Higher level of plasma nitric oxide in spontaneously hypertensive rats.

We had detected a slightly, but significantly, higher level of plasma nitrite/nitrate in the spontaneously hypertensive rat (SHR) by using the nitric oxide (NO) analyzer (Sievers 280 NOA), which converts nitrate (including nitrate converted from nitrite) to NO. Here, we examined whether the release of NO from protein-bound dinitrosyl nonheme iron complexes (DNIC) contributes to the elevated plasma nitrate level in the SHR. The SHR and their genetic normotensive controls, Wistar-Kyoto rats (WKY), were anesthestized and cannulized for monitoring blood pressure, collecting a blood sample, and the administration of endotoxin (lipopolysaccharide [LPS]). The nitrate levels (an indicator of NO formation) in the plasma and the aorta were measured by an NO analyzer. In addition, the relaxation of acetylcholine (ACh) in the presence or absence of N(omega)-nitro-L-arginine methyl ester (L-NAME) was also examined in thoracic aortae obtained from both strains. The slight, but significant, increase of basal nitrate levels in the plasma and aorta were observed, and the former was further enhanced in SHR treated with LPS for 3 h. In vitro, the ACh-induced relaxation was attenuated in the aortae obtained from SHR. However, this difference between SHR and WKY (without LPS treatment) was abolished by treatment of rings with L-NAME (30 micromol/L), suggesting that an impairment of NO formation was observed in the SHR. After rats were treated with LPS for 3 h, the ACh-induced relaxation was reduced in the WKY, but not in the SHR. In addition, a 10-fold increase of L-NAME was needed to abolish the difference in ACh-induced relaxation between SHR and WKY, indicating an expression of inducible NO synthase in both strains treated with LPS. We suggest that the elevated plasma NO level in SHR may be due to the release of NO from DNIC in the vascular bed to combat the hypertensive state.     

Brain nitric oxide synthase activity in spontaneously hypertensive rats during the development of hypertension

OBJECTIVES: Blockade of neuronal nitric oxide synthase (nNOS) in the brain induced an increase in mean arterial pressure of spontaneously hypertensive rats (SHR). We hypothesize that increased nitric oxide (NO) synthesis in the brain compensates for hypertension. Therefore, we measured NOS activity in different brain regions in SHR at prehypertensive, onset and established hypertension, and compared with age-matched Wistar-Kyoto (WKY) rats. METHOD: NOS activity was measured by the ability of tissue homogenate to convert [3H]l-arginine to [3H]l-citrulline in a Ca2+- and NADPH-dependent manner. RESULTS: NOS activity was impaired in the cerebral cortex and brainstem of prehypertensive SHR. At established hypertension, SHR showed an augmentation in NOS activity in hypothalamus and brainstem. Chronic treatment of SHR with the angiotensin-1 converting enzyme (ACE)-inhibitor, enalapril, and the AT(1) receptor antagonist, losartan, normalized NOS activity in the hypothalamus but not in the brainstem. Treatment with a peripheral vasodilator, hydralazine, did not affect NOS activity. CONCLUSION: Attenuated NOS activity in the cortex and brainstem of prehypertensive SHR may play a role in the pathogenesis of hypertension. The upregulated NOS activity in the hypothalamus and brainstem of SHR possibly serves to compensate for hypertension. Hypothalamic, but not brainstem, NO is involved in antihypertensive effects of ACE inhibition and AT(1) receptor blockade. Since a blood pressure decrease per se had no effect on NOS activity, it appears that central sympathetic activity influenced by endogenous angiotensin II, rather than blood pressure, represents the stimulus for the increased NOS activity in the hypothalamus of SHR.     

