Presynaptic alpha 2-adrenoceptor mediated regulation of norepinephrine release in perfused mesenteric vasculatures in young and adult spontaneously hypertensive rats

The present study was designed to evaluate the role of the presynaptic alpha 2-adrenoceptor in the pathogenesis of hypertension. Norepinephrine overflow during sympathetic nerve stimulation and its changes by presynaptic alpha 2-adrenoceptor inhibition were examined in the perfused mesenteric vasculatures of young and adult spontaneously hypertensive rats (SHR) compared with age-matched Wistar Kyoto rats (WKY). Electrical sympathetic nerve stimulation caused significantly greater overflow of endogenous norepinephrine from the adrenergic nerve terminals in young SHR than in age-matched WKY. Yohimbine, an alpha 2-adrenoceptor blocking agent, facilitated norepinephrine overflow from the adrenergic nerve terminals. The effects of yohimbine on norepinephrine overflow and pressor responses to electrical nerve stimulation were less in young SHR than in age-matched WKY. Norepinephrine overflow in adult SHR was similar to that in adult WKY, and differences in the effect of yohimbine on norepinephrine overflow between SHR and WKY were not marked at this chronic stage. These results suggest that enhanced norepinephrine overflow in the mesenteric vasculatures can be observed only in young SHR; this may be due in part to an impaired negative feed-back mechanism on the nerve terminals by presynaptic alpha 2-adrenoceptors.     

Low-sodium diet and alpha-adrenoceptors of renal basolateral membrane in spontaneously hypertensive rats.

To clarify the effect of dietary sodium restriction on the mechanism regulating sodium and water in the development of hypertension, we determined the number of the alpha-adrenoceptors in renal basolateral membrane in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The rats had been fed a low-sodium (0.5%) or normal-sodium (0.4%) diet from 3 weeks of age. The experiments were performed at 6, 8 and 20 weeks of age in both rat groups. Renal basolateral membranes were prepared using Percoll and radioligand binding studies were performed using 3H-prazosin and 3H-rauwolscine. Systolic blood pressure in SHR was already elevated at 6 weeks of age compared with that in WKY rats and rose to hypertensive levels at 8 weeks of age. The sodium balance in WKY rats on both diets decreased at 8 weeks of age, but that of SHR decreased at 20 weeks of age. The maximum number (Bmax) for the alpha 1-adrenoceptor did not differ in any groups of the WKY rats or SHR. Bmax for the alpha 2-adrenoceptors increased at 8 weeks of age in the low-sodium SHR compared with normal-sodium SHR, but did not increase in WKY rats. The data show that the increases in blood pressure in the SHR occur prior to significant increases in the alpha 2-adrenoceptor density of renal basolateral membrane, and that the modulation of alpha 2-adrenoceptor density in SHR differs from that in WKY rats under sodium restriction. The results suggest that renal alpha 2-adrenoceptors in SHR could relate the regulatory mechanism to sodium reabsorption under sodium restriction rather than to the primary cause of the development of hypertension in SHR. There may be the possibility of an abnormality in renal alpha 2-adrenoceptor mechanism in SHR.     

Prostaglandin E2 inhibits noradrenaline release and purinergic pressor responses to renal nerve stimulation at 1 Hz in isolated kidneys of young spontaneously hypertensive rats

