Hypertensive Male Rats Research Articles

Effect of cicletanine on reperfusion-induced arrhythmias and its relation to 6-keto-PGF1α and thromboxane B2 release

Isolated hearts, excised from spontaneously hypertensive male rats treated orally with cicletanine, a new furopyridine anti-hypertensive drug, were subjected to 30 min of global ischemia followed by 10 min of reperfusion. The effect of cicletanine on reperfusion-induced arrhythmias in relation to 6-keto-PGF1 alpha and thromboxane (TXB2) release was studied. After 30 min of global ischemia, the incidence (total) of ventricular fibrillation (VF) and ventricular tachycardia (VT) was reduced by 2-week pretreatment of the rats with 30 and 100 mg/kg of cicletanine (VF, 33% at 30 mg/kg and 25% at 100 mg/kg vs. 91% in untreated rats; VT, 42% at 30 mg/kg and 42% at 100 mg/kg vs. 100% in untreated rats), while lower doses of cicletanine (3 and 10 mg/kg) failed to reduce the incidence of reperfusion-induced rhythm disturbances. Reperfusion of the ischemic myocardium resulted in a fivefold increase of 6-keto-PGF1 alpha and TXB2 release in the perfusion effluent of fibrillated hearts but not in the perfusion effluent of nonfibrillated hearts. Cicletanine failed to influence the reperfusion-stimulated release of 6-keto-PGF1 alpha and TXB2. These results indicate that the anti-arrhythmic effect of cicletanine in the reperfused myocardium is not related to PGI2 and thromboxane A2 release.

Sexual dimorphism in renal function and hormonal status of New Zealand genetically hypertensive rats

Renal water and electrolyte handling and related plasma hormone levels were measured in male and female New Zealand genetically hypertensive and normotensive rats, in an attempt to establish any potentially important sex-related differences in these parameters. Male hypertensive rats had higher blood pressure than female hypertensive rats, but normotensive rats showed no such sex difference. Both groups of males had higher fluid turnover rates than respective females, and this was associated with raised plasma vasopressin in hypertensive males. Female hypertensive rats excreted more sodium, potassium and chloride in association with lower plasma aldosterone and higher corticosterone levels compared with the other groups. Plasma electrolytes did not differ between the four groups, but plasma osmolality was higher in hypertensive than normotensive rats of both sexes. A higher rate of electrolyte loss and lower fluid turnover in association with reduced plasma vasopressin may contribute to the lower blood pressure of female compared with male hypertensive rats.

Blood and tissue zinc levels in spontaneously hypertensive rats.

Zinc (Zn) determinations were performed on blood plasma and red cells, liver, heart, adrenals, and spleen of spontaneously hypertensive (SHR) and control normotensive (WKY) male rats, 20 weeks of age. SHR revealed higher red cell (p = 2 x 10(-5)) and heart (p = 0.007) Zn levels than WKY rats. The water content of organs was the same in the two strains. When compared with published data, these results suggest an association between high cell Zn levels and hypertension, the meaning of which is briefly discussed.

Exercise training and incidence of cerebrovascular lesions in stroke-prone spontaneously hypertensive rats

To assess the effects of moderate exercise [40-70% maximal oxygen uptake (VO2max)] on resting blood pressures, the presence of cerebrovascular lesions, and the life spans of stroke-prone hypertensive rats, nontrained and trained male and female rats were assigned to two experimental groups. The first (n = 48) were exercise trained after 38 days of age, whereas the second (n = 44) initiated exercise training when the animals were 134 days of age. To facilitate cerebrovascular lesions, the sodium concentrations in the rat chow and in the drinking solutions were increased. Symptoms utilized to denote the presence of cerebrovascular lesions were irritability, hyperresponsiveness, ataxia, lethargy, unwillingness to run, and combinations thereof. All brains were removed immediately after death, fixed, and evaluated grossly and microscopically for lesions. In the study with the younger animals, training was associated with a 7-9% increase in VO2max that was statistically significant only in animals with no histological evidence of cerebrovascular lesions. For the older animals, a significant 5-8% increase in VO2max was noted for animals with or without lesions. After 42 days of training for both groups, resting blood pressures for the trained groups with histological lesions were significantly lower. However, this trend did not continue, and the older trained rats appeared to have strokes earlier and to die sooner than their nontrained controls. Although 83% of the older animals had subjective evidence for a stroke before they died, the percentage of animals with lesions ranged from 42 to 58%, with the trained groups having higher percentages.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between left ventricular systolic resistance and contractile rate processes

