Blood Pressure In SHR Research Articles

홍국 장기투여가 SHR의 혈압 및 혈중 콜레스테롤 조성에 미치는 영향

홍국의 장기섭취가 자연발증 고혈압 쥐(SHR)의 혈압상승 및 혈중 콜레스테롤 조성에 미치는 영향을 조사하였다. Monascus ruber IFO 32318 균주로 제조한 홍국을 각각 0.03%, 0.1%, 0.3% 첨가한 식이를 8주간 섭취시킨 후 모든 실험군을 일반식이로 전환시켜 다시 2주간 사육하였다. 식이 섭취 2주 째부터 대조군에 비해 홍국 섭취군에서 수축기혈압, 이완기혈압 및 평균혈압의 유의적인 상승 억제효과가 나타났으며 그 효과는 식이에 첨가된 홍국의 양에 비례하였고 홍국첨가 식이를 중단하면 실험군 간의 각 혈압의 유의적인 차이는 사라졌다. 또한 홍국은 SHR의 혈중 VLDL-C의 함량을 유의적으로 저하시켰으며 TC 및 LDL-C은 홍국 첨가량이 많을수록 낮은 경향을 나타내었고 HDL-C은 대조군, group Ⅰ 및 group Ⅱ가 거의 동일하였으며 홍국 첨가량이 가장 많은 group Ⅲ에서만 약간 높은 경향을 나타내었다. 또한 동맥경화의 지표가 되는 TC과 HDL-C의 비율 및 non-HDL-C과 HDL-C의 비율은 홍국 섭취량이 증가할수록 감소하는 경향을 보였고 LDL-C과 HDL-C의 비율 또한 홍국 섭취군이 대조군보다 유의적으로 낮은 값을 나타내었다. 이러한 모든 효과는 홍국을 식이 섭취량의 0.1% 이상 첨가한 실험군에서 뚜렷이 나타났다.

Genetic isolation of a quantitative trait locus on chromosome 18 associated with blood pressure and salt sensitivity in the SHR

Genetic isolation of a quantitative trait locus on chromosome 18 associated with blood pressure and salt sensitivity in the SHR

SPINAL NICOTINIC RECEPTOR ACTIVITY IN A GENETIC MODEL OF HYPERTENSION

Intrathecal cytisine, a nicotinic receptor agonist, elicits greater dose-dependent increases in blood pressure, heart rate and nociceptive responses in SHR than normotensive rat strains. Similar to adult rats, cardiovascular and nociceptive responses were augmented in prehypertensive SHR than age-matched WKY. While hydralazine or captopril pretreatment significantly lowered blood pressure in both SHR and WKY rats, responses to i.t. cytisine were still greater in SHR. By contrast, i.t. cytisine elicited responses were not exaggerated in DOCA-salt hypertensive WKY rats. Pressor and irritation responses to i.t. cytisine can be divided into a transient, initial and persisting, late phases. Both are augmented in SHR. In F1 rats, only the late phase pressor and pain responses to i.t. cytisine are similar in magnitude to those observed in SHR suggesting a possible dominant trait in the SHR. Overall, our findings suggest that hyper-responsiveness in nociception and pressor activity to spinal cytisine in SHR may be pathogenetically associated, but not a consequence, of hypertension.

The Relationship Between Angiotensin II (ANG II) and Oxidative Stress in the Maintenance of Mean Arterial Pressure (MAP) of Spontaneously Hypertensive Rats.

