Angiotensin II and IGF-I may interact to regulate tubulointerstitial cell kinetics and phenotypic changes in hypertensive rats.

Angiotensin II and insulin-like growth factor-I (IGF-I) are known to be actively involved in the pathogenesis of progressive renal injury, particularly in cell proliferation and phenotypic changes that contribute to tubulointerstitial injury. To investigate the possible mechanisms by which angiotensin II type 1 receptor antagonist (AIIA) ameliorates renal injury in a renal ablation model and to determine the contribution of phenotypic changes and IGF-I to morphological changes, we examined 1) whether AIIA attenuated phenotypic changes as markers of alpha-smooth muscle actin (SMA) and vimentin, 2) whether AIIA altered renal IGF-I expression, and 3) the changes of tubulointerstitial cell kinetics between apoptosis (tested via terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling, TUNEL) and cell proliferation (a test of proliferating cell nuclear antigen, PCNA). Following a sham operation (sham) or 5/6 nephrectomy (Nx), we administered E4177, a potent, selective competitive angiotensin II type 1 receptor antagonist (AIIA), for 10 weeks. In Nx rats, SMA and vimentin expressions developed in injured tubulointerstitium, particularly in hypoperfused scar-adjacent areas, and there was an increase in renal IGF-I expressions. The TUNEL score increased 5-fold and PCNA increased 8-fold, compared with TUNEL and PCNA measurements in sham-operated rats. Renin expression in the juxtaglomerular apparatus was markedly suppressed in the Nx group, although de novo tubular renin expression appeared in Nx, compared with that in the sham group. E4177, both 10 mg/kg (AIIA 10) and 1 mg/kg (AIIA 1), markedly ameliorated renal injury, although blood pressure was less affected in AIIA 1. Both AIIA 10 and AIIA 1 suppressed the neoexpressions of SMA and vimentin in an association with decreased IGF-I expression. Regarding cell kinetics, neither AIIA 10 nor AIIA 1 decreased the TUNEL score; rather, tended to increase, while PCNA was significantly suppressed by AIIA. In conclusion, one of the underlying protective mechanisms of AIIA in this model may be related to the modulations of angiotensin II-induced phenotypic changes and tubulointerstitial cell kinetics through IGF-I.     

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

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

Thromboxane and vascular smooth muscle cell growth in genetically hypertensive rats

The vascular wall has the capacity to produce thromboxane A2. However, the role of vascular thromboxane A2 is still uncertain. In this study, we examined the relationship between vascular thromboxane A2 generation and vascular smooth muscle cell growth in spontaneously hypertensive rats (SHR). Vascular thromboxane A2 generation was significantly enhanced by 49% in 5-week-old and by 117% in 15-week-old SHR as compared with age-matched Wistar-Kyoto rats (WKY). Thromboxane A2 generation was also significantly enhanced by 59% in the cultured vascular smooth muscle cells of SHR when compared with production in WKY. Vascular smooth muscle cells of SHR exhibited a significantly shortened doubling time (by 32%) and greater [3H]thymidine uptake (by 56%), as compared with those of WKY. OKY 046 (10(-5) M), a thromboxane synthase inhibitor, significantly tempered the rapid vascular smooth muscle cell growth in SHR by 9% for doubling time and by 10% for [3H]thymidine uptake. OKY 046 did not influence the doubling time of WKY. Conversely, a stable analogue of thromboxane A2 dose-dependently stimulated the [3H]thymidine uptake by vascular smooth muscle cells of WKY, and, at a concentration of 10(-5) M, shortened the doubling time of vascular smooth muscle cells of WKY by 11%, whereas it showed slight effects on SHR. These data indicate that vascular thromboxane A2 is involved in the regulatory mechanism of vascular smooth muscle cell growth and that enhanced vascular thromboxane A2 generation is partly responsible for the rapid proliferation of vascular smooth muscle cells of SHR. The alterations of vascular thromboxane production may be a key trait for genetic hypertension.     

