The effect of midazolam on left ventricular pump performance and contractility in anesthetized patients with coronary artery disease: effect of preoperative ejection fraction.

Forty patients undergoing coronary artery bypass grafting were studied, of whom 24 had depressed global left ventricular (LV) function at preoperative catheterization, to evaluate the effects of midazolam on LV pump performance and contractility. Transesophageal echocardiography and simultaneous hemodynamic measurements were used to assess LV preload, afterload, and systolic performance during inhalation of 100% O2 and after 0.1 mg/kg of midazolam. Systolic function indices were expressed as a percent of the predicted value for observed end-systolic stress to estimate LV contractility. In the entire study population, midazolam did not affect cardiac index. Heart rate and mean arterial pressure were reduced (63 +/- 13 to 59 +/- 12 bm; P < 0.0006 and 89 +/- 15 to 76 +/- 16 mm Hg; P < 0.0001) as were pulmonary capillary wedge pressure, central venous pressure, and systemic and pulmonary vascular resistance. Afterload, as measured by end-systolic stress, was reduced (55 +/- 33 to 48 +/- 26 kdyne/cm2; P = 0.007) with no change in fractional shortening or percent area change. As a result, systolic function decreased in relation to observed end-systolic stress, providing evidence of reduced LV contractility. Thus, midazolam administration (0.1 mg/kg) caused no change in cardiac pump performance but decreased LV contractility in the entire population. Myocardial contractility was lower at baseline and after the administration of midazolam in the depressed ejection fraction group, but the decrease in contractility was not exaggerated in the depressed ejection fraction group.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of nitrous oxide on left ventricular pump performance and contractility in patients with coronary artery disease: effect of preoperative ejection fraction.

To elucidate the effects of nitrous oxide (N2O) on left ventricular (LV) pump performance and contractility, 28 patients undergoing coronary artery bypass graft surgery were studied, of whom 15 had depressed global LV function at preoperative catheterization. Transesophageal echocardiography and simultaneous hemodynamic measurements were used to assess LV preload, afterload, and systolic performance during inhalation of 100% oxygen (O2) and 60% N2O:40% O2. Systolic function indices were expressed as a percent of the predicted value for observed end-systolic stress to provide estimates of LV contractility. In the entire study population, N2O reduced pump performance (cardiac index 2.4 +/- 0.8 to 2.2 +/- 0.6 L.min-1 x m-2; P < 0.02). Heart rate and mean arterial pressure were reduced (67 +/- 13 to 64 +/- 13, P < 0.01, and 87 +/- 9 to 80 +/- 15, P < 0.005) as were left and right ventricular stroke work index. Preload, as measured by end-diastolic stress, was unchanged but afterload, as measured by end-systolic stress, tended to decrease (88 +/- 31 to 78 +/- 28, P = 0.053). In the 13 patients with normal preoperative LV function, mean arterial pressure and LV stroke work index decreased significantly (91 +/- 8 to 84 +/- 14, P < 0.04, and 40 +/- 13 to 34 +/- 10, P < 0.04, respectively) and end-systolic stress tended to decrease (P = 0.054).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic control of endocrine thermogenesis.

Hypothalamic and ruminal cooling raised serum thyrotropin (TSH), adrenocorticotropin (ACTH), norepinephrine (NE), and glucose in conscious goats in 20 degree C ambient temperature. Cooling of the preoptic anterior hypothalamus (POAH) for 2 h initially evoked shivering and vasoconstriction, leading to 1.5 degree C rise in rectal temperature (Tr). Pituitary-thyroid activation by POAH cooling was shown by peak rises in TSH of 60% at 40 min, in triiodothyronine (T3) of 54% at 80 min, and in thyroxine (T4) of 40% at 140 min. At 60 min, ACTH and NE peaked at 57 and 65%, respectively. TSH, ACTH, and NE declined during the 2nd h of POAH cooling as Tr plateaued; when POAH cooling was stopped, these hormones fell below basal level as vasodilation and panting restored Tr to normal. In contrast to the core hyperthermia evoked by POAH cooling, ruminal intubation with O degree C water (1 liter/10 kg) led to general hypothermia, Tpoah and Tr falling 1.6 degree C at 40 min. Pituitary-thyroid responses were less but ACTH and NE more, compared with POAH cooling. TSH peaked at 37% at 20 min, T3 at 55% at 60 min, and T4 at 18% at 200 min. ACTH peaked at 250% at 30 min and NE at 120% at 20 min. Thermosensitive neurons in the POAH seem to mediate more sensitive and complete control over TSH than over ACTH, or NE release, whereas extrahypothalamic core thermosensitivity (e.g., brain stem, spinal cord, abdomen) may influence ACTH and NE more than TSH release.

