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)     

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)     

Calcium infusion increases plasma atrial natriuretic factor in spontaneously hypertensive rats

The effect of calcium on plasma atrial natriuretic factor (ANF) concentration was determined in spontaneously hypertensive rats (SHR) and their control, Wistar-Kyoto (WKY) rats. CaCl2 10.5 mg (0.095 mmol) in 0.54 ml 5% glucose or an equal volume of vehicle alone was infused intravenously for 30 minutes into conscious precannulated SHR (vehicle, n = 16; CaCl2, n = 16) and WKY rats (vehicle, n = 25; CaCl2, n = 15). Direct systolic blood pressure was measured throughout the infusion period. Blood samples for serum total calcium and plasma ANF were obtained at the end of each experiment. The systolic blood pressure did not change significantly during infusion of the vehicle or CaCl2 in either strain. No significant difference was observed in serum total calcium concentration between SHR and WKY rats after vehicle (9.8 +/- 0.1 [mean +/- SEM] mg/dl vs. 10.0 +/- 0.1) or after CaCl2 infusion (12.2 +/- 0.3 vs. 12.2 +/- 0.2). Plasma ANF concentrations after both vehicle and CaCl2 infusion were significantly higher in SHR than in WKY rats (vehicle, 211 +/- 24 pg/ml vs. 129 +/- 11, p less than 0.05; CaCl2, 395 +/- 21 vs. 278 +/- 33, p less than 0.05). There were high degrees of correlation between serum total calcium and plasma ANF both in SHR (r = 0.77, p less than 0.001) and in WKY rats (r = 0.76, p less than 0.001). No significant difference was observed in the slopes of the regression lines of ANF as a function of the serum total calcium concentration between SHR and WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic balances of sodium and water in young spontaneously hypertensive rats and the effects of chronic inhibition of the conversion enzyme

In order to show in SHR to what extent the kidneys excrete salt and water in proper relation to intake and whether antihypertensive action of converting enzyme inhibition (CEI) involves changes in salt--and water--balance, metabolic studies were conducted during 12 weeks following weaning (wk 4 to 15) on 4 groups of 9 male rats: SHR, WKY and SHR.C, WKY.C (C: given 30 mg captopril/kg body wt every 12 hr by gavage), all fed a standard rat chow (sodium 104 +/- 3 meq/g) in metabolic cages with free access to distilled water. SHR exhibited a higher weekly sodium retention than WKY only up to the end of wk 9 (5.2 +/- 0.5 vs 3.4 +/- 0.6 mEq/wk, p less than 0.001). This was due to lower urinary excretion and greater intakes since fecal losses were higher. From ages 10 through 15 wk, weekly sodium retention was the same in both strains although urinary sodium excretion in SHR was still significantly lower. SHR also retained more water at 7 and 8 wk than age-matched WKY due to lower urinary excretion. From ages 4 to 15 wk, SHR exhibited a reduced relationship of urinary sodium and water excretion to systolic arterial pressure. From ages 4 to 15 wk, weekly sodium retention in SHR.C (2.9 +/- 0.9 mEq/wk) was below that in SHR (4.5 +/- 0.9 mEq/wk, p less than 0.05) and not different from that in WKY (3.7 +/- 0.8 mEq/wk). As intakes and fecal losses were unchanged by CEI, this was due to increased urinary sodium excretion in SHR.C over that in SHR (by 1.4 +/- 0.5 mEq/wk.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of oxidative stress in the sex differences in blood pressure in spontaneously hypertensive rats

