Renal and systemic effects of endothelin-1 in diabetic-hypertensive rats

The Cohen-Rosenthal Diabetic Hypertensive rat (CRDH) is a unique animal model in which genetic hypertension and diabetes developed after crossbreeding of Cohen diabetic rats sensitive substrain (CDR) and spontaneously hypertensive rats (SHR). The present study examined: 1) The acute effects of ET-1 on the systemic and renal hemodynamics in CRDH rats, CDR, and SHR; 2) The expression of ET-1 and its receptors in the renal tissue of CRDH rats. Intravenous injection of ET-1 (1.0 nmol/kg) into anesthetized SHR rats resulted in a significant immediate depressor response (mean arterial pressure (MAP) decreased from 165 ± 3 to 124 ± 12 mmHg, p < 0.0001) followed by a minor hypertensive phase (MAP increased to 170 ± 2 mmHg). Simultaneously, the administration of ET-1 caused a significant decrease in renal blood flow (RBF) from 5.8 ± 0.9 ml/min to 3.2 ± 0.5 ml/min (p = 0.026). These responses were blunted in CRDH rats and CDR. Analysis of intra-renal blood flow by laser-Doppler in CRDH rats revealed that ET-1 injection caused a decrease in cortical blood flow (Δ = -12 ± 2.9%). However, in contrast to its well-known renal medullary vasodilatory effect, ET-1 produced a significant decline in the medulla blood flow (Δ = -17.5 ± 3.4%) (p = 0.0125). These findings suggest that CDR and CRDH rats have reduced sensitivity to vascular and renal action of ET-1. Furthermore, in the CRDH rats, the expected ET-1-induced medullary vasodilatation was abolished and even reversed into prolonged vasoconstriction.     

Noninvasive characterization of myocardial blood flow in diabetic, hypertensive, and diabetic-hypertensive rats using spin-labeling MRI

OBJECTIVE: Microvascular alterations in the diabetic and hypertensive heart are likely to contribute to heart failure. In this work, myocardial blood flow and left ventricular function were measured in vivo in diabetic, hypertensive, and diabetic-hypertensive rats using MRI methods. METHODS: An 8-week-duration type 1 diabetes was induced by streptozotocin (STZ) in 8 Wistar-Kyoto (WKY) rats (STZ) and in 11 spontaneously hypertensive (SHR) rats (STZ-SHR). Fourteen WKY and 12 SHR served as control and hypertensive groups. Myocardial blood flow quantification was performed using an arterial spin-labeling MRI method. Left ventricular morphology and function were assessed during the same experiment using cine-MRI. RESULTS: Respective myocardial blood flow values for each group were 6.4 +/- 1.1 (WKY), 6.0 +/- 1.9 (STZ), 5.5 +/- 1.3 (SHR), and 4.3 +/- 0.9 mL. g(-1). min(-1) (STZ-SHR). Myocardial blood flow was significantly decreased in STZ-SHR rats compared with the other groups (p <.05, STZ-SHR vs. all groups). Cine-MRI showed morphological alterations in all pathological groups. No alteration of the ejection fraction was observed in the pathological groups. CONCLUSION: Myocardial blood flow is altered in vivo before any sign of heart failure when rats have type 1 diabetes and hypertension simultaneously. When only one of the pathologies occurs, MBF does not vary significantly.     

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.     

Central cardiovascular action of urotensin II in spontaneously hypertensive rats.

We have previously reported that urotensin II acts on the central nervous system to increase blood pressure in normotensive rats. In the present study, we have determined the central cardiovascular action of urotensin II in spontaneously hypertensive rats (SHR). Intracerebroventricular (ICV) injection of urotensin II elicited a dose-dependent increase in blood pressure in both SHR and normotensive Wistar-Kyoto rats (WKY). The changes in mean arterial pressure induced by ICV urotensin II at doses of 1 and 10 nmol in the WKY were 8 +/- 2 and 23 +/- 3 mmHg, respectively. ICV administration of urotensin II caused significantly greater increases in blood pressure in SHR (16 +/- 3 mmHg at 1 nmol and 35 +/- 3 mmHg at 10 nmol, respectively) compared with those in WKY. Urotensin II (10 nmol) elicited significant and comparable increases in heart rate in SHR (107 +/- 10 bpm) and WKY (101 +/- 21 bpm). Plasma epinephrine concentrations after ICV administration of 10 nmol urotensin II were 203 +/- 58 pmol/ml in SHR and 227 +/- 47 pmol/ml in WKY, which tended to be higher than those in artificial cerebrospinal fluid-injected rats (73+/- 7 and 87 +/- 28 pmol/ml, respectively, p < 0.1). The immunoreactivity of urotensin II receptor GPR 14 was expressed extensively in the glial cells within the brainstem, hypothalamus, and thalamus. These results suggest that central urotensin II may play a role in the pathogenesis of hypertension in SHR. Since GPR 14 was expressed in the glial cells of the brain, urotensin II may act as a neuromodulator to regulate blood pressure.     

