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We investigated pressor sensitivity to infused phenylephrine (PE), 0.05 to 0.4 micrograms/kg/min, and angiotensin II (Ang II), 2.5 to 10 ng/kg/min, in 35 patients with mild-to-moderate hypertension, before and at the end of a 4-week treatment period with the angiotensin-converting enzyme (ACE) inhibitor, cilazapril, 2.5 or 5.0 mg/day. Cilazapril lowered the mean systolic and diastolic blood pressure by 10.6/3.5 mm Hg, but had no effect on the dose-response curves of dose of PE or Ang II vs. the increase in systolic, diastolic, or mean blood pressure, or heart rate. There were also no significant effects of cilazapril on PD20 values, i.e., the dose of PE or Ang II required to increase mean arterial blood pressure (MAP) by 20 mm Hg, or on delta R-R/delta MAP (ratio of the increase of the ECG R-R interval to the increase in mean arterial blood pressure) as a measure of baroreflex sensitivity. Plasma renin activity was significantly increased by cilazapril therapy, but there were no changes in plasma concentrations of Ang II or atrial natriuretic factor. We conclude that cilazapril, an ACE inhibitor, does not alter alpha 1-adrenoceptor and Ang II receptor sensitivity to selective agonists, nor does it affect baroreflex sensitivity.

We investigated the hypothesis that at least part of the vasopressor activity of noradrenaline (NA) and angiotensin II (Ang II) in humans is due to the activation of receptor-dependent calcium channels. Thirty patients (15 aged 50-65 years and 15 aged 66-80 years) with diastolic blood pressure of 95-120 mm Hg were given placebo (P) for 4 weeks, and then nitrendipine (N) 20-40 mg/day for 12 weeks. After 4 weeks on placebo, and again after 12 weeks on nitrendipine, NA 40, 80, 160, and 320 ng/kg/min, followed by Ang II 2.5, 5, and 10 ng/kg/min, was infused intravenously, and steady state systolic, diastolic, and mean arterial blood pressure and heart rate were measured. Older patients were found to be significantly less sensitive than younger patients to the pressor effects of NA. N decreased NA sensitivity, more in younger than older patients. Older patients were significantly more sensitive than younger patients to the pressor effects of Ang II. N also decreased Ang II sensitivity, more in older than younger patients. We conclude that at least some of the vasopressor activity of NA and Ang II is due to activation of calcium channels, and that these effects are age dependent.

During the i.v. infusion of a depilatory dose (100 micrograms/kg bodyweight) of mouse epidermal growth factor (EGF) into ovariectomized Merino ewes the frequency of pulsatile LH release was significantly reduced. However, the amplitude of pulses of LH secretion, either those naturally occurring or those induced by LHRH injection, was unchanged or only slightly reduced. Similar infusions of mouse EGF were made in progestagen-treated anoestrous Merino ewes in which LH secretion was maintained by injections of LHRH. These ewes did not experience oestrus or ovulate in response to PMSG injected 1 day after mouse EGF treatment (2 days before progestagen withdrawal); both responses occurred in controls. The EGF-treated ewes experienced oestrus and ovulated following progestagen-PMSG treatment 6 weeks later. These results suggest that mouse EGF inhibits the hypothalamic pulse generator responsible for LH release in the ewe but has little if any effect on pituitary sensitivity to LHRH; and mouse EGF apparently has a direct effect on the ovaries, temporarily impairing their ability to ovulate in response to exogenous gonadotrophin.

