Stimulation of the nitric oxide-guanosine 3', 5'-cyclic monophosphate pathway by sildenafil: effect on rectal muscle tone, distensibility, and perception in health and in irritable bowel syndrome.
OBJECTIVE
Nitric oxide, a neurotransmitter in the noncholinergic, nonadrenergic nervous system, is a mediator of relaxation of GI smooth muscle and of visceral nociception mainly studied in vitro. Sildenafil stimulates the nitric oxide guanosine 3', 5'-cyclic monophosphate (NO-cGMP) pathway through inhibition of phosphodiesterase 5. The aims of this study were to evaluate in vivo the effect of stimulation of the NO-cGMP pathway on rectal tone, distensibility, and perception in healthy individuals and in patients with irritable bowel syndrome (IBS).


METHODS
In eight healthy subjects and four patients with IBS rectal tone, distensibility and perception thresholds were measured with an electronic barostat both before and 60 min after administration of sildenafil (50 mg p.o.). Perception was scored on a graded scale of 0-6. At the end of a distension series an anatomic questionnaire was filled out by the subjects.


RESULTS
Sildenafil significantly reduced rectal tone in healthy subjects (intrabag volume predrug: 145.5 +/- 18.7 ml vs postdrug: 164.4 +/- 16.9 ml, p = 0.01) and IBS (111.3 +/- 25.2 ml vs 136.5 +/- 33.3 ml; p = 0.01) but did not alter rectal compliance (healthy subjects: 5.8 +/- 0.4 vs 6.3 +/- 0.6 ml/mm Hg, p > 0.05; IBS subjects: 6.1 +/- 0.6 vs 7.1 +/- 1.0 ml/mm Hg, p > 0.05). Intrabag pressure and rectal wall tension to reach perception thresholds for initial sensation, sensation of stool, and urgency were not altered by sildenafil. However, intrabag volumes to reach these thresholds were significantly increased by sildenafil both in healthy subjects and in patients with IBS. Viscerosomatic referral was unchanged.


CONCLUSIONS
Stimulation of the NO-cGMP pathway decreases rectal tone but does not influence rectal distensibility. Relaxation of the rectum is accompanied by an increase in rectal volumes to reach perception thresholds in healthy subjects and in patients with IBS, but no direct effect on rectal perception can be demonstrated.
Fritz
Eva
E
Universitätsklinik für Innere Medizin IV, Abteilung für Gastroenterologie und Hepatologie, University of Vienna, Vienna, Austria.
Hammer
Johann
J
Schmidt
Barbara
B
Eherer
Andreas J
AJ
Hammer
Heinz F
HF
D000328:Adult; D016022:Case-Control Studies; D006152:Cyclic GMP / Q000378:metabolism*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D043183:Irritable Bowel Syndrome / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009129:Muscle Tonus / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage*; D011312:Pressure; D011336:Probability; D011446:Prospective Studies; D011687:Purines; D012007:Rectum / Q000187:drug effects* / Q000502:physiology; D012016:Reference Values; D012680:Sensitivity and Specificity; D012684:Sensory Thresholds; D012720:Severity of Illness Index; D000068677:Sildenafil Citrate; D018709:Statistics, Nonparametric; D013450:Sulfones
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D006152:Cyclic GMP