Adult Hypertensive Rats Research Articles

Glucocorticoids, feto-placental 11β-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease

Increasing human epidemiological data suggest that events that subtly retard intrauterine growth may determine common disorders, such as hypertension and non-insulin-dependent diabetes, in adult life. The underlying mechanisms are unknown. However, excessive fetal exposure to glucocorticoids retards growth and “programs” adult hypertension in rats. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) catalyzes the rapid inactivation of cortisol and corticosterone to inert 11 keto-products. Normally, 11β-HSD2 in the placenta and some fetal tissues is thought to protect the fetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11β-HSD2, and enzyme activity correlates with birth weight. Moreover, inhibition of feto-placental 11β-HSD2 in the rat reduces birth weight and produces hypertensive and hyperglycaemic adult offspring, many months after prenatal treatment; effects are dependent upon intact maternal adrenals, suggesting a direct action on the fetus or placenta. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11β-HSD2 activity. These data suggest that feto-placental 11β-HSD2, by regulating fetal exposure to maternal glucocorticoids, crucially determines fetal growth and the programming of later disorders. Deficiency of the barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and feto-placental programming of later disease. These data may, at least in part, explain the human observations linking early life events to the risk of subsequent disease.

Kallikrein gene therapy in newborn and adult hypertensive rats

Kallikrein gene therapy in newborn and adult hypertensive rats

Placental 11β-hydroxysteroid dehydrogenase and the programming of hypertension

Excessive foetal exposure to glucocorticoids retards growth and “programmes” adult hypertension in rats. Placental 11β-hydroxysteroid dehydrogenase (11β-HSD), which catalyses the conversion of corticosterone and cortisol to inert 11 keto-products, normally protects the foetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11β-HSD, and enzyme activity correlates with birth weight. Moreover, inhibition of placental 11β-HSD in the rat reduces birth weight and produces hypertensive adult offspring, many months after prenatal treatment with enzyme inhibitors; these effects are dependent upon maternal adrenal products. These data suggest that placental 11β-HSD, by regulating foetal exposure to maternal glucocorticoids, crucially determines foeto-placental growth and the programming of hypertension. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11β-HSD activity. Thus, deficiency of the placental barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and foeto-placental programming of later disease. These data may, at least in part, explain the human epidemiological observations linking early life events to the risk of subsequent hypertension. The recent characterization, purification and cDNA cloning of a distinct human placental 11β-HSD (type 2) will aid the further study of these intriguing findings.

Acetylcholine-induced currents in acutely dissociated sympathetic neurons from adult hypertensive and normotensive rats have similar properties.

Whole-cell patch-clamp recordings were used to compare the amplitude and kinetics of acetylcholine-induced currents (IACh) in acutely isolated superior cervical ganglion (SCG) neurons from spontaneously hypertensive (SHR) rats and Wistar-Kyoto (WKY) rats, to determine if altered postsynaptic transmitter responsiveness underlies the increased sympathetic nerve activity in SHR rat neurons. Rapidly activating and slowly inactivating inward currents were recorded in response to rapid application of ACh (5 microM to 2 mM). Concentration/response relationships for SCG neurons isolated for SHR and WKY rats had dissociation constants of 161 microM and 169 microM, maximum responses of 26 nS/pF and 24 nS/pF, and Hill coefficients of 1.8 and 1.9, respectively. Activation of the currents was fitted well by a single exponential function with concentration-dependent time constants, whereas inactivation was fitted well by a double exponential function also with concentration-dependent time constants. The time constants of both activation and inactivation for SHR and WKY rats were not significantly different at any concentration tested. The results demonstrate that the postsynaptic effects of ACh are similar between SHR and WKY rat postganglionic neurons and, therefore, probably do not contribute to the observed differences in ganglionic transmission between SHR and WKY rat nerves.