OBJECTIVE: The hypothesis was tested that differences in oxidative stress play a role in the sex differences in the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). DESIGN AND METHODS: Male and female SHR [and Wistar-Kyoto (WKY) rats in the long-term study] (n = 6-12 per group) received tempol (30 mg/kg per day) or tap water for 6 weeks from 9 to 15 weeks of age or from birth until 15 weeks of age. Blood pressure [mean arterial pressure (MAP)] and kidney tissue F2-isoprostane (IsoP) were measured at 15 weeks of age. RESULTS: In SHR given tempol for 6 weeks, blood pressure and IsoP were reduced in males, but not in females. In SHR given tempol from birth, MAP was higher in SHR than WKY rats (SHR males, 181 +/- 2 mmHg; SHR females, 172 +/- 3 mmHg; WKY males, 100 +/- 2 mmHg; WKY females, 101 +/- 2 mmHg, P < 0.01), and tempol reduced MAP by 14% (156 +/- 3) and 26% (127 +/- 4) in male and female SHR, respectively, but had no effect on WKY rats. IsoP was higher in SHR than WKY rats and higher in male SHR than female SHR (SHR males, 5.18 +/- 0.23 ng/mg; SHR females, 3.71 +/- 0.19 ng/mg, P < 0.01; WKY males, 1.72 +/- 0.45 ng/mg; WKY females, 2.21 +/- 0.08 ng/mg, P < 0.05, compared with SHR). Tempol reduced IsoP in SHR to levels found in WKY rats, but had no effect on IsoP in WKY rats. CONCLUSIONS: Development of hypertension in SHR is mediated in part by oxidative stress independent of sex. Also, tempol is effective in reducing blood pressure in females only when given prior to the onset of hypertension.     

Interaction of angiotensin II type 1 and D5 dopamine receptors in renal proximal tubule cells

Angiotensin II type 1 (AT1) receptor and D1 and D3 dopamine receptors directly interact in renal proximal tubule (RPT) cells from normotensive Wistar-Kyoto rats (WKY). There is indirect evidence for a D5 and AT1 receptor interaction in WKY and spontaneously hypertensive rats (SHR). Therefore, we sought direct evidence of an interaction between AT1 and D5 receptors in RPT cells. D5 and AT1 receptors colocalized in WKY cells. Angiotensin II decreased D5 receptors in WKY cells in a time- and concentration-dependent manner (EC50=2.7x10(-9) M; t(1/2)=4.9 hours), effects that were blocked by an AT1 receptor antagonist (losartan). In SHR, angiotensin II (10(-8) M/24 hours) also decreased D5 receptors (0.96+/-0.08 versus 0.72+/-0.08; n=12) and to the same degree as in WKY cells (1.44+/-0.07 versus 0.92+/-0.08). However, basal D5 receptors were decreased in SHR RPT cells (SHR 0.96+/-0.08; WKY 1.44+/-0.07; n=12 per strain; P<0.05) and renal brush border membranes of SHR compared with WKY (SHR 0.54+/-0.16 versus WKY 1.46+/-0.10; n=5 per strain; P<0.05). Angiotensin II decreased AT1 receptor expression in WKY (1.00+/-0.04 versus 0.72+/-0.08; n=8; P<0.05) but increased it in SHR (0.96+/-0.04 versus 1.32+/-0.08; n=8; P<0.05). AT(1) and D5 receptors also interacted in vivo; renal D5 receptor protein was higher in mice lacking the AT1A receptor (AT1A-/-; 1.61+/-0.31; n=6) than in wild-type littermates used as controls (AT1A+/+; 0.81+/-0.08; n=6; P<0.05), and renal cortical AT1 receptor protein was higher in D5 receptor null mice than in wild-type littermates (1.18+/-0.08 versus 0.84+/-0.07; n=4; P<0.05). We conclude that D5 and AT1 receptors interact with each other. Altered interactions between AT1 and dopamine receptors may play a role in the pathogenesis of hypertension.     

