Urapidil in normotensive and spontaneously hypertensive rats: the effects on systemic and regional haemodynamics and cardiac mass

The effects of treatment for three weeks with urapidil (10 mg/kg p.o. twice daily) on systemic and regional haemodynamics and cardiac mass were studied in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Urapidil decreased mean arterial pressure and total peripheral resistance index (176 +/- 3 versus 145 +/- 5 mmHg and 0.61 +/- 0.02 versus 0.49 +/- 0.02 units, respectively; each P less than 0.01) in SHR without affecting heart rate, cardiac index or cardiac mass. No systemic haemodynamic changes were observed in WKY rats. All organ vascular resistances decreased significantly in SHR and blood flow increased to skin (P less than 0.01) and kidneys (P less than 0.05). These data indicate that urapidil is a potent antihypertensive agent in SHR which reduced mean arterial pressure through a decreased total peripheral resistance that was distributed throughout all circulations. Despite these haemodynamic changes, cardiac mass did not change.     

Hemodynamic Effects of Prolonged Treatment with Diltiazem in Conscious Normotensive and Spontaneously Hypertensive Rats

To determine systemic and regional hemodynamic effects of prolonged treatment with the calcium antagonist diltiazem (30 mg/kg twice daily by gastric gavage, for 3 weeks), data from 12 Wistar-Kyoto (WKY) and 10 spontaneously hypertensive (SHR) rats were compared with those obtained from 11 WKY and 10 SHR controls treated with the vehicle. Systemic and regional hemodynamics were determined in the conscious, unrestrained state using the reference sample microsphere method. Mean arterial pressure (MAP) decreased in SHR by 9% (183±4 to 167±4 mmHg; p < 0.05) but remained unchanged in WKY, while cardiac index (CI) tended to decrease in both strains; heart rate fell by 15% only in WKY (481·;10 to 354·13 beats/min; p < 0.05). Total peripheral resistance index (TPRI) tended to decrease in SHR but to increase in WKY. Organ blood flow in SHR decreased in skin and splanchnic organs, while organ vascular resistance decreased in brain and increased in splanchnic organs. In contrast, organ blood flow increased in heart and decreased in kidneys and skin of the WKY, while organ vascular resistance decreased in heart and increased in kidneys and skin. Thus, diltiazem produced nonuniform and different hemodynamic effects in the two strains. Further, diltiazem did not alter the cardiac mass in either rat strain. We therefore conclude that diltiazem demonstrated a mild hypotensive effect in SHR that was associated with slight reductions in CI and TPRI, the latter being non-uniformly distributed in the component organ circulations.     

Corticosteroid Modulation of the Renin System and Blood Pressure in the Spontaneously Hypertensive Rat

This study examines the role of gluco- and mineralcorticoids in the regulation of the renin-angiotensin system and blood pressure in the spontaneously hypertensive rat (SHR). Effects of adrenalectomy and selective treatment with either aldosterone (30 μg/kg/day) or dexamethasone (60 μg/kg/day) on plasma renin substrate, active renin (PRA), total renin and blood pressure were studied in 10 week old SHR and control WKY rats. Systolic blood pressure was moderately lower in adrenalectomized rats (129±2 mm Hg vs 137±4 mm Hg in control WKY and 145±4 mm Hg vs 160±3 mm Hg in control SHR) but could be restored to the control range by aldosterone. Dexamethasone repletion induced substantial increments of systolic blood pressure to comparable levels in both species (202±8 mm Hg in WKY and 192±6 mm Hg in SHR). Renin substrate was markedly lower in adrenalectomized, saline repleted rats. This could be reversed by dexamethasone in both species and by aldosterone in WKY rats only. Both PRA and total renin were higher (p<0.01) in the adrenalectomized, saline repleted state. This increase was not observed in aldosterone repleted rats. However, dexamethasone inhibited the adrenalectomy associated increase of PRA and total renin in SHR but not in WKY rats. Differences in blood pressure between SHR and WKY persist even in adrenalectomized state despite comparable stimulation of the renin system. Conversely, while blood pressure of both species responds similarly to selective corticosteroids therapy, the response of the renin-angiotensin system in SHR and WKY rats is distinct. Therefore factors other than the adrenal gland and the renin system must be involved in the determination of the high blood pressure in SHR.     