Enzyme-histochemical changes in arteries of genetically hypertensive rats (SHR, SP-SHR)

To determine the effect of the duration and severity of hypertension on arterial wall metabolism 28 enzyme activities and several macromolecular complexes were histochemically studied in normotensive (WK), moderately (SHR) and strongly hypertensive (SP-SHR) rats at various ages. The results indicate that the abnormalities of 5' nucleotidase, acid esterase, cholinesterase and Alk.P. appeared in prehypertensive 4 w.old SHR. The posthypertensive changes, fluctuating in relation to the duration of hypertension, concerned: the pentose pathway, Krebs cycle and glycolosis -linked dehydrogenases; lysosomal enzymes; glycogen-phosphorylase and MAO; glycosaminoglycan and glycoprotein content. The structural and metabolic response presented several local and regional differences. The metabolic changes were greater in the aorta than in the caudal and femoral arteries. The comparison between SHR and SP-SHR indicates that the blood pressure (BP) at 170 mm Hg seems well tolerated during a long period of time. Severe lesions such as degeneration and failure of lipolytic activity in aortic smooth muscle cells (SMC), notable and early (8 mo.) in SP-SHR with 240 mm Hg were less intense and appeared later (13 mo.) in SHR with 190 mm Hg. The level of hypertension, rather than its duration, appears as a determining factor of posthypertensive vascular damage.     

Calcium channel activation in arterioles from genetically hypertensive rats.

Enhanced contractile responsiveness to the calcium channel agonist Bay K 8644 has been documented in large conduit arteries and small muscular arteries from hypertensive rats. The present study examined the effects of Bay K 8644 on the intracellular calcium concentration ([Ca2+]i) in microvessels from stroke-prone spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. Using microspectrofluorometry of fura-2, [Ca2+]i was measured in smooth muscle cells localized on arteriolar fragments (15-35 microns external diameter) isolated after collagenase digestion of the pancreas. Resting [Ca2+]i in hypertensive arterioles (94 +/- 6 nM, n = 29) did not differ from that in normotensive vessels (81 +/- 4 nM, n = 40). KCl (50 mM), applied alone and in the presence of Bay K 8644 (30 nM), stimulated increases in [Ca2+]i that were reversed in calcium-free solution and with nifedipine (10 microM), consistent with activation of potential-operated calcium channels. Potassium-induced calcium transients were consistently potentiated by Bay K 8644. The change in [Ca2+]i evoked by KCl alone or in combination with Bay K 8644 did not differ between arterioles from hypertensive and normotensive rats. In 24% of the vessels from hypertensive rats and in 29% of those from normotensive rats, Bay K 8644 evoked an increase in [Ca2+]i that did not differ significantly between the two strains. The findings indicate that, in contrast to observations made in larger arteries, there is no evidence of a functional abnormality in potential-operated calcium channels in very small arterioles from genetically hypertensive rats.     

Cardiac aldosterone production in genetically hypertensive rats

Aldosterone is synthesized in extra-adrenal tissues, both blood vessels and brain. We undertook the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibition, and angiotensin II on aldosterone synthesis in the heart. To clarify the pathophysiological role of cardiac aldosterone in the hypertensive heart, we compared the synthesis of aldosterone in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied. Isolated rat hearts were perfused for 2 hours, and the perfusate was analyzed with HPLC and mass spectrometry. The activity of aldosterone synthase was estimated on the basis of the conversion of [(14)C]deoxycorticosterone to [(14)C]aldosterone. The levels of aldosterone synthase gene (CYP11B2) mRNA were determined with competitive polymerase chain reaction. Aldosterone production, the activity of aldosterone synthase, and the expression of CYP11B2 mRNA were increased in hearts from adrenalectomized rats and rats treated with angiotensin II. ACE inhibitors decreased cardiac aldosterone synthesis. Cardiac aldosterone, aldosterone synthase activity, and CYP11B2 mRNA levels in hearts from 2- and 4-week-old SHRSP were significantly greater than those of age-matched Wistar-Kyoto rats. Spironolactone prevented cardiac hypertrophy in adrenalectomized SHRSP. These results suggest that the rat heart produces aldosterone and that endogenous cardiac aldosterone may affect cardiac function and hypertrophy in hypertension in rats.     

Markedly elevated specific renin levels in the adrenal in genetically hypertensive rats.

The specific renin (EC 3.4.99.19) activity in the adrenal of spontaneously hypertensive rats was determined by a method that is capable of distinguishing renin from nonspecific renin-like activity of proteases by using specific antibody to renin. The renin level in the adrenals of adult spontaneously hypertensive rats with established hypertension was found to be 6-8 times as high as that of the normotensive control Wistar-Kyoto strain. The large difference in the adrenal renin level was observed even in 3-wk-old rats in which hypertension has not yet developed. The adrenal renin level was increased by bilateral nephrectomy in both the hypertensive and normotensive strains. A larger quantity of renin was found in the adrenal cortex than in the medulla, and the difference between the hypertensive strain and the normotensive strain was more prominent in the cortex than in the medulla. These results suggest possible involvement of adrenal renin in the development and in the early maintenance phase of hypertension in this animal mode of human essential hypertension by affecting the adrenocortical or adrenomedullary activity, or both.     