To test the hypothesis that left ventricular (LV) systolic resistance is determined by the intrinsic rate processes of the contractile system, we studied 40 spontaneously hypertensive male rats (SHR). Thyroid hormone manipulation was used to alter isomyosin composition and consequently the rate processes of the contractile system. Seven groups of rats were studied: control (SHRC, n = 9); propylthiouracil (PTU) treated for 10 days (SHRP-10, n = 5), 20 days (SHRP-20, n = 5), and 30 days (SHRP-30, n = 6); and thyroxine treated for 5 days (SHRT-05, n = 5), 10 days (SHRT-10, n = 5), and 15 days (SHRT-15, n = 5). In situ (n = 40) and isolated (n = 14; 5 SHRP-30, 5 SHRC, and 4 SHRT-15) heart experiments were performed. In comparison to SHRC, we observed the following: 1) LV pump performance was not different in any of the thyroxine-treated groups, whereas with PTU, pump performance was significantly depressed in rats with greater than 80% slow myosin. 2) Normalized LV peak elastance (Emaxn) was significantly increased in the SHRP-30, whereas it was not altered after thyroxine. These observations were further confirmed in the isolated heart on the basis of peak isovolumetric stress-strain relations. 3) Thyroxine increased and PTU decreased theoretical maximum flow (Qmax; a measure of LV resistance); thus an inverse relation between Qmax and percent slow myosin was observed (r2 = 0.86). 4) The time to peak isovolumetric pressure was increased in SHRP-30 and decreased in SHRT-15. The relaxation process was significantly slower for SHRP-30 group and was unchanged for SHRT-15 group. These observations support our hypothesis that LV systolic resistance quantifies an intrinsic rate-dependent property of the myocardium and that isomyosin composition is one of its determinants. In addition, with changes in isomyosin composition toward predominantly slow myosin, the responses in Emaxn and Qmax are discordant, which may be responsible for the preservation of pump performance. This underscores the importance of quantifying both LV systolic resistance and elastance in the assessment of the functional status of the LV as a mechanical pump.

Chronic treatment with the angiotensin I converting enzyme inhibitor, perindopril, restores the lower limit of autoregulation of cerebral blood flow in the awake renovascular hypertensive rat

Chronic hypertension shifts the lower limit of cerebral blood flow autoregulation to a higher pressure level. Although acute administration of angiotensin converting enzyme inhibitors restores the lower limit of cerebral blood flow autoregulation the chronic effects have not received much attention. We studied the effect of the angiotensin converting enzyme inhibitor, perindopril, on mean arterial pressure, basal cerebral blood flow and cerebral blood flow autoregulation in renovascular hypertensive (two-kidney, one clip model) and normotensive male Wistar rats. Seven weeks after renal artery clipping or sham operation rats received daily intraperitoneal injections of perindopril. The dose was increased from 1 to 8 mg/kg over the first 4 weeks until blood pressure was normalized. Chronic renovascular hypertension caused a marked shift in the lower limit of cerebral blood flow autoregulation but did not alter basal cerebral blood flow. Treatment of hypertensive rats with perindopril normalized blood pressure and restored cerebral blood flow autoregulation. Chronic treatment of normotensive rats with perindopril increased basal cerebral blood flow. In conclusion, chronic treatment of renovascular hypertensive rats with perindopril causes a shift in the lower limit of cerebral blood flow autoregulation towards the value observed in normotensive rats.

