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We investigated the therapeutic effect of nimodipine or parathyroidectomy in old, diseased stroke-prone spontaneously hypertensive rats by observing 98 male 1-year-old rats over 5 months. After stroke had occurred, the rats were divided into three groups: 1) parathyroidectomy, 2) nimodipine, and 3) controls. In the nimodipine group, the rats survived longer than those in the other groups. Blood pressure of the controls did not differ from the nimodipine-treated and parathyroidectomy animals. The increase in calcium content of brain and kidney tissues and of plasma renin activity, urea, and creatinine was attenuated by nimodipine or parathyroidectomy. The histology of the kidneys revealed widespread fibrinoid necrosis of arteries in all rats. In the nimodipine-treated or parathyroidectomy groups, healing of the lesions was detectable. Cerebral lesions were mainly characterized by fibrinoid necrosis. Nimodipine-treated as well as parathyroidectomied animals showed significantly fewer hypertensive cerebral lesions. In old, diseased stroke-prone spontaneously hypertensive rats, therapy with nimodipine or parathyroidectomy increased their survival rate. The cerebrovascular and renovascular lesions of treated animals were attenuated, and morphologic signs of healing were observed. Reduction of calcium overload by nimodipine or parathyroidectomy, even in an advanced stage of disease, had a therapeutic effect.

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In order to clarify the etiology of a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats, the nephrotoxicity of p-dichlorobenzene (p-DCB) was investigated in a subchronic study. Groups of ten male and ten female Fischer 344 rats were dosed by gavage with 0 (controls), 75, 150, 300 or 600 mg p-DCB/kg/day in corn oil. Half of the animals were sacrificed after 4 weeks and the remainder after 13 weeks. Increased urinary LDH and epithelial cell excretion and exacerbation of hyaline droplet accumulation in the cytoplasm of renal cortical cells were observed in male rats over the entire dose range investigated. Tubular single cell necrosis, dilated tubules with granular cast formation in the outer zone of the medulla, were evident in male rats after 4 and 13 weeks of treatment with doses of 150-600 mg/kg/day. In female rats there was no indication of a nephrotoxic action of p-DCB. The effects on the kidney, both in their morphological characteristics and the fact that they occur exclusively in male animals, correspond to the light hydrocarbon nephropathy observed as a result of short-term treatment with a number of aliphatic and cyclic hydrocarbons. The development of cortical renal tumors seems to be associated with this kind of kidney damage which is unique to male rats. The literature on this subject generally regards these renal effects as not predictive for man.

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The effects of chronic dietary salt-loading and nifedipine therapy on hypertension-prone (SBH), -resistant (SBN) and parental (SB) Sabra rats were investigated. Salt diet for 12 weeks resulted in a sustained hypertension and heart hypertrophy only in SBH. Nifedipine therapy (300 p.p.m. = 300 mg/kg of food) introduced after week 7 on a salt diet, achieved small changes in salt-loaded SBN and SB rats, but resulted in a marked decrease in blood pressure in SBH rats within 1 week and in a regression of cardiac hypertrophy. Plasma renin activity rose slightly in nifedipine treated SB and SBN rats, but decreased significantly in treated SBH rats. Histopathological investigations revealed hypertensive vasculopathy in three out of nine untreated SBH rats, whereas there were no morphological changes in the treated rats.

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Pathomorphological studies were undertaken to investigate the therapeutic effect of the Ca2+-antagonist nifedipine on malignant hypertensive arteriopathy in Dahl salt-sensitive rats. The individual course of disease was followed by comparing pre-treatment biopsies of the mesenteric arteries with post-treatment findings at necropsy. Within seven weeks, continuous therapy with nifedipine resulted in healing of early vascular lesions and in partial repair of the more advanced ones. Under normalization of blood pressure, vascular fibrinoid exacerbations were prevented and existing intramural fibrin insudates were completely or partially removed. Lamellar fibroelastosis of the intima occurred as a characteristic of repair.

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To substantiate further the hypothesized importance of increased calcium influx into vascular smooth muscle, salt-sensitive Dahl rats (DS/JR, John Rapp), on either a low or a high salt diet, were treated with 100 or 300 ppm (i.e. mg/kg food) BAY k 8644, a calcium agonist. Simultaneously, salt-resistant Dahl rats (DR/JR) on a high salt diet received 300 ppm BAY k 8644. Blood pressure rose more rapidly in the agonist-treated DS/JR rats than in the untreated DS/JR controls on high salt diet. On the low salt diet, blood pressure was only slightly higher in the agonist-treated DS/JR. Although an increased calcium influx seems to be involved in salt-induced hypertension, the presence of high sodium chloride is apparently essential for its development. In addition, since DR/JR rats remained resistant to the effect of the calcium agonist, calcium per se is not the decisive factor responsible for the sensitivity or resistance of Dahl rats to salt load.

