Lise Peters-Haefeli

Influence of streptozotocin-induced diabetes on blood pressure and on renin formation and release

SummaryI.v. injection of 40 mg/kg or 65 mg/kg streptozotocin reliably induced diabetes in female Sprague-Dawley rats, but failed to induce hypertension within the following 42 days. In most animals injected with the higher dose and in some animals injected with the lower dose, the tail blood flow was permanently impaired so that no blood pressure signals could be obtained by tail plethysmography. This phenomenon occurred also when the drug was injected into the jugular vein and thus was not due to a local effect of streptozotocin. 15 days after 65 mg/kg streptozotocin, the mean arterial pressure of the rats was similar to that of controls, when measured in the awake state (carotid cannula) or under ether anaesthesia. 42 days after streptozotocin, under pentobarbital anaesthesia, the blood pressure was again normal in the animals given 40 mg/kg of the drug and depressed in the animals given 65 mg/kg of the drug 42 days previously. The increase of blood pressure induced by 1 μg/kg (−)-noradrenaline i.v. was similar in the latter group of animals and in controls.The renal cortical renin concentration was much lower than in controls 42 days after either dose of streptozotocin, while the plasma renin activity was normal (40 mg/kg) or increased (65 mg/kg). The low renal renin content may have been due to the diabetic state, rather than to the drug itself. Adrenal medullary dopamine-beta-hydroxylase activity was increased 42 days after the higher dose of streptozotocin.

Effect of peripheral clonidine on ingestive behavior.

Abstract The effect of parenteral clonidine, a central alpha-sympathomimetic agent, on eating and drinking was studied in rats. Small (37.5–75 μg/kg) and large (150–300 μg/kg) doses of clonidine acutely depressed water intake for periods up to 6 hours. The antidispsogenic effect was followed by a delayed increase of fluid intake apparently due to the diuretic effect of the drug in rats, and this was suppressed by nephrectomy. With daily injections for periods up to 3 days large doses depressed both water and food intake. When daily injections were continued for more than 4 days, an appetite-stimulating effect was noted. It was concluded that clonidine primarily depresses water and food intake. The delayed, apparently dipsogenic, effect observed is due to a primary diuretic effect. The appetite-stimulating effect of clonidine observed with chronic treatment may be a primary cerebral effect unmasked when tolerance develops to the (presumably) peripheral, anorectic effect.

The role of circulating renin in drinking in response to isoprenaline.

1. In nephrectomized rats, S.C. (0·12 mg. kg body wt.−1) or intracerebroventricular ( I.C.V.: 0·03 mg. kg−1), isoprenaline failed to elicit drinking. However, when preceded (5‐20 min) by a non‐dipsogenic dose of I.V. pig renin, S.C. isoprenaline induced a marked, and I.C.V. isoprenaline a smaller drinking response. 2 hr after I.V. renin, S.C. isoprenaline no longer caused drinking.

General and renal toxicity of phenacetin, paracetamol and some anti-mitotic agents in the rat.

The general and the renal toxicity of large doses of phenacetin, paracetamol, some antimitotic drugs and other constituents of analgesic mixtures was investigated in medium term toxicity tests in a large number of rats. Phenacetin and paracetamol depressed food intake and retarded growth. 800–1200 mg/kg · day paracetamol induced a larger mortality than 1500–3000 mg/kg · day phenacetin. Both analgesics and isophthalanilide, an antimitotic agent, induced hyperchromic anemia. Phenacetin induced methemoglobinemia more readily than paracetamol. Neither the analgesics, nor caffeine, sodium nitrite, isophthalanilide or mercaptopurine depressed GFR, maximal urinary concentration after dehydration plus vasopressin, urinary dilution after hypotonic expansion, or urinary acidification. Phenacetin, paracetamol and isophthalanilide depressed the fractional excretion of urea by the kidney. Very large doses of paracetamol slightly increased the proteinuria and the urinary excretion of tubular cells. Phenacetin and paracetamol induced degenerative histological alterations in cortical proximal and distal tubules, detected and quantitated under blind conditions. There were no inflammatory changes, nor any medullary or papillary lesions. The degenerative lesions could not be explained by the presence of methemoglobinemia or hemolysis. Isophthalanilide actually “improved” the histological appearance of the kidneys. The urinary excretion of tubular cells was not significantly correlated with the severity of the histological changes. It was concluded that neither phenacetin nor paracetamol exert major nephrotoxic effects in rats.ZusammenfassungDie allgemeine und renale Toxicität von großen Dosen von Phenacetin, Paracetamol und potentiell nephrotoxisehen Antimitotica, sowie anderen üblichen Bestandteilen von analgetischen Mischpräparaten wurde an Ratten in 30–60 Tage-Versuchen untersucht. Phenacetin und Paracetamol hemmten Futteraufnahme und Wachstum. 800–1200 mg/kg · Tag Paracetamol tötete mehr Tiere als 1500–3000 mg/kg · Tag Phenacetin. Die beiden Analgetica und das Antimitoticum Isophthalanilid riefen hyperchrome Anämie hervor. Phenacetin verursachte mehr Methämoglobinämie als Paracetamol. Weder dieser Analgetica, noch Coffein, noch Natriumnitrit, noch Isophthalanilid, noch Mercaptopurin verringerten das Glomerulusfiltrat, die maximale Harnkonzentrierungsfähigkeit nach Durst unter Vasopressin, die Harnverdünnuungsfähigkeit nach hypotonischen Infusionen oder die renale H+-Ionen-Sekretion. Phenacetin, Paracetamol und Isophthalanilid verringerten die fraktionelle renale Harnstoffausscheidung. Sehr große Dosen von Paracetamol steigerten leicht die Proteinurie und die Ausscheidung von Tubuluszellen im Harn. Phenacetin und Paracetamol verursachten degenerative Veränderungen im histologischen Bild der corticalen, proximalen und distalen Tubuli, die unter Blindbedingungen untersucht wurden. Es traten weder entzündliche Veränderungen, noch Schädigungen des Nierenmarks oder der Papille auf. Die corticalen degenerativen Veränderungen ließen sich nicht als Folge von Methämoglobinämie oder Hämolyse erklären. Isophthalanilid verursachte eine „Normalisierung” des histologischen Bilds der Nierenrinde über die Norm hinaus. Die Ausscheidung von Tubuluszellen im Harn war nicht signifikativ mit der Schwere der histologischen Veränderungen korreliert. Die Befunde führen zum Schluß, daß weder Phenacetin, noch Paracetamol bei der Ratte ausgeprägte nephrotoxische Wirkungen besitzt.