N-acetylcysteine improves nitric oxide and alpha-adrenergic pathways in mesenteric beds of spontaneously hypertensive rats

BACKGROUND: The aim of this study was to assess the effects of N-acetylcysteine (NAC) on nitric oxide and adrenergic pathways in mesenteric artery from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). METHODS: Rats were treated with 4 g x kg(-1) x day(-1) of NAC during 4 weeks or mesenteric beds were treated with 10 mmol/L of NAC during 20 min. RESULTS: In conscious rats, the NAC treatment produced a significant reduction of mean arterial pressure (MAP) and heart rate in SHR (P <.001). N(omega)-nitro-L-arginine methyl ester (L-NAME) caused a MAP increase in NAC-treated SHR of magnitude similar to that in WKY, which was significantly higher than that observed in control untreated SHR (P <.05). Chronic treatments with NAC improved the maximal relaxation of mesenteric arteries to A23187 in SHR (P <.001). Acute NAC treatment in vitro induced a vasodilation in Phe preconstricted arteries (P <.001) that was stronger in SHR than in WKY (P <.05) and was not abolished by L-NAME. The vasoconstrictory response and increases in inositol phosphate production induced by superoxide anion were attenuated by NAC treatment through its superoxide scavenging properties. In contrast, chronic and acute NAC treatments did not alter the vasodilatory response to beta-adrenergic receptor stimulation. CONCLUSIONS: The increase in NO-mediated vasodilator tone and the possible decrease in adrenergic vasoconstriction induced by NAC treatment in SHR could explain the hypotensive effect of NAC in this model of hypertension.     

Distribution of nitric oxide synthases and nitrotyrosine in the kidney of spontaneously hypertensive rats

OBJECTIVES: To study the cellular distribution and the expression of the major isoforms of NO synthase (NOS) and of nitrotyrosine in the kidney in spontaneous hypertension. DESIGN AND METHODS: We have studied by immunohistochemistry the location of the endothelial (eNOS), neuronal (nNOS) and inducible (iNOS) isoforms and nitrotyrosine in kidney slices from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) using specific antibodies. In order to quantify the expression of these proteins, we have analyzed dissected renal cortical and medullary sections by means of Western blot. RESULTS: Tubular cells were immunoreactive to nNOS and more numerous in the renal medulla of the SHR compared with that of the WKY, specifically in the outer medulla and the papillary region. Western blot also showed higher expression of nNOS in the renal medulla, but not the renal cortex of the SHR. In contrast, iNOS and eNOS distribution and expression were similar in the kidneys of WKY rats and SHR. Immunohistochemistry showed immunoreactive cells to nitrotyrosine in a variety of renal cells similarly distributed in SHR and WKY kidneys. Western analysis detected three proteins of 14.5, 23.7 and 39 kDa immunoreactive to nitrotyrosine, showing a higher expression in the renal cortex compared to the renal medulla. CONCLUSIONS: The expression of nNOS is higher in the renal medulla of the SHR, and the distribution of eNOS, iNOS and nitrotyrosine is similar in SHR and WKY rats. It is proposed that the higher expression of the neuronal isoform in the medullary tubular cells is a protective mechanism aimed to improve renal function in spontaneous hypertension.     

Modulation of endothelin-1 coronary vasoconstriction in spontaneously hypertensive rats by the nitric oxide system

To determine whether nitric oxide contributes to the augmented vasoconstrictive response to endothelin-1 (ET-1) in coronary vessels of hypertensive hearts, and also whether l-arginine administration can inhibit the augmented response to ET-1, we designed experiments to measure coronary perfusion resistance in isolated hearts of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with or without l-arginine administration (0.5 g/L) for 2 weeks. The hearts were paced at a constant rate and perfused by the Langendorff technique at constant pressure (75 mm Hg). Perfusion flow and pressure were monitored, and coronary vascular resistance (CVR) was calculated. ET-1 infusion elicited dose-dependent increases in CVR in both WKY and SHR. At an ET-1 concentration of 1.5 × 10⁻⁹ mol/L, the response was significantly greater in SHR. In L-NAME–treated WKY and SHR, responses to ET-1 were augmented, compared with those of nontreated rats, and this augmentation was greater in WKY. l-arginine administration reduced the CVR response to ET-1 in SHR, whereas it did not change responses to ET-1 in WKY. These findings suggest that the augmented vasoconstriction of the coronary artery induced by ET-1 in hypertensive hearts was due to a reduction in nitric oxide release in coronary vessels and that l-arginine can partially inhibit the vasoconstrictive response of the coronary artery.     