The effects of prostaglandin E2 (PGE)2 and the thromboxane A2 (TxA2) receptor agonist U-46619 on noradrenaline release and pressor responses to renal nerve stimulation (RNS) at 1 Hz were investigated in isolated kidneys of spontaneously hypertensive rats (SHR; 5-7 weeks) and age-matched Wistar-Kyoto rats (WKY). After incubation with 3H-noradrenaline, the renal nerves were stimulated. The stimulation-induced (S-I) outflow of radioactivity was taken as an index of noradrenaline release. Absolute S-I outflow of radioactivity was lower in SHR than in WKY but pressor responses to RNS were greater in SHR than in WKY. Tetrodotoxin (1 mumol/l) abolished S-I outflow of radioactivity and pressor responses to RNS in both strains. PGE2 (0.06 mumol/l) inhibited S-I outflow of radioactivity in SHR but not in WKY kidneys. PGE2 (0.6 mumol/l) inhibited S-I outflow of radioactivity in both strains. In SHR, PGE2 (0.6 mumol/l) decreased pressor responses to RNS, but increased them in WKY. In WKY, but not in SHR kidneys, pressor responses to RNS were markedly reduced by the alpha 1-adrenoceptor antagonist prazosin (0.1 mumol/l). The prazosin-resistant pressor responses to RNS were blocked by alpha, beta-methylene adenosine triphosphate (ATP; 1 mumol/l). In kidneys of SHR, pretreated with 6-OH-dopamine (50 mg/kg intravenously, 24 and 48 h before isolation of the kidneys) to destroy sympathetic nerve endings, pressor responses to RNS and S-I outflow of radioactivity were almost abolished. U-46619 (0.1 mumol/l) increased perfusion pressure in SHR and WKY kidneys and this effect was blocked by the TxA2 receptor antagonist daltroban (BM 13505; 3 mumol/l). U-46619 did not significantly modulate S-I outflow of radioactivity. The results suggest that activation of prejunctional PGE2 receptors in kidneys of SHR and WKY inhibits noradrenaline release. The prejunctional inhibitory PGE2 receptor mechanism on renal sympathetic nerves seems to operate more effectively in SHR than in WKY. There is no evidence for prejunctional TxA2 receptors in the kidneys of SHR or WKY. Pressor responses to RNS at 1 Hz in SHR kidneys seem to be due entirely to release of a purinergic co-transmitter from renal sympathetic nerves, and PGE2 possibly reduces pressor responses to RNS by inhibiting release of this purinergic co-transmitter.     

Decrease in alpha 1-adrenoceptor reserve in mesenteric arteries isolated from spontaneously hypertensive rats

The characterization of alpha-adrenoceptor-mediated contractile responses and the effects of the calcium channel blocker nifedipine on these responses were investigated in mesenteric arterial strips from 13-week-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Contractile responses to the alpha-adrenoceptor agonists phenylephrine and clonidine were mediated through the activation of alpha 1-adrenoceptors. The dose producing a half-maximum response (ED50) for the agonists was higher in SHR than in WKY. Affinities of alpha 1-adrenoceptors were similar between the two strains. When arterial strips from both strains were treated with the same concentration of phenoxybenzamine, the maximum response to each agonist was weaker in SHR. The alpha 1-adrenoceptor occupancy-response relationship for phenylephrine was hyperbolic and less steep in SHR, while the relationship for clonidine was linear in SHR but not in WKY. Alpha 1-adrenoceptor occupancy at a half-maximum response to each agonist was greater in SHR. Nifedipine inhibited the maximum responses to the agonists more profoundly in SHR than in WKY. This inhibition was greater in the response to clonidine than in the response to phenylephrine in both strains. When the maximum response to phenylephrine was reduced to the same extent in both strains by treatment with different concentrations of phenoxybenzamine, the responses to phenylephrine were more susceptible to inhibition by nifedipine. Under these conditions, the effects of nifedipine were similar between SHR and WKY. These results suggest that alpha 1-adrenoceptor reserve is reduced in SHR mesenteric artery compared with WKY, which may be responsible for the greater inhibition by nifedipine of the alpha 1-adrenoceptor-mediated contractions in SHR.     