Catecholamine-related gene expression correlates with blood pressures in SHR

In this study we aimed to determine whether the levels of gene expression for phenylethanolamine-N-methyltransferase (PNMT), noradrenaline transporter (NAT), alpha1A-receptor (alpha1A-R), and alpha2A-receptor (alpha2A-R) vary with resting systolic blood pressure in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) or Sprague-Dawley (SD) rats. Sites examined included central and peripheral regions associated with the control of arterial pressure. Twenty week old SD (n=6), WKY (n=6), and SHR (n=6) were used. Systolic blood pressure was measured using tail cuff plethysmography 2 weeks before tissue extraction. RNA was isolated and reverse-transcribed into cDNA. Gene expression levels were measured, using quantitative real time PCR, relative to the expression of GAPDH. PNMT, NAT, and alpha(1A)-R mRNA expression was significantly greater in SHR tissue samples compared with normotensives. In the rostral ventrolateral medulla, PNMT mRNA in SHR was 3 times greater than that in WKY (SHR: 0.82+/-0.02%; WKY: 0.29+/-0.02%). The amount of alpha(2A)-R mRNA was significantly lower in SHR compared with normotensives. For example, the level of alpha(2A)-R mRNA in spinal cord of SHR was 3 times less than that found in WKY (SHR: 1.85+/-0.04%; WKY: 3.26+/-0.07%). PNMT, NAT, and alpha(1A)-R mRNA levels were positively correlated with systolic blood pressure in all central tissue investigated. Conversely, alpha2A-R mRNA levels in central sites were negatively correlated with systolic blood pressure. Clearly, a decrease in central alpha2A-R and an increase in alpha1A-R is consistent with the elevated blood pressure and sympathetic activity observed in SHR.     

Potentiation of the baroreceptor-heart rate reflex by sympathectomy in conscious rats

In both animals and humans, stimuli leading to sympathetic activation are accompanied by an impairment of the baroreceptor-heart rate reflex. To determine whether sympathetic activity normally interferes with this reflex function we examined in conscious Wistar-Kyoto (WKY) rats the effect of chemical sympathectomy by 6-hydroxydopamine on the bradycardic response to baroreceptor stimulation induced by raising blood pressure via intravenous phenylephrine boluses; control rats received vehicle. Spontaneously hypertensive rats were also studied because in these animals there is both a baroreceptor reflex impairment and a sympathetic overactivity. Baroreceptor reflex sensitivity, calculated as the ratio of the peak increase in pulse interval to the peak increase in mean arterial pressure, was 75% greater in sympathectomized WKY rats than in control WKY rats (1.28 +/- 0.15 versus 0.73 +/- 0.10 msec/mm Hg, mean +/- SEM; p less than 0.01). The sympathectomy-induced increase in sensitivity was even larger in spontaneously hypertensive rats (SHR) (1.26 +/- 0.12 versus 0.44 +/- 0.06 msec/mm Hg in sympathectomized SHR versus control SHR, +186%; p less than 0.01) so that the impaired baroreceptor reflex sensitivity observed in control SHR as compared with control WKY rats (-40%, p less than 0.01) was no longer detectable in the sympathectomized groups. To establish whether the sympathectomy-induced potentiation of the reflex was due to an increase in cardiac responsiveness to vagal stimuli, we subjected separate groups of anesthetized, vagotomized SHR and WKY rats to graded electrical stimulation of the right efferent vagus. The bradycardic effects of vagal stimulation, however, were similar in sympathectomized and control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Normalization of active urinary kallikrein excretion by young spontaneously hypertensive rats by chronic inhibition of conversion enzyme

This study was designed to investigate the decreased urinary kallikrein excretion (Ukall.V) in Okamoto-Aoki spontaneously hypertensive rats (SHR) and the effect of long-term converting enzyme inhibition. From ages 4 to 7 weeks, Ukall.V was determined (amidolytic assay: nanokatals/wk) in 4 groups of 6 male rats housed into individual metabolic cages and fed a normal sodium diet: SHR and normotensive Wistar-Kyoto rats (WKY); SHR-C and WKY-C which were given captopril: 30 mg/kg BW every 12 hours by gavage. Ukall.V was each time lower in SHR than in age-matched WKY, even at 4 wks of age (54.6 +/- 9.1 vs 108.5 +/- 16.1 nkat/wk; p less than .01) when systolic blood pressure (s.BP) was already higher. In SHR-C, s.BP was identical or slightly lower to that in WKY. Ukall.V was still lower at wk 4 when captopril was first administered (60.9 +/- 8.4 nkat/wk; p less than .01), but identical to that in WKY at each subsequent age (105.7 +/- 25.9 vs 114.1 +/- 5.6 nkat/wk at wk 5; 219.8 +/- 44.5 vs 253.4 +/- 22.4 nkat/wk at wk 7). Excretion of active kallikrein was highly correlated to s.BP in WKY (r = .87), SHR (r = 0.91) and SHR-C (r = 0.95). The slope of the regression line relating Ukall.V with s.BP was significantly less in SHR than WKY (1.33 +/- 0.35 vs 3.36 +/- 0.84 nkat/wk/mmHg; p less than .01); the slope in SHR-C (3.35 +/- 0.77 nkat/wk/mmHg) was significantly steeper than in SHR (p less than .01) and identical to that in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic, neurohumoral, and hemodynamic influences on spontaneously hypertensive rat heart development in oculo

