An analysis of the effects of urethane on cardiovascular responsiveness to catecholamines in terms of its interference with Ca++ mobilization from both intra and extracellular pools

Summary Urethane (1×10^–2–1×10^–1 M) reduced, in a concentration-dependent manner, both intra and extracellular Ca⁺⁺ dependent noradrenaline-induced contractions of perfused rabbit ear artery as well as the tonic contractions produced by perfusion with high K⁺ solution. However, a quantitative analysis of the data indicated that for urethane concentrations similar to those found in plasma during anesthesia urethane antagonism is confined to noradrenaline-induced contractions which depend upon the mobilization of Ca⁺⁺ from intracellular storage sites. In KCl-contracted arteries, urethane enhanced the relaxant effects of isoprenaline.—Urethane reduced the amplitude of contractions of spontaneously beating guinea-pig right atrium at concentrations which have only a limited effect on frequency. In addition, it decreased in a concentration-dependent manner the amplitude of isoprenaline-activated electrically driven, and K⁺ depolarized guinea-pig right ventricular strips. Urethane had no effect on the chrono and inotropic actions of isoprenaline on cardiac preparations. In in vivo experiments the chronotropic response to low doses of isoprenaline was significantly higher in urethane-treated as compared to unanesthetized rats. The higher dose of isoprenaline tested produced a significant fall in systolic blood pressure in urethane-anesthetized rats. A significant correlation exists between the chronotropic response to isoprenaline and resting heart rate values in urethane-anesthetized rats. These results indicate that urethane, at concentrations similar to those found in plasma during anesthesia selectively interferes with mobilization of Ca⁺⁺ from intracellular storage sites. In addition, the interference of urethane anesthesia with the isoprenaline chronotropic effect in vivo cannot be explained by a direct interference of urethane with -adrenoceptors at cardiac level.     

Is the renal vasodilatation induced byβ-adrenoceptor stimulants in the dog mediated through dopamine receptor?

Summary In chloralose-anaesthetized dogs the renal vasodilator effect of isoprenaline is depressed by blockade of either dopamine or -adrenoceptors but the renal vasodilator effect of dopamine is depressed only by blockade of dopamine receptors. This suggests that the vasodilatation induced by -stimulants within the canine kidney is due in part to activation of dopamine receptors.This study was supported by the Life Insurance Medical Research Fund of Australia and New Zealand and by the Australian Kidney Foundation.We thank Mr S. Marshall for technical assistance.     

Aging and endothelin-1 induced vascular contractions

Summary Contractions produced by endothelin-1 (0.3–30 nM) have been investigated in aorta, renal arteries and mesenteric arteries from 2- and 24-month-old Sprague-Dawley rats. In senescent rats the EC₅₀ values of endothelin-1 for aorta and renal artery were significantly increased (aorta: from 6.2 to 12 nM; renal artery: from 5.2 to 7.8 nM). For mesenteric artery the EC₅₀ value (4.3 nM) was unchanged by aging, whereas the maximal contractile response to endothelin-1 was enhanced (from 8.3 to 11.7 mN). In contrast, there was no significant age-related difference in the maximal endothelin-1 response of aorta and renal artery. The present data demonstrate a reduced sensitivity for aorta and renal artery and an enhanced maximal response to endothelin-1 in the mesenteric artery in senescent rats.     

Aging and endothelin-1 induced vascular contractions

Contractions produced by endothelin-1 (0.3-30 nM) have been investigated in aorta, renal arteries and mesenteric arteries from 2- and 24-month-old Sprague-Dawley rats. In senescent rats the EC50 values of endothelin-1 for aorta and renal artery were significantly increased (aorta: from 6.2 to 12 nM; renal artery: from 5.2 to 7.8 nM). For mesenteric artery the EC50 value (4.3 nM) was unchanged by aging, whereas the maximal contractile response to endothelin-1 was enhanced (from 8.3 to 11.7 mN). In contrast, there was no significant age-related difference in the maximal endothelin-1 response of aorta and renal artery. The present data demonstrate a reduced sensitivity for aorta and renal artery and an enhanced maximal response to endothelin-1 in the mesenteric artery in senescent rats.     