Changes in hemodynamics with advancing age in conscious spontaneously hypertensive rats

The changes of hemodynamics were measured in spontaneously hypertensive rats (SHR) of increasing ages. Male SHR and Wistar rats of the Kyoto strain (WKY) at 4, 12, 24 and 48 weeks of age were used. The right jugular vein and the left femoral artery were cannulated and a thermistor was placed in the ascending aorta. After 24-hour rest, heart rate (HR), mean arterial pressure (MAP) and cardiac output (CO) were measured. The ratio of left ventricular weight (LVMI) of 4 week-old SHR had already increased significantly when compared to WKY. The HR in 4-week-old SHR was significantly higher than WKY. The increased HR in young SHR indicates the hypersensitivity of the sympathetic nervous system. Increased CO in 4 week-old SHR was due to high HR. The ratio of heart work to left ventricular mass (HW/LVM) of SHR at all age groups was not different from that of WKY, although the ratio of heart work to body weight (HWI) had a tendency to rise in SHR as compared to that in WKY. Our conclusion is that the development of LVM adapts to HW.     

The effect of acute and chronic hematocrit changes on cardiovascular hemodynamics in spontaneously hypertensive rats.

Heparin given over a long term by a subcutaneous route consistently lowers blood pressure in the hypertensive rat models. The decrease in blood pressure is accompanied by a parallel decrease in hematocrit suggesting a causal relationship between hematocrit and blood pressure. The aim of this study was to define the relationships between acute and chronic hematocrit changes and blood pressure in the normotensive and hypertensive states. Normotensive Wistar (NWR) and spontaneously hypertensive (SHR) rats were used. Hematocrit was decreased acutely by blood-letting, and chronically by treatment with either heparin (H) or phenylhydrazine (P) for 4 weeks. Acute and chronic hematocrit increase was accomplished by packed cells transfusion. Systolic blood pressure was measured weekly; and at the end of the experimental period, plasma volume, cardiac output, and mean arterial pressure were obtained. Acute hematocrit decrease or increase (hematocrit ranging from 25 to 65%) did not affect blood pressure in either strain of rats; whereas chronic hematocrit changes (hematocrit ranging from 35 to 61%) significantly affected blood pressure only in SHR. Thus, chronic hematocrit decrease induced by H or P resulted in a significant fall in blood pressure compared to control (201 +/- 3 v 175 +/- 4, 167 +/- 4 mm Hg, respectively; P < .05). Conversely, a chronic hematocrit increase resulted in a significant rise in blood pressure (201 +/- 3 v 219 +/- 4 mm Hg; P < .05). Similar hematocrit changes produced in NWR, as in SHR, did not affect blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Persistent cardiovascular effects of chronic renin-angiotensin system inhibition following withdrawal in adult spontaneously hypertensive rats