Effect of inhibition of Na, K-ATPase on cytosolic free sodium and calcium in platelets of spontaneously hypertensive rats.

Cytosolic free sodium concentrations ([Na+]i) in intact platelets of 18 spontaneously hypertensive rats (SHR) and of 18 age-matched normotensive Wistar-Kyoto rats (WKY) were measured using the sodium-sensitive fluorescent dye sodium-binding-benzofuran-isophthalate. In resting platelets [Na+]i tended to be higher in SHR compared to WKY (20.5 +/- 3.5 mmol/L v 15.1 +/- 1.9 mmol/L, mean +/- SEM), but the differences were not statistically significant. Stimulation of the Na-H-exchange by 1.0 U/mL thrombin increased [Na+]i in SHR by 22.9 +/- 4.3 mmol/L and in WKY by 35.0 +/- 5.6 mmol/L in a similar way. After inhibition of Na, K-ATPase by 1 mmol/L ouabain there was a significant rise of [Na+]i both in platelets of SHR to 38.0 +/- 5.1 mmol/L (P < .01 compared to resting platelets) and in platelets of WKY to 26.5 +/- 4.3 mmol/L (P < .01). However, no significant difference could be observed between these two groups. Using the calcium-sensitive dye fura-2, resting cytosolic free calcium concentrations ([Ca2+]i) were found to be significantly higher in platelets of SHR compared to WKY (171.9 +/- 21.5 nmol/L v 93.14 +/- 19.7 nmol/L, P < .05). After the addition of ouabain [Ca2+]i was significantly higher in SHR compared to WKY (245.5 +/- 32.6 nmol/L v 159.6 +/- 22.5 nmol/L, P < .05). The results do not support the hypothesis that altered sodium-calcium exchange causes elevated cytosolic free calcium in SHR.     

Calcium binding capacity of erythrocyte membrane in human hypertension and spontaneous hypertensive rats

Several abnormalities of calcium transport have been reported in human essential hypertension (EHT) and spontaneous hypertensive rat (SHR). 45Ca binding capacity to erythrocyte membrane was measured in this study by filtration technique in the presence of 80 nmol/L Ca concentration. Results showed: (1) It was much lower in EHT (33 cases) than normal control (19 men) group, being 0.22 +/- 0.13 versus 0.35 +/- 0.18 nmol Ca2+/mg membrane protein (P less than 0.01), and correlated positively with blood pressure levels. (2) The average Ca binding capacity in young offsprings (15 adolescents) with both parents hypertensive was lower, but statistically not significant. (3) The average Ca binding capacity was also lower in SHR (9 rats) than control WKY (10 rats) group, being 0.83 +/- 0.27 versus 0.98 +/- 0.24 nmol Ca2+/mg membrane protein, yet statistically not significant. Therefore a decrement of membrane binding capacity might be related to the occurrence and maintenance of hypertension.     

Prolonged QT interval is associated with blood pressure rather than left ventricular mass in spontaneously hypertensive rats

QT interval is prolonged in hypertensive individuals, although the factors responsible for this increase are not completely understood. We questioned whether enhanced left ventricular mass (LVM) or increased systemic blood pressure represents the principal factor determining QT prolongation in the period of development of hypertension and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR). In 12-and 20-week-old SHR (SHR12 and SHR20) and age-matched normotensive Wistar-Kyoto rats (WKY12 and WKY20), arterial systolic blood pressure (sBP) was measured using tail-cuff technique. Orthogonal Frank ECG was registered in anaesthetized animals in vivo, and bipolar ECG was measured in spontaneously beating isolated hearts in vitro. Progressive increase of sBP and LVM resulted in significant QT prolongation in SHR20 as compared to WKY12, WKY20, and also to SHR12 in vivo (WKY12: 82 +/- 9 ms, WKY20: 81 +/- 9 ms, SHR12: 88 +/- 15 and SHR20: 100 +/- 10, respectively; p < 0.05) but not in isolated hearts (WKY20: 196 +/- 39 ms and SHR20: 220 +/- 55, respectively; NS). In whole animals, QT duration was positively related to sBP (r = 0.6842; p < 0.001) but not to LVM (r = 0.1632, NS) in SHR20. The results suggest that QT prolongation in SHR developing hypertension and LVH depends on blood pressure rather than increase in LVM. In this period, myocardial hypertrophy is probably the predisposition for QT prolongation, but the significant change manifests only in the presence of elevated systemic factors.     