Intrathecal capsaicin enhances one-kidney renal wrap hypertension in the rat

Afferent renal nerves (ARN) have been implicated in the development of one-kidney renal wrap (1K-WRAP) hypertension. The role of renal nerves in desoxycorticosterone acetate-salt (DOCA) hypertension, a low-renin model of hypertension, is controversial. The present study was designed to determine if spinal substance P (SP) and/or calcitonin gene-related peptide (CGRP) in ARN affects the development of 1K-WRAP or DOCA hypertension in adult rats. Selective long-term partial depletion of spinal SP and CGRP within small primary afferent nerve fibers including unmyelinated ARN was achieved by intrathecal administration of capsaicin. After capsaicin treatment, 1K-WRAP hypertension was induced by removing the right kidney and wrapping the left kidney with a figure-8 ligature. In a second group of rats, DOCA hypertension was induced by subcutaneous application of desoxycorticosterone pellets after unilateral nephrectomy. Systolic arterial pressure was monitored for 8 weeks by tail cuff plethysmography after which direct blood pressure measurement was performed followed by immunohistochemistry. Intrathecal capsaicin administration had no significant effect on SP-ir and CGRP-ir of ARN soma located within thoracic dorsal root ganglia whereas immunoreactivity against these peptides was reduced by one third to one half in the dorsal horn, indicating effective long-term spinal depletion of these neuropeptides. Intrathecal capsaicin enhanced the development of 1K-WRAP hypertension, since arterial pressure was greater in the treated group. In contrast, DOCA hypertension was unaffected by capsaicin pretreatment. Considering the neurotoxic action of capsaicin for SP-ir and CGRP-ir unmyelinated primary afferent neurons, we hypothesize that spinal SP, CGRP and/or related peptides existing in ARN and other capsaicin-sensitive unmyelinated primary afferent neurons in the lower thoracic spinal cord may ameliorate 1K-WRAP hypertension, but not DOCA hypertension.

30 Effects of angiotensin II on cytosolic calcium releases in isolated ventricular myocytes from adult normal and hypertensive rats

Methods: This study investigated the effects of angiotensin II (Ang II; 10-9-10-7mol/l) on calcium releases in ventricular myocytes from normal and renal hypertensive adult rats (Goldblatt two kidney one clip). Newly isolated myocytes were loaded with fluorescent indo-1/AM and studied at rest or under electrical stimulation. The variation of the ratio of indo-1 emission (405/480 nm) was taken as a measure of cytosolic calcium variation. Five parameters were investigated from each peak systolic indo-1 ratio before and after Ang II addition: amplitude variation, duration with analysis of a rise time and a fall time, and frequency of spontaneous calcium releases. Results: The following changes were observed: (1) in unstimulated myocytes exhibiting spontaneous contractile activity, an increase in the frequency of calcium transients, at 10-7mol/l, in normal cells (+157±27%, P<0.01) and at each Ang II concentration in hypertrophied cells (+79±31%, P<0.01; +82±25%, P<0.01; +285±50%, P<0.01 at 10-9, 10-8 and 10-7 mol/l); (2) in stimulated myocytes, prolongation of the duration of calcium transients, explained by the occurrence of calcium releases during fall time. In addition, 50% of myocytes exhibited spontaneous releases of calcium in the interstimulus interval. The increase in calcium transient duration was statistically significant, regardless of the Ang II concentration in hypeitrophied cells (+36±20%, P<0.05; +39±18%, P 0.01; +77±34%, P<0.01 at 10-9, 10-8, 10-7mol/l) and only at 10-7mol/l in normal cells (+68±22%, P<0.01). Similar results were observed in fall time. Conclusion: Thus, in both normal and hypertrophied myocytes, Ang II induced calcium release, and hypertrophied cells became increasingly sensitive to Ang II. This occurrence of calcium release is a possible cause of arrhythmias, known as ‘triggered activity'.

Signal transduction mechanisms of the vasoconstriction in hypertension

We tested the hypothesis that vascular smooth muscle in genetic hypertension is characterised by hypereactivity to vasoactive agonists, by abnormalities in Ca 2+ handling and the phosphoinositide signalling system. Activation of these signal transduction mechanisms by noradrenaline and endothelin-1 was compared in isolated perfused tail arteries from adult hypertensive and normotensive Wistar Kyoto rats. Basal cytosolic Ca 2+ was greater in arteries from hypertensive rats, but basal perfusion pressure and basal inositol phosphate accumulation were unchanged. Contractile responses and Ca 2+ mobilisation after noradrenaline, but not endothelin-1, were enhanced in arteries from hypertensive rats. Total inositol phosphates accumulation was similar in hypertensive and normotensive rats after either noradrenaline or endothelin-1 stimulation. In both hypertensive and normotensive rats, for a given Ca 2+ mobilisation, higher contractile responses and higher levels of inositol phosphates were observed after endothelin-1 than noradrenaline stimulation. In conclusion, changes in contractility associated with modifications in the Ca 2+ handling between hypertensive and normotensive rats suggested that alterations in the signal-transduction system occur with hypertension. The different effects of endothelin-1 and noradrenaline could be related to interactions with other signalling pathways.