OBJECTIVES: It is generally accepted that short-term (4 weeks) inhibition of the renin-angiotensin system (RAS) of young spontaneously hypertensive rats (SHR) in their prehypertensive phase confers long-lasting protection from fully hypertensive levels in adulthood. However, there is very little data pertaining to the effects of such treatment in adult SHR with established hypertension. Therefore, we determined the relative effects of angiotensin converting enzyme (ACE) inhibition (perindopril), AT1 receptor blockade (candesartan cilexetil) and RAS-independent vasodilatation (hydralazine) and their withdrawal in adult SHR, on blood pressure measured by radiotelemetry, as well as on cardiac and vascular structure. METHODS: Adult male SHR were instrumented with radiotelemetry probes to measure blood pressure and heart rate continuously. SHR were given either vehicle, perindopril (1 mg/kg per day), candesartan cilexetil (2 mg/ kg per day) or hydralazine (30 mg/kg per day) at equieffective depressor doses for 4 weeks (treatment study). Separate groups of animals were also given identical treatments but were then monitored for a further 8 weeks after drug withdrawal (withdrawal study). An indirect in-vivo assessment of whole body vascular hypertrophy (mean arterial pressure during maximum vasoconstriction) was made during and after drug withdrawal, as was the pressor activity evoked by angiotensin I and angiotensin II. The effect of antihypertensive treatment on microalbuminuria was also assessed during and after drug withdrawal. Finally, left ventricular: body weight (Iv: bw) and mesenteric media: lumen ratios were determined either immediately after 4-week treatment (treatment study) or 8 weeks later (withdrawal study). RESULTS: Perindopril persistently lowered blood pressure in adult SHR whereas blood pressure returned to vehicle levels within approximately 4 and 15 days after withdrawal of hydralazine and candesartan cilexetil, respectively. Cardiac hypertrophy was reduced by all three treatments, but to a lesser extent by hydralazine (treatment study), and this regression of cardiac hypertrophy persisted only with both types of RAS inhibition (withdrawal study). Vascular hypertrophy, measured indirectly and directly, was also reduced by all three treatments, with perindopril and candesartan cilexetil causing hypotrophic and eutrophic remodelling, respectively (treatment study), although these changes were generally not maintained after drug withdrawal (withdrawal study). Angiotensin I-induced pressor responses were equally inhibited during treatment with either candesaran cilexetil or perindopril (and were unaffected by hydralazine) but normalized rapidly in both groups (within approximately 2-4 days) after withdrawal of RAS inhibition. In addition, there was a small age-related increase in microalbuminuria over the study period, which was not significantly affected by any treatment. CONCLUSIONS: Following 4-week treatment, candesartan cilexetil, perindopril and hydralazine caused similar antihypertensive effects; however, only perindopril persistently reduced blood pressure following drug withdrawal. Both types of RAS inhibition and hydralazine caused marked cardiac and vascular remodelling during treatment, whereas only the RAS inhibitors persistently regressed cardiac hypertrophy 8 weeks later. Collectively, these results indicate the importance of the RAS for the maintenance of hypertension and cardiovascular hypertrophy in adult SHR, as well as identifying differential effects of ACE inhibition and AT1 receptor blockade on persistent blood pressure reduction.     

Converting enzyme inhibition normalizes QT interval in spontaneously hypertensive rats

We quantified the repolarization time (so-called QT interval) in a rat, an animal species that does not show a well-characterized T wave on surface ECG. We used spontaneously hypertensive rats (SHR) and converting enzyme inhibition to demonstrate a reversible increase in QT interval in pressure-overloaded hearts in the absence of ischemia. An implanted telemetry system recording ECG data in freely moving rats was used to automatically calculate the RR interval. The QT duration was manually determined by use of a calibrated gauge, and a time-frequency domain analysis was used to evaluate heart rate variability. Left ventricular mass was sequentially assessed by echocardiography. Before treatment, 12-month-old SHR had higher left ventricular mass, QT and RR intervals, and unchanged heart rate variability compared with age-matched Wistar rats. A 2-month converting enzyme inhibition treatment with trandolapril reduces systolic blood pressure, left ventricular mass, and QT interval. The RR interval and heart rate variability remains unchanged. There is a positive correlation between the QT interval and left ventricular mass. The SHR is suitable for longitudinal studies on the QT interval. Thus, the detection of the QT interval reflects the phenotypic changes that occur during mechanical overload and, on the basis of these criteria, allows an in vivo determination of the adaptational process.     