Telmisartan in the treatment of Cohen-Rosenthal Diabetic Hypertensive rats: the benefit of PPAR-gamma agonism

The antihypertensive and hypoglycemic effects of telmisartan, which has dual angiotensin II antagonist-PPAR-gamma agonist properties, was studied in Cohen-Rosenthal Diabetic Hypertensive rats (CRDH), a model in which hypertension, insulin resistance, and diabetes co-exist. CRDH, Cohen-diabetic rats (CDR), and SHR received telmisartan (3 mg/kg/day in drinking water) for five months. Telmisartan significantly lowered systolic and diastolic BP in SHR and CRDH, independent of body weight, and remained fairly constant in controls throughout the experiment. Blood glucose levels fell rapidly in the treated animals and remained steady in controls. Results indicate that telmisartan is a prototype of a new approach to treating coexisting diabetes and hypertension.     

High angiotensin converting enzyme (kininase II) activity in the cerebrospinal fluid of spontaneously hypertensive adult rats

Angiotensin converting enzyme (ACE, Kininase II, E.C. 3.4.15.1) activity was measured in the cerebrospinal fluid of 4- and 16-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) normotensive controls. Adult SHR showed higher cerebrospinal fluid enzyme activity than normotensive age-matched WKY (19.6 +/- 1 and 32.3 +/- 5 nmol/h per ml in WKY and SHR, respectively, P less than 0.025). Conversely, there were no significant differences in enzyme activity in the cerebrospinal fluid of young animals. Our results support the hypothesis of enhanced activity of the central angiotensin system during the established phase of spontaneous hypertension in rats.     

Increased expression of vascular endothelial growth factor and capillary density in hearts of spontaneously hypertensive rats

OBJECTIVE: The role of VEGF in vascular remodeling of target organs exposed to chronic hypertension is poorly understood. The authors compared capillary density (CD), capillary-to-fiber ratio (C/F), and VEGF mRNA expression in the hearts (left ventricle [LV]), and skeletal muscles (soleus and anterior tibialis [AT]) of 18-week-old male spontaneously hypertensive rats (SHR) and age-matched male Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. METHODS: CD or C/F in LV, soleus, and AT of SHR, WKY, and SD rats was determined by analysis of randomly acquired digital images of cryosections stained with FITC-conjugated GS-I lectin. VEGF mRNA expressions in the tissues were determined by Northern blot. RESULTS: VEGF mRNA expressions in LV of SHR were 3.84- and 5.05-fold higher, compared to SD and WKY rats, respectively (n = 6; p < .01). There were no significant differences in VEGF mRNA expression in soleus or AT among SHR, WKY, and SD rats (p > .05). CD in LV of SHR (4975 +/- 167) was significantly higher than WKY or SD rats, 4151 +/- 169 and 3807 +/- 187 mm(-2), respectively (p < .05). In LV of SHR, C/F increased (35%) more significantly than CD (increased 20%), compared to WKY rats. CD, or C/F in soleus or AT of SHR was similar to that observed in WKY or 8D rats. CONCLUSIONS: VEGF expression, CD, and C/F in the heart (LV) of SHR are significantly increased, compared to WKY and SD rats. The data are consistent with the possibility that VEGF may contribute to capillary growth as a compensatory response to hypertension.     

Effect of amlodipine and cilazapril treatment on platelet Ca2+ handling in spontaneously hypertensive rats.