A functional study of the development of the cardiac sympathetic neuroeffector junction in the SHR

We studied the function of the cardiac sympathetic nerve varicosity in isolated right atrial preparations of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 4, 9, 14, 20 and 50 weeks of age. Cumulative concentration-atrial period response (C-R) curves to isoprenaline showed similar maximum response and sensitivity (EC50) at all ages but there was an age-related fall in resting atrial rate. Similar results were found for methoxamine (alpha 1-adrenoceptor agonist) although the maximum response was significantly less than for isoprenaline. The time-dependent recovery (T 1/2) of the fall in atrial period in response to sympathetic nerve stimulation from electrical field pulses (1-32 at 1 Hz) was enhanced by neuronal uptake inhibition by desipramine (0.1-1 mumol/l), to a similar degree at all ages. Pre-junctional alpha 2-adrenoceptor stimulation by clonidine caused progressively more inhibition of the number of field pulses-fall in period relationship with age. SHR atria were similar to WKY rat atria at all ages except for a further impairment of the development of pre-junctional alpha 2-adrenoceptors. These studies indicate that the function of the cardiac sympathetic varicosity matures early (by 4 weeks) and overall there is very little impairment in SHR versus WKY rat atria.     

Central alpha 2-adrenoceptor responsiveness in borderline hypertensive rats.

Increased dietary NaCl intake increases the responsiveness of central nervous system alpha 2-adrenoceptors which regulate the neural control of renal function in spontaneously hypertensive rats (SHR) but not Wistar-Kyoto (WKY) normotensive rats. The borderline hypertensive rat (BHR) is the first filial offspring of the SHR and the WKY. With increased dietary NaCl intake, the BHR develops hypertension and expresses other characteristics of the hypertensive SHR parent. This investigation sought to determine whether increased dietary NaCl intake in the BHR enhances the responsiveness of central nervous system alpha 2-adrenoceptors. Six weeks of increased dietary NaCl intake (8% versus 1% NaCl) in BHR augmented the depressor, bradycardic, renal sympatho-inhibitory and diuretic responses to intracerebroventricular administration of graded doses (5, 25 and 125 micrograms) of the alpha 2-adrenoceptor agonist, guanabenz. The results suggest that the potential for an increased responsiveness of central nervous system alpha 2-adrenoceptors is genetically transmitted to the BHR by the SHR and may be exposed in the BHR by increased dietary NaCl intake.     

Renal dopamine receptor signaling mechanisms in spontaneously hypertensive and Fischer 344 old rats

Dopamine plays an important role in the regulation of renal sodium excretion. The activation of D1-like receptors located on the proximal tubules causes inhibition of tubular sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase activity. The D1-like receptors are linked via G proteins to the multiple cellular signaling systems namely adenylyl cyclase and phospholipase C (PLC). A defective renal dopamine receptor function exists in spontaneously hypertensive rats (SHR). In the proximal tubules of SHR, the stimulation of adenylyl cyclase and PLC caused by dopamine was significantly reduced in comparison with Wistar-Kyoto (WKY) rats. Also unlike the effects seen in WKY, D1-like receptor activation did not inhibit Na,K-ATPase and Na,H-exchanger activities in SHR. In addition, reduced quantity of Gq/11alpha proteins was detected in the basolateral membranes of SHR compared to WKY rats. Studies revealed that there may be a primary defect in D1-like receptors leading to an altered signaling system in the proximal tubules and reduced dopamine-mediated effect on renal sodium excretion in SHR. Recently, it has been shown that the disruption of D1A receptors at the gene level causes hypertension in mice. Similar to SHR, dopamine and D1-like receptor agonist failed to inhibit Na,K-ATPase activity in the proximal tubules of old Fischer 344 rats. Unlike the observations in SHR where D1-like receptors were equal to WKY rats, there is a 50% decrease in D1-like receptor number in basolateral membranes of the old rats compared to the adult rats. Dopamine was unable to stimulate G proteins in the basolateral membranes of old rats compared to the adult rats. It is suggested that a defective dopamine receptors/signaling system may contribute to the development and maintenance of hypertension. Also, the inability of dopamine to inhibit Na,K-ATPase may lead to a reduced renal sodium excretion in response to dopamine in old rats.     