48 Spontaneously hypertensive rats (SHR) reportedly have inappropriately high levels of Ang II despite normal plasma renin activity (PRA). Because Ang II stimulates oxidative stress, which in turn quenches nitric oxide, it is possible that Ang II-induced increases in oxidative stress contribute to the increase in blood pressure. Indeed, administering either a converting enzyme inhibitor (to decrease Ang II) or Tempol (a potent antioxidant) reduces blood pressure in SHR. We tested whether decreasing Ang II with a converting enzyme inhibitor reduces oxidative stress as well as MAP in SHR. For this, we divided 12 weeks old SHR into two groups (n=5 each). One group was treated with captopril (100 mg/kg/day added to the drinking water) and the other served as our untreated time controls. After 16 days of treatment, the rats were anesthetised and we measured MAP and collected blood samples to determine PRA, and the plasma levels of Ang II and thiobarbituric acid-reactive substances (TBARS). The captopril-treated rats had a lower MAP than the untreated rats (92±4 vs. 160±5 mmHg, respectively) and an increased PRA (42±1 vs. 26±6 ng/ml/h; captopril-treated vs. untreated rats, respectively). The decreased MAP in the captopril-treated SHR was accompanied by reduced plasma levels of Ang II (630±47 vs. 836±205 pg/ml) and TBARS (5.4±1.0 vs. 3.0±0.2 nmol/ml). Despite the significant decrease in Ang II levels in the captopril-treated SHR, they are still 20-fold higher rhan in normotensive Sprague-Dawley rats (34.0±8.8 pg/ml). In summary, captopril-induced decreases of MAP in SHR are accompanied not only by reduced levels of Ang II, but also by reduced oxidative stress. Because antioxidants also lower MAP in SHR, it suggests that oxidative stress induced by Ang II may play a role in the pathogenesis of the increased blood pressure in SHR.

Synthesis and Function of Cytochrome P450 4A1-Derived 20-Hydroxyeicosatetraenoic Acid in Rat Renal Arteries

22 20-hydroxyeicosatetraenoic acid (20-HETE) is the principal arachidonic acid metabolite in tubular and vascular structures of the rat kidney. In the tubules it inhibits sodium reabsorption, while in the renal microcirculation it is a vasoconstrictor and a regulator of myogenic tone. 20-HETE synthesis is catalyzed by the cytochrome P450 (CYP) 4A isoforms (4A1, 4A2, 4A3 and 4A8). Our studies indicated that despite the high homology, these isoforms display distinct catalytic properties. CYP4A1 is the low Km isoform and thus, by far, the most efficient 20-HETE synthesizing enzyme. Whereas CYP4A1 is solely an ω-hydroxylase, CYP4A2 and CYP4A3 also catalyze arachidonate 11,12-epoxidation. Systemic administration of CYP4A1 antisense oligodeoxynucleotides reduced the level of CYP4A proteins and 20-HETE synthesis in renal vessels by 50%, and decreased blood pressure in SHR from 137±3 to 121±4 mmHg (p 50 = 0.07±0.02 vs 0.37±0.04 μM). The increased constrictor responses to phenylephrine were greatly attenuated by DDMS, a selective inhibitor of 20-HETE synthesis (EC 50 from 0.07±0.01 to 0.74±0.11 μM) and by 20-HEDE, a specific 20-HETE antagonist (to 0.54±0.05 μM) without affecting the maximal response. The inhibitory effect of DDMS was reversed by addition of 20-HETE further substantiating the notion that increased endogenous levels of 20-HETE contributed to the increased vascular reactivity to phenylephrine in vessels expressing the CYP4A1 cDNA. Thus, 20-HETE of vascular origin serves as a stimulatory regulator of vascular responses to phenylephrine.

Synthesis and Function of Cytochrome P450 4A1-Derived 20-Hydroxyeicosatetraenoic Acid in Rat Renal Arteries