Mesenteric vascular smooth muscle cells from spontaneously hypertensive rats display increased calcium responses to angiotensin II but not to endothelin-1

To determine the differential calcium responses to two vasoconstrictor peptides, angiotensin II (Ang II) and endothelin-1, in vascular smooth muscle cells derived from mesenteric arteries from young and adult normotensive and hypertensive rats. Effects of Ang II and endothelin-1 on cytosolic free calcium concentration in primary cultured unpassaged single vascular smooth muscle cells from mesenteric arteries of Wistar-Kyoto (WKY), Wistar and spontaneously hypertensive rats (SHR) aged 3, 9 and 17 weeks were examined microphotometrically using fura-2 methodology. Basal cytosolic free calcium concentration was significantly increased in cells from SHR aged 9 and 17 weeks compared with cells from age-matched WKY and Wistar rats. Ang II and endothelin-1 significantly increased cell cytosolic free calcium in all rat groups at all ages. Responses to low concentrations of Ang II (1 nmol/l) were significantly higher in cells from SHR aged 9 and 17 weeks than in age-matched controls. This was confirmed in cells from rats aged 17 weeks with full concentration-response curves, which also showed that the pD2 for Ang II for WKY rats was significantly different from that of SHR. In cells from SHR at all ages Ang II-stimulated cytosolic free calcium remained persistently high, whereas in cells from WKY and Wistar rats basal levels were reached within 100 s after the maximal response. Low concentrations of endothelin-1 elicited significantly lower cytosolic free calcium responses in cells from SHR aged 17 weeks compared with age-matched controls. The time course of cytosolic free calcium responses to endothelin-1 were similar in the groups. In primary cultured unpassaged mesenteric vascular smooth muscle cells from adult SHR, cytosolic free calcium concentration responses to Ang II are enhanced, whereas responses to low concentrations of endothelin-1 are slightly reduced. The differential effects of these two vasoconstrictor peptides may contribute to their relative roles in modulating vascular smooth muscle cell cytosolic free calcium in SHR.

Ontogenesis of sympathetic responsiveness in spontaneously hypertensive rats. II. Renal G proteins in male and female rats.

Previously we have reported an increased renal alpha 1- and beta-adrenergic receptor expression in male spontaneously hypertensive rats that occurred ontogenetically in parallel with blood pressure elevation. However, increased receptor numbers were not accompanied by enhanced stimulation of inositol phosphate and cyclic AMP formation, respectively, indicating relative desensitization. We have now quantified alpha-subunits of the G proteins Gs (Gs short and Gs long), G(i), and Gq by immunoblotting and pertussis toxin-catalyzed ADP-ribosylation in renal membranes from 3-, 6-, 8-, and 28-week-old normotensive and spontaneously hypertensive male Wistar-Kyoto rats; additionally, 28-week-old female normotensive and spontaneously hypertensive rats were studied. During ontogenesis of male normotensive rats, Gs short increased, Gs long remained unchanged, and G(i) alpha and Gq alpha decreased. In adult normotensive rats no sex differences were detected for Gs short, Gs long, and G(i) alpha. When male rats from the normotensive and spontaneously hypertensive strains were compared, all G protein alpha-subunits were similar in the prehypertensive phase (3 weeks). In established hypertension (28 weeks), Gs long and Gq alpha were reduced, whereas Gs short and G(i) alpha remained unchanged. Gs long was also reduced during the development of hypertension (6 and 8 weeks), whereas Gs short and G(i) alpha were not consistently altered in this phase. The reduction in Gs long seen in male adult hypertensive rats was not detectable in female hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related changes in linoleic acid bioconversion by isolated hepatocytes from spontaneously hypertensive and normotensive rats.