Rebound hypertension after sodium nitroprusside-induced hypotension.

Patients undergoing surgical procedures using sodium nitroprusside-induced hypotension were studied to determine the role of the renin-angiotensin system in the pathogenesis of rebound hypertension (RH) after discontinuing sodium nitroprusside (SNP) infusion. Retrospective observations documented RH in 9 of 12 patients (group I) with a systolic blood pressure (SBP) increase from 112 +/- 3.92 before SNP to 144 +/- 5.60 torr 10 min after SNP (p less than 0.001). In 12 patients (group II), plasma renin activity (PRA) rose from 950 +/- 432 to 3,611 +/- 1.874 pg/ml/hr (p less than 0.0005) during SNP and remained elevated (2,504 +/- 792 pg/ml/hr) 30 min after cessation of SNP. SBP rose from a control (pre-SNP) value of 112 +/- 5.24 to 129 +/- 8.52 torr after discontinuation of SNP (p less than 0.05). Significant PRA and SBP changes did not occur in a matched group of patients (group III) who did not receive SNP. That RH after cessation of SNP infusion was associated with persistent elevation of PRA leads us to suggest that RH may be attributable to the unopposed effects of the renin-angiotensin system after the rapid plasma disappearance of SNP.

Noradrenergic and dopaminergic regulation of GH and prolactin in baboons.

Aminergic regulation of growth hormone (GH) and prolactin (Prl) was studied in male adolescent baboons by i.v. infusion of dopamine (DA), norepinephrine (NE), thyrotropin-releasing hormone (TRH), phentolamine, haloperidol, and inhibitors of DA-beta-hydroxylase and peripheral decarboxylase. 20-min infusion of DA (40 microgram/kg.min) and 60-min infusion of NE (0.4 microgram/kg.min) stimulated GH release. The DA-induced GH release was suppressed by concomitant infusion of FLA 63 (inhibitor of NE synthesis from DA) and by phentolamine, indicating alpha-adrenergic mediation of GH release. Microinfection of DA (0.8 microgram/kg) into the medial basal hypothalamus (MBH) lowered basal GH. Prl was released by i.v. TRH, and this effect was suppressed by i.v. DA but not by i.v. NE. Blockade of peripheral decarboxylase by carbidopa elicited a marked and sustained rise in Prl which was inhibited by i.v. DA. Microinjection of NE (0.8 microgram/kg) into the MBH released Prl. These data indicate that in the MBH, alpha-adrenergic mechanisms release GH and Prl, and that dopaminergic mechanisms suppres GH.

Inhibition of dopamine-induced release of growth hormone by thyrotropin-releasing hormone.

The effects of thyrotropin-releasing hormone (TRH) and dopamine (DA) on serum growth hormone (GH) levels were examined in the adolescent male baboon. Intravenously administered DA (40 microgram/kg-min-1 for 20 min) raised serum GH and glucose and lowered serum insulin concentrations but caused no increase in blood pressure. Concomitant intravenous infusion of TRH at 2 doses (96 ng/kg-min-1 and 40 microgram/kg-min-1 for 20 min) blocked the DA-induced increase in serum GH. The relatively low effective doses of TRH used to suppress the DA-induced GH increase suggest an interaction with catecholamines at the hypothalamic and/or pituitary to influence GH release.

Localization of hypophysiotropic neurohormones by assay of sections from various brain areas.

The results of studies of the localization of the hypothalamic hypophysiotropic factors based on their direct determination in sections or nuclear punches are described. Luteinizing hormone-releasing hormone was found in high concentrations in the median eminence-arcuate nucleus complex, in lower concentrations in the mediobasal zone of the preoptic area. In addition to these hypothalamic sites, it is present in all four periventricular organs, especially in the organum vasculosum laminae terminalis. Thyrotropin releasing hormone has a widespread distribution. High concentrations are in the median eminence, arcuate nucleus, dorsomedial nucleus, and anterior part of the ventromedial nucleus. Lower concentrations are in several other structures of the hypothalamus, preoptic area and septum, and low but measurable quantities are found in most of the structures of the brain. Somatostatin is also present in most structures of the central nervous system, with highest concentrations in the median eminence, arcuate nucleus, ventromedial nucleus and periventricular nucleus. There are indications that the ventromedial nucleus or its immediate vicinity contains growth hormone releasing factor. Prolactin releasing activity was present in the median eminence and mediobasal parts of the anterior hypothalamus, whereas prolactin inhibitory activity was in the dorsolateral parts of the anterior hypothalamus and/or preoptic area.