Fetal liver cell transplantation fails to transfer hypertension from genetically hypertensive rats to normotensive rats of the Lyon strain.

The involvement of an auto-immune mechanism has been suggested in the development and/or the maintenance of hypertension in male, genetically hypertensive rats of the Lyon strain (LH). The aim of this study was to determine whether hypertension may be transferred, by lymphoid cells, from hypertensive donors to male, normotensive rats of the Lyon strain (LN). Experiments designed to induce a resistance to hypertension in LH rats by transfer of lymphoid cells from LN animals were also performed. Since LH and LN are mismatched at the major histocompatibility complex, transfers of fetal liver cells (FLC) from fetuses of 13-14 days gestation were performed. These experiments demonstrate the ability of FLC to allow a prolonged survival (over 17 weeks) without graft versus host disease in the rat. As regards the blood pressure level, no LN recipient having received FLC from LH donor became hypertensive, thus showing that hypertension cannot be transferred by lymphoid cells in normotensive animals. Resistance to hypertension was so weakly transferred to hypertensive rats (results being significantly different only at 10 weeks post-grafting) that it may be considered doubtful.     

Intracellular calcium stores and oscillatory contractions in arteries from genetically hypertensive rats.

Strips of tail artery from stroke-prone spontaneously hypertensive rats (SHRSP), but not from normotensive Wistar Kyoto (WKY) rats, exhibit oscillatory activity after stimulation with norepinephrine. In addition, oscillatory activity is observed in response to tetraethylammonium (TEA) in vessels from both SHRSP and WKY rats. Mechanistically, the oscillatory contractions are associated with calcium (Ca2+)-driven action potentials. We have tested the hypothesis that intracellular Ca2+ stores participate in the generation of norepinephrine-induced oscillatory contractions in tail arteries from SHRSP. Additionally, the role of intracellular Ca2+ stores on TEA-induced contractions were evaluated. Contractile force in strips of tail artery from SHRSP and WKY rats was measured, using standard muscle bath procedures, and the effect of interventions that affect the storage of intracellular Ca2+ on the oscillatory contractions was evaluated. Depletion of intracellular Ca2+ stores, with ryanodine, or inhibition of Ca2+ uptake into the sarcoplasmic reticulum (SR), with thapsigargin and cyclopiazonic acid (CPA), did not inhibit oscillatory contractions induced by norepinephrine in SHRSP vessels. However, these agents inhibited the amplitude of TEA-induced contractions in WKY strips. Bay K 8644 and A23187 inhibited TEA-induced oscillatory contractions in WKY vessels. In SHRSP tail artery Bay K 8644 inhibited both norepinephrine and TEA-induced contractions, while A23187 did not have any effect. The phospholipase C inhibitor, NCDC (3X 10(-5) M), blocked oscillatory activity induced by norepinephrine in SHRSP tail artery and TEA-induced oscillations both in SHRSP and WKY vessels. These observations suggest that Ca2+ release and Ca2+ uptake into intracellular Ca2+ stores are not involved in the contraction-relaxation cycles that characterize norepinephrine-induced oscillatory activity in SHRSP tail artery. Similarly, SR Ca2+ stores may modulate but are not essential for TEA-induced oscillatory contractions.     

Selective effects of alpha-methyldopa on myocardial cell components independent of cell size in normotensive and genetically hypertensive rats

Alpha methyldopa has been shown to modify left ventricular mass and normalize mitochondria/myofibrils volume ratio in spontaneously hypertensive rats (SHR) when administered during the stage of developing cardiac hypertrophy (Tomanek et al., Cardiovas Res 23: 173, 1979). To evaluate the long-term effects of this antihypertensive agent, the drug was administered to SHR and normotensive (WKY) rats between the ages of 1 and 12 months. In another group of SHR and WKY, treatment was delayed until the age of 12 months and the animals were then treated for 3 months. Treatment with alpha-methyldopa had similar effects on systolic blood pressures in both SHR groups; group means (+/- SEM) were 151 +/- 1 in the long-term treatment group and 157 +/- 5 in the delayed treatment group compared to 178 +/- 4 and 176 +/- 3 for their respective controls. While left ventricular weight and cell size were significantly lower after early long-term treatment (compared to nontreated SHR), delayed treatment had no significant effect on these indices of left ventricular mass. Despite the effectiveness of early long-term treatment in modifying left ventricular mass, the relative volumes of mitochondria and myofibrils, as well as other cellular components (sarcoplasm), were not altered. In contrast, delayed treatment caused a significant increase (approximately twofold) in relative sarcoplasmic volume and a decrease in relative myofibrillar volume in both SHR and WKY. These findings indicate that shifts in the relative volumes of intracellular components after alpha-methyldopa are independent of cell size and blood pressure. Furthermore, the data suggest that the effects of alpha-methyldopa on the myocardial cell are dependent on or influenced by factors associated with the development or stabilization of hypertrophy and/or age.     

