Corwin M. Mokler

Metabolism of clomiphene in the rat. Estrogen receptor affinity and antiestrogenic activity of clomiphene metabolites.

Incubation of the nonsteroidal antiestrogen clomiphene with rat liver microsomes resulted in the formation of the 4-hydroxy-, N-desethyl-, and N-oxide metabolites, in qualitative contrast to results previously obtained analogously with rabbit microsomes, with which only the first two metabolites were detected. Metabolites were characterized by thin-layer chromatography in comparison with synthetic standards. They were similarly compared using low resolution electron ionization mass spectrometry, except for the N-oxide which was best characterized by fast atom bombardment mass spectrometry. Oral administration of clomiphene resulted in no detectable urinary elimination of the drug or its metabolites; 4-hydroxyclomiphene was the sole detectable elimination product in fecal extracts. The relative uterine cytosol estrogen receptor binding affinities, at 4 degrees, of 4-hydroxyclomiphene and the E-isomers of clomiphene, desethylclomiphene, and clomiphene N-oxide were, in turn, 331, 0.71, 0.62, and 0.88 (estradiol = 100). In the 3-day immature rat uterotropic assay, 4-hydroxyclomiphene had no significant uterotropic effect at doses up to 50 micrograms/day, but substantially inhibited that of estradiol (0.5 micrograms/day) at doses of 2 micrograms/day.

Altered regional vasodilator responses to glossopharyngeal nerve stimulation in spontaneously hypertensive rats.

The hindlimb and renal vasodilator responses produced by electrical stimulation of the glossopharyngeal nerve were examined in adult (six to eight months) male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) normotensive rats to ascertain whether central neurogenically activated vasodilator capacity of these regional vascular beds is altered in SHR. Changes in systemic blood pressure and regional blood flow were simultaneously measured, and vascular resistance was calculated. Glossopharyngeal nerve stimulation (3.0 volts, 0.3 ms) at the frequency of 10 Hz resulted in a significantly greater vasodilation (% decrease in resistance) in SHR than in WKY control for both the hindlimb (SHR - 13.0 +/- 1.5% versus WKY - 3.4 +/- 1.6%, P less than 0.01) and renal (SHR - 7.6 +/- 0.6% versus WKY - 1.3 +/- 0.4%, P less than 0.01) vascular beds. The linear portion of the frequency-response curves of hindlimb or renal vasodilation of SHR was shifted parallel to the left of the WKY curve. Stimulus frequencies required to produce a 20% reduction in hindlimb resistance and a 10% reduction in renal resistance were lower in SHR (hindlimb 17.0 +/- 1.8 Hz; renal 19.9 +/- 1.4 Hz) than in WKY control (hindlimb 24.6 +/- 1.1 Hz; renal 39.3 +/- 4.8 Hz; P less than 0.01). The maximal vasodilator response to glossopharyngeal nerve stimulation in the hindlimb vascular bed was similar in SHR and WKY control, but in the renal vascular bed SHR showed a greater maximal response compared to WKY normotensives (SHR - 16.3 +/- 0.9% versus WKY - 12.7 +/- 1.6%, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Reflex cardiovascular responses induced by electrical stimulation of glossopharyngeal nerves in the rat