Alpha-receptor subsensitivity of isolated atria from rats following repeated injections of phenylephrine or isoprenaline

Summary Daily injections of phenylephrine or isoprenaline for 4 or 7 days lowered the chronotropic sensitivity of -adrenoreceptors in isolated rat atria.This study was supported by grants from the National Science Council of Finland.     

The effect of cyclic AMP on dog renal function

Summary The infusion of dibutyryl-cyclic AMP into the dog renal artery in vivo leads to diuresis, natriuresis and glucosuria. Addition of the nucleotide to the incubation medium bathing dog renal cortex slices in vitro causes inhibition of p-amino-hippurate accumulation and stimulation of glycine and -methyl-glucoside transport. The results are interpreted in terms of the development of a blood-lumen flux of sodium and water in the renal proximal tubule, analogous to that seen in the intestine.We are grateful to Mrs P. Ganguillet, S. Henriot, Miss M. Augstburger and D. Mettraux technical skilful technical assistance, and to the Fonds National Suisse for financial support.     

Opposite effects ofβ-adrenoceptor stimulation and 8-bromo-cyclic AMP on potassium efflux in mammalian heart muscle

Summary -adrenoceptor stimulation by isoprenaline increases the potassium efflux in beating guinea-pig atria. This effect is not mimicked by 8-bromo-cyclic AMP, a cyclic AMP analogue which exerts a positive inotropic effect in this preparation.     

Quantitative changes in β-adrenergic responses of isolated atria from hyper- and hypothyroid rats

Summary Concentration-response curves for the chronotropic and inotropic effects of isoprenaline, in the absence and presence of propranolol, were obtained on heart atria isolated from normo- or dysthyroid rats. Hyperthyroidism increased the chronotropic potency and efficacy of the -adrenergic agonist. The results are compatible with the view that thyroid hormone increases the density of functional -adrenoceptors in cardiac pacemaker tissue.This study was supported by the Swiss National Science Foundation grant No. 3.374.-0.78. We thank Dr Bachmann from the Central Laboratory of the University Hospital Bern for the estimation of plasma thyroxine levels.     

Isoprenaline-like effects of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine on mechanical,biochemical and electrophysiological parameters in the mammalian heart

Summary The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) mimicked the effects of isoprenaline on the force of contraction, the cAMP content and the slow Ca⁺⁺ inward current (I_si) in isolated guinea pig papillary muscles. The results support the hypothesis that phosphodiesterase inhibitors and -adrenoceptor agonists exert their positive inotropic effects by increasing I_si via the common mediator cAMP.Acknowledgment. This work was supported by the Deutsche Forschungsgemeinschaft.     

On the role of the decreased renal vascular resistance in the mechanism of volume natriuresis

Summary Acute hypohysectomy (AH) prevented the increase of the cardiac output, renal cortical blood flow (e.g. the decrease of the renal vascular resistance) and renal sodium excretion during the ECFV expansion. The non-occurrence of natriuresis in AH rats is suggested as being partly in causal relation to the inability to decrease the renal vascular resistance and thus to increase the peritubular hydrostatic pressure.Expert technical assistance of Mrs.E. Blaková, J. Kyselicová and Mr.. Kaloai is sincerely acknowledged.     

Gefässkonstriktion durch synthetisches Bradykinin und ihre pharmakologische Beeinflussbarkeit

Summary The divided hindlimb of the cat was perfused through the femoral artery with tyrode solution. Synthetic bradykinin administered via the artery elicits a vasoconstriction,- and-sympathicolytics decrease the vasoconstriction, cocain and guanethedin emphasize it, whilst iproniacid and reserpin have no influence on it. It is assumed that bradykinin acts directly on adrenergic structures of the vessels of the hindlimb of the cat.     