22 20-hydroxyeicosatetraenoic acid (20-HETE) is the principal arachidonic acid metabolite in tubular and vascular structures of the rat kidney. In the tubules it inhibits sodium reabsorption, while in the renal microcirculation it is a vasoconstrictor and a regulator of myogenic tone. 20-HETE synthesis is catalyzed by the cytochrome P450 (CYP) 4A isoforms (4A1, 4A2, 4A3 and 4A8). Our studies indicated that despite the high homology, these isoforms display distinct catalytic properties. CYP4A1 is the low Km isoform and thus, by far, the most efficient 20-HETE synthesizing enzyme. Whereas CYP4A1 is solely an ω-hydroxylase, CYP4A2 and CYP4A3 also catalyze arachidonate 11,12-epoxidation. Systemic administration of CYP4A1 antisense oligodeoxynucleotides reduced the level of CYP4A proteins and 20-HETE synthesis in renal vessels by 50%, and decreased blood pressure in SHR from 137±3 to 121±4 mmHg (p < 0.05). Immunoblot analysis and inhibitor studies indicated that within the renal vasculature CYP4A1 is primarily localized to the interlobar arteries. Transfection of CYP4A1 cDNA, cloned into the expression plasmid pcDNA3.1, to renal interlobar arteries increased CYP4A immunoreactivity by 3-fold and 20-HETE synthesis from 92±10 to 239±71 pg 20-HETE/mg/h. CYP4A1-transfected arteries demonstrated a marked increase in the constrictor responses to phenylephrine (EC 50 = 0.07±0.02 vs 0.37±0.04 μM). The increased constrictor responses to phenylephrine were greatly attenuated by DDMS, a selective inhibitor of 20-HETE synthesis (EC 50 from 0.07±0.01 to 0.74±0.11 μM) and by 20-HEDE, a specific 20-HETE antagonist (to 0.54±0.05 μM) without affecting the maximal response. The inhibitory effect of DDMS was reversed by addition of 20-HETE further substantiating the notion that increased endogenous levels of 20-HETE contributed to the increased vascular reactivity to phenylephrine in vessels expressing the CYP4A1 cDNA. Thus, 20-HETE of vascular origin serves as a stimulatory regulator of vascular responses to phenylephrine.

Tempol, Vitamin C and Vitamin E Improve Endothelial Dysfunction, Regress Vascular Hypertrophy and Prevent Progression of Hypertension and Renal Dysfunction in Stroke-Prone Shr

P35 Antioxidant vitamins reduce oxidative stress in vascular injury associated with atherosclerosis and balloon injury. The role of these agents in the pathogenesis of hypertension is unclear. We investigated effects of vitamins C and E and the superoxide dismutase (SOD) mimetic, tempol, on development of blood pressure, vascular structure and endothelial function in salt-loaded stroke-prone SHR (SHRSP). 16 week-old SHRSP (n=26) on a high salt diet (4% NaCl) were randomly divided into 4 groups: control (C), Vit C (1000 mg/d), Vit E (1000 IU/d) and tempol (1 mmol/d). Systolic blood pressure (SBP) and renal function were assessed weekly. 6 weeks after treatment rats were killed. Vascular structure (media:lumen ratio) and endothelial function (acetylcholine (Ach)-induced vasodilation) were assessed in small mesenteric arteries mounted as pressurized preparations. SBP increased from 204± to 265±6 mmHg in C group. Progression of hypertension was prevented in Vit C (234±4 mmHg), Vit E (227±11mmHg) and tempol (208±8 mmHg) groups. Development and severity of proteinuria was delayed in all treated groups compared with C. The media:lumen ratio was reduced (p<0.001) in the Vit E (7.4±0.5%) and tempol (7.2±0.01%) groups compared with C group (12±0.1%). Structure was not significantly altered in the Vit C group. Maximal Ach-induced dilation was significantly improved in all treated groups, particularly in the Vit C group (85±4 % vs C 40±9 %, p<0.01). In conclusion antioxidant vitamins and tempol prevent progression of hypertension and improve renal dysfunction in SHRSP. These processes are associated with improved endothelial function and regression of vascular hypertrophy in small arteries. Our data suggest that oxidative stress plays a role in vascular and renal damage associated with severe hypertension in salt-loaded SHRSP.