Seasonal changes in pulsatile luteinizing hormone (LH) secretion in ovariectomized ewes were examined over the course of 2 yr in relation to annual changes in environmental photoperiod, shifts in response to estradiol negative feedback control of LH secretion, and timing of the breeding season. Under natural environmental conditions, the frequency of LH pulses in individual ovariectomized ewes changed gradually and in close association with the annual cycle of day length. As days became shorter in late summer and autumn, LH pulse frequency increased; conversely, as day length increased in late winter and spring, frequency declined. Under artificial conditions in which ovariectomized ewes were exposed to different photoperiods, a similar inverse relationship was observed between day length and LH pulse frequency. The seasonal changes in frequency of LH pulses in ovariectomized ewes, although symmetric with the annual photoperiodic cycle, were not temporally coupled to the dramatic shifts in response to estradiol feedback inhibition of LH secretion at the transitions between breeding season and anestrus. The feedback shifts occurred abruptly and at times when LH pulse frequency in ovariectomized ewes was at, or near, the annual maximum or minimum. The tight coupling between LH pulse frequency and photoperiod leads to the conclusion that there is a photoperiodic drive to the LH pulse-generating system of the ewe. The temporal dissociation between changes in this photoperiodic drive and the seasonal shifts in response to estradiol negative feedback support the hypothesis that the neuroendocrine basis for these two phenomena is not one and the same.

The effect of hypothalamic lesions on estradiol-induced changes in plasma luteinizing hormone (LH) concentration was studied in ovariectomized ewes. The ewes had stainless steel electrodes chronically implanted in the hypothalamus (HYP), and electrolytic lesions were made within 1 h after the injection of 50 microgram estradial benzoate (EB) i.m. Blood samples were collected at 2--6 h intervals for 30 h after EB, and the plasma was subsequently assayed for LH. None of the lesions produced had any effect on the normal immediate (within 12 h after injection) inhibitory effect of estrogen on LH release. However basal hyothalamic lesions, ranging from the suprachiamatic region back over the optic chiasma down to include the anterior tuberal region, effectively inhibited the normal stimulatory effect of estrogen (12--30 h after injection) on LH release. The results are consistent with the interpretation that, in the normal biphasic LH response to injected estrogen in the ewe, the early inhibition of LH release results from direct inhibition of pituitary sensitivity to endogenous LH-releasing factor (LRF). On the other hand the estrogen-induced LH release which occurs subsequent to this inhibitory phase is principally the result of increased LRF secretion by the HYP.

In estrous estrogen-primed female rabbits with electrodes chronically implanted in various subcortical regions of the brain, the intraventricular injection of an ovulation-inducing dose of norepinephrine (NE) stimulated a prolonged episode of high amplitude 40-60 cps electroencephalographic (EEG) activity in the olfactory bulb (OB) and its projections. This activity, which started usually between 30 and 60 min after NE injection and was maintained continously for periods up to an hour thereafter, was regularly absent in the same rabbits when they were pseudopregnant and non-ovulatory to NE. Similar OB-EEG activity and ovulation had been observed earlier in response to intraventricular histamine under light pentobarbital anesthesia. The ovulatory response to histamine was eliminated by massive midbrain lesions or removal of the olfactory bulb, but intraventricular NE still induced ovulation after such losses. The ovulatory effectiveness of NE was blocked, however, by low doses of pentobarbital or high doses of atropine, neither of which inhibited the ovulatory response to intraventricular epinephrine. Atropine and alpha-adrenergic blocking agents also prevented the ovulatory response to intraventricular histamine. It is suggested that histamine activates pituitary-ovarian function by stimulating central noradrenergic elements and that NE has more of the physiological-pharmacological characteristics of a natural central nervous activator of luteinizing hormone-releasing hormone than has epinephrine.

The administration of the metabolic inhibitor, 2-deoxy-D-glucose (2DG), to four well fed heifers just before and during the time of expected oestrus, and to another heifer following the removal of the corpus luteum, prevented both the occurrence of oestrus and the formation of corpora lutea in all animals. Plasma progesterone concentrations remained low for at least 10-21 days after the last dose of 2DG. The results suggest that the inhibition of glycolysis is associated with the failure of both oestrus and formation of functional corpora lutea, and they support the hypothesis that hypoglycaemia is the primary biochemical change responsible for infertility induced by acute energy deficiency in lactating cattle.

