Lipid peroxidation in the aorta of normotensive and spontaneously hypertensive rats with diabetes mellitus]

We have studied the effects of streptozotocin-induced (STI) diabetes on the lipid peroxidation in the aorta from normotensive (NTR) and spontaneously hypertensive (SHR) rats. In the control SHR quantity of malonyldialdehyde (MDA), conjugated dienes (CD) and arterial pressure where higher than in NTR analogous group. It has been shown that Diabetes in NTR results in significantly increased arterial pressure and quantity of MDA and CD. Under certain conditions in SHR arterial pressure and the other factors remain almost unchanged. It is likely that completely different changes in intensity of lipid peroxidation may evidence breaking adaptation mechanism in diabetic SHR.     

Organization of cells and extracelluar matrix in mesenteric arteries of spontaneously hypertensive rats

Summary Biochemical studies have been used to assess the quantitative changes in elastin and collagen in hypertensive vs. normotensive arteries. However, the relative distribution and organization of these fibrous proteins is likely to be equal in importance to their absolute amounts. In this study we have used scanning electron microscopy in association with selective digestion techniques to assess the organization of cellular and extracellular components of the tunica media of mesenteric arteries of spontaneously hypertensive rats. Superior and small mesenteric arteries were digested with acid, alkali, or bleach to exposure cells, collagen, or collagen and elastin, respectively. We observed that hypertension does not cause a qualitative change in the 3-dimensional arrangement of cells, collagen, or elastin in spontaneously hypertensive arteries when compared to normotensive arteries. However, cells in the superior artery are significantly different in overall shape and surface features when compared to cells of small arteries. These differences in surface morphology of cells are present in hypertensive and normotensive vessels and suggest that superior and small mesenteric artery cells transmit load to the isotropic matrix in different ways. In the elasto-muscular superior artery, force is transmitted across digitations throughout the cell surface. In the muscular small artery, force is transmitted across the tapered, smooth cell surface.     

Increased vasodilator responsiveness to BRL 34915 in spontaneously hypertensive versus normotensive rats: contrast with nifedipine

The blood pressure-lowering potency and activity of BRL 34915, a new vasodilator and putative stimulator of potassium efflux from vascular smooth muscle, was investigated in conscious spontaneously hypertensive rats (SHR) and normotensive rats (NTR) after intravenous administration and compared with that of the calcium channel blocker, nifedipine. In SHR, BRL 34915 (3-100 micrograms/kg) or nifedipine (10-3000 micrograms/kg) produced similar reductions in mean arterial pressure of 58 +/- 3% and 55 +/- 3%, respectively. BRL 34915 (ED30% = 13.8 micrograms/kg) was 15.3 times more potent than nifedipine (ED30% = 207 micrograms/kg) in SHR. In contrast, only a 1.7-fold difference in potency was observed in NTR between BRL 34915 (ED30% = 123 micrograms/kg) and nifedipine (ED30% = 182 micrograms/kg). The potency ratio (ED30% NTR/ED30% SHR) for BRL 34915 was 8.83 whereas nifedipine had a ratio of 0.88, reflecting the greater responsiveness of the SHR to BRL 34915. Systemic hemodynamics were monitored in anesthetized SHR and NTR to determine the basis for the reductions in blood pressure. BRL 34915 (3-100 micrograms/kg iv) lowered mean arterial pressure in both groups solely by decreasing total peripheral vascular resistance, since no changes in cardiac output were observed. Relaxation responses were also obtained in phenylephrine-contracted isolated aortic strips from both strains of rat to ascertain whether differences in responsiveness existed at this level of the vasculature. No significant difference in the potency of BRL 34915 (3-10 microM) as a vasodilator was found in aortas from SHR or NTR. These results indicate that, unlike nifedipine, BRL 34915 is a more potent vasodepressor agent in SHR than in NTR and suggests that the potassium efflux stimulator may preferentially relax resistance vessels in the hypertensive rat.     

