Experimental Hypertensive Rats Research Articles

The cardiovascular effects of intraventricular 5,6-dihydroxytryptamine in conscious hypertensive rats.

1. Conscious experimental hypertensive rats injected intraventricularly with 5,6-dihydroxytryptamine (50 microgram) responded with a rapid and long-lasting (4 days) fall in blood pressure and this was accompanied by a bradycardia of similar duration. 2. The acute actions of 5,6-dihydroxytryptamine on the cardiovascular system were not modified by pretreatment with bromolysergide (0.5 mg/kg, i.p.), methysergide (2.5 mg/kg, i.p.) or intraventricular phentolamine (200 microgram). 3. The results suggest that central serotonergic neurones play an important role in the regulation of blood pressure. However, the site of action remains to be investigated.

An increased reactivity in hypertensive rats unaffected by prolonged antihypertensive therapy.

1. Isolated perfused mesenteric arteries obtained from chronic experimental hypertensive rats (deoxycorticosterone/NaCl) exhibited an increased reactivity to noradrenaline, 5-hydroxytryptamine and adenosine 5'-triphosphate (ATP) when compared with similar preparations from age-matched normotensive animals. 2. The dose-response curves to all three vasoconstrictor agents obtained from hypertensive animals exhibited a steeper slope, and higher maximum without any significant change in the threshold dose suggesting that adaptive/structural changes in the blood vessels had taken place. 3. Ten week treatments with antihypertensive combinations of hydrallazine, hydrochlorothiazide and reserpine or hydrallazine and mecamylamine lowered the systolic blood pressures of the hypertensive rats to those of normotensive animals and also reversed secondary changes such as periarteritis nodosa of the mesentery and cardiac hypertrophy. 4. The reactivity of these blood vessels to all these vasoconstrictor agents from the hypertensive rats with a normalized blood pressure was similar to those obtained with untreated hypertensive animals. 5. The persistent increased reactivity in the hypertensive rats after long-term anti-hypertensive treatment suggests that the hyperresponsiveness is secondary to the elevated blood pressures and that the adaptive/structural changes of the blood vessels in chronic hypertensive rats cannot be reversed by prolonged antihypertensive therapy.

Proceedings: Fine structure of retinal arterioles in experimental hypertensive rats.

Proceedings: Fine structure of retinal arterioles in experimental hypertensive rats.

Vascular reactivity in hypertensive rats after treatment with anti-hypertensive agents

Isolated perfused mesenteric arteries obtained from experimental hypertensive rats (spontaneous and deoxycorticosterone/NaCl) exhibit an increased vascular reactivity to noradrenaline and 5-hydroxytryptamine. The dose response curves obtained exhibited in the threshold dose. After 4 weeks of antihypertensive therapy (a combination of hydrallazine, hydrochlorothiazide and reserpine) which lowered the blood pressures of hypertensive rats to normotensive levels the arteries from the hypertensive animals still exhibited an increased reactivity to vasoconstrictor agents. These results support the hypothesis that the increased reactivity observed in hypertensive animals may be partially due to adaptive structural changes in the blood vessels. However, the persistence of the hyperactivity after antihypertensive therapy seriously questions its involvement in the maintenance of the elevated blood pressure.

Cerebral arterial lesions in experimental hypertensive rats: Electron microscopic study of middle cerebral arteries

In the branches of the cerebral arteries of hypertensive rats, medial damage preceded intimal fibrinoid degeneration. The hypertensive medial damage was characterized by degeneration, necrosis, and disappearance of the smooth muscle cells. The lesions of the medial smooth muscle cells were characterized by focal cytoplasmic necrosis and formation of dense granular, vesicular, and tubular cell debris in the necrotic areas. Furthermore, coagulation necrosis, liquefaction necrosis, and edematous change of the cytoplasm were observed. The cytoplasm bordering on the focal cytoplasmic necrosis in the peripheral areas of the smooth muscle cells produced a new cytodemarcating membrane. Around damaged smooth muscle cell was observed lamellar or reticular increase of basement membrane. This may have resulted from the repetition of necrosis and disappearance of peripheral cytoplasm of the smooth muscle cells and re-formation of the basement membrane.

On the morphogenesis of massive cerebral hemorrhage in experimental hypertensive rats.