This study points out the hepatocyte interconversion of the linoleic acid family during hypertension. Hepatocyte delta 6 desaturase activity was higher in 1 month-old spontaneously hypertensive rats than in normotensive controls. A similar tendency was observed in 6 month-old SHR. delta 5 desaturase activity was higher only in 1 month-old spontaneously hypertensive rats as compared to controls. Desaturase activities were particularly high at the age of 6 months. The hepatocyte fatty acid composition showed an impairment of n-6 polyunsaturated fatty acid metabolism in spontaneously hypertensive animals. Changes were greater in the young prehypertensive rats than in adults. A storage of n-3 long chain fatty acids is remarkable in adult hypertensive rats, suggesting an alteration in peroxisomal oxidation. Such modifications may be related to the prostaglandin precursors availability to peripheral tissues such as kidney.

Induction of hypertension in adult rats, mediated by exposure to maternal low-protein diets in utero

Induction of hypertension in adult rats, mediated by exposure to maternal low-protein diets in utero

Ultrastructural study of the choroid plexus of spontaneously hypertensive rats.

We previously gave an account of an increased ion transport activity in choroid plexus from spontaneously hypertensive rats. We have since examined this organ in scanning and transmission electronic microscopy. In the choroid plexus from young spontaneously hypertensive rats, the epithelial cells showed the following: a partial loss of the brush border and infoldings of basolateral membranes, an increased number of Golgi apparatus, vesicles, and mitochondria, and an activated nucleus. In adult hypertensive rats, the mitochondria had increased in number and tended to fill the cytoplasma while the nuclei had returned to a resting level. These ultrastructural changes furthermore suggest an increased secretory activity in the choroid plexus in spontaneously hypertensive rats.

Fetal neocortical grafts implanted in adult hypertensive rats with cortical infarcts following a middle cerebral artery occlusion: Ingrowth of afferent fibers from the host brain

This study is focused on the survival of fetal neocortical grafts placed in the infarcted adult host cortex of the spontaneously hypertensive rat and describes the ability of host axonal regeneration into the graft after a focal ischaemic lesion. Five to seven days following ligation of the right middle cerebral artery, dissociated neocortical primordium from fetuses of gestational age 12–18 days was implanted into the infarcted cortical area. Surviving transplants were seen in all rats, although grafts derived from gestational age 12–14 days displayed an irregular morphology rich in sinusoid-like cavities and containing fewer cells of apparently mature neuronal morphology. Grafts from older donors contained perikarya of neuronal appearance; however, they lacked normal cortical lamination. Ten days post-grafting, fibers stained by acetylcholinesterase histochemistry, dopamine-β-hydroxylase, and 5-hydroxytryptamine immunohistochemistry were found in the grafts, and by 10–23 weeks after transplantation the fiber density had increased substantially. When the retrograde tracer Fluoro-Gold was injected into the grafted tissue, labeled cells were found in several subcortical nuclei of the host, including the nucleus basalis of Meynert, ventral pallidum, thalamus, dorsal raphe, locus coeruleus, as well as the ipsilateral and contralateral neocortex. This study shows that grafts of dissociated neocortical tissue exhibit good survival and growth potential when implanted into infarcted neocortex and that several nerve fiber systems of the adult host have a regenerative capacity sufficient to innervate the grafted tissue.

Importance of cardiac, but not vascular, hypertrophy in the cardiac baroreflex deficit in spontaneously hypertensive and stroke-prone rats

In the present study, we examined whether antihypertensive treatment of young and adult hypertensive rats with the angiotensin-converting enzyme (ACE) inhibitor perindopril could restore the baroreflex vagal deficit and whether this was related to prevention of cardiac or vascular hypertrophy. Spontaneously hypertensive (SHR), stroke-prone spontaneously hypertensive (SHR-SP), and Wistar-Kyoto (WKY) rats were untreated or treated with perindopril (3 mg/kg/day) in the drinking water from 4–9 and from 14–20 weeks of age. Steady-state sigmoidal mean arterial pressure (MAP)-heart rate (HR) reflex curves were obtained in the conscious rats by the injection of pressor and depressor agents before and after atenolol (vagal component). Increased left ventricle to bodyweight ratio (LV/BW) indicated cardiac hypertrophy. After ganglion blockade, the minimum MAP produced by nitroprusside and the maximum produced by methoxamine were used as indications of vascular hypertrophy. Perindopril treatment reduced cardiac and vascular hypertrophy to different extents in SHR and SHR-SP. The 4–9 and 14–20 week treatments reduced MAP and both minimum and maximum blood pressure of the SHR to the levels of the untreated WKY. However, only in the older animals was LV/BW restored. In the SHR-SP, early treatment had a much greater effect on vascular hypertrophy than on LV/BW. The reverse occurred for the 14–20 week animals. In untreated hypertensive animals the baroreflex curves were shifted to the right with reduced vagal HR range. Perindopril treatment shifted the baroreflex curves back towards the WKY curves. Vagal HR range was strongly correlated with the LV/BW, whereas vagal HR range was less well related to the level of vascular hypertrophy or blood pressure. These results suggest that antihypertensive treatment can restore cardiac baroreflex function and that it is related to the reduction in cardiac hypertrophy. Although the mechanism of this relationship remains to be elucidated, these findings suggest that cardiac vagal afferents may be important.