Sex hormones correlated with sex skin swelling and rectal temperature during the menstrual cycle of the pigtail macaque (Macaca nemestrina).

Daily measurement of serum luteinizing hormone, estradiol-17beta, and progesterone were made during the menstrual cycle in nine pigtail macaques (Macaca nemestrina). All data were normalized to the day of the luteinizing hormone peak. Serum estradiol-17beta increased from approximately 100 pg/ml during the early follicular phase to 442 +/- 156 pg/ml during the maximum midcycle concomitant with the luteinizing hormone peak, and a small increase in serum estradiol-17beta was observed during the luteal phase coincident with the progesterone peak. Serum progesterone values increased slightly at the time of the luteinizing hormone peak and increased from 0.2-0.3 ng/ml during the midfollicular phase to peak levels of 8.3 +/- 1.75 ng/ml 9 days after the luteinizing hormone surge. Serum luteinizing hormone remained low and relatively constant throughout the early and midcycle, then sharply increased approximately four-fold to peak values of 6.25 +/- 0.9 ng/ml. Sex skin swelling increased slowly during the follicular phase and declined slowly throughout the early luteal phase. Rectal temperature did not change significantly throughout the menstrual cycle. The similarity of plasma sex hormone changes during the menstrual cycle between women and the pigtail macaque suggested that this nonhuman primate should be a useful animal model for studying human reproduction.

Effect of acute exposure to cold on the activity of the hypothalamic-pituitary-thyroid system.

The effects of a sudden but sustained exposure to cold (1 to 6C) on serum TSH, thyroxine (T4) and triiodothyronine (T3) (all measured by radioimmunoassay), pituitary TSH concentration, pituitary TSH secretory responsiveness to hypothalamic extract or synthetic thyrotropin-releasing hormone (TRH) in vitro as well as in vivo, and the changes of the thyrotropin-releasing activity in three TRF-rich hypothalamic areas were determined. In normal animals, serum TSH underwent a series of oscillations, first rising then returning to the basal levels, then rising again, whereas serum T4 and T3 increased within 2 h of cold exposure and remained elevated. Pituitary TSH concentration and the in vitro pituitary responsiveness declined after an initial elevation, whereas the in vivo responsiveness to TRH was diminished throughout the whole exposure to cold. Thyroid-blocked animals with steady, low levels of serum T4 and T3 showed a step by step increase of serum TSH levels and no changes in the other parameters. It is therefore assumed that the decrease of TSH secretion following the initial rise is due to a feedback inhibition by the increased levels of thyroid hormones as is the decreased pituitary responsiveness of TRH in vivo. The pituitary responsiveness in vitro seems to be determined by TSH pituitary concentrations, the changes of which are probably also secondary to the changes of the thyroid hormone levels. The mechanism of the second rise of serum TSH levels is not clear. Thyrotropin-releasing factor (TRF) activity was higher after 2 and 24 h of cold exposure in the median eminence and after 8 h in the anterior hypothalamus-preoptic area, but lower after 8 and 24 h in the dorsomedial hypothalamus. Since the changes of TRF activity in the median eminence coincided with the elevated serum TSH, they are assumed to reflect increased TRF production and secretion. The significance of the TRF changes in the other two areas is not clear.

The effect of various prostaglandins and a prostaglandin synthetase inhibitor on rat anterior pituitary cyclic AMP levels and hormone release in vitro (38475).

(U)Prostaglandins E-1, E2,F-1alpha or F-2 alpha significantly increased the release of GH, with a parallel increase in intracellular cAMP concentrations, while they only protentiated HE-stimulated TSH release. (2) None of the prostaglandins examined consistently effected either the basal or HE-altered release of LH,FSH or prolactin. (3) The prostaglandin synthetase inhibitor, indomethacin, inhibited GH and TSH release and, at high doses of the drug, inhibited prolactin release. In contrast, the drug appeared to potentiate both He and sLRF-stimulated gonadotropin release. It had no significant effect on intracellular cAMP concentration.