An elective-titration study of the comparative effectiveness of two angiotensin II-receptor blockers, irbesartan and losartan. Irbesartan/Losartan Study Investigators.

This multicenter, randomized, double-masked, elective-titration study was designed to compare the effectiveness, safety, and tolerability of irbesartan and losartan, two angiotensin II subtype AT1-receptor blockers, in the treatment of patients with mild-to-moderate hypertension. After a 3-week, single-masked, placebo lead-in period, 432 patients with a mean seated diastolic blood pressure (SeDBP) of 95 to 115 mm Hg were randomly allocated to receive either irbesartan 150 mg once daily (n = 213) or losartan 50 mg once daily (n = 219). At week 4, if SeDBP at trough (i.e., 24 +/- 3 hours after the previous dose) was > or = 90 mm Hg, the daily dose was doubled (to irbesartan 300 mg or losartan 100 mg). At week 8, if trough SeDBP was > or = 90 mm Hg, hydrochlorothiazide 12.5 mg once daily was added to the regimen; consistent with the prescribing information for losartan, the dose of losartan was reduced to 50 mg once daily on the addition of hydrochlorothiazide. A total of 370 patients (178 irbesartan and 192 losartan) were evaluable for efficacy. The mean change in trough SeDBP at week 8, the primary efficacy end point, was significantly greater in patients receiving irbesartan monotherapy than in those receiving losartan monotherapy (-10.2 mm Hg vs -7.9 mm Hg, respectively). At week 12, reductions in trough SeDBP and seated systolic blood pressure were greater with irbesartan treatment than with losartan treatment (-13.8 mm Hg vs -10.8 mm Hg and -18.0 mm Hg vs -13.9 mm Hg, respectively), and a greater proportion of irbesartan patients responded to therapy (i.e., trough SeDBP < 90 mm Hg or reduction in trough SeDBP > or = 10 mm Hg) compared with losartan patients (78% vs 64%, respectively). Both regimens were well tolerated.

Sex and sodium intake in the rat.

Female rats drink more 3% NaCl solution than do males, both when they need sodium (need-induced sodium intake or sodium appetite) and when they do not (need-free sodium intake). The sexual dimorphism of sodium intake is a secondary sexual characteristic because after castration at 1 day of age male rats drank 3% NaCl in adulthood in a manner similar to that of females in both the need-free and need-induced state, and females given long-term, neonatal testosterone drank low, malelike volumes of 3% NaCl on a daily need-free basis, but their response to sodium depletion was unchanged. This sexual dimorphism of sodium intake seems to be governed by testosterone that has been converted in the brain to estrogen because treatment of Day 1 castrated females with a nonaromatizable androgen, dihydrotestosterone, did not change either their need-free or their need-induced 3% NaCl intake. Castration in adulthood of male and female rats did not change their sodium consumption. However, when castrated adults received testosterone, need-free intakes of NaCl were suppressed in both sexes, but the suppression of 3% NaCl intake occurred only while the steroid was present. Exogenous testosterone also lowered the need-induced sodium intake of adult castrated females. Thus, in castrated adults, need-free intake was actively suppressed by exogenous testosterone in both sexes, whereas need-induced intake of NaCl was suppressed only in females. These data indicate that sodium intake in the rat is a sexually dimorphic behavior that is organized neonatally and can be actively suppressed in adulthood by testosterone.

Evidence for "memory" of cervical stimulation for the promotion of pregnancy in rats.

Successful pregnancy in the female rat depends upon two sets of physiological events: (1) transport of gametes (sperm and egg) through the reproductive tract so that fertilization can be effected and (2) establishment of an appropriate hormonal environment (progestational state) so that the fertilized egg can implant in the uterus and be maintained during subsequent gestation. This study highlights the independence of the mechanisms controlling the gametic and hormonal aspects of pregnancy by temporally separating the introduction of sperm into the female from the stimulation that triggers the progestational hormonal response. The progestational state was initiated by electrical stimulation of the cervix, and sperm was introduced directly into the uterus by artificial insemination. Although these two events were separated by up to 3 days, pregnancy could ensue. Cervical stimulation, normally a consequence of male intromission behavior, establishes a condition in the central nervous system, a "memory" that signals the probable induction of pregnancy. Without this "memory," animals with a short estrous cycle would continue to cycle after mating, thereby producing a hormonal environment incompatible with implantation. The "memory" is manifested by daily surges of prolactin irrespective of fertilization. This is the first physiological demonstration that a "memory" of cervical stimulation can be called upon to support a viable pregnancy.