Effects of Acetylcholine and Nitroprusside on Systemic and Regional Hemodynamics in Hypertensive Rats

This study was performed to investigate the in vivoeffects of acetylcholine, a stimulator of endogenous NO production, and nitroprusside, an exogenous NO-donor, on hemodynamics in the normotensive (WKY) and the hypertensive (SHR) rat. Anesthetized rats were given microspheres for the measurement of cardiac index (CI), total vascular resistance (TPRI), regional blood flow and vascular resistance. Infusion of acetylcholine (2 μg/kg/min) caused a marked decrease in TPRI by (?35±5%, ±SEM) in the WKY (n=8), whereas in the SHR (n=8) a less pronounced reduction was seen (?14±3%, p<0.01 between groups). CI increased by 27±9% in the WKY, but was unaltered in the SHR. Blood pressure decreased similarily (17–20%). Acetylcholine significantly increased blood flow by about 40% in the kidneys and the heart in the WKY, but had no significant effect in the SHR. Other tissues, such as skeletal muscle and cerebral tissues, showed no major changes. Infusion of nitroprusside (1μg/kg/min) reduced blood pressure by 5 to 10% in the strains. The regional effects of nitroprusside did not differ between the strains. In conclusion, the acetylcholine-induced vasodilation in the kidney and the heart was attenuated in the SHR compared to the WKY. These findings might suggest a difference in the endothelial response between the SHR and the WKY in some, but not in all, tissues     

Effect of Insulin on Norepinephrine Overflow at Peripheral Sympathetic Nerve Endings in Young Spontaneously Hypertensive Rats

To determine how the effect of insulin is related to the development of salt-induced hypertension, and whether a hyporesponse to insulin exists in the peripheral sympathetic nerves of a hypertensive model rat, we measured norepinephrine overflow from the periarterial nerve of isolated mesenteric arteries exposed to insulin in spontaneously hypertensive rats (SHR) as well as Wistar-Kyoto rats (WKY) fed diets that were high and low in salt. Salt loading (diet containing 8% salt for 4 weeks) accelerated the development of hypertension in young, spontaneously hypertensive rats (SHR) (157 ± 5 mm Hg υ 198 ± 4 mm Hg, P < .01) but did not affect the blood pressure of Wistar-Kyoto rats (WKY) (102 ± 7 mm Hg υ 104 ± 6 mm Hg, P = NS). Basal norepinephrine overflow did not differ in the SHR and WKY rats, but the overflow of norepinephrine after periarterial electrical stimulation (8 Hz 1 min.) was significantly greater in SHR (0.806 ± 0.079 ng/g) than in WKY (0.723 ± 0.022 ng/g P < .01). Although insulin reduced the norepinephrine overflow by periarterial nerve stimulation in both WKY and SHR, the decrease with insulin was significantly greater in the SHR than in WKY (−18.4% ± 4.0% υ −32.0% ± 4.6%, P < .05). The inhibitory effect of insulin on norepinephrine overflow was reduced by salt loading in SHR (−8.8% ± 4.0%, P < .05), but not in WKY (−32.5% ± 4.7%, P = NS). Cocaine and ouabain completely blocked the effect of insulin in all four groups. In contrast to insulin, direct stimulation of Na⁺-K⁺ ATPase with a high-potassium buffer (12 mmol/L) reduced NE overflow to the same extent among the four groups. These findings show that SHR have a blunted response to the suppression by insulin of norepinephrine overflow. Salt loading reduced the insulin response at peripheral sympathetic nerves of young SHR, but did not affect that of age-matched WKY. Thus, hyporeactivity to insulin may play a role in the development of salt-induced hypertension in young SHR, possibly through a reduced suppression of norepinephrine overflow from sympathetic nerve endings. Am J Hypertens 1996;9:1119–1125     

Exaggerated Response to Electrical Nerve Stimulation of Angiotensin II Release in Isolated Perfused Hind Legs of Spontaneously Hypertensive Rats

