Samuel Finkielman

Hemodynamic Patterns in Essential Hypertension

Hemodynamic studies, including cardiac output, arterial blood pressure, run-off index, flow cessation pressure, and blood volume, were performed in 20 normotensive control subjects, 17 labile hypertensive patients and 20 patients with fixed hypertension, 10 of them with a mild elevation of the diastolic pressure and 10 classified as severe because of a diastolic blood pressure above 110 mm. Hg.In labile hypertension cardiac output was elevated, whereas blood volume, peripheral resistance, run-off index and flow cessation pressure were normal when blood pressure was high. This hemodynamic pattern was interpreted as due to an enhanced myocardial contractile energy or a restriction of the capacity vascular bed.In mild fixed hypertension total peripheral resistance and flow cessation pressure were uniformly increased, but cardiac output and run-off index were normal. This pattern may be explained by the influence of flow autoregulation and the barostatic mechanism.In severe fixed hypertension blood volume, cardiac output, and peripheral resistance were found to be high. Renal ischemia and secondary hyperaldosteronism may determine the development of this last stage of hypertension.

Low lymphocyte interferon-gamma production and variable proliferative response in anorexia nervosa patients

Interferon-gamma (IFN-γ) production by peripheral blood mononuclear cells (PBMC) in 14 patients with anorexia nervosa (AN) was significantly lower than in 14 age-matched healthy controls. Follow-up samples in four patients displayed low levels, except in two when they recovered the IFN-γ production as the hormonal cycles were restored. A large interindividual variation for the lymphocyte proliferative response was observed in 30 AN patients. DNA synthesis of PBMC was normal in 8 patients (27%), significantly increased in 6 (20%) (P<0.001), and significantly decreased in 16 (53%) (P<0.001). IFN-γ inhibition was reversed by culturing a control lymphocyte population with monocytes from patients with AN. This was not observed in cultures of control monocytes and AN lymphocytes. IL-2 receptor (TAC subunit) was assessed and no difference was found in the number of TAC-positive cells between patients and controls. These results point out impaired production of the immunomodulator cytokine IFN-γ as a major functional defect of AN peripheral lymphocytes.

Neurogenic hypertension after depletion of norepinephrine in anterior hypothalamus induced by 6-hydroxydopamine administration into the ventral pons: Role of serotonin

Destruction of the ventral noradrenergic pathway elicited by administration of 6-hydroxydopamine (6-OHDA, 5 micrograms into each side of the ventral pons) reduced the content of norepinephrine (NE) in the anterior hypothalamus (-80%) and induced an increase in arterial blood pressure (ABP) and in heart rate. These hypertensive rats, showed hypersensitivity to the hypotensive effect of NE (0.5-2 micrograms) and clonidine (0.75-1.5 micrograms) administered into the anterior hypothalamic preoptic (AH/PO) region. Methysergide (1-2 micrograms) and, to a lesser extent, ketanserin (1-2 micrograms) administered into the anterior hypothalamic preoptic region also reduced the arterial blood pressure in these rats treated with 6-OHDA. Bilateral administration of 5,7-dihydroxytryptamine (5,7-DHT, 8 micrograms) into the median forebrain bundle decreased the content of serotonin (5-HT) in the hypothalamus (-85%) without change in arterial blood pressure but largely prevented the development of hypertension after treatment with 6-OHDA in the ventral pons. These results suggest that neurogenic hypertension is produced after the removal of NE tonic depressor activity in the anterior hypothalamus and that serotonergic mechanisms play a major role in the development of the increased arterial blood pressure in this preparation.

Thyrotropin-releasing hormone increases the number of muscarinic receptors in the lateral septal area of the rat brain

Stereotactic injection of acetylcholine (0.5-2 micrograms) into the lateral septal region of the rat brain produces a long-lasting sympathetic-mediated increase of the arterial blood pressure. This effect is mediated by muscarinic receptors since 1 microgram atropine abolishes this response. In this same brain region, TRH (0.5-4 micrograms) did not elicit any significant change in the arterial blood pressure, but potentiated the effect of acetylcholine. This phenomenon is apparently due to an increase of the number of muscarinic receptors in the lateral septal area of the rat brain.

Serotonin mediates cardiovascular responses to acetylcholine, bradykinin, angiotensin II and norepinephrine in the lateral septal area of the rat brain

The infusion of acetylcholine, bradykinin, angiotensin II, norepinephrine and serotonin into the lateral septal area produced a dose-dependent increase of arterial blood pressure and heart rate. A pattern of inhibition of these cardiovascular responses, produced by pretreatment of the lateral septal area with phentolamine, 6-hydroxydopamine, methysergide and 5,7-dihydroxytryptamine was disclosed. These results suggest that the effects of acetylcholine, bradykinin and partially of angiotensin II, depend on the release of norepinephrine and the actions of this neurotransmitter in turn depend on the integrity of the serotonergic system in the lateral septal area.

Cholinergic hyperactivity in the lateral septal area of spontaneously hypertensive rats: Depressor effect of hemicholinium-3 and pirenzepine

In the lateral septal area of spontaneously hypertensive rats, but not in Wistar-Kyoto rats, the selective M1 antagonist, pirenzepine, and the depletion of acetylcholine storage, by hemicholinium-3 (HC-3), decreased blood pressure. The selective M1 agonist McNeil-A-343, produced a pressor response only after treatment of the lateral septal area with HC-3 in spontaneously hypertensive rats. Carbachol, at doses that mainly affect M2 muscarinic receptors, caused no cardiovascular changes in either strain, pointing to the main intervention of the M1 subtype of muscarinic receptor in the hypertensive condition. In addition, increases in the density of binding sites for [3H]QNB and in Vmax of sodium-dependent, HC-3-inhibitable, high affinity uptake of choline were demonstrated, without significant changes of the activity of choline acetyltransferase in the lateral septal area of spontaneously hypertensive rats. These results suggest that a hyperactivity of the cholinergic system of this area could play a role in the development and/or maintenance of hypertension in spontaneously hypertensive rats.