A prenatal source for defeminization of female rats is the maternal ovary.

Sexual behavior in laboratory rats is influenced by a variety of factors in the perinatal environment. Male rats are masculinized and defeminized in response to circulating testosterone perinatally. Females undergo a process of feminization but in some cases are exposed to testosterone. Previous work has shown that during prenatal development female rats normally undergo a partial masculinization and defeminization of sexual behavior as reflected by altered responsiveness to gonadal hormones in adulthood. In the present study we investigated whether the maternal ovary influences adult females' responsiveness to gonadal hormones. Pregnant rats were ovariectomized on Day 10 of pregnancy and their offspring tested for sexual behavior in adulthood. Following ovariectomy pregnancies were maintained by administration of systemic progesterone. In addition the ovariectomized pregnant rats were given one of three daily treatments (Days 10-21): 0.2 microgram estradiol benzoate in sesame oil and 0.1 cc propylene glycol, 5 mg of the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) in 0.1 cc propylene glycol, or 0.1 cc propylene glycol. A control group was generated from SHAM operated mothers given daily control injections of propylene glycol and sesame oil. Offspring were ovariectomized in adulthood and tested for display of feminine sexual behavior in response to estradiol benzoate and progesterone or estradiol benzoate alone. Masculine sexual behavior was measured in response to testosterone propionate (TP). Feminine sexual behavior was enhanced in offspring from ovariectomized mothers given only progesterone replacement during pregnancy. Offspring from mothers treated with ATD displayed the greatest elevations in feminine sexual behavior. Estradiol treatments of ovariectomized mothers prevented the increase in feminine potential seen in offspring in the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal antiandrogen feminizes behavioral but not neurochemical response to estrogen.

In ovariectomized female rats, estrogen activates high levels of female sexual behavior and induces an increase in the number of cholinergic muscarinic binding sites in the medial basal hypothalamus, an area known to regulate this behavior. Male rats normally show low levels of female sexual behavior and no alteration in muscarinic binding in response to estrogen treatment. An experiment was conducted to determine if a prenatal treatment that feminizes the sexual behavior of male rats would also establish the potential for estrogen to increase muscarinic binding in the male hypothalamus. Results indicate that prenatal exposure to the antiandrogen, flutamide, enhanced estrogen-activated female sexual behavior in male rats but failed to reverse the inability of estrogen to increase muscarinic binding in the medial basal hypothalamus.

The proestrous surge of prolactin enhances sexual receptivity in the rat.

The influence of the proestrous surge of prolactin (Prl) on expression of feminine sexual behavior (lordosis) has been investigated. In the first experiment, proestrous rats were treated with a dopamine agonist, bromocriptine (CB-154; 100 micrograms at 1200, 1300, and 1600 h), which blocked the proestrous surge of Prl without affecting the preovulatory surge of luteinizing hormone. Such animals displayed depressed lordosis quotients (LQs) when compared to control animals at 2000 h on proestrus. However, in CB-154-treated animals given ovine Prl (10 I.U.) at 1400 h on proestrus, LQs were restored to control levels. Ovariectomized (OVX) rats primed with estradiol benzoate (EB; 2 micrograms for 2 days) produced surges of Prl that were similar in timing to those of proestrous. Once again, CB-154 treatment blocked this Prl surge and significantly depressed the LQ, whereas replacement with ovine Prl returned the LQ to control values. These results suggest that the Prl surge facilitates the expression of lordosis. Ovariectomized/adrenalectomized (ADX) and OVX/sham ADX rats were treated with EB (2 micrograms for 2 days) and tested for lordosis on Day 3. Adrenalectomized rats responded with lower levels of lordosis than did sham controls. Administration of progesterone (P4) to ADX rats on Day 3 enhanced the LQ compared to sham ADX values. CB-154 was ineffective in reversing the enhanced LQ, indicating that Prl may be acting through stimulation of adrenal progestins. These data taken together suggest that the proestrous surge of Prl contributes to the normal expression of feminine sexual behavior on proestrus.

Secretion of luteinizing hormone (LH) and pituitary receptors for LH-releasing hormone as modified by the proestrous surge of progesterone.