The mechanism of the augmentation of the pressor response to angiotensinamide and to adrenaline by β-adrenoceptor blocking agents in the rat

SummaryIn normal or nephrectomized rats, unanaesthetized or anaesthetized with urethane i.v., D,L-propranolol (0.25 or 0.5 mg/kg) or practolol (2.5 or 5 mg/kg) provoked a short-lasting peak of blood pressure (BP) which was abolished by adrenalectomy. D-propranolol (0.25 mg/kg) or lidocaine (0.25 mg/kg) caused a similar peak which was abolished by phentolamine (0.5 mg/kg). This initial pressor peak appears to be due to an enhanced release of adrenaline and/or of noradrenaline from the adrenal medulla. Acute pressor responses to D,L-propranolol and practolol, but not to D-propranolol or lidocaine, were followed by an elevation of base line BP. The pressor response to β-blocking agents appears to be due to a depression of the continuous vasodilator effect of endogenous adrenaline. In spite of an increase in base line BP, D,L-propranolol or practolol enhanced pressor responses to single injections of 3–25 ng/kg angiotensinamide or 0.4–1.5 ng/kg adrenaline, or to continuous infusion of 45 ng/kg · min angiotensinamide.Pentolinium did not interfere with the effects of D,L-propranolol. Pentobarbital anaesthesia abolished the pressor responses to D,L-propranolol but not its propensity to enhance the pressor responses to angiotensinamide or to adrenaline. D,L-propranolol failed to increase pressor responses to angiotensinamide in adrenalectomized, prednisolone-substituted rats. Since the pressor responses to angiotensinamide are partially mediated by release of catecholamines from the adrenal medulla, the data are interpreted as indicating that β-adrenoceptor blocking agents enhance pressor effects of adrenaline and/or noradrenaline by suppressing their vasodilator effects.

The replenishment of the juxtaglomerular renin store after temporary renin depletion

SummaryRenal cortical and plasma renin activities and the electron microscopic appearance of juxtaglomerular epitheloid cells were investigated in the unclamped renin-depleted kidney of rats with two-kidney-Goldblatt hypertension after removal of the clamped kidney. Within 24 h the renal renin content fell to still lower values, on the 2d day, it rose to one half its normal value, on the 7th day it reached its control value. Renin activity of plasma did not significantly differ from zero until the 3d day after removing the clamped kidney, reached 20% of normal on the 7th day and normal values between the 7th and the 21 st day. Sparse secretory granules appeared in the remaining renal cortex 12 h after removal of the clamped kidney. After 24 h secretory granules were formed by confluence of Golgi vesicles. After 2 days cisternae appeared in the rough-surfaced endoplasmic reticulum. After 4 days the electron-microscopic picture became normal. Renin appears to be elaborated in the rough-surfaced endoplasmic reticulum and concentrated into granules by the Golgi-apparatus. A fraction of the renal renin does not appear to be available for secretion.

The Role of Plasma and Renal Renin in the Rise in Blood Pressure Following Unilateral Renal Artery Constriction

Constriction of the artery to the remaining kidney of control rats uninephrectomized 24 h previously induced a sixfold rise in plasma renin level from 11 +/- 1 to 60 +/- 11 ng AI ml-1 h-1, a 43% decrease of renal cortical renin level, and a 21% rise of mean arterial pressure from 119 +/- 2 to 144 +/- 3 mm Hg. Constriction of the artery to a renin-depleted kidney (with a renin level which was 5% of normal) was not followed by any significant increase in plasma renin level or mean blood pressure. Renin-depleted kidneys were produced by removing the clipped kidney from two-kidney one-clip hypertensive rats, 24 h before the experiment. Such a maneuver induces renin depletion but does not completely normalize blood pressure. When a large dose of frusemide (50 mg/kg i.p.) was injected immediately following removal of the clipped kidney, mean arterial pressure (117 +/- 7 mm Hg) returned to control values 24 h later but again constriction of the remaining renal artery failed to induce a rise in plasma renin level or mean arterial pressure. By 7 days after removal of the clipped kidney, plasma renin level and mean arterial pressure were normal and clipping of the remaining kidney (in spite of the fact that kidney renin level was still low) now produced a wave of renin release and an increase in mean arterial pressure. These results suggest that the initial, rapid increase in mean arterial pressure following unilateral renal artery constriction is dependent on an increase in plasma renin level. Our results from animals with kidneys of varying renin levels suggest the existence of a cortical renin content of about 20% of normal below which the kidney is incapable of responding to renal artery constriction with significant renal release. Complete recovery of the renin (and blood pressure) response to clipping occurred when the renin content had reached about 75% of normal.