The morphogenesis of massive cerebral hemorrhagic lesions was studied in 6 experimental hypertensive rats. Hemorrhage due to rupture of arteries caused by hypertensive arterial lesions (plasmatic arterionecrosis) was found in the middle cerebral arteries in the subarachnoid space and immediately after their penetrating into the cerebral parenchyma. This primary hemorrhage induced, through circulatory disturbances, secondary bleedings of small vessels and veins, which were all combined to give rise to a massive hemorrhagic lesion. The hypertensive arterial lesions, which were the direct cause of the cerebral hemorrhage, were constituted by necrosis and disappearance of smooth muscle cells and blood plasma infiltration in the media, blood plasma infiltration, especially deposition of fibrin, having periodic cross striation of about 200 Å (fibrinoid degeneration) in the intima, and dissolution and disappearance of the internal elastic lamina.

Electron microscopic studies on the adrenal medulla and adrenal cortex of hypertensive rats. 2. Experimental hypertensive rats.

DOCA hypertension, renal hypertension, and cerebral hypertension were induced in Wistar rats. In the acute and chronic stages, noradrenaline storing cells of the adrenal medulla and cells of the zona fasciculata in the adrenal cortex were studied, both electron microscopically and histometrically, in order to compare them with their respective controls. 1. (a) In the acute stage of DOCA hypertension, (i) the number of noradrenaline storing granules was not different from that in the controls. Vesicles were about 1.6 times as numerous as those in the controls. Some of the granules and vesicles varied greatly in size. However, only a few of them probably representing initial secretory granules were noted. (ii) A large number of relatively large secretory granules of moderate electron density were found within the cytoplasm of cells of the zona fasciculata of the adrenal cortex. Both the number of the mitochondria and the number of ribosomes were decreased. (b) In the chronic stage of DOCA hypertension, (i) the nor-adrenaline storing granules and vesicles showed findings similar to those described in the acute stage. Especially noted were giant granules and vesicles. (ii) Cells of the zona fasciculata of the adrenal cortex also gave findings similar to those in the acute stage. 2. (a) In the acute stage of renal hypertension, (i) the number of noradrenaline storing granules was not significantly different from the controls. The number of vesicles was 1.7 times as great as that of the controls. Granules and vesicles varied in size and small ones were also found in abundance. (ii) In the cells of the zona fasciculata of the adrenal cortex, secretory granules probably representing lipid droplets were also found to be rather abundant as compared with controls. (b) In the chronic stage of renal hypertension, (i) no remarkable changes were noted in the number of noradrenaline storing granules and vesicles. Morphological changes were not remarkable except for slightly larger vesicles than those in the controls. (ii) In the cells of the zona fasciculata of the adrenal cortex, there were more abundant round secretory granules of moderate electron density than those in the controls. Dilatation and an increase of smooth-surfaced endoplasmic reticulum and ribosomes were noted. 3. (a) In the acute stage of cerebral hypertension, (i) the number of noradrenaline storing granules was unchanged and the number of vesicles was about 1.9 times that of the controls. As to the morphology, both granules and vesicles were larger than the controls. (ii) In the cells of the zona fasciculata of the adrenal cortex, large secretory granules of low electron density probably representing lipids were noted. Dilatation and an increase of smooth-surfaced endoplasmic reticulum and an increase of ribosomes were noted. (b) In the chronic stage of cerebral hypertension, (i) noradrenaline storing granules were increased (1.2 times those in the controls) and vesicles were also found abundantly (2.6 times those in the controls). Both granules and vesicles were variable in size and there were abundant small granules as well. (ii) In the cells of the zona fasciculata of the adrenal cortex, secretory granules of medium electron density probably representing lipids were found to be abundant. The smooth-surfaced endoplasmic reticula were di-