Intestinal calcium transport in spontaneously hypertensive rats and their genetically matched Wistar-Kyoto rats. I. Endoplasmic reticulum

The present study was designed to investigate calcium uptake by the intestinal endoplasmic reticulum in the spontaneously hypertensive rat (SHR) and its genetically matched normotensive control, the Wistar-Kyoto rat (WKY). The calcium uptake was characterized before (weanling) and after (adult) development of hypertension in SHR and their age-matched WKY controls. Adenosine 5'-triphosphate (ATP)-driven calcium uptake with time was stimulated several-fold compared with the no-ATP condition, and the maximal uptake occurred after 15 min in both SHR and WKY. The maximal ATP-dependent calcium uptake was significantly greater in the intestinal endoplasmic reticulum of adult SHR than in that of WKY (P less than 0.05). The initial rate of calcium uptake was linear up to 30 s in both SHR and WKY. The kinetics of ATP-dependent calcium uptake at a concentration between 0.1 and 1.0 mumol/l showed a maximal uptake (Vmax) of 1.89 +/- 0.3 and 1.06 +/- 0.1 nmol/mg protein per 15 s for adult SHR and WKY, respectively (P less than 0.02), and binding constant (Km) values of 0.15 +/- 0.08 and 0.12 +/- 0.05 mumol/l, respectively. The ontogeny of calcium uptake by intestinal endoplasmic reticulum was characterized before the development of hypertension in weanling (3-week-old) SHR and WKY. In both SHR and WKY weanlings, calcium uptake by the intestinal endoplasmic reticulum was enhanced several-fold by the presence of ATP compared with the no-ATP condition, and the maximal uptake occurred after 15 min. The maximal ATP-dependent calcium uptake was significantly greater in 3-week-old SHR than in age-matched WKY (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Catecholamines in kidneys of normotensive and genetically hypertensive rats. Effects of salt load

The tissue content of norepinephrine, dopamine, and epinephrine was determined in different zones of the kidney in normotensive Sprague-Dawley and Otago Wistar rats and in genetically hypertensive Otago Wistar rats. One kidney in each animal was chronically denervated to allow estimation of the neuronal contribution to renal catecholamine content. In all strains, the renal cortex contained negligible amounts of nonneuronal norepinephrine and dopamine, while outer and inner medullary layers contained progressively larger amounts. Nonneuronal epinephrine was distributed fairly evenly through cortex and medulla. Neuronal norepinephrine content was similar in inner and outer cortex, substantially less in outer medulla, and not discernible in inner medulla. The amounts of neuronal dopamine were consistent with its localization predominantly in noradrenergic nerves. The renal cortices of normotensive Wistar rats contained more neuronal norepinephrine and less neuronal dopamine than those of Sprague-Dawley rats, and the cortices of hypertensive Wistar rats contained slightly more norepinephrine than those of normotensive Wistar rats. In both normotensive strains, long-term salt loading decreased selectively the neuronal norepinephrine in renal cortex. By contrast, in hypertensive animals, cortical norepinephrine was not reduced by salt loading. These results indicate that the genetically hypertensive rat may have an abnormal sympathetic reflex response to increased blood volume.     

Azelnidipine attenuates cardiovascular and sympathetic responses to air-jet stress in genetically hypertensive rats.