Renal protein phosphatase 2A activity and spontaneous hypertension in rats

The impaired renal paracrine function of dopamine in spontaneously hypertensive rats (SHR) is caused by hyperphosphorylation and desensitization of the renal D(1) dopamine receptor. Protein phosphatase 2A (PP(2A)) is critical in the regulation of G-protein-coupled receptor function. To determine whether PP(2A) expression and activity in the kidney are differentially regulated in genetic hypertension, we examined the effects of a D(1)-like agonist, fenoldopam, in renal cortical tubules and immortalized renal proximal tubule cells from normotensive Wistar-Kyoto rats (WKY) and SHR. In cortical tubules and immortalized proximal tubule cells, PP(2A) expression and activities were greater in cytosol than in membrane fractions in both WKY and SHR. Although PP(2A) expressions were similar in WKY and SHR, basal PP(2A) activity was greater in immortalized proximal tubule cells of SHR than WKY. In immortalized proximal tubule cells of WKY, fenoldopam increased membrane PP(2A) activity and expression of the regulatory subunit PP(2A)-B56alpha, effects that were blocked by the D(1)-like antagonist SCH23390. Fenoldopam had no effect on cytosolic PP(2A) activity but decreased PP(2A)-B56alpha expression. In contrast, in immortalized proximal tubule cells of SHR, fenoldopam decreased PP(2A) activity in both membranes and cytosol but predominantly in the membrane fraction, without affecting PP(2A)-B56alpha expression; this effect was blocked by the D(1)-like antagonist SCH23390. We conclude that renal PP(2A) activity and expression are differentially regulated in WKY and SHR by D(1)-like receptors. A failure of D(1)-like agonists to increase PP(2A) activity in proximal tubule membranes may be a cause of the increased phosphorylation of the D(1) receptor in the SHR.     

Specific changes in hypothalamic alpha-adrenoceptors in young spontaneously hypertensive rats

Changes in the activity of hypothalamic and brain-stem adrenergic neurons have been reported in young spontaneously hypertensive rats (SHR) prior to the development of hypertension. We have measured central alpha- and beta-adrenoceptor concentrations in 4-week-old SHR and Wistar-Kyoto (WKY) controls by direct radioligand binding studies using [3H]prazosin (alpha 1), [3H]clonidine (alpha 2), and [125I]iodohydroxybenzlpindolol (beta). The concentration of alpha 2-adrenoceptors was significantly elevated in the hypothalamus of the SHR, 156.9 +/- 10.4 compared with WKY, 119.4 +/- 10.0 fmole/mg protein (n = 7, mean +/- SEM, p less than 0.0125). Alpha 2-adrenoceptor concentrations in both the brain stem and cerebral cortex were similar in the two groups of animals. The increase in hypothalamic adrenoceptors was specific for alpha 2-adrenoceptors, since similar concentrations of alpha 2- and beta-adrenoceptors were found in this region.     

Protein phosphatase 2A B56alpha during development in the spontaneously hypertensive rat

Mistargeting of the regulatory subunit of protein phosphatase 2A (PP2A), B56alpha is involved in the hyperphosphorylation and desensitization of the D1 dopamine receptor in renal proximal tubules of spontaneously hypertensive rats (SHRs). However, the renal expression of B56alpha before hypertension develops is not known. Therefore, we studied the expression of B56alpha and PP2A activity in the kidney during development in the SHR and its normotensive control, the Wistar-Kyoto (WKY) rat. PP2A B56alpha was expressed in proximal and distal tubules with no differences in the pattern of expression in WKY and SHRs at any age. In brush border membranes of renal proximal tubules, PP2A B56alpha protein was greatest in the immature rats and decreased with development. However, PP2A activity did not change with age. PP2A B56alpha protein and PP2A activity were similar in WKY and SHRs except at 2 weeks when both PP2A B56alpha protein and PP2A activity were higher in SHRs than in WKY rats. The PP2A catalytic subunit co-immunoprecipitated with the D1 receptor in renal proximal tubule cells. It is possible that the increased expression of PP2A B56alpha and increased basal PP2A activity in the young, especially in the SHRs, may serve as a compensatory mechanism in the increased phosphorylation and decreased renal D1 receptor function, including D1-receptor mediated stimulation in renal proximal tubules of SHRs.     