18-Hydroxy-Deoxycorticosterone Secretion in Experimental Hypertension in Rats

18-Hydroxy-Deoxycorticosterone Secretion in Experimental Hypertension in Rats

18-Hydroxy-Deoxycorticosterone Secretion in Experimental Hypertension in Rats

Adrenal steroidogenesis was studied in vitro and in vivo in rats which have been specifically bred for susceptibility (S strain) or resistance (R strain) to the hypertensive effects of salt. A marked quantitative difference was found between S and R rats in the adrenal biosynthetic pathways which are subsequent to deoxycorticosterone (DOC). There was a twofold difference in the ability to 18-hydroxylate DOC to form 18-hydroxy-deoxycorticosterone (18OH-DOC) with the greater activity in the S rats. This increment in 18-hydroxylation of DOC in S over R rats was offset by an equal decrement in 11β-hydroxylation of DOC to form corticosterone (B) in S compared with R rats. These alterations in metabolic pathways gave rise to characteristic 18OH-DOC/B ratios for S and R animals that were obvious both in vitro and in vivo. The data suggest, therefore, that in selectively breeding rats on the basis of blood pressure response to salt, a gene (or genes) which affects the 18OH-DOC/B ratio has been segregated in the S and R strains. Although this segregation is in itself good evidence for an effect of 18OH-DOC (or 18OH-DOC/B ratio) on blood pressure in rats, it was also emphasized that there is evidence for more than one gene affecting blood pressure in rats. Thus, the steroid difference described is likely to be controlled by only one of several genes affecting the quantitative character of blood pressure. Comparison of 18OH-DOC/B ratios in S and R strains with other strains of rats showed that the high ratio in S rats was quite common, but that the low ratio in R rats was rather unique. Thus, it seems that the low 18OH-DOC/B ratio of R animals connotes resistance to salt, while the higher ratio in S and unselected strains probably only connotes normal susceptibility to salt. The extreme sensitivity of S rats to salt must therefore be accounted for by other genes.

18-Hydrox-deoxycorticosterone secretion in experimental hypertension in rats.

Adrenal steroidogenesis was studied in vitro and in vivo in rats which have been specifically bred for susceptibility (S strain) or resistance (R strain) to the hypertensive effects of salt. A marked quantitative difference was found between S and R rats in the adrenal biosynthetic pathways which are subsequent to deoxycorticosterone (DOC). There was a twofold difference in the ability to 18-hydroxylate DOC to form 18-hydroxy-deoxycorticosterone (18OH-DOC) with the greater activity in the S rats. This increment in 18-hydroxylation of DOC in S over R rats was offset by an equal decrement in 11β-hydroxylation of DOC to form corticosterone (B) in S compared with R rats. These alterations in metabolic pathways gave rise to characteristic 18OH-DOC/B ratios for S and R animals that were obvious both in vitro and in vivo. The data suggest, therefore, that in selectively breeding rats on the basis of blood pressure response to salt, a gene (or genes) which affects the 18OH-DOC/B ratio has been segregated in the S and R strains. Although this segregation is in itself good evidence for an effect of 18OH-DOC (or 18OH-DOC/B ratio) on blood pressure in rats, it was also emphasized that there is evidence for more than one gene affecting blood pressure in rats. Thus, the steroid difference described is likely to be controlled by only one of several genes affecting the quantitative character of blood pressure. Comparison of 18OH-DOC/B ratios in S and R strains with other strains of rats showed that the high ratio in S rats was quite common, but that the low ratio in R rats was rather unique. Thus, it seems that the low 18OH-DOC/B ratio of R animals connotes resistance to salt, while the higher ratio in S and unselected strains probably only connotes normal susceptibility to salt. The extreme sensitivity of S rats to salt must therefore be accounted for by other genes.

Cardiovascular reactivity in the experimental hypertensive rat.

1. In pithed preparations, deoxycorticosterone (DOCA)/NaCl-induced hypertensive rats showed increased cardiovascular reactivity to injected noradrenaline, DMPP, tyramine, angiotensin and to sympathetic nerve stimulation.2. Pithed, chronic renal hypertensive rats showed similar hyperreactivity to noradrenaline, DMPP and tyramine but responses to sympathetic nerve stimulation were within normal limits.3. In the isolated, Krebs perfused mesentery preparation, vessels obtained from both DOCA/NaCl and renal hypertensive rats showed hyperreactivity to injected noradrenaline. Responses to periarterial nerve stimulation were also markedly increased in preparations from DOCA/NaCl hypertensive rats, while preparations from renal hypertensive rats showed this effect only at higher rates of stimulation (12 and 25 Hz).

Experimental hypertension of the rat: reciprocal changes of norepinephrine turnover in heart and brain-stem.

In experimental hypertensive rats (DOCA-implantation, 1% saline as drinking-water, encapsulation of the left kidney), the norepinephrine turnover in peripheral sympathetically innervated organs and the central nervous system was determined either by the decay in endogenous norepinephrine after inhibition of tyrosine hydroxylase or by the ecayd in the specific norepinephrine activity after intravenous or intraventricular administration of3H-norepinephrine. In the heart, the norepinephrine turnover was accelerated in proportion to the rise in blood pressure. In hypothalamus and medulla oblongata, the turnover was delayed reciprocally to the acceleration in the heart. No changes were seen in the residual parts of the brain.