To distinguish among genetic, neurohumoral, and hemodynamic explanations for structural and functional differences in the hearts of young spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) control rats, embryonic SHR and WKY rat heart tissue was cultured in the anterior eye chamber of adult SHR and WKY rats. In study 1, atria from E-12 WKY rat embryos grafted into anterior eye chambers of either SHR or WKY host rats achieved a larger size than did SHR grafts by 8 weeks in oculo (2.98 +/- 0.75 and 2.55 +/- 0.32 mm2 vs. 1.80 +/- 0.20 and 2.04 +/- 0.44 mm2). Beating rates did not differ between SHR and WKY rat atria implanted into SHR or WKY host rats. In study 2, ventricles from E-13 embryonic SHR and WKY rat hearts grew to similar size and weight when implanted into SHR or WKY host rats (e.g., SHR hearts, 1.81 +/- 0.32 vs. 1.74 +/- 0.33 mm2; WKY rat hearts, 1.75 +/- 0.29 vs. 2.29 +/- 0.32 mm2). Ventricle grafts from SHR embryos into SHR host rats beat more rapidly (165 +/- 19 beats/min) during weekly measurements than either WKY rat ventricles (92 +/- 9 beats/min in SHR hosts and 99 +/- 9 beats/min in WKY host rats) or SHR ventricles grafted into WKY host rats (109 +/- 7 beats/min, p less than 0.001). In study 3, atria from E-13 SHR and WKY rat embryos were grafted into sympathectomized and intact eye chambers of SHR or WKY host rats. Sympathectomy of the eye chamber compromised growth of grafts into WKY host rats (1.54 +/- 0.24 vs. 0.90 +/- 0.14 mm2) but not SHR hosts (1.54 +/- 0.25 vs. 1.73 +/- 0.24 mm2). Grafts into sympathectomized eye chambers of WKY host rats beat more slowly than grafts into eye chambers with sympathetic innervation intact (282 +/- 14 vs. 202 +/- 14 beats/min); sympathectomy did not alter beating rate of grafts in SHR hosts (266 +/- 14 vs. 255 +/- 18 beats/min). These results suggest that the growth and beating rate of SHR atrial grafts may be less sensitive to sympathetic innervation than WKY rat atrial grafts. In these studies, SHR grafts did not grow larger than WKY heart grafts and did not show an increased intrinsic beating rate, suggesting that the cardiac hypertrophy and increased intrinsic beating rate observed in intact SHR are unlikely to result from direct genetic programming.     

Differential expression of AT1 receptors in the pituitary and adrenal gland of SHR and WKY

