Niels Korsgaard

Effect of acute and long-term treatment with 17-β-estradiol on the vasomotor responses in the rat aorta

This study sought to evaluate whether the effects of acute and long‐term treatment with 17‐β‐estradiol on the vasomotor responses in rat aortic rings are mediated through the same mechanism. Ovariectomized rats were treated daily with either 17‐β‐estradiol‐3‐benzoate (100 μg kg−1) or vehicle for 1 week. The effect of long‐term 17‐β‐estradiol treatment on the responses to cumulative doses of phenylephrine, 5‐HT, calcium, potassium and 17‐β‐estradiol was determined in aortic rings. In the same rings, the effect of acute exposure to 17‐β‐estradiol (5 and 10 μM) on the dose response curves for phenylephrine, 5‐HT, calcium, potassium and acetylcholine were estimated. The measurements were made in rings with and without intact endothelium. The tone‐related basal release of nitric oxide (NO) was measured in rings with intact endothelium. Long‐term 17‐β‐estradiol treatment reduced the maximum developed contraction to all contracting agents studied. This effect was abolished in endothelium denuded vessels. Acute 17‐β‐estradiol treatment also reduced maximal contraction. This effect, however, was independent of the endothelium. Long‐term 17‐β‐estradiol treatment significantly increased the ability of the rings to dilate in response to acetylcholine whereas acute exposure to 17‐β‐estradiol had no effect. The tone‐related release of NO was significantly increased after long‐term exposure to 17‐β‐estradiol. In conclusion, this study indicate that the acute and long‐term effects of 17‐β‐estradiol in the rat aorta are mediated through different mechanisms. The long‐term effect is mediated through the endothelium most likely by increasing NO release. In contrast, the acute effect of 17‐β‐estradiol seems to be through an effect on the vascular smooth muscle cells.

Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits.

The purpose of this study was to investigate whether endothelium-derived nitric oxide (NO) is involved in the plasma lipid-independent antiatherogenic effect of estrogen and levormeloxifene, a partial estrogen receptor agonist. 85 rabbits were ovariectomized and balloon-injured in the middle thoracic aorta. The rabbits were fed a cholesterol-enriched diet supplemented with 17beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 microg/ml NG-nitro- -arginine methyl ester (-NAME), an NO synthase inhibitor, in their drinking water for 12 wk. Plasma cholesterol was maintained at 25-30 mmol/liter by individualized cholesterol feeding. In the undamaged aorta, the extent of atherosclerosis in the estrogen group was only one-third that in the placebo group. Simultaneous administration of -NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given -NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas -NAME combined with estrogen significantly increased atherogenesis (P < 0.05). The effects of levormeloxifene were almost similar to those of estrogen. Active vascular concentrations of -NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given -NAME. Thus, in this study a considerable part of the plasma lipid-independent antiatherogenic effect of estrogen was mediated through its effect on endothelial NO in cholesterol-fed rabbits. The results for levormeloxifene suggest a common mechanism of action for estrogen and partial estrogen receptor agonists on atherogenesis.

A Partial Estrogen Receptor Agonist With Strong Antiatherogenic Properties Without Noticeable Effect on Reproductive Tissue in Cholesterol-Fed Female and Male Rabbits

Estrogen replacement therapy retards the development of cardiovascular disease and osteoporosis in postmenopausal women. However, long-term unopposed use increases the risk of cancer in endometrium and possibly in breast. The racemic compound ormeloxifene, widely used in India as an antifertility agent, is a partial estrogen receptor agonist with antiosteoporotic properties. The present study was undertaken to investigate the effect of the L-enantiomer (levormeloxifene) and the d-enantiomer (d-ormeloxifene) on the development of atherosclerosis. In a short-term experiment (6 weeks), 4 x 10 ovariectomized female rabbits were fed a 0.25% cholesterol-enriched diet and the effect on plasma cholesterol levels was studied. In a long-term experiment (13 weeks), 4 x 15 ovariectomized female and 4 x 15 shamoperated male rabbits were maintained at a similar plasma cholesterol level of 25 mmol/L and the effect on undamaged and balloon-injured arterial wall was studied. In both experiments, the rabbits were treated with levormeloxifene, d-ormeloxifene, 17 beta-estradiol, or placebo, respectively. In the short-term experiment, levormeloxifene, in contrast to d-ormeloxifene, significantly reduced plasma cholesterol by 30% compared with the placebo group. In the long-term experiment, levormeloxifene, in contrast to d-ormeloxifene, significantly reduced atherosclerosis by 50% in the undamaged arterial wall of both female and male rabbits. Because these rabbits were cholesterol-clamped, the antiatherogenic effect was not mediated via plasma cholesterol lowering. Like estrogen, levormeloxifene did not inhibit atherosclerosis in the endothelium-denuded site of aorta. The antiatherogenic effects of levormeloxifene were thus similar to those of estrogen, but produced in the absence of any noticeable estrogenic effect on uterine or testicular tissue.

Synthesis and pharmacological evaluation of novel cis-3,4-diaryl-hydroxychromanes as high affinity partial agonists for the estrogen receptor.

The syntheses and in vitro pharmacological evaluation of a number of cis-3,4-diaryl-hydroxy-chromanes are reported, along with the results of a thorough in vivo profiling of the tissue-selective estrogen partial-agonist NNC 45-0781 [3, (-)-(3S,4R)-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane]. These studies showed that NNC 45-0781 is a very promising candidate for the prevention of post-menopausal osteoporosis, and the treatment of other health issues related to the loss of endogenous estrogen production.

The preferential dopamine D3 receptor agonist cis-8-OH-PBZI induces limbic Fos expression in rat brain

The affinity, selectivity and agonistic properties of a constrained dopaminergic compound, the benz[e]indole cis-8-hydroxy-3-(n-propyl)1,2,3a.4,5,9b-hexahydro-1H-benz[e]indole (cis-8-OH-PBZI), for the dopamine D3 receptor were evaluated in competition binding experiments with cloned human dopamine receptor subtypes and, to further extend its profile, in in vitro radioligand binding assays. The Ki value measured for competition binding of this compound to the dopamine D3 receptor was 27.4+/-3.1 nM; this was 775-fold, 550-fold, 90-fold and 10-fold higher affinity than that measured at dopamine D1A, D5, D2s and D4 receptors, respectively. Evidence of dopamine receptor activation by cis-8-OH-PBZI was obtained by measuring dose-dependent increases in extracellular acidification rates and decreases in cAMP synthesis. In vivo, cis-8-OH-PBZI potently induced Fos protein immunoreactivity in the rat medial prefrontal cortex and shell region of the nucleus accumbens, but only marginally in the motor dorsolateral striatum, indicating a selective limbic site of action. In conclusion, the present data identify cis-8-OH-PBZI as having preference for the dopamine D3 receptor in vitro, and as having dopamine agonist activity and limbic sites of action in vivo.

Benign Prostatic Hypertrophy

IN BRIEF: Benign prostatic hypertrophy is one of the common complaints of older men who visit their primary care physicians. Nonoperative therapy, such as drug therapy or lifestyle modification, is aimed primarily at reducing bothersome lower urinary tract symptoms and preventing serious morbidity such as urinary retention and renal function impairment. As more men reach advanced age, it becomes crucial for the primary care physician to be aware of the epidemiology, pathophysiology, natural history, clinical presentation, and therapeutic modalities available for the treatment of clinically significant cases.