Abnormal Ca2+ handling and enhanced aggregation response have been reported in platelets from spontaneously hypertensive rats (SHR) and patients with essential hypertension, and thought to be involved in the progression of target organ damage of hypertension. It is important to examine whether antihypertensive therapy can improve the abnormal platelet response in hypertension. We investigated the effect of antihypertensive treatment such as amlodipine and cilazapril on Ca2+ handling and aggregation response in SHR platelets. Four-week-old male SHR were divided into three groups. Each group was treated with amiodipine (A: 10 mg/kg/day), cilazapril (C: 10 mg/kg/day) or vehicle (V) for 8 weeks by gavage. At 12-week-old, platelet [Ca2+]i was measured with fura-2 in each group of SHR and age-matched Wistar-Kyoto rats (WKY) as normal control. Systolic blood pressure in amlodipine and cilazapril treated groups were similar with WKY and significantly lower than vehicle treated group (A: 124 +/- 9, C: 126 +/- 9, WKY: 122 +/- 10 and V: 180 +/- 9 mmHg, respectively). The basal [Ca2+]i in the three groups of SHR were similar and higher than WKY (A: 47 +/- 1.7, C: 47 +/- 1.2, V: 48 +/- 3.9 and WKY: 40 +/- 4.0 nmol/l, respectively). There were no significant differences in thrombin (0.1 U/ml)-stimulated [Ca2+]i rise in the presence or absence of extracellular Ca2+ among the three groups of SHR and these were higher than WKY. Intracellular Ca2+ discharge capacity, assessed by the ionomycinstimulation was similar in the all groups. Thrombin-induced maximum platelet aggregation responses in the three groups of SHR were similar and higher than WKY. The antihypertensive treatment of Ca2+ antagonist or ACE inhibitor gave no change in intraplatelet Ca2+ metabolism in SHR. These results support the hypothesis that an abnormal Ca2+ handling in SHR platelet is genetically determined and not improved by hypotensive therapy.     

Alterations in catecholamine release in the central nervous system of spontaneously hypertensive rats.

The aim of the present study was to investigate alterations in catecholamine release in the central nervous system of spontaneously hypertensive rats. Slices of hypothalamus, medulla oblongata and striatum were prepared from spontaneously hypertensive rats (SHR: 9-10 weeks old) and age-matched Wistar Kyoto rats (WKY). The slices were incubated with (3H)norepinephrine (NE) or (3H)dopamine (DA), superfused with Krebs-solution in vitro, and the release of the catecholamines was compared between the two strains. The basal release of hypothalamic (3H)NE did not differ between SHR and WKY slices. However, stimulation (1 Hz)-evoked (3H)NE release was significantly greater in SHR than in WKY (percent fractional release of total tissue NE: WKY 0.494 +/- 0.019%, n = 6, SHR 0.730 +/- 0.053%, n = 6, p less than 0.05). The stimulation-evoked (3H)NE release from the medulla oblongata did not differ significantly between SHR and WKY slices. Finally stimulation-evoked release of striatal (3H)DA was significantly depressed in SHR (percent fractional release of total tissue DA: WKY 2.048 +/- 0.24%, n = 6, SHR 1.460 +/- 0.068%, n = 6, p less than 0.05). These results indicate that the release of hypothalamic NE and striatal DA are altered in SHR. It is suggested that enhanced hypothalamic noradrenergic activity and reduced striatal dopaminergic activity can increase sympathetic outflow to the periphery, which may play a role in the pathogenesis of this form of hypertension.     

Calcium currents are altered in the vascular muscle cell membrane of spontaneously hypertensive rats

Calcium currents were recorded during whole-cell voltage clamp in cultured azygos venous muscle cells from 1-3-day-old normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Different holding potentials were used to separate total cell current into its transient (T) and sustained or long-lasting (L) components. In recordings from 30 WKY and 30 SHR vascular cells, total cell calcium current was the same between cells from normotensive (167 +/- 20 pA) and hypertensive (139 +/- 15 pA) rats. However, the relative proportion of T and L calcium currents was different between WKY and SHR cells. In WKY cells, the peak amplitude of the L current was less than that of the T current (42 +/- 30% of total current), whereas in SHR cells, the L current was greater (62 +/- 3% of total current). Calcium currents in vascular muscle cells from SHR were activated and inactivated at more positive potentials than in cells from WKY. This study directly compares transmembrane calcium current in isolated cells from WKY and SHR blood vessels and shows that the proportions of T and L calcium channels activated by depolarization are altered in this genetic model of hypertension.     