Reflex cardiovascular responses to electrical stimulation of glossopharyngeal nerves (GPN) were studied in Dial-Urethane anesthetized rats. GPN stimulation at 3 V, 0.3 msec and 50 Hz produced maximal reflex depressor (34 +/- 2 mmHg) and bradycardia (21 +/- 2 beats/min) responses that were altered as follows: pentolinium (0.25 mg/kg, i.a.) blocked approximately 72% and 89% of control values of depressor and bradycardia responses, respectively; tripelennamine (5 mg/kg, i.a.) significantly reduced depressor responses (76%); whereas atropine (0.4 mg/kg i.a.) blocked only bradycardia (85%). Regional blood flow studies showed that GPN stimulation reduced systemic arterial pressure (approximately 25%), and increased iliac artery blood flow (5%), and decreased blood flow through the renal (14%) and superior mesenteric (13%) arteries. Hence, decreases in vascular resistance during GPN stimulation were greater in the hindlimb vascular bed (28%) than in the renal (14%) or the mesenteric vasculatures. In addition, the magnitude of decreases in hindlimb vascular resistance by GPN stimulation was reduced (80%) by pretreatment with tripelennamine, but not by atropine. The results suggest that reductions in arterial blood pressure and hindlimb vascular resistance of the rat in response to GPN stimulation may be mediated via a histaminergic vasodilator mechanism, and that there may be a differential pattern of reflex vascular adjustments of blood flow and vascular resistance among regional vasculatures of the rate.

Lack of an aging effect on responses to disopyramide in rabbit ventricle. A brief note

The hearts of older animals, including man, undergo physiological changes and exhibit an increased sensitivity to antiarrhythmic drugs which may be due in part to an increased sensitivity of the heart to the drug. Isolated perfused hearts from young (2-4 months) and old (43-63 months) rabbits were driven at 3 Hz and the electrical strength-interval relationship was determined by interposing a test stimulus at known intervals after every tenth driving stimulus. This revealed the diastolic threshold for stimulation and the effective refractory period. Disopyramide at therapeutic concentrations increased the effective refractory period in both young and old hearts to the same extent without significantly altering the diastolic threshold. Thus, the increased sensitivity of older animals to type I antiarrhythmic drugs is probably due to some factor other than increased cardiac electrophysiologic effects.

Unaltered Maximum Reflex Vasodilatory Capacity of the Perfused Hindquarters of Spontaneously Hypertensive Rats

Hindquarter reflex vasodilation (RVD delta mmHg decrease in perfusion pressure) in response to arterial pressure elevations by intravenous norepinephrine (NE) was examined in young (2 1/2-3 months) and mature (8-10 months) spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) normotensive rats to ascertain whether maximum reflex vasodilatory capacity is altered in the developmental and/or established stages of spontaneous hypertension. The maximal RVD was not significantly different in young or mature SHR (young 26.2 +/- 1.9 and mature 36.2 +/- 3.2) compared to age-matched WKY controls (young 23.9 +/- 1.8 and mature 29.6 +/- 2.3) (P greater than 0.05 between SHR vs. WKY at both ages). However, the rise in mean systemic arterial pressure by NE which produced maximal RVD was greater in mature SHR (116.0 +/- 7.4 mmHg) than in WKY controls (78.3 +/- 6.2 mmHg) (P less than 0.01), whereas no such differences were found between young SHR (85.1 +/- 6.5 mmHg) and its WKY controls (87.5 +/- 2.3 mmHg). There was no difference in the dose of NE that required maximal responses of reflex vasodilation in young or mature SHR compared to WKY controls. In each age group of SHR or WKY rats, RVD was linearly related to the arterial pressure increments. The slope (a +/- SEM) of the regression line for the correlation between the pressure rises and resultant RVD was similar in young SHR (a = 0.424 +/- 0.061) and WKY controls of (a = 0.458 +/- 0.013). In contrast, the slope of the regression line for these two parameters in mature SHR (a = 0.250 +/- 0.004) was significantly smaller than that of either WKY controls (a = 0.364 +/- 0.010) or young SHR (P less than 0.01). The direct hindquarter vasodilation of mature SHR in response to intra-arterial administration of histamine or nitroglycerin was not different compared to that of WKY controls. The results indicate an unaltered maximum hindquarter reflex vasodilatory capacity during the developmental and established stages of genetic hypertension in SHR. An additional finding in the present study was the abnormal responsiveness of the baroreceptor reflex vasodilator system of mature SHR to a wide range of arterial pressure elevations. This abnormal responsiveness may contribute to the maintenance of high blood pressure in the established stage of hypertension.