Transfer of the Human Heme Oxygenase-1 Gene Decreases Blood Pressure and Promotes Growth in Spontaneously Hypertensive Rats

P203 Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, free iron and carbon monoxide (CO). Both heme and CO have been implicated in the regulation of vascular tone. We report the successful cloning of the human HO-1 cDNA (HHO-1) into a LXSN retroviral vector (LSN-HHO-1). A single intra-left ventricular delivery of 1×10 10 pfu/ml of LSN-HHO-1 to 5-day-old spontaneously hypertensive rats (SHR; n = 32) resulted in extended expression of the human HO-1 (mRNA and protein) in several tissues, including the kidney, liver, spleen, lung, heart, brain and aorta. The expression of HHO-1 was associated with a 2-3 fold increase in HO activity in these tissues. Mean blood pressure (MBP) of SHR injected with LSN-HHO-1 was significantly lower than that of SHR injected with the control empty vector LXSN, by 4 weeks of age (144±4.6 mmHg vs 164.8±6.5 mmHg, n=32, * p <0.01). SHR treated with LSN-HHO-1 demonstrated a consistent reduction in MBP of ≈20 ± 4 mmHg when compared with the control LXSN injected SHR throughout the 20 weeks of the experiment. Administration of the HO inhibitor, stannic mesoporphyrin (Sn MP), to LSN-HHO-1-treated SHR resulted in a 15 to 18 mmHg rise of MBP, further suggesting that increased HO expression underlie, at least in part, the blood pressure lowering effect of LSN-HHO-1. Rats expressing HHO-1 showed significant reduction in the urinary excretion of the vasoconstrictor cytochrome P-450 arachidonate metabolite, 20-HETE. Moreover, gracilis muscle arterioles (≈ 55μm in diameter) isolated from HHO-1 transgenic SHR showed less contractile responses to increased intraluminal pressure than vessels isolated from LXSN-treated SHR; this effect was reversed by the addition of SnMP. Interestingly, HHO-1 transgenic rats showed significant proportionate increase in somatic growth, i.e., nose to tail length, fibula length and body weight gain. These studies demonstrate that delivery of the human HO-1 gene by a retroviral vector results in permanent expression of HHO-1, long-term reduction in blood pressure together with growth promoting activity in the SHR.

Attenuated Development of Hypertension by Antioxidant Vitamins in Stroke-Prone Shr Is Associated with Increased Vascular Superoxide Dismutase Activity and Decreased Oxidative Stress.

P34 Oxidative stress has been implicated in the pathophysiology of cardiovascular diseases. We investigated effects of antioxidant vitamins and tempol, superoxide dismutase (SOD) mimetic, on vascular superoxide anion (×O 2 - ) concentration, NADPH oxidase activity, SOD activity, plasma antioxidant levels and blood pressure in stroke-prone SHR (SHRSP). 16 week-old SHRSP on a high salt diet (4%NaCl) were divided into 4 groups: control (C), Vit C (1000mg/day), Vit E (1000 U/day) and tempol (1 mmol/d). Systolic blood pressure (SBP) and antioxidant status were measured weekly for 6 weeks. Aortic ×O 2 - concentration and NADPH oxidase activity were measured by luminometry using lucigenin (5 μmol/L) and aortic SOD activity and total plasma antioxidant status were measured using a spectrophotometric assay system. SBP and plasma antioxidant levels were similar in all groups prior to treatment. Table demonstrates results after 6 weeks treatment. Data are means ± SEM. Data from this study demonstrate that antioxidant vitamins and tempol attenuate the development of hypertension in SHRSP. This is associated with decreased vascular ×O2- production, increased activity of SOD and increased plasma antioxidant concentrations. We demonstrate the novel findings that Vits E and C induce their antioxidant effects, in part, by stimulating SOD activity. Thus increased oxidative stress is an important factor underlying vascular changes associated with severe hypertension in SHRSP.

Genetic isolation of chromosome 2 QTL affecting blood pressure in the SHR

Genetic isolation of chromosome 2 QTL affecting blood pressure in the SHR

Effect of cadmium or magnesium on calcium-dependent central function that reduces blood pressure.