Effects of verapamil and nifedipine on systemic hemodynamics in spontaneously hypertensive rats

Verapamil (1 mg/kg, i.v.) and nifedipine (0.3 mg/kg, i.v.) were tested at equi-antihypertensive doses for systemic hemodynamic responses in conscious spontaneously hypertensive rats (SHR) using the Fick method. Systemic hemodynamic effects of these agents were also evaluated in areflexic, spinal cord-transected and vagotomized SHR using the electromagnetic flowmetry technique. Both verapamil and nifedipine lowered mean arterial pressure (MAP:verapamil = -24%; nifedipine = -28%) in conscious SHR by decreasing total peripheral resistance (TPR:verapamil = -48%; nifedipine = -59%) with a concomitant rise in cardiac output (CO: verapamil = 48%; nifedipine = 86%) and stroke volume (SV:verapamil = 54%; nifedipine = 65%), but verapamil prevented tachycardia, whereas nifedipine increased heart rate (HR:13%). Verapamil and nifedipine also altered systemic hemodynamics in the areflexic SHR; verapamil reduced MAP (-31%) by reducing CO (-18%) with associated bradycardia (-25% HR), whereas nifedipine also lowered MAP (-21%) by decreasing TPR (-18%) without changes in CO and HR. It is concluded that, firstly, the antihypertensive action of verapamil and nifedipine in conscious SHR is due to systemic vasodilation that is associated with reflexly increased CO; secondly, that verapamil has a direct negative chronotropic effect, but nifedipine appears to be devoid of such an effect, and finally that the ability of verapamil to decrease TPR may depend upon resting sympathetic tone.     

Effect of increasing age on hemodynamics of spontaneously hypertensive rats.

Arterial pressure, cardiac output, and total peripheral resistance were compared between spontaneously hypertensive rats (SHR) and normotensive control rats (NCR) at 4, 7, and 12 months of age. The rats were anesthetized with pentobarbital sodium, thoracotomized and kept under positive pressure respiration. Cardiac output was measured with an electromagnetic flowmeter probe placed at the ascending aorta. On all the age groups, arterial pressure and total peripheral resistance were significantly higher in SHR than in NCR, while cardiac output per body weight was not different. However, the significant differences in pressure and resistance at each age disappeared after ganglion blockade with hexamethonium bromide. Total peripheral resistance was not higher in SHR than in NCR even after cardiac output, which had once been diminished by blockade, was restored to the pre-blockade level by dextran infusion. Phenoxybenzamine, an alpha adrenergic receptor blocker, also equalized arterial pressure and total peripheral resistance between SHR and NCR, both aged about 10 months, without decrease in cardiac output. It is concluded that, in both young and old SHR's, the hypertensive state is maintained by an increase in total peripheral resistance ascribable to sympathetic activity.     

Irbesartan lowers superoxide levels and increases nitric oxide bioavailability in blood vessels from spontaneously hypertensive stroke-prone rats

OBJECTIVE : To determine the effects of the angiotensin II receptor antagonist irbesartan, the calcium-channel blocker amlodipine, and hydrochlorothiazide/hydralazine on superoxide, NAD(P)H oxidase and nitric oxide bioavailability in spontaneously hypertensive stroke-prone rats (SHRSP). METHODS : Drugs or vehicle were administered for 8 weeks to SHRSP and blood pressure was measured weekly by tail-cuff plethysmography. After 8 weeks, superoxide levels in carotid arteries and aortas were measured by lucigenin chemiluminescence and p22phox expression quantified by immunohistochemistry. In vitro the effects of exposure to drugs and vehicle for 30 min and 4 h on superoxide levels and nitric oxide bioavailability were examined. The latter was expressed as the increase in contractile responses of carotid arteries to phenylephrine in the presence of the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester(l-NAME). RESULTS : In vivo irbesartan, amlodipine and hydrochlorothiazide/hydralazine produced similar falls in blood pressure, from 162 +/- 4 to 125 +/- 5, 132 +/- 4 and 131 +/- 6 mmHg, respectively, but irbesartan caused a greater reduction in superoxide and p22phox; superoxide levels in carotid arteries being 3.1 +/- 0.3, 1.1 +/- 0.2, 1.9 +/- 0.3 and 2.0 +/- 0.3 nmoles/mg per min, respectively. In vitro 4 h exposure to irbesartan decreased superoxide levels in the aorta from 2.08 +/- 0.68 to 1.48 +/- 0.62 nmoles/mg per min and increased nitric oxide bioavailability in carotid arteries. Neither 30 min incubation with irbesartan nor 4 h with amlodipine or hydrochlorothiazide/hydralazine altered superoxide levels. CONCLUSIONS : These studies support the hypothesis that AT1 receptor blockade has beneficial effects on superoxide production and nitric oxide bioavailability above that of other classes of antihypertensive agents. Reduced expression of components of the NAD(P)H oxidase may contribute to these effects.     