Pituitary glands of proestrous (PRO) rats display enhanced LH secretory response to LHRH when compared to pituitary glands of estrous (EST) rats. In addition proestrous pituitary glands display a self-potentiating (priming) response to LHRH, whereas estrous pituitary glands do not. This study addresses the role of the proestrous surge of progesterone in converting the proestrous-like LH secretory responses of the pituitary gland to those of estrus. Anterior pituitary glands were obtained from PRO and EST rats. In addition, Pro rats were treated with pentobarbital alone (PRO/PB) or with pentobarbital plus progesterone (PRO/PB-P4). Pentobarbital was given to prevent proestrous surges of LH and progesterone. Pentobarbital-treated animals were killed the day after treatment, estrus. Pituitary glands from each group were tested for LH secretory response in a superfusion chamber with exposure of two 15-min pulses of 10 nM LHRH separated by 90 min, or assayed for LHRH receptor content using iodinated D-Ala6-LHRH. Anterior pituitary glands from PRO rats secreted higher levels of LH than EST rats in response to an LHRH pulse. Only PRO anterior pituitary glands secreted priming responses to LHRH. Though anterior pituitary glands obtained from pentobarbital-treated rats showed LH responses of similar magnitude to anterior pituitary glands of PRO rats after initial LHRH challenge, they did not display priming responses. Progesterone replacement (PRO/PB-P4) led to depressed secretory responses when compared to PRO pituitary glands similar to EST rats. LHRH receptor concentrations in pituitary glands of EST rats was lower than those in pituitary glands of PRO rats. Depression of pituitary LHRH receptor concentration from proestrus to estrus was prevented by pentobarbital-treatment on proestrus. Estrus-like depression of receptor concentration was restored after progesterone treatment (PRO/PB-P4). These data suggest the LHRH receptor depression on estrus is a consequence of the secretion of progesterone on proestrus. Further, the declining magnitude of the in vitro LH-secretory response to LHRH follows a declining LHRH receptor concentration; however no correlation exists between receptor number and ability to prime.

Pharmacological and anatomical aspects of cholinergic activation of female sexual behavior.

Forebrain infusion of cholinergic agonists activated the sexual response, lordosis, in ovariectomized female rats that had been primed with a low dose of estrogen. Carbachol, an agonist with both muscarinic and nicotinic properties, and oxotremorine, an agonist with a primarily muscarinic action, produced dose-related increases in the frequency of lordosis elicited by stimulus male rats. This facilitation of lordosis was prevented when females were pretreated systemically with atropine or scopolamine, two muscarinic receptor antagonists. These results indicate that the effect of carbachol and oxotremorine on lordosis is mediated by cholinergic muscarinic receptors. The location of these receptors within the brain has not been identified. Ventricular infusion of carbachol was as effective as infusion directly into the medial preoptic area (POA) and more effective than infusion directly into the ventromedial hypothalamus (VMH). Furthermore, when carbachol or oxotremorine was delivered to the POA through cannulae angled to avoid traversing the lateral ventricles, no facilitation of lordosis was observed. These data suggest that muscarinic receptors stimulated by central infusion of cholinergic agonists may not be located in either the POA or the VMH, two regions traditionally implicated in the regulation of lordosis.

Alteration of muscarinic binding in specific brain areas following estrogen treatment.

Systemic administration of estradiol benzoate (EB) to ovariectomized female rats significantly altered cholinergic muscarinic binding of [3H]quinuclidinyl benzilate in discrete brain regions. Specifically, EB increased muscarinic binding in the medial basal hypothalamus (MBH) and decreased muscarinic binding in the medial preoptic area (POA). These alterations were dose-dependent and appeared to reflect changes in the number of muscarinic binding sites. Treatment with EB failed to significantly affect binding in several control areas in females or in the MBH and POA of males.

Cholinergic influences on estrogen-dependent sexual behavior in female rats.

The ability of cholinergic agents to influence hormone-dependent sexual behavior in female rats was examined. In the first experiment, female sexual behavior, indicated by the incidence of lordosis, was significantly increased in estrogen-treated female rats following bilateral infusion of a cholinergic receptor agonist, carbachol (.5 microgram/cannula), into the medial preoptic area of the brain. Infusion of an artificial cerebrospinal fluid vehicle failed to facilitate lordosis. The incidence of lordosis was normally highest 15 min after carbachol infusion, began to wane by 45 min, and had returned to control levels by 90 min. Further, centrally administered carbachol activated lordosis at lower levels of estrogen priming than did systemically administered progesterone. In a second experiment, female rats, brought into sexual receptivity by administration of estrogen and progesterone, received preoptic infusions of an acetylcholine synthesis inhibitor, hemicholinium-3. Significant reductions in the incidence of lordosis were observed following bilateral infusion of hemicholinium-3 (1.25 microgram/cannula). This inhibition of lordosis was prevented when carbachol (.5 microgram/cannula) was infused along with hemicholinium-3. Results confirm the importance of cholinergic influences on sexual behavior in female rats.