Aldosterone increases RAMP1 expression in mesenteric arteries from spontaneously hypertensive rats

OBJECTIVE: We analysed the effect of aldosterone on calcitonin gene-related peptide (CGRP) mediated vasodilation in noradrenaline precontracted endothelium denuded mesenteric arteries segments from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) and the effect of aldosterone on calcitonin receptor-like receptor (CL receptor) and receptor activity modifying protein 1 (RAMP1) expression in endothelium-denuded mesenteric arteries from SHR rats. RESULTS: CGRP 0.1 nM-0.1 microM induced a concentration-dependent relaxation that was enhanced by aldosterone 1 microM in SHR only. Incubation with RU 486 10 microM significantly reduced the enhancement of CGRP-relaxation produced by aldosterone in SHR. CL receptor expression was not modified in either strain, while RAMP1 expression was enhanced in SHR by aldosterone 1 microM 120 min and 0.1 microM 120 min. This up-regulation of RAMP1 was prevented by RU 486 10 microM. CONCLUSIONS: Aldosterone, through glucocorticoid receptor activation, increases the vasodilatory effect of CGRP in SHR mesenteric arteries, which seems to be mediated by increased RAMP1 expression.     

Pressor responses to endothelin-1 in normotensive and spontaneously hypertensive rats

In freely moving rats, endothelin-1 (0.0135–4.5 nmol/kg) administered as an intravenous bolus injection, produced an immediate, short-lasting, dose-related fall in blood pressure followed by a long-lasting, dose-related increase in blood pressure. There was a higher sensitivity in the pressor responses to endothelin-1, in spontaneously hypertensive (SH) rats (ED₅₀ = 0.11 ± 0.02 and 0.28 ± 0.02 nmol/kg, in SH and normotensive rats, respectively), but no change in the maximal pressor effect of endothelin-1 in SH rats.

In rat isolated aorta, endothelin-1 induced a greater vasocontractile effect in SH rats than in normotensive rats. In both rat strains, removal of the endothelium did not change the concentration-effect curves obtained in endothelium-intact preparations. These data add further support to the hypothesis that endothelin-1 could play a role in genetic hypertension, at least in the maintenance of high blood pressure.     

Reactivity of the aorta and mesenteric resistance arteries from the obese spontaneously hypertensive rat: effects of glitazones

The obese spontaneously hypertensive rat (SHROB) is a model of metabolic syndrome in which, to our knowledge, vascular function has never been studied. The actions of insulin sensitizers (glitazones) on vascular function have not been analyzed either. Our purpose was to characterize microvascular and macrovascular responses of the SHROB and to study the effects of glitazones on these responses. The reactivity of mesenteric resistance arteries (MRAs) and the aorta from SHROBs and control rats to cumulative concentrations of phenylephrine, ACh, and sodium nitroprusside (SNP) was myographically analyzed. Some animals were orally treated with rosiglitazone (3 mg·kg(-1)·day(-1), 3 wk), and myography was performed. Phenylephrine, ACh, and SNP dose-response curves were impaired to different extents in arteries of SHROBs. Incubation with N-nitro-L-arginine methyl ester caused little effects on phenylephrine and ACh curves in MRAs but enhanced phenylephrine contractions and abolished ACh-induced relaxations of aortae. Incubation with indomethacin reduced phenylephrine reactivity and improved ACh-induced relaxations of all vessels studied. NS-398 and tempol increased relaxations to ACh of MRAs. Incubation with pioglitazone or rosiglitazone (both 10(-5) M) or oral treatment with rosiglitazone improved, to different extents, ACh and SNP curves in all vessels. Glitazone incubation diminished aortic ACh sensitivity. The release of thromboxane A(2) and PGI(2) metabolites (thromboxane B(2) and 6-keto-PGF(1α)) was analyzed. ACh increased the MRA release of thromboxane B(2) from SHROBs but not control rats, and the former was prevented by rosiglitazone coincubation. In contrast, in aortae, ACh failed to alter the release of metabolites, and rosiglitazone treatment increased that of 6-keto-PGF(1α). Thus, SHROBs displayed microvascular and macrovascular dysfunction. MRAs, but not aortae, of SHROBs revealed an impaired endothelial nitric oxide pathway, whereas both, but especially MRAs, displayed an impaired cyclooxygenase pathway. Glitazones elicited beneficial effects on macrovascular and, especially, microvascular function of SHROBs.     