Effects of homotaurine on blood pressure and cardiac actions

Homotaurine (HT) elicited a cardio-stimulant action at high concentration on isolated frog hearts, guinea-pig atria and guinea-pig hearts, though it brought about no actions in the heart lung preparation of dogs. In rabbits, HT showed a mild cardiac-stimulating as well as a hypotensive effect. The hypotensive effect was likewise observed in rats and was shown to be more potent in experimental renal hypertensive rats than that in normal rats. These cardiovascular effects were decreased when it was administered repeatedly. The cardio-stimulant action of HT was retained after administration of adrenergic α and β-blocking agents, and, although HT showed a mild protective effect against the cardio-depressant action of dinitrophenol and large doses of CaCl2, cardiac action of autonomic drugs, CaCl2 and KCl were not affected by HT. From these results, it has been suggested that HT has a hypotensive and a cardiotonic effect, its cardiac effect being due to its direct action.

Catecholamine Metabolism in Hypertensive Rats

The possible role of catecholamines in two forms of experimental hypertension in rats was investigated further. Inbred, spontaneously hypertensive (SH) Wistar rats had unchanged endogenous levels of norepinephrine (NE) in the three tissues studied, and a significantly ( P <0.05) decreased rate of NE synthesis ( 14 C-tyrosine technique) in heart and brainstem but not in gut, in comparison to normotensive Wistar rats. Also, the levels of free fatty acids (FFA) and major urinary catecholamine metabolites in plasma revealed no evidence of increased catecholamine turnover or release. Sprague-Dawley rats rendered hypertensive by treatment with desoxycorticosterone acetate and 1% salt had decreased cardiac NE concentration and increased cardiac NE turnover ( 3 H-NE technique) and cardiomegaly, confirming the work of others. However, urinary normetanephrine and plasma FFA did not differ from those in normal rats. These and other results fail to support but do not completely exclude a primary role for catecholamines in either type of hypertension.

EXPERIMENTAL HYPERTENSION OF THE RAT: RECIPROCAL CHANGES OF NOREPINEPHRINE TURNOVER IN HEART AND BRAIN-STEM

In experimental hypertensive rats (DOCA-implantation, 1% saline as drinking-water, encapsulation of the left kidney), the norepinephrine turnover in peripheral sympathetically innervated organs and the central nervous system was determined either by the decay in endogenous norepinephrine after inhibition of tyrosine hydroxylase or by the ecayd in the specific norepinephrine activity after intravenous or intraventricular administration of3H-norepinephrine. In the heart, the norepinephrine turnover was accelerated in proportion to the rise in blood pressure. In hypothalamus and medulla oblongata, the turnover was delayed reciprocally to the acceleration in the heart. No changes were seen in the residual parts of the brain. Administration of chlorisondamine, a quaternary ganglionic blocking agent which does not cross the blood-brain barrier, resulted in a normalization of the increased cardiac norepinephrine turnover, whereas the changes in the brain persisted. Implantation of DOCA alone produced neither a rise in blood pressure nor changes in norepinephrine turnover. The results presented are compatible with the hypothesis that, in this form of experimental hypertension, the delay in norepinephrine turnover in the brain-stem is causally related to the increased activity of the peripheral sympathetic nervous system.

Effects of diet on blood pressure in experimental renal hypertensive rat.

Many factors have been implicated in the etiology of hypertension. The experiments to be reported here were done to study the effects of diets on blood pressure in a total of 263 Dawley rats in which unilateral renal artery was constricted by silver clip and 82 normal rat served as controls.As regards the environmental factors, experiment I was done under the natural condition while experiment II was made under the condition of constant temperature and constant humidity.In experiment I, both normal control and renal hypertensive rats were divided into 9 groups respectively and fed various experimental diets by the combinations of protein, fat and salt according to the experimental design. In experiment II, they were divided into 5 groups respectively by the combination of protein and salt.From these experiments, it was observed that low protein diet combined with high salt causes significant elevation in blood pressure of Goldblatt hypertensive rats compared to the other experimental diet, while not in the normal control rats fed the diets of similar composition. There were no significant differences in blood pressure elevation between two environmental conditions.

Behavior patterns and sensitivity to experimental hypertension in rats.

SummaryRats from two inbred strains with opposite genetic predispositions to hypertension had different behavior patterns after a standard change in their environment. After removal of the cage lid, the number of “explorations” and “crossings” between two adjacent cages were consistently higher in the strain resistant to hypertension than in the strain prone to hypertension (p < .01). This difference in behavior was present in young rats before experimental hypertension was produced indicating that the behavioral pattern was not the result of the hypertension. It is not yet clear that these behavioral differences play a direct role in the sharply different proclivities to hypertension present in the two strains of rat.

A method for production of experimental hypertension in rats.