Hemodynamics in acute renal failure: Pathogenesis of hyperkinetic circulation∗

Abstract Hemodynamic studies were performed in 20 patients with acute renal failure who were not overhydrated. Cardiac index and heart rate were found to be high. Average mean arterial blood pressure was higher than that of controls but was still in normal range. In 6 patients arterial blood pressure was above normal values. Total peripheral resistance and upper limb resistance to flow were low. Stroke volume, total blood volume and critical closing pressure were normal. The hyperkinetic circulation of acute renal failure is not explained either by fever or hypo-vitaminosis (B 1 ). A circulatory compensation mechanism to anemia, anoxia or to a general fall in peripheral resistance does not seem to be operating. The high cardiac index found was not an adjustment to increased blood volume. A primary circulatory derangement cannot be excluded by this study, and the location of decreased arterial resistance seems to be the body carcass. The high blood levels of angiotensin in patients with acute renal failure suggest some sort of impairment of vasoconstrictor activity leading to decreased peripheral resistance.

Thyrotropin-Releasing Hormone Hyperactivity in the Preoptic Area of Spontaneously Hypertensive Rats

Thyrotropin-releasing hormone (TRH) plays an important role in central cardiovascular regulation through the activation of different neurotransmitter systems at distinct extrahypothalamic sites. To study possible alterations in the TRH system in the hypertensive state, we measured TRH concentration in cerebrospinal fluid and TRH content of the preoptic area in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) by radioimmunoassay. In addition, we also measured the density of the TRH receptor in this area by a rapid filtration technique using [3H]methyl-TRH. We found a significant increase in both the TRH content (634 +/- 61 versus 350 +/- 26 pg/mg protein, SHR versus WKY; P < .01, n = 5) and density of TRH receptors without changes in affinity (Bmax, 5.0 +/- 0.1 versus 3.3 +/- 0.1 fmol/mg protein, P < .01, n = 4). An increase in TRH concentration was also found in the cerebrospinal fluid of SHR (30 +/- 3 versus 21 +/- 2 pg/mL, P < .01, n = 5), suggesting increased TRH release in the central nervous system. Northern blot analysis indicated a threefold augmented abundance of TRH precursor mRNA in the preoptic area of SHR. A polyclonal antibody raised against TRH injected peripherally or intracerebroventricularly lowered arterial blood pressure in SHR but not in WKY. In addition, long-term treatment with enalapril (5 mg/kg twice daily), which was effective in inhibiting serum angiotensin-converting enzyme activity by more than 50%, decreased arterial blood pressure and preoptic area TRH content of SHR, whereas another vasodilator, diltiazem (10 mg/kg every 8 hours), failed to produce a similar change.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitogenic activation of the human lymphocytes induce the release of proenkephalin derived peptides

Several reports indicate that enkephalins participate in lymphocyte proliferation and several events of the immune response. It has been proposed that peptides involved in these processes may originate in the nervous system or endocrine glands. We have found that human peripheral blood lymphocytes (PBL) activated with a mitogenic agent contain and release proenkephalin derived peptides. The kinetics of met-enkephalin and cryptic products of proenkephalin in PBL activated with phytohemaglutinin (PHA) were studied. Peptides were released to the supernatant of stimulated PBL, reaching the highest values after 18 to 24 hours. The material secreted corresponds to high, intermediate and low molecular weight peptides derived from proenkephalin, displaying met-enkephalin and synenkephalin (proenkephalin 1-70) immunoreactivity. Therefore, an intrinsic lymphocytic proenkephalin system is induced by PHA and may play an important role in the regulation of the immune response.

Angiotensinase activity in rat and dog brain

ANGIOTENSIN 1 seems to modify adrenergic function via a neurogenic mechanism, and is the only hormone that has been demonstrated to increase transmitter release (HUGHES and ROTH, 1971). Furthermore, angiotensin I1 can also accelerate the synthesis of norepinephrine in various sympathetically innervated tissues (BOADLE, H U ~ H E S and R m , 1969). Recently this polypeptide has been postulated to be a mediator of a variety of physiological mechanisms involving the central nervous system, such as the release of antidiuretic hormone ( M o m etal., 1971), the excitation of supraoptic neurosecretory cells (NICOLL and BARKER, 1971), and the control of drinking behaviour (FITZSIMONS and SXMONS, 1969). Moreover, the polypeptide has a central pressor effect mediated by the sympathetic nervous system (SMOOKLER et at., 1966). However, it is known that angiotensin I1 does not have a ready access to the brain (VOLICER and Lorn, 1970). The findings of renin (FISCHER-FERRARO et al., 1971 ; GANTEN et al., 1971b), angiotensins I and I1 (FISCHER-FERRARO et al., 1971; GOLDSTEIN et al., 1970; GANTEN et al., 1971~) and converting enzyme (ROTH, WEITZMAN and PIQUELOUD, 1969) in the central nervous system of the rat and the dog are important clues to account for the local formation of the polypeptide. However, no definitive evidence has been advanced to characterize angiotensin I1 as a neurotransmitter. In any case, some mechanism is required for terminating the pharmacological actions of the polypeptide in the central nervous system. We decided to search in the brain tissue of the rat and the dog for the presence of enzymes capable of specifically inactivating angiontensin 11. We followed the isolation procedure described for hog kidney angiotensinase C (YANG et al., 1970) with the use of fresh brains from Wistar rats and mongrel dogs.