Azelnidipine is a new dihydropyridine calcium channel blocker that causes minimal stimulation of the sympathetic nervous system despite its significant depressor effect. In the present study, we examined the effects of oral or intravenous administration of azelnidipine on cardiovascular and renal sympathetic nerve activity (RSNA) responses to air-jet stress in conscious, unrestrained stroke-prone spontaneously hypertensive rats. Oral administration of high-dose azelnidipine (10 mg/kg per day) or nicardipine (150 mg/kg per day) for 10 days caused a significant and comparable decrease in blood pressure, but low-dose azelnidipine (3 mg/kg per day) did not. Air-jet stress increased mean arterial pressure (MAP), heart rate (HR) and RSNA. High-dose azelnidipine significantly attenuated the increases in MAP, HR and RSNA in response to air-jet stress while nicardipine did not. Low-dose azelnidipine significantly attenuated the pressor response with a trend of decrease in RSNA. Intravenous injection of azelnidipine induced a slowly developing depressor effect. To obtain a similar time course of decrease in MAP by azelnidipine, nicardipine was continuously infused at adjusted doses. Both drugs increased HR and RSNA significantly, while the change in RSNA was smaller in the azelnidipine group. In addition, intravenous administration of azelnidipine attenuated the responses of MAP, HR, and RSNA to air-jet stress; by comparison, the inhibitory actions of nicardipine were weak. In conclusion, oral or intravenous administration of azelnidipine inhibited cardiovascular and sympathetic responses to air-jet stress. This action of azelnidipine may be mediated at least in part by the inhibition of the sympathetic nervous system.     

Beneficial effects of pioglitazone on left ventricular hypertrophy in genetically hypertensive rats.

Beneficial effects of thiazolidinediones, peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, on cardiovascular injuries have been reported. However, the effects of these agonists on left ventricular (LV) hypertrophy have not been clarified. To investigate whether pioglitazone improves LV hypertrophy, we used 32-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) that had been treated or not treated with pioglitazone (10 mg/kg/day) for 8 weeks, and Wistar Kyoto rats (WKY). We evaluated LV geometry by echocardiography; myocyte hypertrophy, tissue fibrosis, and appearance of myofibroblasts by histological examination; mRNA expression by real-time polymerase chain reaction (PCR); protein expression by Western blot; activities of matrix metalloproteinase (MMP) by zymography; and production of reactive oxygen species (ROS) by electron spin resonance spectroscopy or thiobarbituric acid reactive substances (TBARS). SHR-SP showed concentric hypertrophy of the LV, but WKY did not. The myocyte diameter, fraction of tissue fibrosis, and number of myofibroblasts were greater in SHR-SP. mRNA expressions of collagen type I and type III, tissue growth factor (TGF)-beta1, and brain natriuretic peptide (BNP); protein expression of connective tissue growth factor (CTGF); activities of MMP2 and MMP9; and ROS were increased in SHR-SP. Pioglitazone did not decrease blood pressure, but partially normalized LV geometry in addition to decreasing myocyte diameter, interstitial fibrosis and number of myofibroblasts; mRNA levels of collagen type I and BNP; MMP2 activity; and protein level of CTGF. However, the mRNA level of collagen type III and TGF-beta1, MMP9 activity, and ROS production were not improved. In conclusion, pioglitazone reversed the concentric LV remodeling independently from blood pressure or oxidative stress in chronic hypertension.     

Dissociation of hypertension and genetically enhanced cell growth capacity in skin fibroblasts of F2 hybrid spontaneously hypertensive rats/Wistar-Kyoto rats.

Skin fibroblasts from newborn spontaneously hypertensive rats (SHR) grow faster in culture than Wistar-Kyoto rat (WKY) cells. Similar results have been described for vascular smooth muscle cells from prehypertensive and adult SHR. This suggests the existence of an intrinsic abnormality in vascular and nonvascular cells of mesodermal origin affecting cell growth control in those rats. In an attempt to determine the relation between high blood pressure and this trait, we cultured skin fibroblasts from adult SHR, WKY, F1, and F2 hybrid SHR/WKY populations by explant technique. Their growth capacity was determined by culture well DNA doubling time and by [3H]thymidine incorporation. Adult SHR fibroblasts grew more quickly (doubling time [DT] = 37.2 +/- 2.3 h, n = 8) than WKY ones (DT = 53.9 +/- 3.6 h, n = 6). Female SHR were crossed with male WKY to produce an F1 and an F2 hybrid generation presenting a Mendelian distribution of blood pressure. Skin fibroblasts were cultured from 21 rats belonging to the highest and the lowest blood pressure groups. No difference was observed between the two groups in either growth (DT = 47.5 +/- 4.1 h, n = 11 v DT = 44.6 +/- 3.2 h, n = 10) or epidermal growth factor-induced [3H]thymidine incorporation. These observations suggest that the increased growth capacity observed in SHR is not a determinant of high blood pressure initiation but may be involved in early cardiovascular enlargement.     