Changes in Growth Hormone Secretion in Spontaneously Hypertensive Rats

Secretion of the growth hormone (GH) in spontaneously hypertensive (SH) male rats has been determined and compared with that of normotensive Wistar-Kyoto (WKY) controls. In a first set of experiments, plasma GH concentration and pituitary GH content were measured in SH rats 30, 60 and 90 days old. 30-day rats showed reduced GH plasma and pituitary levels, whereas in 60- and 90-day-old rat no differences in GH plasma concentration and increased GH pituitary content were observed. In a second set of experiments, 90-day-old SH male rats anesthetized with sodium pentobarbital and intravenously injected with growth hormone-releasing factor (GRF) showed an amplitude and duration of response to injected hormone higher than WKY controls. In a third set of experiments, hemipituitaries of 90-day-old SH males were incubated for 2 h in Krebs-Ringer-bicarbonate either in the presence or in the absence of GRF. In the absence of GRF stimulation, the in vitro release of GH was higher than in WKY controls, whereas in the presence of GRF the sensitivity and the maximum response to GRF was reduced in comparison with normotensive male rats. These results indicate that SH rats have decreased pituitary content and plasma GH concentration before puberty. Besides, they showed increased pituitary GH content in adulthood and opposite changes in the in vivo and in vitro response to GRF.

Role of platelets as a factor aggravating cerebral ischemia.

In order to clarify the role of platelets as a factor aggravating cerebral ischemia, an experimental model of ischemia was investigated using thrombocytopenic rats. In addition, the prostacyclin derivative (OP-41483) and the thromboxane A2 synthetase inhibitor (OKY-046), both of which inhibit platelet aggregation, were tested for possible beneficial effects on cerebral ischemia. Cerebral ischemia was produced in spontaneously hypertensive male rats using bilateral common carotid artery ligation (BLCL). Thrombocytopenia was produced with an antiplatelet antiserum which reduced the platelet count to less than 6 x 10(4)/microliters by 24 h. OP-41483 was administered four times hourly (500 ng/kg x 4, i.p.), beginning 1 h prior to BLCL. Similarly, OKY-046 was injected four times hourly (10 mg/kg x 4, i.p.). Brain metabolites such as ATP, lactate and pyruvate and water content were determined after 3 h of cerebral ischemia. Brain levels of ATP in the ischemic rats with thrombocytopenia were higher than those of the ischemic rats without thrombocytopenia. In addition, thrombocytopenia reduced the increase of lactate and water content in the ischemic brain. Animals treated with OP-41483 also maintained higher levels of ATP and lower levels of lactate and water compared to animals given a vehicle. OKY-046 significantly reduced brain water content, but had no effect on the ischemic alteration of brain metabolite levels. These results indicate that platelets play an important role in the progression of metabolic change during ischemia.

Reduced inhibitory effects of clonidine and neuropeptide Y on 3H-noradrenaline release from synaptosomes of the medulla oblongata of the spontaneously hypertensive rat.

The release of 3H-noradrenaline (3H-NA) evoked by high-K+ (15 mM) was studied in synaptosomes isolated from the medulla oblongata of the normotensive Wistar-Kyoto and spontaneously hypertensive male rat (14 weeks old) using a superfusion apparatus. Based on concentration-response curves clonidine was shown to have a reduced ability to inhibit 3H-NA release in synaptosomes isolated from the spontaneously hypertensive rat (SHR) versus the normotensive rat. Furthermore, only a high concentration of NPY (100 nM) had the ability to enhance the inhibitory effects of clonidine on 3H-NA release in synaptosomes isolated from the medulla oblongata of the SH male rat, while 1 nM of NPY was effective in synaptosomes isolated from the medulla oblongata of the normotensive Wistar-Kyoto rat. These results may indicate a reduced presynaptic alpha 2-adrenoceptor and NPY receptor function to inhibit 3H-NA release from NA and/or adrenaline (A) nerve terminals in the medulla oblongata of the adult 14 weeks old SHR.

Effects of diet and metoprolol on lipid levels in the blood plasma and morphology of the heart and intramural branches of coronary arteries of spontaneously hypertensive male rats. A 9-month study.

Semipurified diets containing 0.5% cholesterol were used in a 9-month study with spontaneously hypertensive male rats to characterize the effects of the protein source (casein vs. soybean protein), and the selective beta 1-adrenoceptor antagonist metoprolol on both lipid levels in blood plasma and the aorta, and on the morphology of intramural branches of coronary arteries. Raised blood lipid levels were observed in these rats. A significant decline in HDL2 cholesterol took place, while plasma cholesterol belonging to lipoprotein fractions of lower density increased. Metoprolol treatment led to a substantial elevation of the plasma triacylglycerol level and, with time, a reduced cholesterolemic response. The use of soybean protein instead of casein had a persistent plasma lipid-lowering effect. Arteriosclerotic changes in the form of musculo-elastic thickenings, intimal cushions and homogeneous hyalin deposits appeared in the intramural coronary arteries of rats in all groups after 9 months on the diet. However, intimal deposition of lipid was only present in rats belonging to the casein group not treated with metoprolol. Rats of this group also showed more severe myocardial lesions in the form of scar tissue with or without inflammatory cell reaction.