Previously we reported that a large amount of immunoreactive angiotensin II (Ang II) was released from isolated perfused rat hind legs at steady rates for several hours. In view of a recent intriguing hypothesis that the vascular renin-angiotensin system plays an important role in the maintenance of high blood pressure in certain forms of experimental hypertensive models, the release of immunoreactive Ang II from isolated hind legs of spontaneously hypertensive rats (SHR) was examined in comparison with normotensive rats of Wistar-Kyoto strain (WKY) by using a Sep-Pak C₁₈ cartridge directly connected to the perfusion system. We also examined effect of electrically-induced nerve stimulation on the release of immunoreactive Ang II in the two strains. High performance liquid chromatography demonstrated the presence of Ang II in the prefusate. The spontaneous release of immunoreactive Ang II was as high as about 300 to 500 pg/30 min, tended to be higher in SHR rats (435.0±68.2 pg/30 min) than in WKY rats (342.1±65.1 pg/30 min), and stable up to 3 hours of perfusion for both strains. Periarterial nerve stimulation elicited a significant increment in the release of immunoreactive Ang II in either SHR (p<0.02) or WKY rats (p<0.05); however, the amount of released immunoreactive Ang II evoked by nerve stimulation was significantly greater in SHR than in WKY rats (781.3±89.6 vs 498.8±54.6 pg/30 min, p<0.05). These results further provide evidence for local generation and release of Ang II in peripheral vascular tissues, and are consistent with the hypothesis that the vascular renin-angiotensin system is one of important factors responsible for the maintenance of blood pressure.     

Functional and structural postglomerular alterations in the kidney of prehypertensive spontaneously hypertensive rats

The kidney plays a major role in the development of hypertension. Following the Borst-Guyton theory of an altered set-point for fluid and electrolyte homeostasis we aim to investigate functional and structural renal parameter during the development of hypertension. Therefore we focus on counter current exchange related factors. We compared 4 and 8 weeks old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) concerning basic renal parameters as creatinine and phosphorus clearance and urinary osmolality. Mean arterial pressure (MAP) was measured intra-arterially. Vasa recta were investigated using immunohistochemistry for alpha-smooth-muscle actin (ASMA) and plastification for geometric analyses. Blood pressure was not yet significantly elevated in SHR at 4 weeks but at 8 weeks it was higher in SHR (116+/-7 vs. 102+/-4 mm Hg; p<0.01). Kidney weight/body weight ratio was lower in SHR at both ages. In 4 weeks old SHR, phosphorus clearance and urinary osmolality were decreased compared to WKY [0.02+/-0.01 vs. 0.05+/-0.02 (ml/min* 100 g BW) p < 0.03; 14.2+/-2.2 vs. 18.9+/-2.9 (osmol/kg*24 h urine) p < 0.051 indicating reduced tubular reabsorption. At 8 weeks phosphorus clearance and urinary osmolality were comparable to WKY. alpha-Actin was found in vasa recta in a 4-times higher degree in SHR with a predominant location in the outer medulla. Radii of vasa recta in the outer medulla decreased during development. In plastificated sections vasa recta of SHR revealed sphincter-like pattern. Functional and structural alterations related to the counter current exchanger are already evident in prehypertensive SHR. During development of hypertension both factors get adapted to higher blood pressure level. Sphincter-like structures in vasa recta suggest contractility of pericytes/vascular smooth muscle cells (vSMC). As these were just seen in SHR that might allude to a higher potential to contract. We conclude that differences in postglomerular structure and function may contribute to the development of hypertension in SHR.     

Increased Atrial Natriuretic Factor Receptor Density in Cultured Vascular Smooth Muscle Cells of the Spontaneously Hypertensive Rat: Revised

To explore the role of the atrial natriuretic factor (ANF) system in the pathophysiology of hypertension we examined the binding kinetics of synthetic ANF to cultured vascular smooth muscle cells (VSMCs) derived from the spontaneously hypertensive rat (SHR) and two normotensive controls-the Wistar Kyoto (WKY) and American Wistar (W). The number of maximal binding sites (Bmax) per cell (mean ± SEM; × 10³) were: SHR = 278.0 ± 33.0, WKY = 28.3 ± 7.1 and W = 26.6 ± 4.2. The differences between the SHR and normotensive strains were significant at p<0.001. The equilibrium dissociation constant (Kd; × 10^?9M) was higher in SHR VSMCs (0.94 ± 0.14) than in WKY (0.22 ± 0.09; p <0.01) and W (0.39 ± 0.14; p <0.02) cells. The plasma levels of the imnunoreactive ANF were higher in SHR than the normotensive controls. We suggest that the relatively greater ANF receptor density in cultured VSMCs of the SHR represents a response to the invitro environment which is relatively more deficient in ANF for VSMCs of the SHR as compared with the normotensive rats. Thus, the capacity of the SHR VSMC to regulate ANF receptor density appears to be independent of the blood pressure level.     