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The antihypertensive effect of nitrendipine cannot be explained only by its reduction of the increased peripheral vascular resistance. In contrast to the antihypertensive vasodilators, nitrendipine improves impaired renal function and prevents generalized vasculopathy in hypertensive animals. Chronic treatment with nitrendipine prevents spontaneous (Okamoto rats) and salt-induced (Dahl rats) hypertension and cardiac hypertrophy. In rats with established hypertension, nitrendipine normalizes blood pressure, reduces cardiac hypertrophy, and improves renal ischaemia. In salt-induced malignant hypertension in stroke-prone spontaneously hypertensive rats, nitrendipine only slightly reduces blood pressure but dramatically improves survival and prevents vascular lesions in the heart, brain, and kidneys. Nitrendipine reduces the intracellular availability of calcium ions in vascular smooth muscle responsible for the increased peripheral and renovascular resistance in hypertension. Moreover, in preventing the deleterious calcium overload, nitrendipine preserves tissue integrity and increases life span in malignant hypertension.

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In this paper we have described the microbiology of the granuloma pouch model in rats. We studied the biochemical parameters of pouch exudates infected with Escherichia coli. Data revealed that the inflammatory response increased during the course of infection since lactate dehydrogenase levels as well as alpha 2 and gamma-globulin fractions were increased in comparison to uninfected controls. Infection of the pouches did not spread. We also monitored the growth characteristics of four different E. coli strains. In vitro incubation of these strains in human and rat serum as well as in pouch exudate, and the in vivo growth rate in infected pouches revealed that the degree of serum sensitivity was clearly related to viability in vivo. Serum-resistant strains grew well in pouch exudate, whereas serum-sensitive strains were eliminated from the infected pouches. Since elimination of these strains was dependent on the challenge dose, we concluded that cellular and/or humoral host defense mechanisms became locally exhausted or inactivated. Thus, the granuloma pouch represents a local bacterial infection of a poorly defended, inflamed body cavity.

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In animal experiments calcium antagonist drugs decrease peripheral vascular resistance, improve renal sodium excretion and thus, diminishing the volume load, reduce cardiac hypertrophy. In experimental malignant hypertension these drugs preserve tissue integrity by inhibiting the deleterious calcium overload of vessels.

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The "granuloma pouch" model in rats was evaluated on the basis of biochemical, haematological and histological factors. Seven days after formation of the pouch following the intramuscular injection of air and a mixture of 1% croton oil in olive oil as an irritant, the pouch was filled by approximately 5 ml of haemorrhagic exudate. Biochemical assessment of the exudate revealed that its main characteristics were increased lactate dehydrogenase levels as well as increased alpha 2- and gamma-globulin fractions. Histological sections of the surrounding tissue showed a typical granulomatous inflammatory response. The granuloma pouch can therefore be characterized as a local, chronic inflammation caused by the creation of a body cavity. The biochemical data of the pouch exudate were compared with those of human wound fluid obtained after surgery; since the values were in very good agreement, it is assumed that the granuloma pouch model reflects the clinical situation in inflamed wound cavities following the extirpation of organs.

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In female "salt-sensitive" (S) Dahl rats, with hypertension induced by 8% sodium chloride (NaCl) in the diet for six weeks, a severe generalized arteriopathy was observed histopathologically. Fibrinoid degeneration, medial hyperplasia and periarteritis were especially pronounced in the preglomerular arterial system of the kidneys. Necrosis of afferent glomerular arterioles led to regressive changes in the renal corpuscles. Numerous dilated renal tubules were filled with protein casts. In the heart, arterial lesions were predominantly localized in the outer wall of the right ventricle. Occlusion of intracardiac arteries was accompanied by focal myocardial necrosis and fibrous replacement of the myocardial fibres. A left ventricular hypertrophy was found. The degree of renal arteriopathy inversely correlated with the magnitude of the hematocrit. S rats treated with nifedipine, 300 ppm in addition to 8% NaCl in the diet remained normotensive. No changes in vessels, tissues or in the hematocrit were seen in any of the nifedipine-treated rats. The same picture was observed in "salt-resistant" (R) rats on a high (8%) and on a low (0.4%) NaCl diet. S rats fed a low NaCl diet showed only dilated renal tubules containing protein casts. It is assumed that nifedipine primarily decreases the renovascular resistance in S rats under salt load, enabling the kidney to eliminate excess sodium without inducing pressure natriuresis. Organ damage in salt-loaded S rats is thus due to a fulminant increase in blood pressure, compensating for the sluggish natriuresis.

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Fluorescence microscopic studies of the skin of hairless mice showed that a fluorescent whitening agent (FWA) of the bis(phenyltriazolyl)stilbenedisulfonate type did not penetrate into the subepithelial layers (dermis and subcutaneous tissue) of the skin after cutaneous application.

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