The renin-angiotensin (ANG) system has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Because SHR are more susceptible to stress than normotensive Wistar-Kyoto rats (WKY), we measured the mRNA expression of AT1A, AT1B, and AT2 receptors in the hypothalamo-pituitary-adrenal (stress) axis of male SHR in comparison to age-matched WKY at prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension. AT1A receptor mRNA was mainly expressed in the hypothalamus and adrenal gland. AT1B receptor mRNA was detected in the pituitary and adrenal gland. AT2 receptor mRNA was prominent only in the adrenal gland. When compared with WKY, SHR showed increased AT1A receptor mRNA levels in the pituitary gland at all ages in contrast to reduced pituitary AT1B receptor mRNA levels. In the adrenal gland of SHR, AT1B receptor mRNA levels were decreased at the hypertensive stages when compared with WKY. The reduced expression of adrenal AT1B receptor mRNA was localized selectively in the zona glomerulosa by in situ hybridization. No differences were observed between WKY and SHR in the expression of hypothalamic ANG receptors. ANG significantly increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in dexamethasone-treated SHR but not in WKY. The aldosterone response to ANG was similar in SHR and WKY. Our results suggest a differential gene expression of AT1A and AT1B receptors in the hypothalamo-pituitary-adrenal axis of SHR and normotensive WKY and imply the participation of AT1 receptors in an exaggerated endocrine stress response of SHR to ANG.     

Reduced calcium sensitivity of dihydropyridine binding to calcium channels in spontaneously hypertensive rats.

To explore the role of calcium channels in hypertension, dihydropyridine ([3H]PN200-110) binding to heart, brain, and skeletal muscle microsomes of 4-, 8- and 15-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was measured. At a constant Ca2+ ion concentration (pCa 3.0), maximal binding (Bmax) of dihydropyridine binding to heart and brain microsomes was significantly enhanced in 8- and 15-week-old SHR compared with WKY rats (p less than 0.01), whereas this phenomenon was not observed in 4-week-old SHR and WKY rats. Bmax and dissociation constant (Kd) values for skeletal muscle microsomes from SHR showed no difference compared with WKY rats irrespective of age. Dihydropyridine binding to heart microsomes, brain microsomes, and solubilized skeletal muscle microsomes exhibited strong calcium dependence. The Ca2(+)-dependent dihydropyridine binding curves for heart showed a Hill slope, and pK 0.5 values for 15-week-old SHR and WKY rats were 0.70 +/- 0.12 and 4.66 +/- 0.12 versus 0.72 +/- 0.12 and 5.66 +/- 0.08 (n = 4, mean +/- SD), respectively, indicating that 15-week-old SHR require 10-fold higher calcium concentration than WKY rats to promote dihydropyridine binding. The pK 0.5 values of calcium for brain and solubilized skeletal muscle calcium channels in 15-week-old SHR were also significantly lower than in WKY rats. This difference first became apparent in SHR and WKY rats as early as 4 and 8 weeks after birth. These results suggest that enhancement of calcium channel density might occur in the heart and brain of SHR in response to elevated blood pressure and that reduced calcium sensitivity of dihydropyridine binding to calcium channels might be a primary characteristic of this rat strain.     

Urinary kallikrein activity in conscious spontaneously-hypertensive rats: development as a function of age