Systemic and Regional Hemodynamics in Normotensive and Spontaneously Hypertensive Rats after Slow-Channel Calcium Blocker Nitrendipine

To determine the effects of the recently synthesized slow channel calcium blocker nitrendipine on systemic and regional hemodynamics, mean arterial pressure, heart rate, cardiac index and organ blood flow distribution were measured with the combined radioactive reference sample and microsphere techniques before and one hour after its oral administration (1 mg or 10 mg/kg). Twenty-week-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) conscious male rats were studied. At the 10 mg dose, nitrendipine exerted a hypotensive effect within 15 minutes, and this effect persisted throughout the study. After one hour, mean arterial pressure fell by 14 percent of pretreatment levels in WKY controls; it fell by 25 percent in SHR (p < 0.001). This action was mediated by a fall in total peripheral resistance index (p < 0.01) that was nonuniformly distributed to the organ circulations since blood flow was maintained or increased to brain, heart, kidneys, lungs, and adrenals, but decreased to skin. No change in cardiac index was observed.     

Ouabain Produces Diverse Excitatory Effects on Afferent Baroreceptor Nerve Activity in SHR and WKY Animals

The effect of acute ouabain treatment was evaluated on afferent baroreceptor nerve activity in spontaneously hypertensive rats (SHR) compared with Wistar Kyoto rats (WKY). Under urethane anesthesia (1.2 mg/Kg) the discharge of the recurrent laryngeal nerve was utilized as index of arterial baroreceptor activity (BNA) in rats with the ipslateral vagus cut at a proximal level. The ouabain (30 μg, i.v.) treatment produced an excitatory effect on BNA without changes in basal arterial pressure in both groups studied. This effect was larger in SHR (92±10%) than WKY (37±4%, P < 0.01)

The arterial pressor response to phenylephrine was similar in both SHR and WKY before (20±1 and 22±1.2 mmHg) and after (18±1.4 and 20±2 mmHg, respectively) ouabain. The BNA under phenylephrine-induced peaks of high arterial pressure was significantly higher in SHR (61±15%) than in WKY (41±5% P < 0.01) but after ouabain treatment the opposite was observed (31±5 vs. 61±4% P < 0.01). The inhibitory effects of sodium nitroprusside on arterial pressure and BNA were similar in SHR and WKY groups both before and after the ouabain treatment

These data indicate an excitatory effect of ouabain on baroreceptor nerve activity in normotensive and markedly in hypertensive rats which could contribute to the reflex arterial pressure regulation, besides the known inotropic action on the heart     

基质金属蛋白酶-9在自发性高血压大鼠心室重构的变化及γ-干扰素的干预研究

目的:观察基质金属蛋白酶-9(MMP-9)在自发性高血压大鼠心室重构(SHR)的变化及γ-干扰素(IFN-γ)的干预作用。方法:28只SHR(雄性),随机分为4组(每组7只):高剂量组(SHR-H),中剂量组(SHR-M),低剂量组(SHR-L)和SHR对照组(SHR-C);另7只WKY大鼠(雄性),作为阴性对照组(WKY)。SHR-L组,SHR-M组,SHR-H组每日上午分别腹腔注射INF-γ,5万u/kg,10万u/kg,15万u/kg,连续8w。SHR-C组和WKY组每日上午腹腔注射等量的0.9%氯化钠液,连续8w。分别于治疗前,治疗后4w、8w,采用尾袖法测量尾动脉收缩压(SBP),ELISA法检测血清MMP-9含量。实验第8周,处死大鼠,称取左心室质量(LVM),计算左心室质量指数LVMI(LVWI=LVM/BW);光镜下观察HE染色的心肌组织;采用werstern blot法检测心肌组织MMP-9蛋白表达。结果:各SHR组尾动脉收缩压(SBP)、左心室质量、LVMI及MMP-9的血清水平较WKY组明显升高(P<0.0 5)。应用IFN-γ后,治疗组的各指标较SHR-C均显著下降SBP[(189.57±5.06)vs.(201.57±5.74)mmHg(1 mmHg=0.133kPa)],LVMI[(2.68±0.08)vs.(2.89±0.08)mg/g],MMP-9[(3.20±0.35)vs.(4.90±0.51)mg/L,P<0.05)];心肌组织MMP-9蛋白明显负调表达[(0.49±0.07)vs.(1.05±0.08),P<0.05]。结论:IFN-γ能抑制心肌组织中MMP-9表达,改善高血压心室重构,可能与抑制心肌的慢性炎症有关。     

