal Smooth Muscle in Calcium-Free Solution: A Review

The membrane of most gastrointestinal smooth muscles shows slow waves, slow rhythmic changes in membrane potential. Slow waves serve to bring the membrane potential of smooth muscle cells to a threshold level that elicits a second electrical event known as the spike or action potential. The inward current of the spike, in most gastrointestinal smooth muscle preparations, is carried, at least in part, by calcium. Indeed, considering the narrow diameter of smooth muscle cells, some have hypothesized that the influx of calcium during the spike is sufficient for activation of the contractile machinery. Findings consistent with this include marked reduction in contractility during exposure of muscle segments to blockers of L-type calcium channels or following reductions in external calcium levels. However, it has also been observed that following exposure of muscle segments to external bathing solutions containing no added calcium plus 5 mM EGTA to remove any remaining extracellular calcium, contractions can be triggered following membrane depolarization. It is noteworthy that in isolated smooth muscle cells or in small muscle segments, during incubation in calcium-free solution, depolarization does not induce contractions. The present paper discusses the evidence in support of depolarization-mediated contractions occurring in gastrointestinal smooth muscle segments during incubation in solutions devoid of calcium

Asimadoline and its potential for the treatment of diarrhea-predominant irritable bowel syndrome: a review

Irritable bowel syndrome (IBS) is a multifactorial condition with principal symptoms of pain and altered bowel function. The kappa-opioid agonist asimadoline is being evaluated in Phase III as a potential treatment for IBS. Asimadoline, to date, has shown a good safety profile and the target Phase III population – diarrhea-predominant IBS patients with at least moderate pain – was iteratively determined in a prospective manner from a Phase II dose-ranging study. The clinical data in support of this population are reviewed in this article. Furthermore, the scientific rationale for the use of asimadoline in the treatment of IBS is reviewed. Considering the high patient and societal burdens of IBS, new treatments for IBS represent therapeutic advances

The effects of alterations in internal Ca levels on cat small intestinal slow waves

Control of slow wave frequency in cat small intestinal muscle was investigated with microelectrodes. Exposure of intact muscle or isolated longitudinal muscle to low Ca('2+) saline decreased slow wave frequency with less than a 6 mV change in resting potential. This frequency decline was characterized by a prolongation of the diastolic phase of the slow wave. Raising Ca(,0)('2+) to 2-3 times normal increased slow wave frequency. At Ca(,0)('2+) greater than 4 times normal, the slow wave frequency again decreased. However, this decrease in frequency was characterized by a prolongation of the systolic phase of the waveform. Application of Ca conductance blockers (Co('2+), Mn('2+), D600, verapamil), increasing Mg(,0)('2+) or increasing internal pH decreased slow wave frequency by a prolongation of the diastolic region of the slow wave. Addition of db-cAMP to Krebs saline made hypertonic with sucrose or decreasing internal pH increased slow wave frequency. These results indicate a relationship between internal Ca('2+) and the pacemaker of slow wave frequency. A scheme is proposed to explain that relationship

Pulse Synchronized Contractions (PSCs)

A key platform underpinning the traditional understanding of the cardiovascular system, with respect to the behavior of large arterial vessels, is Otto Frank’s Windkessel Hypothesis [1]. This hypothesis posits simply that the smooth muscle walls of large arteries do not undergo rhythmic contractions in synchrony with the heartbeat but, rather, behave as passive elastic tubes undergoing distension from pulsatile pressure waves. The Windkessel Hypothesis is elegant, well described for over a century, ingrained in the understanding of cardiovascular medicine and physiology, and simply wrong. Several groups have now shown that the arterial smooth muscle wall undergoes rhythmic activation in synchrony with the heartbeat in a variety of tissues, including human brachial artery; canine coronary, femoral, and carotid arteries; rabbit aorta; feline pulmonary artery and rodent aorta [2-8]. The phasing of these events is such that the upstroke of the contraction slightly precedes the upstroke of the pulse wave, suggesting nomenclature for the events as pulse synchronized contractions, or PSCs [3,6-8]. PSCs have been found to be of neurogenic origin, sensitive to the neural blocker tetrodotoxin [3,8]. Although the specific neural pathways regulating PSCs have not been elucidated, the alpha-adrenergic system is at least partially involved, as evidenced by reduction or blockade of PSCs by the alpha-adrenergic blocker phentolamine [8]. Further, PSCs have not been observed following vessel excision in in vitro studies, as an intact nervous system is not present. The pacemaker for the PSC resides in the right atrium, as suggested by two lines of evidence. First, pacing of the right atrial region to faster than spontaneous frequencies leads to a one-to-one correspondence of PSC frequency with the stimulation rate [3]. Additionally, excision of the right, but not the left, atrial appendage results in elimination of PSCs [3]. As the pacemaker region for PSCs and the heartbeat both lie in the right atrium, this may potentially allow for coordination between the heartbeat and pulse wave with PSCs [3,5,8]. Extensive evaluations also have been performed showing the PSC was not an artifact produced either by cardiac contractility or from the vessel distension from the pulse wave [3,5,6]