Sex difference in pressor responsiveness to vasopressin and baroreflex function in DOC-salt hypertensive rats

This study was undertaken to investigate further the possible role of vasopressin in the sexual dimorphism of deoxycorticosterone (DOC)-salt hypertension. The study was carried out 3 weeks after initiating treatment with DOC and salt in uninephrectomized male and female rats. Mean arterial pressure (MAP) was lower in female than in male DOC-salt hypertensive rats (177 +/- 7 versus 198 +/- 4 mmHg; P less than 0.01). Mean arterial pressure did not differ between male and female normotensive control rats. Increases in MAP in response to graded i.v. infusions of vasopressin were markedly attenuated in female normotensive and hypertensive rats, but there was no sex difference in pressor responses to i.v. phenylephrine. Baroreflex sensitivity was reduced in both male and female DOC-salt rats, but to a greater extent in males (P less than 0.01). Diminished pressor responsiveness to vasopressin and a smaller impairment of baroreflex sensitivity may contribute to the reduced development of DOC-salt hypertension in female rats.

Pindolol, not propranolol, reverses cardiac hypertrophy in renal hypertensive rats.

Reversal of cardiac hypertrophy has been obtained by treatment with some antihypertensive drugs but has not been achieved consistently with beta blockers. To investigate whether this difference might be explained by the distinct hemodynamic actions of the drugs, we studied the effects of propranolol and pindolol, beta blockers with distinct modes of action, on cardiac hypertrophy of hypertensive male Wistar rats, two-kidney, one clip (2K1C) Goldblatt model (n = 33) and sham-operated control rats (n = 34). We also assessed the effects of such therapies on the ventricular pumping ability during open-chest, transient aortic occlusion. Four weeks after surgery, propranolol (5 mg/kg/day p.o.) was given to hypertensive (n = 8) and control rats (n = 11); pindolol was also given orally (1 mg/kg/day) to similar groups (n = 7 and n = 5, respectively). Untreated animals served as controls for both groups. Cardiac hypertrophy developed with hypertension in the untreated rats of the propranolol (3.38 +/- 0.18 vs 2.60 +/- 0.08 mg/g; p less than 0.01) and pindolol groups (3.93 +/- 0.21 vs 2.40 +/- 0.03 mg/g; p less than 0.001). Treatment reversed cardiac hypertrophy in the pindolol-treated (3.01 +/- 0.19 vs 3.93 +/- 0.21 mg/g; p less than 0.001, NS) but not in the propranolol-treated rats (3.24 +/- 0.18 vs 3.38 +/- 0.21 mg/g, NS). The maximal pressure that developed during aortic occlusion in the propranolol group was similar to that observed in the pindolol group. These results indicate that cardiac hypertrophy is reversed by pindolol but not by propranolol, and that this reversal does not interfere with left ventricular pumping ability.

Influence of a diet rich in fish oil on blood pressure, body weight and cardiac hypertrophy in spontaneously hypertensive rats.

The effects of a diet rich in fish oil on arterial blood pressure, body weight, left ventricular weight and heart rate have been investigated in 8 month old spontaneously hypertensive male rats (SHR) as compared to age-matched hypertensive controls. A diet containing 10% fish oil decreased blood pressure by about 40 mmHg within 20 days of starting the experiment, and this effect persisted over the observation period of 80 days. Permitting the animals free access to food, the body weight of the diet group increased by 25%. The degree of hypertrophy as evaluated by relating left ventricular weight to tibial length was significantly reduced (10%) in the diet fed group. Heart rate was increased by 53%. The study demonstrates that a diet rich in fish oil can lower arterial blood pressure over several weeks without a recognizable loss in function despite a considerable increase in body weight. It can be assumed that a more marked regression of left ventricular hypertrophy is counteracted by a reflex increase in sympathetic efferentation to the heart.