A high phosphate diet lowers blood pressure in spontaneously hypertensive rats

Plasma phosphate values are significantly lower in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto rats (WKY). In this study, we increased plasma phosphate in SHR by a dietary phosphate intake and followed the effects on blood pressure. Fifteen male WKY and 15 male SHR were housed from 4 weeks of age up to 26 weeks. At 4 weeks of age all SHR manifested a hypophosphatemia compared with age-matched WKY (F = 62, p less than 0.0003). At 5 weeks of age, the rats were divided into three diet groups: a control group, a group receiving 1.41% (wt/vol) KCl in drinking water, and a group receiving 2% (wt/vol) K2HPO4 X KH2PO4 in drinking water. In the control (F = 16.2, p less than 0.02) and KCl groups, (F = 36.3, p less than 0.03), hypophosphatemia persisted throughout the study. The phosphate-supplemented diet normalized plasma phosphate level in SHR but did not change plasma phosphate level in WKY. As a consequence, no difference in plasma phosphate level between WKY and SHR was present in the group receiving additional phosphate from that time on (F = 1.2, p greater than 0.41). The phosphate-supplemented diet significantly decreased systolic blood pressure in both strains. In phosphate-supplemented SHR, a significant decline in systolic blood pressure was observed from 20 weeks of age on (at 20 weeks of age: 222 +/- 3 mm Hg for control SHR vs 198 +/- 5 mm Hg for phosphate-supplemented SHR; p less than 0.0003).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic and coronary effects of intravenous labetalol in coronary artery disease

Labetalol, an alpha and beta receptor blocking agent, was evaluated in 11 patients with documented coronary artery disease and stable angina. The mean dose of labetalol was 1.5 (range 1 to 2) mg/kg. Cardiovascular effects began within 1 minute after injection and were maximal within 10 minutes. Mean arterial pressure decreased from 105 ± 13 to 81 ± 10 mm Hg (p < 0.0001), heart rate from 70 ± 10 to 66 ± 7 beats/min (p < 0.05) and the pressure-rate product from 10,322 ± 2,344 to 7,717 ± 1,650 (p < 0.001). Cardiac output and pulmonary wedge pressure did not change significantly. Mean pulmonary arterial pressure decreased from 20 ± 3 to 16 ± 2 mm Hg (p < 0.005). Systemic and pulmonary resistances also decreased significantly (p < 0.0001 andp < 0.01, respectively). Coronary sinus flow increased from 107 ± 26 to 118 ± 25 ml/min (p < 0.01) and coronary vascular resistance decreased from 1.0 ± 0.2 to 0.77 ± 0.1 mm Hg/ml per min (p < 0.001).Labetalol may be a useful adjunct in the treatment of angina not only because it diminishes myocardial oxygen requirements but also because it improves coronary hemodynamics. Thus, labetalol appears to have some advantage compared with the usual beta blocking agents with their potentially detrimental effects on coronary hemodynamics.     

Assessment of left ventricular performance by on-line pressure-area relations using echocardiographic automated border detection

Objectives. The purpose of this study was to evaluate left ventricular performance by on-line pressure-area relations using echocardiographic automated border detection in the in situ canine heart in a manner similar to pressure-volume analyses.Background. Echocardiographic automated border detection can measure ventricular cavity area as an index of volume and may be interfaced with pressure to construct pressure-area loops on-line.Methods. Eight anesthetized open chest dogs had simultaneous measurement of ventricular pressure, aortic flow and midventricular short-axis area. Pressure-area loops were constructed by a computer workstation interfaced with the ultrasound system. Stroke area (Maximal area — Minimal area) and stroke force (∝P dA [P = pressure; A = area]) values during inferior vena cava (n = 8) and aortic (n = 4) occlusions were compared with stroke volume and estimates of stroke work, respectively. Inotropic modulation was induced with dobutamine infusion (2 to 5 μg/kg body weight per min), followed by propranolol infusion (2 to 5 mg). End-systolic and maximal elastance and preload recruitable stroke force (stroke force versus end-diastolic area) were derived for each period.Results. Changes in stroke area and stroke force were significantly correlated with changes in stroke volume and estimates of stroke work during caval occlusion (n = 8) (r = 0.87 ± 0.02, SEE = 8 ± 1% and r = 0.90 ± 0.03, SEE = 8 ± 2%, respectively). In dogs with aortic occlusion (n = 4), changes in stroke area significantly correlated with changes in stroke volume for pooled data (r = 0.84, SEE = 8%, y = 1.0x + 3). Ventricular performance increased with dobutamine infusion (n = 7): endsystolic elastance 30 ± 11 to 67 ± 24 mm Hg/cm²(p < 0.02 vs. control values); maximal elastance 37 ± 11 to 82 ± 26 mm Hg/cm²(p < 0.02 vs. control values); preload rcruitable stroke force 81 ± 24 to 197 ± 92 mm Hg (p < 0.02 vs. control values). Decreases occurred with propranolol infusion (n = 5) end-systolic elastance 20 ± 4 to 13 ± 4 mm Hg/cm²(p < 0.002 vs. control values); maximal elastance 29 ± 8 to 15 ± 5 mm Hg/cm²(p < 0.002 vs. control values); preload recruitable stroke force 66 ± 14 to 40 ± 9 mm Hg (p < 0.002 vs. control values).Conclusions. On-line pressure-area relations are a potentially useful means to assess left ventricular performance in a manner that is quantitatively similar to the predicted responses of pressure-volume relations.     

