Sex-related difference in the metabolism of isosorbide dinitrate following incubation in human blood.

Isosorbide dinitrate (ISDN) (at a concentration of 100 ng/ml) was incubated aerobically at 37 degrees in whole blood from five male and five female normal volunteers. Following incubation of the blood samples for 0, 30, 60, 120, 240 and 360 min, the samples were centrifuged and the plasma was assayed for ISDN. A linear relationship was observed between the logarithm of the concentration of ISDN remaining and incubation time, and there was a significant difference between the T1/2 of ISDN in blood from males (90.6 min) and females (161.4 min). Very little ISDN metabolism was observed when ISDN was incubated with plasma rather than whole blood. When erythrocytes, resuspended in saline, were incubated with ISDN, there was a time-dependent loss of ISDN from the saline incubation medium. Investigation of the soluble fraction obtained after hemolysis of these erythrocytes also showed a time-dependent loss of ISDN. The saline incubation medium contained sufficient concentrations of the two major ISDN metabolites (isosorbide 2- and 5-mononitrate) to account for the observed disappearance of ISDN. The results indicate that ISDN is metabolized in the cellular compartment of blood and that the metabolic rate in males is greater than that in females.

Response of the bladder to bethanechol after acute spinal cord transection in cats.

Immediately after spinal cord transection, normal bladder reflex activity is lost and voiding contractions in response to cholinergic drugs can no longer be elicited. Intravesical pressure responses to s.c. and i.a. bethanechol were studied in male cats before and after spinal cord transection at T6 to T7. Bethanechol s.c. enhanced spontaneous bladder activity and produced a sustained bladder contraction. The sustained response was abolished by spinal transection. The response of the bladder to i.a. bethanechol consisted of two phases. The first, dose-related phase, which resembled the response to i.a. acetylcholine, was unchanged by spinal cord transection, rhizotomy (L7-S3) or by ganglion blockade with hexamethonium. The second sustained phase, like the s.c. response, was markedly reduced by all three treatments. Because the response to bethanechol in vitro did not differ in control and transected preparations, it is unlikely that the depressant effects are due to a persistent change in bladder muscle responsiveness. No contractions were observed regardless of s.c. injection site; hence, altered drug absorption and distribution are not sufficient to explain the diminished responses observed. Because interruption of pelvic parasympathetic reflex pathways by rhizotomy and ganglion blockade interfered with the responses to s.c. and i.a. bethanechol, we conclude that bethanechol requires intact pelvic reflex pathways in order to produce sustained contractions. The prolonged action of bethanechol is an important feature contributing to its effectiveness. Removal of reflex functions by spinal cord transection might explain the ineffectiveness of cholinergic drugs in both patients and experimental animals in the acute, areflexic stage after spinal cord transection.

Urethral pressure profile in female stress incontinence.

The accuracy of the urethral pressure profile as a measure of sphincteric competence was examined in female subjects. Most profile measurements selected proved to be significantly different in patients with stress incontinence from those in controls. However, the measurement that seemed to have the highest potential for diagnostic accuracy was the maximum closure pressure in the continence zone, recorded with the bladder full and the patient standing. The concept of the continence zone and incorporating the effect of standing were believed to be the main reasons for this high accuracy. The second best measurement was the maximum closure pressure with the bladder full and the patient surpine. To lessen the chances of a diagnostic error it was recommended that both of these measurements should be obtained. The physiological implications of these findings and the clinical role of the urethral pressure profile examination in the assessment of female patients with urinary incontinence are discussed.

Antimuscarinic and noncompetitive antagonist properties of dicyclomine hydrochloride in isolated human and rabbit bladder muscle.

In isolated strips of bladder neck (prostatic capsule) and detrusor of rabbit and man, dicyclomine had minimal effect on the resting tension. Competitive antimuscarinic activity against carbachol could be demonstrated at doses of dicyclomine less than or equal to 1 X 10(-6) M, whereas at higher doses a noncompetitive action against both carbachol and potassium was observed. The ratio of dissociation constants relating to the noncompetitive and competitive actions, respectively, was about 1200, approximately 100 times higher than that previously reported in ileum. Dicyclomine was only about 1/30 as potent as atropine in competitive antimuscarinic activity. Dicyclomine hydrochloride may be useful in the clinical management of "uninhibited bladder."

Urethral pressure profile during the spinal shock stage in man: a preliminary report.

The functional state of the proximal urethra in the spinal shock stage in man is not fully understood. We studied patients with spinal cord injuries during spinal shock and found that the urethral pressure profile had a normal configuration, the peak profile pressure increased with bladder filling and phentolamine (10 mg. intravenously) reduced the peak pressure, with empty and full bladders.