A new and simple procedure for producing experimental hypertension in rats is described. It consists in the complete ligature of the aorta between the origin of the renal arteries. Production of an atrophic left kidney depends closely on the rat's body weight, occurring in about 90% of rats weighing over 300 g and almost never in those weighing under 150 g. The great majority of rats weighing more than 300 g with atrophic left kidneys were hypertensive.

The turnover of noreoinephrine in the heart during experimental hypertension in rats

Experimental hypertension was induced by implantation of cellulose capsule around one kidney followed by contralateral nephrectomy. The turnover of norepinephrine in heart was increased after capsulation and was further enhanced by contralateral nephrectomy. When the nephrectomy was omitted the blood pressure did not rise, the endogenous level of norepinephrine was decreased and the turnover rate of NE was below normal. These results indicate that ab increased activity of the sympathetic nervous system plays a significant role in this model of experimental hypertension.

On the noradrenaline reaction of the adrenal medulla in experimental hypertensive rats, especially in spontaneously hypertensive rats. I. Histochemical and histometrical studies on the noradrenaline storing cell islets of the adrenal medulla in various experimental hypertensive rats.

Spontaneously hypertensive rats, renal hypertensive rats, DCA hypertensive rats, neurogenic hypertensive rats and control rats totalling 360 were killed under minimum stress. The noradrenaline in the adrenal medulla was stained by COUPLAND et al.'s glutaraldehyde osmium tetroxide method and the dimensional changes of noradrenaline storing cell islets were studied. In this experiment, spontaneously hypertensive rats were divided into four stages through their survival duration : until 30th day after birth, the 40th to 60th day after birth, the 5th to 7th month after birth and over one year after birth. Renal hypertensive rats, DCA hypertensive rats and neurogenic hypertensive rats were divided into four stages: the prehypertensive stage, the early stage of the 5th to the 24th day after operation, the middle stage of the 3rd month after operation and late stage of the 6th month after operation. Findings in spontaneously hypertensive rats, renal hypertensive rats, DCA hypertensive rats and neurogenic hypertensive rats were compared with those in control rats with almost the same survival duration. (1) The noradrenaline storing cell islets in the adrenal medulla became stainable from the 6th day after birth in both cases of spontaneously hypertensive rats and control rats. After that, the intensity of staining became stronger and after the 15th day, it maintained constant intensity. (2) The area of noradrenalune storing cell islets of the adrenal medulla in spontaneously hypertensive rats on the 6th day after birth was 9.6 per cent, about 1.2 times as large as that of control rats (8.1%) and after that as days passed, the area became larger. On the 10th day, that of spontaneously hypertensive rats was 14.1 per cent, about 1.5 times as large as that of control rats (9.1%), on the 18th day, 21.7 per cent, about 2 times as large as that of control rats (10.5%), and after that the state was constant until one year after birth, when it decreased a little. Spontaneously hypertensive rats develop hypertension in the 8th week after birth while the area of noradrenaline storing cell islets in the adrenal medulla becomes about 2 times as large as that of control rats before the development of hypertension, and this state remains constant after the development of hypertension. (3) As for the area of noradrenaline storing cell islets in the adrenal medulla of renal hypertensive rats, DCA hypertensive rats and neurogenic hypertensive rats, the following results were obtained : (a) In the prehypertensive stage, the areas in three kinds of hypertensive rats did not increase as in the case of spontaneously hypertensive rats, and there was no significant difference from that of control rats. (b) However, the area of noradrenaline storing cell islets in the adrenal medulla increased immediately after the development of hypertension. (i) Renal hypertensive rats showed an increase in the area; 17.8 per cent in the early stage, 17.9 per cent in the middle stage and 19.1 per cent in the late stage, and their values were 1.3 times, 1.5 times and 1.6 times as large as that of control rats. (ii) In the case of DCA hypertensive rats, the area was 19.9 per cent in the early stage, 20.5 per cent in the middle stage and 20.4 per cent in the late stage, showing an increase of 1.4 times, 1.6 times and 1.7 times in comparison with that of control rats. (iii) In the case of neurogenic hypertensive rats, the area was 21.4 per cent in the early stage, 23.5 per cent in the middle stage, 26.3 per cent in the late stage, and was 1.4 times, 1.7 times and 1.8 times as large as that of control rats, respectively, that is, in renal and DCA hypertensive rats, the grade of increase in the area was always smaller than that of spontaneously hypertensive rats but neurogenic hypertensive rats showed almost the same value as that of spontaneously hypertensive rats in the late stage. (c) The intensity of staining of noradrenaline storing cell islets did not show any difference fr