Lack of Antihypertensive Effect of Interleukin-2 Administration in Humans

A recent study reported that a single bolus dose of interleukin-2 (IL-2) decreased blood pressure to normal in adult hypertensive rats and prevented the development of spontaneous hypertension in young rats. The Surgery Branch of the National Cancer Institute has had extensive experience with the administration of IL-2. A review was performed focusing on the experience of IL-2 administration to cancer patients with established preexisting hypertension. Seventeen evaluable patients were identified. Sixteen of the patients experienced a return of their hypertension with the completion of therapy. One patient was able to stop his antihypertensive medications and remain normotensive for 3 months' follow-up. One normotensive patient developed hypertension after initiating IL-2 therapy. Our data do not demonstrate significant reduction in blood pressure in previously hypertensive patients undergoing high-dose IL-2 therapy.

Endothelin in hypertensive resistance arteries. Intraluminal and extraluminal dysfunction.

The effects of intraluminal and extraluminal endothelin-1 and its interactions with endothelium-derived relaxing factor were studied in perfused mesenteric resistance arteries of Wistar-Kyoto rats and spontaneously hypertensive rats. Changes in intraluminal diameter were recorded. In adult Wistar-Kyoto rats, but not spontaneously hypertensive rats, low concentrations of intraluminal endothelin-1 (10(-10) to 10(-9) M) caused relaxations of quiescent arteries blocked by indomethacin. After endothelial removal, intraluminal endothelin-1 evoked concentration-dependent contractions in both strains. Extraluminal endothelin-1 caused greater contractions of arteries with endothelium than intraluminal endothelin-1, and the sensitivity was lower in adult hypertensive rats; endothelial removal enhanced the contractions to extraluminal endothelin-1 to a greater extent in hypertensive than in normotensive rats. In arteries without endothelium, intraluminal and extraluminal endothelin-1 caused comparable contractions, but the sensitivity was reduced in adult but not young hypertensive as compared with normotensive rats. Both young spontaneously hypertensive and normotensive rats exhibited a high sensitivity to the peptide. In arteries precontracted with endothelin-1, endothelium-dependent relaxation to intraluminal acetylcholine was reduced in hypertensive as compared with normotensive rats, whereas relaxations to extraluminal acetylcholine were increased in hypertensive rats. Thus, endothelin-1 interacts with both vascular smooth muscle and the endothelium. The sensitivity of vascular smooth muscle to endothelin-1 is reduced in adult hypertensive rats. Intraluminal activation of the endothelium by endothelin-1 or acetylcholine is reduced in spontaneously hypertensive rats, whereas extraluminal activation causes more pronounced responses in hypertensive than in normotensive rats, suggesting a prominent dysfunction of the intraluminal surface of the endothelium in hypertension.

Blood pressure maintenance in hypertensive sympathectomized rats. I. Adrenal medullary catecholamines

To assess the role of the sympathetic nervous system in the development of genetic hypertension, blood pressure (BP) was recorded in conscious adult Lyon hypertensive (LH) and normotensive (LN) rats that had received daily injections of saline or guanethidine at 1-13 wk of age. Guanethidine abolished the pressor response to tyramine, decreased plasma norepinephrine by greater than 70% and plasma 3,4-dihydroxyphenylglycol by approximately 90%, and did not change plasma epinephrine. Bilateral adrenalectomy further reduced plasma norepinephrine to 8 and 5% of control levels in LH and LN rats, respectively. BP was lowered (-7%) in sympathectomized rats, but the mean absolute BP difference between LH and LN rats was unaltered. Despite marked supersensitivity to alpha-adrenoreceptor stimulation, phentolamine induced only a small transient depressor response, which was abolished by adrenalectomy in sympathectomized rats. It is concluded that the sympathetic nervous system is not necessary for the development of hypertension in LH rats. After sympathectomy, circulating catecholamines, which mostly derive from the adrenal medulla, play only a minor role in BP maintenance.