Comparison of somatosympathetic reflex in normotensive and spontaneously hypertensive rats

In chloralose anaesthetized and paralyzed normotensive (Wistar, Wistar--Kyoto) and spontaneously hypertensive rats (SHR), a somatosympathetic reflex in the cervical sympathetic trunk elicited by a single electrical shock to forelimb afferent fibres in the median nerve was recorded. It has been shown that the elicited response of SHR is similar to the response of normotensive rats. Amplitude of somatosympathetic reflex in SHR is larger than that of somatosympathetic reflex in normotensive animals. It is supposed that somatosympathetic reflex in hypertensive and normotensive rats is formed in the same way. However, reflex excitability of sympathetic nervous system in SHR is greater.     

Elastase-like enzyme in the aorta of spontaneously hypertensive rats

In an attempt to obtain information regarding vascular elastase in arterial hypertension, we examined biochemical changes in elastase-like enzyme activity, and the intravascular localization of elastase by immunohistochemical techniques in the aorta of spontaneously hypertensive rats (SHR). In the biochemical study, aortic elastase-like enzyme activity was significantly higher in SHR than in controls. Using an antibody against rat pancreatic elastase raised in the rabbit, it was demonstrated immunohistochemically that the enzyme was localized in the endothelial cells and subendothelial spaces in the aorta of control animals. In SHR, elastase was also demonstrated in medial smooth muscle cells and particularly in the modified smooth muscle cells in areas of intimal thickening. Some vacuoles in the smooth muscle cells also showed positive enzyme staining. Elastase seems to play an important role in the development of hypertensive vascular changes.     

Cold-restraint induced gastric lesions in normotensive and spontaneously hypertensive rats

Spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats were subjected to 2 hr of cold-restraint stress at 2–6°C following a 24 hr fast. WKY rats had a significantly greater incidence and degree of ulceration of the gastric glandular mucosa than did SHR rats. Mean arterial pressure, obtained from a chronic arterial cannula, fell during 2 hr of cold-restraint stress in both SHR and WKY rats. Heart rate was unchanged in WKY but fell significantly in SHR. Plasma norepinephrine (NE) and epinephrine (E), determined by radioenzymatic assay, increased significantly following stress. Increased levels of NE remained similar for both SHR and WKY rats, while post-stress levels of E for the SHR rats greatly exceeded E levels for WKY rats. A greater degree of hypothermia was also noted in SHR rats. Decreased stress induced ulcerogenesis in the SHR may be due to the well-known altered hemodynamic and autonomic nervous system reactivity in this strain or other factors not yet discovered.     

Beta-adrenoceptors in kidney tubules of spontaneously hypertensive and normotensive rats

Beta-adrenoceptor binding characteristics were determined in different fractions of rat kidney tubules using a [125Iodo]-(-)-cyanopindolol (ICYP) binding assay. The highest amount of binding sites was found in a fraction containing predominantly distal tubular fragments. In a separate series of experiments the ICYP binding characteristics were compared in whole tubular fractions from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) of different ages. The maximum number of binding sites was significantly higher both in young (3 weeks) and adult (14 weeks) SHR when compared to age-matched WKY. These studies showed the presence of beta-adrenoceptor binding sites in rat kidney tubules and support the potential importance of tubular beta-adrenoceptors in the development of spontaneous hypertension and in the mechanism of antihypertensive action of beta-blockers.     