Nifedipine, its action on the cationic concentrations in heart, vessels, skeletal muscle and blood in tissues of normotensive and spontaneously hypertensive rats (SHR)

1. 1. The cationic tissue distribution, obtained by atomic absorption spectrophotometry, was different in normotensive (Wistar) and spontaneously hypertensive male rats (SHR). 2. 2. In both groups, nifedipine (4.2 mg/100 g body wt, by gastric intubation, during 10 days) altered the cationic composition mainly in the aorta, atria and in SHR also in the vein. 3. 3. In normotensive Wistar rats (NWR), nifedipine provoked a higher concentration of divalent cations (Ca 2+, Mg 2+ and Zn 2+) in the ascending part of the aorta and reduced the monovalent (Na +) concentration in the aorta, vein and skeletal muscle. 4. 4. In spontaneously hypertensive rats (SHR) the pathognomonic higher cationic concentrations in the aorta, right atrium and vein are significantly ( P < .005) reduced after nifedipine treatment.

Evidence for discrete alterations in central cardiovascular catecholamine and neuropeptide Y immunoreactive neurons in aged male rats and in genetically hypertensive male rats of the Lyon strain.

A computer-assisted morphometrical and microdensitometrical analysis has been performed on cardiovascular noradrenaline (NA), adrenaline (A) and neuropeptide (Y (NPY) neurons in adult and 24-month-old male rats and on hypotensive (LL), normotensive (LN) and hypertensive (LH) male rats of the Lyon strain using the indirect immunoperoxidase procedures. It was found that in NPY/phenylethanolamine-N-methyltransferase (PNMT) costoring neurons of the CI area of the rostral medulla oblongata NPY-like immunoreactivity showed a more marked reduction than the PNMT immunoreactivity. Furthermore, within the parvocellular part of the paraventricular hypothalamic nucleus. NPY immunoreactive nerve terminal profiles were much more affected than the PNMT immunoreactive profiles during aging as revealed by a marked reduction in the number of profiles and by a marked reduction of absorbency values in the microdensitometrical analysis. Thus, in the NPY/PNMT costoring neurons of the A C1 group of the ventrolateral medulla projecting, for example, to the hypothalamus, the peptide transmission line may have a special vulnerability to the aging processes which may contribute to the development of hypertension in old people in view of a vasodepressor role of many central NPY/PNMT neurons. An extensive morphometrical and microdensitometrical analysis of the various catecholamine (CA) cell groups of the medulla oblongata of the LL, LN and LH rats of the Lyon strain was performed. In a comparison between LL and LH rats the A2 cell group of the LH strain showed a trend for an increase in the mean tyrosine hydroxylase (TH) immunoreactive cell body area and the C3 group showed a significant increase in the number of PNMT immunoreactive profiles.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of chronic lead treatment and hypertension on the severity of cardiac arrhythmias induced by coronary artery occlusion or by noradrenaline in anaesthetised rats.

The aim of this study was to investigate whether chronic (3 months) lead (250 or 1000 ppm), administered as lead acetate in the drinking water, commencing either after weaning (in normotensive or spontaneously hypertensive male rats) or from conception (normotensive rats only) altered the susceptibility of the heart to arrhythmias induced either by coronary artery occlusion or by noradrenaline. Treatment with lead alone had no marked effect on the arrhythmias elicited by either method. Spontaneously hypertensive rats treated with either dose of lead exhibited more ectopic beats following coronary artery occlusion than normotensive rats but not more than those observed in control spontaneously hypertensive rats. An enhanced arrhythmogenic effect of noradrenaline was observed only in hypertensive rats administered 250 ppm lead. Both doses of lead accelerated the development of high blood pressure and in normotensive rats the higher dose also resulted in an elevated pressure. Following administration of lead, blood lead concentrations were elevated to 0.96 and 2.11 mumol l-1 after 250 and 1000 ppm, respectively. Accumulation of lead in heart and bone was also observed. We conclude that chronic exposure to these concentrations of lead, when combined with high blood pressure, slightly enhances the susceptibility of the heart to arrhythmias induced by myocardial ischaemia.