Effects of receptor agonists on polyamine concentrations and spermidine/spermine N1-acetyltransferase activity in rat parotid gland

The polyamine putrescine might be formed via a degradation (catalyzed by spermidine/spermine N¹-acetyltransferase, SSAT) of the higher polyamines spermidine and spermine to putrescine. The involvement of different intracellular signal pathways in the regulation of putrescine formation was studied in explants and in cultured cells of rat parotid glands by using receptor agonists that activate separate second messenger systems, and measuring their effects on the concentrations of putrescine, spermidine and spermine and on the SSAT activity. The -adrenoceptor agonist isoprenaline, which is an activator of cAMP formation, increased the putrescine concentration and stimulated the SSAT activity. Pilocarpine, a drug that activates the muscarinic receptors and thereby enhances the phosphoinositide turnover, had no effect on either the polyamine concentrations or on the SSAT activity. Epidermal growth factor (EGF), which induces activation of a protein tyrosine kinase, had no effect on the polyamine concentrations or on the SSAT activity. The adenylate cyclase activator forskolin increased the glandular levels of putrescine. Taken together, these findings suggest that increases in putrescine concentration in cultured rat parotid gland cells are accompanied by accumulation of cAMP.     

N″-cyano-N-4-pyridyl-N′-1,2,2-trimethylpropylguanidine,monohydrate (P 1134): A new,potent vasodilator

Summary N-cyano-N-4-pyridyl-N-1,2,2-trimethylpropylguanidine, monohydrate (P 1134) is a new agent which induces a marked and sustained hypotensive response in normotensive and renal, neurogenic, and spontaneously hypertensive rats, as well as in normotensive and renal hypertensive dogs. The overall potency of this compound is 2–3 times greater than that of hydralazine. The fall of blood pressure is accompanied by an increase in heart rate and cardiac output and a decrease in total peripheral resistance. The hypotensive effect appears to be due primarily to a direct relaxant effect on vascular smooth muscle.Acknowledgment. The helpful comments and advice of Dr W.O. Godtfredsen are greatefully acknowledged.     

Zur Frage der glomerulären Permeation höhermolekularer Proteine

Summary Haptoglobin and isoagglutinin were found in the urine of diabetic patients, and their renal excretion was higher in patients with diabetic angiopathy. It is concluded from these results (the biological activity of the two polypeptides in urine was intact) that the mechanism of proteinuria can perhaps be explained only by an extension of pores of the renal glomerular filter.     

Effet de l'ablation partielle ou totale du tissu rénal sur l'hypertension rénovasculaire chez le rat

Summary Arterial hypertension, elicited in the rat by partial renal artery constriction, appears faster and affects more animals when the controlateral kidney is removed simultaneously. Excision of the ischemic kidney after hypertension of 1 to 3 weeks duration is not followed by any fall of blood pressure during the first 24 h. If the arterial constriction is not accompanied by controlateral nephrectomy, hypertension disappears after removal of the ischemic kidney, diminishes after bilateral nephrectomy and is increased by excision of the un-touched kidney.

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Ce travail bénéficie du soutien financier du Fonds National Suisse de la Recherche Scientifique (crédit No. 5315) et d'un crédit de recherche de Robapharm SA, Bâle.     

Irreversible shock in rats after injection of microspheres into the renal artery

Summary After injection of microspheres into both renal arteries of rats, an irreversible shock syndrome develops, resulting in death within 4–12 h. Ligation of both renal pedicles after injection of microspheres prevents the shock. It is presumed that kininogenases released from the kidneys participate in the pathogenesis of the shock syndrome.These studies were supported in part by the Deutsche Forschungsgemeinschaft within the SFB 90, Cardiovasculäres System.     

The oxidative metabolism ofα-chlorohydrin and the chemical induction of spermatocoeles

Summary -Chlorohydrin (I) is oxidatively metabolized to -chlorolactic acid (III) and oxalic acid (IV). Deposition of calcium oxalate within the renal tubules is responsible for the toxic effects of-chlorohydrin and a similar action on the epididymis or epididymal blood vessels could initiate the formation of spermatocoeles from this and other male antifertility agents.     

Brain ischemia hypertension

Summary Hypertension was produced in anesthetized and conscious dogs when cerebral perfusion was reduced. It lasted up to 19 days in chronic studies, was not abolished by carotid sinus denervation nor with beta receptor blockade, but was absent after removal of brachiocephalic artery constriction (BCAC). The cardiovascular features of this neurogenic hypertension are presented.