Modulation of noradrenergic transmission by neuropeptide Y and presynaptic alpha 2-adrenergic receptors in the hypothalamus of spontaneously hypertensive rats.

Neuropeptide Y (NPY) has a wide and specific distribution in the central nervous system, and is colocalized with catecholamines in specific neuronal systems. In this study, in order to investigate the regulatory mechanisms of NPY and presynaptic alpha 2-adrenergic receptors on central noradrenergic transmission in hypertension, we have examined the effects of NPY and the alpha 2-agonist, UK 14,304, on (3H)-noradrenaline (NA) release from hypothalamic slices of spontaneously hypertensive rats (SHR). Electrical stimulation (1 Hz)-evoked (3H)-NA release was significantly greater in the hypothalamic slices of SHR than in those of Wistar Kyoto rats (WKY). NPY and the alpha 2-agonist, UK 14,304, inhibited the stimulation-evoked (3H)-NA release in a dose-related manner. The inhibitory effects of NPY and UK 14,304 on NA release were significantly attenuated in SHR compared with WKY. These results suggest that NPY and alpha 2-adrenoceptors might be involved in the regulation of central sympathetic nervous activity in hypertension.     

Decreased Phorbol Ester-Induced Inhibition of Inositol Trisphosphate Formation Mediated by Alpha1-Adrenoceptors in Myocytes of Spontaneously Hypertensive Rats

Alpha₁-adrenoceptors, norepinephrine(NE)-stimulated formation of inositol trisphosphate (IP3) and inhibitory effect on this formation by 12-o-tetradecanoyl phorbol 13-acetate (TPA) were studied in isolated myocytes of 8-week-old spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY). The number of alpha₁-adrenoceptors in myocytes of SHR was significantly increased than that of WKY. No significant difference in maximum response or EC50 values of NE-stimulated IP3 formation was observed between the two strains. Both norepinephrine-stimulated and GTPyS-stimulated IP3 formation was inhibited by TPA. The inhibitory effect was less in SHR than in WKY. PA did not change the number and affinity of alphal-adrenoceptors. These results suggest that myocytes of SHR may have abnormality in G protein and/or phospholipase C and that activation of protein kinase C might inhibit IP3 formation less in SHR than in WKY, a step distal to alphal -adrenoceptors, probably at a step distal to alphal -adrenoceptors.     

Impaired prostaglandin E(2)/prostaglandin I(2) receptor-G(s) protein interactions in isolated renal resistance arterioles of spontaneously hypertensive rats

The protective effect of vasodilator agents linked to the cAMP pathway is less effective for buffering the vasoconstrictor effect of angiotensin II in young animals with genetic hypertension. To determine the underlying cellular mechanism, experiments were performed on freshly isolated preglomerular resistance arterioles obtained from kidneys of 7-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Specific high-affinity saturable binding of (3)H-prostaglandin (PG) E(2) revealed 1 receptor class in renal microvessels; PGE(2) receptor density was similar in SHR and WKY (106 versus 115 fmol/mg; P>0.8), as was receptor affinity (3.6 versus 3.5 nmol/L; P>0.7). Basal cAMP activity was similar in renal arterioles from SHR and WKY. A major finding was that PGE(2), PGI(2), and isoproterenol produced weaker stimulation of cAMP formation in arteriolar cells of SHR (P<0.02). In contrast, GTPgammas and forskolin stimulated cAMP generation to a similar degree in both rat strains, which suggests normal adenylate cyclase activity in hypertension-prone SHR. Immunoblots revealed the presence of 3 classes of G proteins (G(s), G(i), and G(q)) in preglomerular arterioles. The relative amounts of discernible G-protein alpha-subunits in renal resistance vessels did not differ between SHR and WKY. These results extend previous in vivo studies of abnormal renal vascular reactivity in SHR and more directly localize defective coupling of the prostaglandin and beta-adrenergic receptors to a stimulatory G protein and cAMP production in freshly isolated preglomerular arteriolar cells of young SHR. This dysfunction may be due to an abnormal interaction between prostaglandin receptors and G(s) protein that leads to inefficient coupling of initiating steps in the cAMP-protein kinase A cascade during the development of hypertension.     