Arterial hypertension, myocardial hypertrophy and disorders of cardiac rhythm induced by ligation of the left coronary artery in the rat

Cardiac hypertrophy and hypertension are major elements in sudden cardiac death in patients with coronary artery disease. To investigate in animals the hypothesis that left ventricular hypertrophy (LVH) and/or hypertension increase the incidence of severe ventricular arrhythmias, we have undertaken a 30 min period of coronary artery ligation in anaesthetized spontaneously hypertensive rats (SHR), normotensive (NT) Wistar Kyoto (WKY) and Wistar (W) rats. Mean systolic blood pressure (SBP) was 190 +/- 4 mmHg in SHR vs 123 +/- 5 mmHg in WKY and 116 +/- 4 mmHg in W (p less than 0.001). LVH index was 2.81 +/- 0.04 in SHR vs 196 +/- 0.03 in WKY and 1.65 +/- 0.05 in W (p less than 0.01). Incidence (IVF) and duration (DVF) of ventricular fibrillation were significantly more elevated in SHR than in NT rats. IVF was 100 p. 100 in SHR vs 36 p. 100 in WKY and 27 p. 100 in W (p less than 0.001); DVF was 61 +/- 17 s in SHR vs 6 +/- 6 s in WKY and W (p less than 0.001). In addition the calcium channel blocker nicardipine (N) has been administered orally to SHR either chronically during eight weeks (20 mg/kg-1 per os twice daily) or acutely as a single dose of 20 mg/kg. After long term treatment (LT) with N the LVH index and SBP were significantly reduced when compared to vehicle treated (VT) SHR; whereas a single administration of N (AT) only decreased SBP without affecting LVH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Active and Inactive Renin-Like Enzymes in the Brain of Spontaneously Hypertensive Rat

Renin-like enzyme(s) in the brain of spontaneously hypertensive rat (SHR) were activated unequivocally by trypsin. The highest concentration of the active renin-like enzyme was localized in the hypothalamus (1.03±0.25 ng angiotensin I/mg of protein per h, mean±S.D.), followed by the striatum (0.51±0.21), thalamus (0.40±0.08), midbrain (0.33±0.04), medulla oblongata (0.25±0.01), cerebral cortex (0.21±0.03), and cerebellum (0.14±0.03), while the highest concentration of the inactive renin-like enzyme was localized in the hypothalamus (0.86±0.17), followed by the striatum (0.47±0.15), thalamus (0.32±0.09), cerebellum (0.29±0.04), midbrain (0.26±0.02), cerebral cortex (0.24±0.04), and medulla oblongata (0.10±0.03). The active renin-like activity in the thalamus of SHR was significantly lower than that of age- and sex-matched normotensive Wistar-Kyoto (WKY) rats. Furthermore, the inactive renin-like activity in the striatum, thalamus, cerebellum, midbrain, and medulla oblongata of SHR was significantly lower than that in the corresponding areas of WKY rats. Although the precise mechanisms underlying the conversion of inactive to active renin-like enzyme in the brain remain to be resolved, these results may offer a new aspect for the role of the brain renin-angiotensin system in the initiation and/or development of hypertension of SHR.     