Atorvastatin causes depressor and sympatho-inhibitory effects with upregulation of nitric oxide synthases in stroke-prone spontaneously hypertensive rats

OBJECTIVE: Recent studies have suggested that statins decrease blood pressure in hypertensive animals and upregulate endothelial nitric oxide synthase (eNOS) expression. However, the effects of statins on the expression of nitric oxide synthase (NOS) in the brain and the sympathetic nervous system remain to be elucidated. The aim of this study was thus to examine the effects of atorvastatin on blood pressure, sympathetic nerve activity, and the expression of NOS in stroke-prone spontaneously hypertensive rats (SHRSP) as well as in Wistar-Kyoto (WKY) rats. METHODS: The animals received atorvastatin (50 mg/kg per day) for 30 days. Systolic blood pressure and heart rate were evaluated using the tail-cuff method. Urinary norepinephrine excretion was measured for 24 h. The expression of eNOS, neuronal NOS (nNOS), and inducible NOS (iNOS) in the brain (cortex, cerebellum, hypothalamus and brainstem), aorta and heart were determined by Western blot analysis. RESULTS: Systolic blood pressure and 24-h urinary norepinephrine excretion were significantly decreased in SHRSP, but not in WKY, after the treatment with atorvastatin. The eNOS and iNOS expression in the brain and aorta was significantly increased in atorvastatin-treated SHRSP and WKY. However, the nNOS expression in the brain was not altered in the atorvastatin-treated group. CONCLUSIONS: These results suggest that atorvastatin decreases blood pressure, at least in part via the reduction of sympathetic nervous system activity in SHRSP. They also suggest that this sympatho-inhibitory effect may be mediated by an increase in NO production, with the upregulation of eNOS expression in the brain.     

Pomace olive oil improves endothelial function in spontaneously hypertensive rats by increasing endothelial nitric oxide synthase expression

BACKGROUND: The effect of dietary pomace olive oil, which has the same concentration of oleic acid but a higher proportion of oleanolic acid (OA) than olive oil, was examined on animal models of hypertension for the first time. METHODS: During 12 weeks, Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were fed with either a control 2% corn oil diet (BD), or high-fat diets containing 15% of refined olive oil (OL), pomace olive oil (POM), or pomace olive oil supplemented in OA (up to 800 ppm) (POMO). Then, vascular reactivity and endothelial nitric oxide (NO) synthase (eNOS) expression were studied in aortic rings. Plasma nitrite + nitrate levels were also determined. RESULTS: Diets had no effects on blood pressure (BP). In contrast to the BD and OL dietary groups, POM intake improved relaxation evoked by acetylcholine in SHR aorta. The POMO intake increased vasodilatation to acetylcholine and attenuated phenylephrine-induced contractions in both strains of rats associated with a major NO participation revealed by inhibition of NOS. The enhanced relaxation shown in POM and POMO SHR aorta was attributed to an increased eNOS protein expression. Plasma nitrite levels were also increased in these groups. Although olive and pomace oils used in diets contained similar fatty acid composition, beneficial effects on endothelial function were absent in the OL group. Therefore, these effects must be associated with some minor components from pomace olive oil such as OA. CONCLUSIONS: Chronic intake of diets rich in pomace olive oil improves endothelial dysfunction in SHR aorta by mechanisms associated with enhanced eNOS expression. Important evidence is provided regarding the effects of pomace olive oil and OA on endothelial function in hypertensive animals.     