Tissue Converting Enzyme Activity Is Low in the Kidney of Spontaneously Hypertensive Rats

Angiotensin-converting enzyme (ACE) activity was measured in the plasma, the kidney, and other organs of 5-, 8-, and 11-week-old spontaneously hypertensive male rats (SHR) of the Okamoto-Aoki strain and compared with that of age-matched Wistar-Kyoto (WKY, bred by Iffa-Credo) or normotensive Wistar rats. ACE activity was measured spectrofluorometrically, using the artificial substrate N-CBZ-L-phe-L-his-L-leu. ACE activity was constantly lower in the plasma and renal cortex of SHR from 5 weeks on than in WKY rats. This difference in the renal cortex ACE activity persisted after 1 h of open circuit perfusion of the isolated kidney with Krebs-Henseleit medium. On the other hand, there lung, the brain occipital cortex, or the abdominal aorta of hypertensive or normotensive rats. The percentage inhibition of ACE activity provoked by 7 days of oral administration of ramipril (Hoe 498, 1 mg/kg/day) was analogous in the kidneys and lungs of WKY rats and SHR. Enalapril (MK 421, 30 mg/kg/day) was equipotent to ramipril in the kidney but had lower inhibitory effects on the pulmonary ACE activities of WKY rats and SHR.

Production of prostaglandins I 2, E 2 and F 2α by blood vessels of normotensive and hypertensive, male and female rats

Prostaglandin (PG) I 2 (mesured as 6-keto-PGF 1α) was the major PG synthesized by aortic homogenates from normotensive and hypertensive male rats, with lesser quantities of PGF 2α and PGE 2. Homogenates of vena cave from the same rats synthesized PGI 2 and PGE 2 in similar quantities. PGF 2α synthesis by aortic homogenates was significantly higher in hypertensive than in normotensive male rats. A similar trend was seen in PGF 2α synthesis by homogenates of the vena cava. Separation of the aorta of normotensive and hypertensive, male rats showed that PGI 2 was the major PG synthesized by endothelial cells and smooth muscle, and that PGF 2α was the major PG synthesized by adventia. PGI 2 synthesis by smooth muscle and PGE 2 synthesis by endothelial cells were lower, and PGF 2α synthesis by endothelial cells and smooth muscle were higher in hypertensive than in normotensive, male rats. PGI 2 was the major PG released from the aorta of normotensive and hypertensive male rats, together with lesser quantities of PGE 2 and PGF 2α. Aortic PGF 2α output, but not PGI 2 and PGE 2 outputs, was significantly higher in hypertensive compared to normotensive, male rats.

Forebrain binding sites for atrial natriuretic factor: Alterations in spontaneously hypertensive (SHR) rats

Binding sites for atrial natriuretic factor (ANF-28) were studied in forebrain areas of spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) normotensive male rats by quantitative autoradiography. The maximum binding capacity of [(125)I]ANF-28 was significantly reduced in the subfornical organ and choroid plexus of 4 and 14 week old SHR rats compared to age-matched WKY controls. In contrast, the affinity constant for [(125)I]ANF-28 binding was elevated in the choroid plexus of 14 week old SHR rats. These findings indicate that marked reductions in the number of ANF-28 binding sites occur in weanling SHRs as well as in adult SHRs with elevated arterial blood pressures. Thus, these persistant reductions in forebrain ANF-28 binding sites in SHR rats may contribute to the development and maintenance of this form of experimental hypertension.

Effect of Brazilin on Plasma Lipid Levels in Spontaneously Hypertensive Rats

AbstractThe levels of plasma lipid and lipoprotein in spontaneous hypertensive male rats (SHR) fed on normal chow diet, SHR fed on normal chow diet containing 2% cholesterol plus 10% olive oil and SHR fed on the same fat rich diet with the administration (100 mg/kg, orally) of brazilin, 7,11b‐Dihydrobenz [b] indeno 1,2‐d) pyran‐3,6a,9,10 [6H]‐tetrol, were determined to elucidate the effects of brazilin on the improvement of abnormalities in plasma lipid and lipoprotein concentrations of essential hypertensive rats. Plasma levels of total cholesterol, triglyceride and high density lipoprotein‐cholesterol of SHR were significantly changed toward normal physiological values by the treatment with brazilin.