Altered insulin-like growth factor-1 and nitric oxide sensitivities in hypertension contribute to vascular hyperplasia

Vascular medial thickening, a hallmark of hypertension, is associated with vascular smooth muscle cell (VSMC) hypertrophy and hyperplasia. Although the precise mechanisms responsible are elusive, we have shown that strain induced regulation of autocrine insulin-like growth factor-1 (IGF-1) and nitric oxide (NO) reciprocally modulate VSMC proliferation. Therefore, we investigated potential IGF-1 and NO abnormalities in young (10-week-old) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and their respective VSMC ex vivo. The SHR had increased mean arterial pressure (173 ± 2 v 128 ± 3 mm Hg, n = 24, P < .05) but similar pulse pressures (31 ± 2 v 30 ± 3 mm Hg; P > .05) v WKY. The SHR exhibited increased aortic wall thickness in comparison with WKY (523 ± 16 v 355 ± 17μm; P < .05). No differences were seen in plasma combined NO₂ and NO₃ (NO_x) (0.48 ± 0.11 mmol/L for WKY v 0.58 ± 0.18 mmol/L for SHR) or plasma IGF-1 (1007 ± 28 ng/mL for WKY v 953 ± 26 ng/mL for SHR). Aortic VSMC from SHR displayed enhanced proliferation in comparison with WKY (P < .05). Underlying this enhanced proliferation was altered SHR VSMC sensitivity to the antiproliferative NO donor 2,2"[Hydroxynitrosohydrazono] bis-ethanimine (DETA-NO) (ID₅₀: 270 ± 20 mmol/L for SHR; 150 ± 11 mmol/L for WKY; P < .05). Basal cyclic guanosine monophosphate (cGMP) secretion from SHR VSMC was 65-fold greater than that seen from WKY (P < .001). In response to DETA-NO, cGMP secretion from SHR VSMC increased modestly (1.5-fold; P < .01), whereas treatment of WKY VSMC resulted in a 26-fold (P < .001) increase in cGMP. The SHR VSMC did not respond to exogenous IGF-1, whereas WKY VSMC exhibited a dose dependent increase in proliferation with IGF-1 (10⁻¹⁰ to 10⁻⁷ mol/L). These data suggest that VSMC hyperplasia in early hypertension is not reflected by imbalances in plasma IGF-1 or NO. Rather, altered SHR VSMC sensitivity to NO is likely responsible in part for the observed hyperproliferation seen in early stages of hypertension.     

Elevated 12-Lipoxygenase Activity in the Spontaneously Hypertensive Rat

We have previously demonstrated that administration of inhibitors of the lipoxygenase (LO) pathway of arachidonic acid metabolism lowers blood pressure in hypertensive rats. In addition, we have shown that LO inhibition attenuates pressor agonist-induced vascular reactivity in vitro and calcium mobilization in cultured vascular smooth muscle cells (VSMC). To further elucidate the relationship between elevated LO activity and hypertension, 4, 8, and 12 week old hypertensive SHR were compared with age-matched Wistar-Kyoto (WKY) rats for plasma 12(S)-hydroxyeicosatetraenoic acid (12-HETE) concentration. 12-HETE levels were significantly elevated in the SHR compared to the WKY (SHR elevated by 154%, 159%, and 272% compared to WKY at 4, 8, and 12 weeks, respectively, P < .01 for all ages). There were no differences in plasma potassium levels between SHR and WKY at any of the ages tested. Plasma aldosterone levels and plasma renin activity were in the normal range at the three ages. At 12 weeks of age, both serum (4.72 ± 0.23 v 2.18 ± 0.33 μg/mL, P < .01), and aortic smooth muscle 12-HETE levels (0.94 ± 0.09 v 0.66 ± 0.08 μg/mg protein, P < .05) were elevated in SHR compared with WKY. The 12 week old SHR were given a bolus of the LO inhibitor 5,8,11-eicosatriynoic acid (ETI, 7 mg/kg, intravenously) and blood pressure measured after 20 min. ETI reduced mean systolic blood pressure from 175.8 ± 4.2 to 141.6 ± 5.9 mm Hg (P < .05). To investigate these effects of HETEs, cultured vascular smooth muscle cells were pretreated for 1 min with 12(S)HETE and then challenged with angiotensin II (AngII). The addition of 12(S)HETE increased AngII-induced intracellular calcium levels in normal cultured rat vascular smooth muscle cells by 78% compared to vehicle (P < .05). Thus, LO products, which are high in SHR, may contribute to vascular tone through alterations in the intracellular calcium signal by potentiating calcium responses to pressors such as Ang II.     