Day-night variation in the in vitro contractility of aorta and mesenteric and renal arteries in transgenic hypertensive rats

TGR(mREN2)27 (TGR) rats develop severe hypertension and an inverted circadian blood pressure profile with peak blood pressure in the daytime rest phase. The present study investigated the in vitro responsiveness of different arteries of TGR rats during day and night. Twelve-week-old TGR rats and normotensive Sprague-Dawley (SPRD) controls, synchronized to 12h light, 12h dark (LD 12:12) (light 07:00 19:00), were killed at 09:00 (during rest) and 21:00 (during activity), and endothelium-dependent relaxation by acetylcholine and vascular contraction by angiotensin II were studied by measuring isometric force in ring segments of abdominal aorta and mesenteric and renal arteries. In SPRD rats, consistent day-night variation was found, with greater responses to angiotensin II during the daytime rest span. In TGR rats, biological time-dependent differences were found in the renal vasculature, but not in the aorta and mesenteric artery. Relaxation of SPRD rat aorta and mesenteric artery by acetylcholine was greater at 09:00, whereas in TGR rats, day-night variation was absent (mesenteric artery) or inverted (aorta). In conclusion, based on the study of two time points, daynight variation in vascular contractility of aorta and mesenteric artery is blunted in TGR rats, whereas renal artery segments showed an unchanged daynight pattern compared to SPRD controls. (Chronobiology International, 18(4), 665 681, 2001)     

Pharmacological responses to acute morphine administration in normotensive Wistar-Kyoto and spontaneously hypertensive rats

The effect of acute administration of morphine on analgesia, hyperthermia, hypothermia and catalepsy was determined in spontaneously hypertensive (SH) rats and normotensive Wistar-Kyoto (WKY) rats. A greater analgesic and hyperthermic response to morphine was observed in SH rats than in WKY rats. A dose of morphine (50 mg/kg ip) which produced hypothermia in WKY rats produced pronounced hyperthermia in SH rats. The cataleptic response to morphine was lower in SH rats. The cataleptic response to morphine was lower in SH rats than in WKY rats. The brain and plasma levels of morphine in SH rats were significantly lower as compared to the WKY rats at any dose of morphine used but the ratio of brain to plasma did not differ. It is concluded that SH rats exhibit altered sensitivity to morphine in comparison with their normotensive counterparts.     

Increased reactivity in the mesenteric artery of spontaneously hypertensive rats to phorbol ester

The contraction responses of mesenteric artery from 10 week old spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto controls (WKYs) to phorbol 12, 13 - dibutyrate (PDBu) and agents acting on the potential-operated calcium channels were compared. The vessels from the SHR were significantly more sensitive to PDBu than those from the WKY. The PDBu-induced contractions were inhibited by nifedipine. The vessels from the SHR were also more sensitive to Bay K 8644 and KCl than the WKY. Low concentrations of PDBu (1 nM) potentiated the KCl contraction significantly more in the SHR than the WKY. It is suggested that the increased reactivity to PDBu in the SHR may in part be related to changes in the activity of the potential-operated calcium channels.     

Prolonged isobaric relaxation time in small mesenteric arteries of the spontaneously hypertensive rat

Prolonged isometric relaxation in hypertensive aortic and caudal arterial smooth muscle has been demonstrated; however, isobaric relaxation in resistance arteries is more pertinent to studies in hypertension. A comparative study of mesenteric arterial isobaric relaxation times was made using spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and MK-421 treated SHR (treatment commenced at 8 weeks of age and was maintained until sacrifice). Relaxation rates of vessels constricting against a range of pressures and achieving different degrees of narrowing or changes in circumference were analyzed. Comparisons were made between SHR, WKY, and MK-421 treated SHR arteries that had constricted from the same initial circumference and against the same magnitude of pressure. The SHR mesenteric arteries relaxed at a slower rate than did the WKY vessels. The normotensive MK-421 treated SHR showed the same prolonged relaxation rate as did the untreated SHR preparations. Thus the slower rate of relaxation in SHR arteries does not appear to be a consequence of the hypertension. Such prolonged time for narrowing would function to increase the average peripheral resistance and thus may contribute to the initiation and maintenance of increased blood pressure.