Urinary excretion of active kallikrein was determined every day (amidolytic assay) in 6 male Okamoto-Aoki spontaneously hypertensive rats (SHR) and in 6 male normotensive Wistar-Kyoto rats (WKY) from ages 3 to 6 weeks and from 12 to 16 weeks. The rats were placed into individual metabolic cages and allowed free access to food having normal sodium content and to tap water. Urinary kallikrein excretion (UKall V, nKat/24 h) was lower in 3-week-old SHR (7.8 +/- 1.4 nKat/24 h) than in WKY (15.5 +/- 2.3 nKat/24 h, p less than 0.01) at a moment when systolic blood pressure (BP) in SHR (85.5 +/- 4.0 mmHg) was already higher than in WKY (76.3 +/- 4.6 mmHg, p less than 0.01). The slope of the increase in kallikrein excretion from week 3 to week 6 was not different for SHR and WKY (y = 6.39 x - 12.09, r = 0.95 vs y = 7.49 x - 9.40, r = 0.93). In contrast, from week 12 to week 15, this slope was slightly negative for SHR (y = 1.08 x + 59.38, r = 0.66) and became significantly different (p less than 0.05) from the slope in WKY which remained positive (y = 5.09 x + 7.05, r = 0.48). The relation between kallikrein excretion and systolic BP was an exponential curve for both SHR and WKY. But the curve of SHR (y = 1.22.e0.03x, r = 0.91) was significantly different (p less than 0.01) from the curve of WKY (y = 1.08.e0.03x, r = 0.95). For each identical systolic BP, UKall V was always lower in SHR than in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention of coronary vasodilator reserve decrement in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) demonstrate an elevated minimal coronary vascular resistance by the seventh month of age. In an attempt to determine the role of long-standing hypertension in the etiological process of the elevated minimal coronary vascular resistance, we treated SHR and normotensive Wistar-Kyoto rats (WKY) with the vasodilator hydralazine from the time of weaning (1 month) until they were 7 to 8 months of age. The animals were instrumented 24 hours after their last drug dose and then studied on the following day. Using microspheres we measured myocardial perfusion in conscious rats at rest and during maximal coronary dilation induced with dipyridamole infusion. Hydralazine maintained arterial blood pressures in the normotensive range throughout the experimental period, but had little effect on left ventricular weight/body weight ratios (control SHR = 2.95 +/- 0.07, treated SHR = 2.73 +/- 0.08, control WKY = 2.39 +/- 0.09, mean +/- SEM). In treated SHR, left ventricular minimal coronary vascular resistance (per 100 g of tissue) was markedly lower (0.10 +/- 0.01) than in the controls (0.16 +/- 0.01) and not significantly different from that of WKY (0.11 +/- 0.01). Similar differences were noted in the nonhypertrophic right ventricle (treated SHR = 0.08 +/- 0.01, control SHR = 0.16 +/- 0.01, control WKY = 0.10 +/- 0.01). Total minimal coronary vascular resistance was also lower in both ventricles of the treated SHR compared with their nontreated controls. In WKY, hydralazine treatment significantly reduced blood pressure and total minimal coronary vascular resistance (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood pressure, lanthanum-, and norepinephrine-induced mechanical response in thoracic aortic tissue

The responses of isolated thoracic aortic rings to 10(-5) M norepinephrine (NE) and 5 mM lanthanum chloride (La3+) were compared in tissues from 6- to 8-week-old and 12- to 16-week-old rats. Twelve strains of rats were selected: spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), genetically related outcross F1 and F2, backcross BC1(S) and BC1(W), and Wistar, SHR/Wistar, and Wistar/WKY crosses, Sprague-Dawley (SD), and also Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The La3+ response, expressed as the percentage of the maximal response to NE, demonstrated both age and blood pressure (BP) components in the SHR, WKY, F1, F2, and BC rats; however, when the La3+ response was expressed as mg force/mg tissue, no significant differences within these same groups were noted. The magnitude of the NE response in the same group of rats was inversely related to the BP of the 12- to 16-week-old animals (r = -0.45), and was not affected by treatment of the animal from conception with alpha-methyldopa. Aortic tissues from DS, but not DR or SD rats, demonstrated a response to La3+ which increased with the BP of the rat. This was not observed in prehypertensive DS rats and was prevented by the control of hypertension with either hydrochlorothiazide or MK-421 (a converting-enzyme inhibitor). We conclude that the reduced NE response in aortic tissues from SHR and related hypertensive rats reflects an inherent defect in the vascular smooth cell of the rat and is unaffected by BP control with antihypertensive drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced intracellular pH in lymphocytes from the spontaneously hypertensive rat