On the pathogenetic mechanism of hypercalciuria in genetically hypertensive rats of the Milan strain.

The aim of this study was to investigate the pathogenesis of hypercalciuria in the Milan strain of genetically hypertensive rats. Dietary calcium intake and urinary and fecal calcium output were measured simultaneously with indices of sodium and phosphate homeostasis in male rats of the Milan hypertensive and normotensive strains. In addition, urinary calcium and creatinine excretion rates, calcium, phosphate and creatinine serum concentrations, and bone calcium content were also measured in these rats after an overnight fast. Under fed steady-state conditions dietary calcium, sodium, and phosphate intakes, were similar in the two groups of rats, but hypertensive rats had twofold higher urinary calcium excretion and normal urinary excretion of sodium and phosphate. Fecal calcium output was slightly but significantly higher in the adult hypertensive rats while fecal sodium and phosphate excretion was normal. Because of increased urinary and fecal calcium loss, net calcium balance was significantly less positive in hypertensive than in control rats. Under fasting conditions hypertensive rats were confirmed to have hypercalciuria despite normal serum calcium concentrations and normal creatinine clearance. In accordance with balance data and fasting hypercalciuria, bone calcium content was found to be significantly reduced in hypertensive rats. These findings confirm that hypercalciuria in the Milan hypertensive rats is explained by an altered renal calcium handling; it is also associated with a slightly increased fecal calcium output and, therefore, with a less positive calcium balance and reduced bone calcium content.

Lenticular rubidium uptake in hypertensive 'cataract-prone' salt-sensitive rats.

We have previously reported a high incidence of cataract formation in adult hypertensive salt-sensitive rats, suggesting that hypertension may be an important cataractogenic risk factor. Weanling salt-sensitive rats that eventually developed cataracts showed a marked increase in the pressor response to a high-sodium diet compared to salt-sensitive rats that did not develop cataracts. A lens and aqueous fluid electrolyte imbalance occurred in all adult salt-sensitive rats examined, but was greater in the salt-sensitive rats that developed cataracts, suggesting an alteration in lens and/or ciliary ion transport in cataracts associated with hypertension. In the present study, lens 86Rb uptake was measured in adult hypertensive salt-sensitive rats prior to cataract formation. 'Cataract-prone' salt-sensitive hypertensive rats (increased pressor response to a high sodium diet given at weanling age), salt-sensitive hypertensive rats unlikely to develop cataracts and control salt-resistant rats were studied at the age of 16 weeks. Total and ouabain-insensitive lens 86Rb uptake were measured for the determination of ouabain-sensitive uptake, an index of Na+,K+-ATPase activity. Lens ouabain-sensitive 86Rb uptake was low in adult hypertensive cataract-prone salt-sensitive rats before cataract formation compared with values in control resistant rats. Intermediate values were observed in hypertensive salt-sensitive rats unlikely to develop cataracts. These data suggest that altered ion transport may play a pivotal role in cataractogenesis associated with this model of hypertension. The data are also consistent with the concept of a generalized defect in epithelial ion transport, at least in salt-sensitive hypertension.

Endothelium-dependent and endothelium-independent vasodilation in resistance arteries from hypertensive rats.

The endothelium-dependent and presumed endothelium-independent vasodilators acetylcholine and sodium nitroprusside, respectively, were used to characterize relaxation responses of mesenteric resistance arteries from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY). Vessels were preconstricted using concentrations of norepinephrine or 5-hydroxytryptamine, which reduced their diameters by 50 to 60%. Relaxation responses to acetylcholine (10(-8) - 10(-7) M) were significantly smaller (p less than 0.05) in vessel segments from SHRSP, but the maximal relaxations at higher concentrations were the same in both strains. However, SHRSP vessels relaxed to a greater extent than did those of the WKY at all concentrations of sodium nitroprusside. Endothelium removal significantly enhanced sodium nitroprusside-induced dilations in both rat strains, and the dilations were significantly greater in segments from SHRSP in the concentration range of 3 X 10(-8) to 10(-6) M. The decreased relaxation to acetylcholine in resistance arteries from adult hypertensive rats compared with those from the normotensive strain suggests that functional alterations in the endothelium may play a role in hypertensive disease.