Aging increases neuronal nitric oxide release and superoxide anion generation in mesenteric arteries from spontaneously hypertensive rats

We hypothesized that neuronal NO release as well as its bioavailability and vasomotor response could be affected when aging and hypertension are present simultaneously. The neuronal nitric oxide (NO) release, its metabolism and vasomotor response induced by electrical field stimulation was analyzed in isolated segments of endothelium-denuded mesenteric arteries from young and old spontaneously hypertensive rats (SHR). The nitric oxide synthase (NOS) inhibitor N(G)-nitro-arginine-methyl ester (L-NAME) and NOS inhibitor 7-nitroindazole both strengthened electrical field stimulation-elicited contractions more in arteries from young than aged SHR rats. Superoxide dismutase (SOD) potentiated the L-NAME effect in segments from old rats, whereas catalase decreased the contractions induced by electrical field stimulation and noradrenaline but did not modify the L-NAME effect. In noradrenaline-precontracted segments, sodium nitroprusside induced a similar relaxation in arteries from both experimental groups. This relaxation was increased by SOD in old SHR. 8Br cGMP induced greater relaxation in segments from old than from young SHR. Electrical field stimulation induced a tritium release in arteries preincubated with [(3)H]-noradrenaline, that was similar in both young and old SHR rats. Electrical field stimulation induced NO(2)(-) formation, which was greater in segments from old than young SHR rats. Basal cGMP levels and those stimulated with sodium nitroprusside were similar in segments from both groups. Superoxide anion production was greater from old than young SHR rats. Peroxynitrite production induced by electrical field stimulation was only detected in segments from old SHR. The results obtained in mesenteric arteries from old SHR showed increased neuronal NO release and superoxide anion production with respect to those observed in arteries from young SHR rats. This induced decreased NO bioavailability through peroxynitrite formation. The final effect is to decrease the involvement of neuronal NO in electrical field stimulation-induced vasomotor response in arteries from old SHR rats.     

Effects of chronic nitric oxide synthase inhibition on cerebral arterioles in Wistar-Kyoto rats

OBJECTIVE: Cerebral arterioles in stroke-prone spontaneously hypertensive rats (SHRSP), but not in Sprague-Dawley rats with hypertension induced by nitric oxide (NO) synthase inhibition, undergo inward remodeling. The goal of this study was to determine whether development of vascular inward remodeling may depend on genetic factors. DESIGN: We examined effects of NO synthase inhibition on the structure of cerebral arterioles in Wistar-Kyoto rats (WKY), a rat strain genetically distinct from Sprague-Dawley. METHODS: Pressure (servonull), diameter (cranial window) and cross-sectional area of the vessel wall (CSA, histologically) were measured in maximally dilated (EDTA) cerebral arterioles in WKY, untreated (n = 8) or treated for 3 months with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg per day, n = 10) in the drinking water, and in untreated SHRSP (n = 7). RESULTS: Treatment with L-NAME in WKY increased mean cerebral arteriolar pressure (69 +/- 7 versus 47 +/- 7 mmHg, P < 0.05) and pulse pressure (30 +/- 3 versus 17 +/- 1 mmHg, P < 0.05) to levels significantly lower than in SHRSP (98 +/- 5 and 35 +/- 1 mmHg respectively, P < 0.05). CSA was significantly greater in L-NAME-treated WKY and SHRSP than in untreated WKY (1692 +/- 50 and 1525 +/- 98 microm respectively, versus 1224 +/- 85, P < 0.05). External diameter was significantly less in L-NAME-treated WKY than in untreated WKY (119 +/- 5 versus 135 +/- 4 microm, P < 0.05) but significantly greater than in SHRSP (98 +/- 1 microm, P < 0.05). CONCLUSION: Cerebral arterioles undergo hypertrophy and remodeling in WKY with L-NAME-induced hypertension. These findings suggest that genetic factors present in WKY and SHRSP may play a role in the development of vascular inward remodeling during chronic hypertension in rats.