The effect of intracerebroventricular (i.c.v.) administration of cadmium or magnesium on central calcium-dependent blood pressure regulation was investigated. The systolic blood pressure of spontaneously hypertensive rats (SHR; male, 13 weeks of age) decreased following i.c.v. administration of cadmium chloride (20 nmol/rat), and increased following i.c.v. administration of magnesium chloride (20, 600, and 1,200 nmol/rat). The hypotensive effect of cadmium was suppressed by i.c.v. administration of W-7 (a calmodulin antagonist, 30 microg/rat). Taking into consideration these results with our previous reports, it is suggested that cadmium binds to the calcium-binding sites of calmodulin and activates calcium/calmodulin-dependent enzymes in a disorderly manner, whereas magnesium does not. Therefore, cadmium increases dopamine synthesis in the brain via a calmodulin-dependent system, and the resultant increase in dopamine levels inhibits sympathetic nerve activity and reduces blood pressure in SHR.

Effect of dopamine receptor antagonists on the calcium-dependent central function that reduces blood pressure in spontaneously hypertensive rats

The effects of intracerebroventricular (i.c.v.) administration of dopamine receptor antagonists on the calcium-dependent brain function that reduces blood pressure were investigated. The systolic blood pressure of spontaneously hypertensive rats (SHR; male, 13 weeks of age) was reduced following i.c.v. administration of calcium chloride (100 μg/rat), and this effect of calcium chloride was attenuated by i.c.v. injection of eticlopride (dopamine D2 receptor antagonist, 100 μg/rat), but not by i.c.v. injection of SCH 23390 (dopamine D1 receptor antagonist, 30 μg/rat). Taking into consideration these results with our previous reports, it is suggested that calcium enhances dopamine synthesis in the brain through a calmodulin-dependent system, and that the resultant increase in dopamine levels inhibits sympathetic activity via the dopamine D2 receptor in the brain and reduces the blood pressure in SHR.

Acute effects of bezafibrate on blood pressure and renal haemodynamics in SHR and WKY rats

Acute effects of bezafibrate on blood pressure and renal haemodynamics in SHR and WKY rats

Possible Participation of ATP in Changes of Blood Pressure in SHR and Old Rats

Possible Participation of ATP in Changes of Blood Pressure in SHR and Old Rats

Protective Effects of Valsartan and Benazeprilat in Salt-Loaded Stroke-Prone Spontaneously Hypertensive Rats

These experiments examined the effectiveness of chronic blockade of the renin angiotensin system with either valsartan or benazeprilat on survival, blood pressure and end-organ damage in salt-loaded stroke-prone SHR. Valsartan or benazeprilat given continuously by subcutaneous osmotic minipump beginning at 10.5 weeks of age lowered blood pressure, as determined by radiotelemetry, prevented proteinuria, prolonged survival and decreased the severity of histopathological changes in the heart and kidney. These results indicate that angiotensin receptor blockade affords a similar degree of protection as inhibition of angiotensin converting enzyme in salt-loaded stroke-prone SHR. Furthermore, our results are consistent with a primary contribution of angiotensin I1 to the maintenance of blood pressure and support a principal role for angiotensin II-dependent mechanisms in the development of end-organ damage in the salt-loaded strokeprone SHR.

Sympathetic nervous activity and arterial pressure responses during rest and acute behavioral stress in SHR versus WKY rats