Calcimimetic NPS R-568 induces hypotensive effect in spontaneously hypertensive rats

BACKGROUND: The discovery of calcium receptors and calcimimetics created the possibility of "pharmacologic parathyroidectomy" (phPTX), which decreased secretion of parathormone (PTH). Parathyroid glands of spontaneously hypertensive rats (SHR) and of patients with primary hyperparathyroidism and hypertension secrete parathyroid hypertensive factor (PHF). Parathyroidectomy decreases blood pressure in these rats and in patients. The present study determined whether phPTX induced by calcimimetics decreases mean arterial blood pressure (MAP) in hypertensive rats. METHODS: Hypertensive SHR and normotensive Wistar Kyoto (WKY) rats were used. Clearance experiments were performed and the effect of 1 mg/kg body weight (given intravenously) synthesized NPS R-568 (NPS) on MAP in the presence or absence of thyroparathyroidectomy (TPTX) was monitored. RESULTS: The success phPTX and TPTX were proven by a significant decrease in plasma Ca(2+) concentration and a decrease in urinary fractional phosphate excretion (FE Pi). The administration of NPS significantly decreased blood pressure in SHR versus SHR/control: Delta(0-50 min of experiment) MAP -16.5 +/- 2.5 mm Hg v -3.2 +/- 1.5 mm Hg (P < .002). The TPTX decreased blood pressure in SHR versus SHR/control and was not different versus SHR/TPTX/NPS (DeltaMAP: -10.2 +/- 1.6 mm Hg v -3.2 +/- 1.5 mm Hg (P < .01) and v -8.3 +/- 2.2 mm Hg (P = not significant). In normotensive WKY rats application of NPS did not reach significance in DeltaMAP: -6.7 +/- 1.8 mm Hg v -2.6 +/- 2.8 mm Hg (P = not significant) in WKY/control. The TPTX lowered blood pressure in WKY versus WKY/control and remained unchanged versus WKY/TPTX/NPS (DeltaMAP: -11.3 +/- 1.7 mm Hg v -2.6 +/- 2.8 mm Hg (P < .04) and v -11.4 +/- 2.6 mm Hg (P = not significant). CONCLUSIONS: We conclude that phPTX with NPS R-568 is responsible for a decrease of MAP in SHR.     

Characterization of contractile function in diabetic hypertensive cardiomyopathy in adult rat ventricular myocytes

Diabetes and hypertension both produce myocardial dysfunction that accelerates cardiovascular morbidity and mortality. Coexistence of the two often results in a more severe cardiomyopathy than either process alone. The purpose of this study was to characterize the contractile function of diabetic hypertensive cardiomyopathy at the single myocyte level. Adult spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were made diabetic with a single injection (55 mg/kg) of streptozotocin (STZ). Contractile properties of ventricular myocytes were evaluated, including peak shortening (PS), time-to-peak shortening (TPS), time-to-90% relengthening (TR90) and maximal velocities of shortening/relengthening (+/-dL/d t). The experimental animals exhibited enlarged heart size, elevated blood glucose and systolic blood pressure. PS was unchanged (SHR), enhanced (WKY-STZ) or depressed (SHR-STZ) compared to control (WKY). Myocytes from all experimental groups displayed prolonged TPS and TR90 compared to the WKY group, although only those from the hypertensive groups (SHR, SHR-STZ) were associated with reduced +/-dL/d t. Additionally, myocytes from the WKY-STZ but not the SHR or the SHR-STZ groups exhibited impaired responsiveness to increased extracellular Ca2+. Myocytes from the SHR-STZ group displayed a leftward shift of the stimulus frequency-peak shortening response curve compared to the WKY group. These results confirmed observations at the multicellular levels that combination of diabetes and hypertension results in a greater impairment of cardiac contractile function than is seen with either disease alone.     

Renal sympathetic nerve responses to tempol in spontaneously hypertensive rats

Recent studies have implicated a contribution of oxidative stress to the development of hypertension. Studies were performed to determine the effects of the superoxide dismutase (SOD) mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol) on vascular superoxide production and renal sympathetic nerve activity (RSNA) in anesthetized Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Compared with WKY rats (n=6), SHR showed a doubled vascular superoxide production, which was normalized by treatment with Tempol (3 mmol/L, n=7). In WKY rats (n=6), Tempol (30 mg/kg IV) significantly decreased mean arterial pressure (MAP) from 108+/-5 to 88+/-6 mm Hg and HR from 304+/-9 to 282+/-6 beats/min. In SHR (n=6), Tempol significantly decreased MAP from 166+/-4 to 123+/-9 mm Hg and HR from 380+/-7 to 329+/-12 beats/min. Furthermore, Tempol significantly decreased RSNA in both WKY rats and SHR. On the basis of group comparisons, the percentage decreases in MAP (-28+/-4%), HR (-16+/-3%) and integrated RSNA (-63+/-6%) in SHR were significantly greater than in WKY rats (-17+/-3%, -9+/-2%, and -30+/-4%, respectively). In SHR, changes in integrated RSNA were highly correlated with changes in MAP (r=0.85, P<0.0001) during administration of Tempol (3, 10, and 30 mg/kg IV). In both WKY rats and SHR (n=4, respectively), intracerebroventricular injection of Tempol (300 micro g/1 micro L) did not alter MAP, HR, or RSNA. Intravenous administration of a SOD inhibitor, diethyldithio-carbamic acid (30 mg/kg), significantly increased MAP, HR, and integrated RSNA in both WKY rats and SHR (n=6, respectively). These results suggest that augmented superoxide production contributes to the development of hypertension through activation of the sympathetic nervous system.     