This study was designed to determine the cytoplasmic pH (pHi) profile of lymphocytes from a rat model of genetic hypertension that is well suited for study before and after the development of spontaneous hypertension. For this purpose, pHi was measured in thymic lymphocytes obtained from spontaneously hypertensive rats (SHR) and from age-matched Wistar-Kyoto (WKY) control rats using 2',7'-bis carboxyethyl-5,6-carboxyfluorescein (BCECF), a pH-sensitive fluorescence probe. At the age of 16-20 weeks, pHi of lymphocytes suspended in a HCO3-free HEPES-buffered solution, was markedly lower in the SHR than in the WKY rats (7.07 +/- 0.02, n = 16 and 7.22 +/- 0.01, n = 15, respectively, p less than 0.001), whereas systolic blood pressure was higher in SHR than in WKY rats (175 +/- 5.0 and 105 +/- 3.0 mm Hg, respectively, p less than 0.001). In rats less than 5 weeks of age, pHi was also lower in SHR than in WKY rat lymphocytes (7.12 +/- 0.04, n = 11 and 7.23 +/- 0.04, n = 11, respectively, p less than 0.05), although at this age systolic blood pressure was not different between the two groups (87 +/- 4.0 and 85 +/- 3.0 mm Hg, respectively). In lymphocytes suspended in a more physiological HCO3/CO2-buffered solution, pHi was again lower in the adult SHR than in the WKY rat (7.18 +/- 0.02, n = 16 and 7.31 +/- 0.02, n = 16, respectively, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Free cytosolic calcium in renal proximal tubules from the spontaneously hypertensive rat

Free intracellular calcium was measured in renal proximal tubules obtained from spontaneously hypertensive rats (SHR) and from age-matched Wistar-Kyoto rats (WKY) ingesting a normal diet. Experiments were performed on renal proximal tubule suspensions using fura-2 to monitor cytosolic calcium. In 4-week-old rats, when systolic blood pressure was not significantly different between the two groups, renal proximal tubule cytosolic calcium was similar (143 +/- 28 and 144 +/- 15 nM, respectively). By the age of 5 weeks, cytosolic calcium increased significantly in both SHR and WKY (214 +/- 24 and 262 +/- 34 nM, respectively, p less than 0.05). Calcium, however, was not significantly different between the two groups, even though at this age blood pressure was higher in SHR than in WKY. As compared with values in 4-week-old rats, cytosolic calcium was also found increased in tubules from both SHR and WKY aged 10 to 12 weeks (261 +/- 42 and 279 +/- 30 nM, respectively) and 20 to 24 weeks (263 +/- 42 and 308 +/- 28 nM, respectively). However, no significant differences in cytosolic calcium were found between SHR and WKY even though at these ages systolic blood pressure increased markedly in the SHR. Moreover, regression analysis failed to reveal a correlation between cytosolic calcium and blood pressure when data from either group of rats of all ages studied were pooled. Exposure to ouabain (10(-3) M) to inhibit Na+,K+-adenosine triphosphatase and increase intracellular sodium had no significant effect on cytosolic calcium in tubules from either SHR or WKY (260 +/- 69 and 250 +/- 45 nM, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Protection of cavernous tissue in male spontaneously hypertensive rats. Beyond blood pressure control

Male erectile dysfunction is increased in prevalence in patients with hypertension. Previous experiments from our group demonstrated morphologic changes in erectile tissue from male spontaneously hypertensive rats (SHR). The aim of the present study was to determine whether blood pressure (BP) control is enough to preserve cavernous tissue from the deleterious effect of arterial hypertension. Eight-week-old male SHR and normotensive Wistar-Kyoto rats (WKY) were studied during 6 months: Group 1 (n = 10) SHR; group 2 (n = 10) SHR with 7.5 mg/kg/d candesartan (C); group 3 (n = 10) SHR with 100 mg/kg/d atenolol (AT); and group 4 (n = 10) WKY. At the end of the experiment all the animals were killed for microscopic studies. Cavernous tissue was processed by hematoxylin-eosin, Masson's trichrome, monoclonal anti-alpha-smooth muscle actin, and anticollagen type III. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries and the amounts of collagen type III were evaluated. At the end of the experiment, SHR with C and AT showed similar control in BP (group 2: 131.3 +/- 5.5 mm Hg; group 3: 136.5 +/- 2.9 mm Hg) compared with untreated SHR (group 1: 199.6 +/- 5.1 mm Hg). However, animals with C presented significantly lower values (P <.01) of CSM layer in cavernous space and VSM in cavernous arteries (P <.01), and lower amounts of collagen type III (P <.01) compared to SHR with AT and untreated SHR. We conclude that C provides a significant protective role against structural changes in vessels as well as in cavernous spaces of the erectile tissue, caused by arterial hypertension in SHR, beyond BP control.