The object of this experiment is to compare changes in renal sympathetic nerve activity (SNA), mean arterial blood pressure (MAP) and heart rate (HR) during rest and behavioral stress in 12–14 week old spontaneously hypertensive rats (SHR; N=12) and normotensive Wistar–Kyoto (WKY; N=12) controls. Animals were behaviorally trained by following a 15 s auditory conditional stimulus (CS+) with a 1/2 s tail shock. Resting MAP was higher ( p<0.001) in SHR (154±3 mmHg, mean±SEM) compared to WKY (116±3 mmHg); conversely, there was no difference in the average resting HR. The pattern of the SNA and MAP changes during the CS+ was similar across groups, but the amplitude was larger in the SHR. The CS+ stress stimulus evoked an initial transient MAP increase averaging 14±2 mmHg in the SHR compared to 4±1 mmHg in the WKY. This pressor response was preceded by a sudden burst of SNA averaging 177±22% over baseline in SHR versus 105±13% for the WKY. HR decreased in SHR only during the second component of the CS+ trial despite the large increase in SNA. We conclude that (1) SHR have higher reactivity than WKY to stress in SNA and MAP; (2) both SHR and WKY have greater SNA and MAP responses to CS+ than CS− (i.e., the discriminative paradigm was effective); (3) control of sympathetic and parasympathetic nervous activity during sustained stress differs remarkably in hypertensive and normotensive subjects; and (4) SHR blood pressure effector mechanisms may have a higher responsiveness to sympathetic nervous activity as compared to WKY.

Cardiac kallikrein in hypertensive and normotensive rats with and without diabetes

This study examined the effects of streptozotocin-induced diabetes on blood pressure and cardiac tissue kallikrein levels in WKYR and SHR. Streptozotocin-induced diabetes caused significant (p< 0.001) increase in SBP and DBP in WKYR and SHR as compared with their respective controls. We also observed that the active cardiac tissue kallikrein levels reduced greatly (p < 0.001) in diabetic WKYR and SHR than the normal rats. These findings suggest for the first time that the cardiac tissue kallikrein formation may have a greater role in the regulation of blood pressure and cardiac function.

Effect of Stress on Plasma Catecholamine and Blood Pressure in SHR

Effect of Stress on Plasma Catecholamine and Blood Pressure in SHR

Dietary linolenic acid-mediated increase in vascular prostacyclin formation.

To define vascular effects of an enhanced dietary alpha-linolenic acid intake, 28 spontaneously hypertensive rats were fed a 3% sunflowerseed oil (44% linoleic acid) diet; in 3 groups (7 rats each), the diet was supplemented with 1, 2.5 or 5% linseed oil containing 62% alpha-linolenic acid. alpha-Linolenic acid was incorporated up to 12% in the aorta of the 5% linseed oil group. The eicosapentaenoic acid content was not significantly increased. The content of arachidonic acid and docosatetraenoic acid was moderately reduced in rats fed 5% linseed oil. The generation of 6-keto-PGF1 alpha (degradation product of prostacyclin) assessed by HPLC/electrochemical detection was, however, markedly increased (p < 0.05) in rats fed 2.5 and 5% linseed oil. The minor prostanoids TXB2, PGE2 and PGF2 alpha were not significantly altered. The high systolic and diastolic blood pressure of SHR monitored by radio telemetry was more effectively reduced (p < 0.05) in the light, i.e. sleep, cycle. An increased prostacyclin formation and lowered vascular arachidonic acid content associated with enhanced dietary alpha-linolenic acid intake would thus be expected to prove beneficial in the prevention of vascular disorders.

Acceleration of renal disease in obese SHR by exacerbation of hypertension.

1. Obese SHR have lower blood pressures than lean littermates on ad libitum diets of standard rat chow and develop spontaneous progressive kidney disease with marked proteinuria, whereas lean SHR have only mild proteinuria. 2. On a high-salt diet, obese SHR show dramatic elevations in blood pressure accompanied by accelerated renal disease and mortality. Lean SHR are also salt sensitive but to a lesser degree. 3. Weight cycling elevates blood pressure in obese SHR to levels comparable to lean SHR littermates. This elevation in blood pressure is accompanied by an exacerbation of kidney disease relative to age-matched controls. 4. Ganglionic blockade reversed the elevation in blood pressure in obese SHR elicited by either high-salt diet or weight cycling. Therefore, excess sympathetic nervous activity contributes to the impact of these hypertensive stimuli. 5. Exacerbation of hypertension accelerates renal disease in obese SHR.