Lymphocyte membrane sodium-proton exchange in spontaneously hypertensive rats

The sodium-proton exchange activity was determined in lymphocytes of spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and domestic Wistar rats. Uptake of sodium was determined by measuring the osmotic swelling of lymphocytes after activation of the exchanger by suspension of the cells in sodium propionate and consequent intracellular acidification by the permeant weak acid. Fractional swelling (mean +/- SEM) in 16 SHR and 16 WKY was 0.44 +/- 0.03 and 0.35 +/- 0.02, respectively (p less than 0.01). The swelling was partially inhibitable by amiloride and, at 10(-4) M concentration, the amiloride-sensitive swelling was 0.21 +/- 0.02 in SHR and 0.11 +/- 0.01 in WKY (p = 0.001). Progressive extracellular ion substitutions of chloride for propionate or of potassium for sodium showed that the exchange activity was related linearly to cellular acidification; however, the dependence on extracellular sodium displayed saturation characteristics, with the same apparent Km for cells from SHR and WKY and a Vmax of 0.54 +/- 0.03 for SHR and 0.39 +/- 0.02 for WKY (p less than 0.002). External lithium could replace sodium on the exchanger but abolished the differences between strains. Results in the domestic Wistar rats were similar to those of WKY. These results suggest that lymphocytes of the SHR have a greater capacity for sodium uptake through the sodium-proton exchanger, as compared with normotensive strains. If shared by other cells, such an increased capacity could have a pathophysiological role in genetic hypertension. In particular, its presence in proximal renal tubular cells would support the hypothesis of a primary role for the kidney in the pathogenesis of genetic hypertension.     

Telmisartan in the Treatment of Cohen-Rosenthal Diabetic Hypertensive Rats: The Benefit of PPAR-γ Agonism

The antihypertensive and hypoglycemic effects of telmisartan, which has dual angiotensin II antagonist-PPAR-γ agonist properties, was studied in Cohen-Rosenthal Diabetic Hypertensive rats (CRDH), a model in which hypertension, insulin resistance, and diabetes co-exist. CRDH, Cohen-diabetic rats (CDR), and SHR received telmisartan (3 mg/kg/day in drinking water) for five months. Telmisartan significantly lowered systolic and diastolic BP in SHR and CRDH, independent of body weight, and remained fairly constant in controls throughout the experiment. Blood glucose levels fell rapidly in the treated animals and remained steady in controls. Results indicate that telmisartan is a prototype of a new approach to treating coexisting diabetes and hypertension.     

DOCA-salt induced malignant hypertension in spontaneously hypertensive rats

DOCA-salt hypertension was produced in 10 male 10-week-old normotensive Wistar-Kyoto (WKY) rats receiving deoxycorticosterone acetate (DOCA; 100 mg/kg, subcutaneous pellet) and 1% NaCl drinking water and was compared with data from 10 age- and sex-matched WKY receiving normal tap water (C). These data were also compared with spontaneously hypertensive (SHR) rats similarly treated. After 10 weeks on these programmes, systemic and regional haemodynamics were determined in conscious rats using microsphere techniques. DOCA-salt treatment increased mean arterial pressure (MAP), total peripheral resistance index (TPRI), cardiac and renal weights in both WKY and SHR. In contrast to SHR (C), the SHR (DOCA) demonstrated more severe MAP elevation (204 +/- 4 versus 185 +/- mmHg; P less than 0.01), more severe systemic and regional (especially renal) vasoconstriction, and malignant vasculitis associated with azotaemia and hyperuricaemia. The hyperuricaemia was related inversely to renal blood flow (r = -0.74; P less than 0.01) and directly to renal vasoconstriction (r = 0.65; P less than 0.05) in SHR (DOCA). These data suggest that in both WKY and SHR, DOCA and salt produced marked cardiovascular changes and SHR rats developed malignant hypertension.