We compared exercise responses in two groups of hypertensive patients treated with an angiotensin converting enzyme (ACE) inhibitor (lisinopril, 20-80 mg/day, n = 17) or a cardioselective beta-blocker (atenolol, 50-200 mg/day, n = 9). Measurements were made at rest and during exercise at 25 W (2.7 mets) and at 50 W (3.8 mets) on a bicycle ergometer (where mets is exercising oxygen consumption/resting oxygen consumption) after 4 weeks of placebo, and again after 12 weeks of drug administration. Both drugs reduced (P less than 0.05) mean arterial pressure. Atenolol caused significant decreases in the heart rate (approximately 25%) and cardiac output (approximately 26%; Defares CO2 rebreathing), and significant increases in total peripheral resistance (approximately 30%) and arteriovenous O2 content (approximately 20%). Lisinopril decreased (P less than 0.05) stroke volume. At the same exercise intensity systolic blood pressure, arteriovenous O2 and total peripheral resistance were lower (P less than 0.05) and the heart rate was higher (P less than 0.05) after lisinopril than after atenolol. After the treatment of hypertension with the ACE inhibitor the responses to exercise were less restrictive than those after treatment with the cardioselective beta-blocker.

The 24 h i.v. infusion of Merino ewes with 60 or 100 microgram mouse epidermal growth factor (EGF)/kg body weight on Days 4, 9 or 14 of the oestrous cycle decreased the strength of wool attachment and caused marked changes in subsequent reproductive performance. In ovaries removed 2 days after EGF treatment all follicles greater than or equal to 0.6 mm diameter were atretic. After 7 days either a normal pattern of atresia or no atresia was evident while after 12 days the pattern of follicular atresia was similar to that in controls. Irrespective of stage of cycle EGF caused dose-dependent increases in plasma FSH concentrations that persisted for up to 14 days. Changes in plasma LH concentrations were generally similar after infusion on Days 4 and 14, but were smaller and shorter-lived after infusion on Day 9. Irrespective of dose, the infusion of EGF on Days 4 and 14 caused immediate luteolysis then the formation of a luteinized follicle in many ewes. Most ewes treated on Day 4 returned to oestrus between Days 17 and 21 with the same ovulation rate (1.3) as the controls. Of those infused on Day 14 oestrus occurred about a cycle length later than expected and their ovulation rate then (1.9) was also similar to that of the controls (1.7). Luteal function was not affected in ewes infused on Day 9, and most returned to oestrus between Days 17 and 20 with an ovulation rate of 3.2. Fertile rams were not placed with the ewes until after the differences in ovulation rate had been observed. Mating occurred generally 2-4 weeks after treatment, and there were no differences between EGF-treated and control ewes in fertility or fecundity. The results are interpreted as indicating that mouse EGF induces ovarian follicular atresia but has differential effects on luteal function according to the stage of the oestrous cycle at which it is given. As a consequence of these two effects, which lead to differential changes in gonadotrophin secretion, ovarian function may be temporarily impaired, little affected or improved.

Two groups, each of 7 crossbred beef cows, which were suckling or not suckling calves, were fed a high quality food ad libitum for 3 months post partum. The non-suckling cows experienced regular ovarian cycles from 10--33 days post partum while the suckling cows did not do so until at least 14 weeks post partum. There was little difference between the groups in growth rate or in plasma glucose concentration. The plasma prolactin concentrations in the non-suckling cows showed a seasonal trend which paralleled ambient temperature and daylight hours; in the suckling cows this trend was less evident. Plasma LH concentrations were lower in suckling cows before Day 30 post partum but were similar thereafter. Most suckling cows also failed to experience oestrus or to exhibit LH release in response to an injection of oestradiol benzoate at about 6 weeks post partum. This failure, together with the earlier lower levels of LH in the suckling cows, is considered to be indicative of malfunction of the hypothalamic mechanism normally responsible for the establishment and maintenance of cyclic ovarian function.