In vitro evidence for genetically determined variations in marrow erythroid cell sensitivity to chloramphenicol.

The effect of chloramphenicol (CAP) was examined on the in vitro growth of CFU-E and CFU-C from four strains of mice: C57L/J, A/HEJ and their first generation hybrid LAF1, and the inbred strain C57BL/6J. The growth of marrow CFU-E from C57L/J and the hybrid LAF1 was inhibited by 82--96% at a CAP concentration of 10 microgram/ml compared to only 22--39% for CFU-E from A/HEJ and C57BL/6J. There was little difference in the degree of inhibition of CFU-C growth by CAP among the four strains, with that of C57L/J showing a slightly greater sensitivity to the drug. These results indicate a genetically-determined variation in the sensitivity of marrow erythroid cells to CAP.     

Intestinal phosphate transport in spontaneously hypertensive rats and genetically matched controls

Hypophosphatemia has been documented in patients with hypertension and in spontaneously hypertensive rats compared with genetically matched control Wistar-Kyoto rats. However, renal tubular reabsorption is increased in spontaneously hypertensive rats. Therefore, it was hypothesized that decreased serum phosphate levels in spontaneously hypertensive rats may be related to a decrease in the intestinal transport of phosphate. To test this hypothesis, sodium-dependent phosphate uptake by jejunal brush-border membrane vesicles of spontaneously hypertensive rats and genetically matched Wistar-Kyoto rats was determined. Phosphate uptake consisted of two components: sodium-independent passive diffusion across the brush border and sodium-dependent, carrier-mediated uptake. The initial rate of uptake in spontaneously hypertensive and Wistar-Kyoto rats was linear up to 20 seconds. The initial rate and time course of jejunal sodium-dependent phosphate uptake was decreased in adult spontaneously hypertensive rats compared with corresponding mean values in Wistar-Kyoto rats. This decrease was secondary to a decrease in Vmax rather than Km, suggesting tha the number and/or the activity of the sodium-phosphate transporters is decreased. Sodium-dependent phosphate uptake was pH dependent, with greater uptake at pH 6.0 than at pH 7.4. However, uptake values were lower in spontaneously hypertensive rats than in Wistar-Kyoto rats at all pH levels tested. In contrast, sodium-dependent phosphate uptake in weanling rats (prehypertensive state) was not significantly different between spontaneously hypertensive and Wistar-Kyoto rats. Vitamin D deficiency in both spontaneously hypertensive and Wistar-Kyoto rats decreased Vmax and Km of sodium-dependent phosphate uptake, whereas 1,25(OH)2 vitamin D3 administration increased Vmax and Km in both spontaneously hypertensive and Wistar-Kyoto rats. These results suggest that the hypophosphatemia seen in adult spontaneously hypertensive rats is secondary to a decrease in sodium-dependent phosphate uptake compared with controls. The sodium phosphate transporter in spontaneously hypertensive rats is responsive to vitamin D administration.     

Attenuated arteriolar dilator responses to calcium in genetically hypertensive rats

Vascular responses to calcium were studied in 14 genetically hypertensive (GH) rats of the New Zealand strain and 16 weight- and age-matched normotensive parent strain control rats under chloralose-pentobarbital anesthesia. Calcium (chloride or gluconate) in an isosmolar solution was infused intraarterially into the hindlimb vascular bed which was vascularly isolated, innervated, and pump-perfused (blood, 1 ml/min). Increases in limb plasma calcium concentrations up to 30 mEq/liter decreased limb vascular resistance, with no evidence for vasoconstriction. In GH rats decreases in limb vascular resistance in response to increments in limb plasma calcium concentrations of 3.6 to 10.8 mEq/liter were significantly (p less than 0.02) attenuated compared to age-matched controls. When responses in GH were compared to weight-matched controls, similar trends toward attenuation reached significance (p less than 0.02) at Ca2+ increments of 10.8 mEq/liter. In eight other GH rats, we measured total serum calcium concentrations and found them reduced (4.94 +/- 0.08 mEq/liter), especially as compared to values in eight rats of an unrelated Wistar strain (5.42 +/- 0.04 mEq/liter; p less than 0.05). These experiments provide evidence that, over physiological ranges, calcium relaxes arteriolar smooth muscle in rats and that this vasodilation is attenuated in genetically hypertensive rats. Thus, both the lower serum levels of calcium and the attenuated responses to calcium may contribute to the elevated peripheral vascular resistance and hypertension in these rats.