Modulation of Nitric Oxide Synthase Activity in Brain,Liver, and Blood Vessels of Spontaneously Hypertensive Rats by Ascorbic Acid: Protection from Free Radical Injury

End organ damage in essential hypertension has been linked to increased oxygen free radical generation, reduced antioxidant defense, and/or attenuation of nitric oxide synthase (NOS) activity. Ascorbic acid (AA), a water-soluble antioxidant, has been reported as a strong defense against free radicals in both aqueous and nonaqueous environment. In this study we examined the hypothesis that antioxidant ascorbic acid may confer protection from increased free radical activity in brain, liver, and blood vessels of spontaneously hypertensive rats (SHR). Male SHRs were divided into groups: SHR + AA (treated with AA, 1 mg/rat/day; for 12 weeks) or SHR (untreated). Wister-Kyoto rats (WKY) served as the control. Mean systolic blood pressure (SBP) in treated and untreated SHR was 145 ± 7 mmHg and 142 ± 8 mmHg, respectively. AA treatment prevented the increase in systolic blood pressure in SHR by 37 ± 1% (p < 0.05). NOS activity in the brain, liver, and blood vessels of WKY rat was 1.82 ± 0.02, 0.14 ± 0.003, and 1.54 ± 0.06 pmol citruline/mg protein, respectively. In SHR, total NOS activity was significantly reduced by 52 ± 1%, 21 ± 3%, and 44 ± 4%, respectively. AA increased NOS activity in brain, liver, and blood vessels of SHR from 0.87 ±.03, 0.11 ±.01, and 0.87 ±.08 pmol citruline/mg protein to 0.93 ± 0.01, 0.13 ± 0.001, and 1.11 ± 0.03 pmol citruline/mg protein (p < 0.05), respectively. Lipid peroxides in the brain, liver, and blood vessels from WKY rats were 0.87 ± 0.06, 0.11 ± 0.005, and 0.47 ± 0.04 nmol MDA equiv/mg protein, respectively. In SHR, lipid peroxides in brain, liver, and blood vessels were significantly increased by 40 ± 3%, 64 ± 3%, and 104 ± 13%, respectively. AA reduced lipid peroxidation in liver and blood vessels by 17 ± 1% and 34 ± 3% but not in brain. Plasma lipid peroxides were almost doubled in SHR (p < 0.01) together with a reduction in total antioxidant status (6 ± 0.1%; p < 0.05), nitrite (53 ± 2%; p < 0.05) and superoxide dismutase (SOD) activity (36 ± 2%; p < 0.05). AA treatment reduced plasma lipid peroxide (p < 0.001), and increased TAS (p < 0.001), nitrite (p < 0.001), and SOD activity (p < 0.001). From this study, we conclude that brain, liver, and blood vessels in SHR are susceptible to free radical injury, which reduces the availability of NO either by scavenging it or by reducing its production via inhibiting NOS. In addition, brain, liver, and blood vessels in SHR; may be protected by antioxidant, which improves total antioxidant status, and SOD thus may prevent high blood pressure and its complications.     

Antianginal and myocardial metabolic properties of verapamil in coronary artery disease

To determine the metabolic cost of administering an experimental calcium antagonist, verapamil, to patients with coronary artery disease, 12 such patients were studied at rest and during stress with atrial pacing before and after intravenous treatment with verapamil (bolus dose of 0.1 mg/kg body weight, followed by infusion at 0.005 mg/kg per min). The mean (±standard deviation) aortic pressure at rest (98 ± 22 mg Hg), coronary sinus blood flow (88 ± 17 ml/min) and myocardial oxygen consumption (10.7 ± 2.4 ml O₂/min) decreased to 88 ± 20 mm Hg (p < 0.0004), 77 ± 14 ml/min (p < 0.03) and 8.8 ± 2.5 ml O₂/min (p < 0.01), respectively, after administration of verapamil. With atrial pacing, these values were 105 ± 25 mm Hg, 151 ± 50 ml/min and 18.5 ± 6.4 ml O₂/min, respectively, before infusion of verapamil, and then decreased to 87 ± 14 mm Hg (p < 0.006), 107 ± 31 ml/min (p < 0.0002) and 13.3 ± 4.4 ml O₂/min (p < 0.001) during infusion. Angina occurred in all patients with atrial pacing before verapamil (threshold to pain: 93 ± 67 seconds). After verapamil, the threshold to pain in six patients increased to 191 ± 183 seconds; and no pain was experienced by the remaining six (p < 0.0005). Before administration of verapamil lactate extraction decreased from 24 ± 9 to 10 ± 11 percent (p < 0.0002) during atrial pacing, and 9 (75 percent) of the 12 patients exhibited electrocardiographic S-T segment depressions. After administration of verapamil lactate extraction normalized to 22 ± 9 percent during atrial pacing, and the electrocardiogram reverted to baseline in all but one patient. These findings indicate that verapamil decreases left ventricular myocardial metabolic demands, and concomitantly greatly increases the threshold to angina.