Role of prostaglandins in the increased vascular responsiveness to bradykinin in kidneys of spontaneously hypertensive rats.

We examined the effects of arterial injections of bradykinin on perfusion pressure and output of PGE2 and 6-keto-PGF1 alpha in isolated kidneys of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The kidneys were perfused with Krebs' bicarbonate buffer containing phenylephrine, both with and without indomethacin (1 microgram/mL). In kidneys perfused without indomethacin, bradykinin increased the output of PGE2 and 6-keto-PGF1 alpha in the kidneys of both WKY and SHR. Bradykinin also reduced perfusion pressure, indicative of renal vasodilation. This effect in the kidneys of SHR clearly exceeded that in the kidneys of WKY. The addition of indomethacin to the perfusion media suppressed the bradykinin-induced output of PGE2 and 6-keto-PGF1 alpha without altering the vasodilatory response to bradykinin in either SHR or WKY kidneys. Hence, the kidneys of SHR demonstrated an increased vasodilatory responsiveness to bradykinin irrespective of whether the peptide stimulated prostaglandin synthesis. We conclude that the augmented responsiveness of SHR kidneys to bradykinin-induced vasodilation cannot be attributed to enhanced expression of prostaglandin-mediated mechanisms of vasodilation.     

Glomerular thrombosis in spontaneously hypertensive rat. II. Immunofluorescence microscopy. III. Effect of heparin.

This study describes immunofluorescence microscopy (IFM) of kidneys of untreated (or saline-treated) spontaneously hypertensive rats (SHR) and compares the findings with those in age-matched, untreated normotensive Wistar Kyoto rats (WKY), and heparin treated (150 units aqueous heparin subcutaneously twice daily for 30 days) SHR. The rats varied in age from 30 to 112 weeks (before treatment) and were divided into young (< 52 weeks) and old (? 52 weeks) groups. Separate sections from the kidneys of all rats were stained with fluorescein-isothiocyanate-conjugated rabbit antisera against rat γ-G (IgG, IgM, and IgA), IgG, fibrinogen (Fib), third component of complement (C₃), and albumin. The kidneys were evaluated also by light microscopy (LM) in all of the rats and by electron microscopy (EM) in half of the rats. A semiquantitative assessment of IFM findings on a 0 to 4+ scale and scoring of LM findings on a 0 to 39 scale were made. The glomerular lesions were more striking and uniform than the arterial vascular lesions in old SHR. The glomeruli of old SHR (av: 93 weeks) were positive for all the fluorescence materials except albumin. Fib was most marked (3+ to 4+) involving 50 to 75% of the glomeruli in 75% untreated (or saline treated) old SHR. Thrombi were found in the glomeruli also by LM and EM (large amounts of fibrin and platelet aggregates). The arterial vessels were unimpressive by IFM with the exception of those with arteritis in which 3+ to 4+ Fib was found. These findings in untreated (or saline treated) old SHR contrast with the inconspicuous LM, EM, and IFM findings in young SHR and WKY of all ages. Heparin-treated old SHR had significant (P < 0.05) decreases of glomerular fibrinogen (IFM), percentage glomeruli with thrombi (LM), and absence of fibrin and platelet aggregates in the glomeruli studied by EM. In these old SHR, the mean arterial pressure (MAP) was significantly (P < 0.05) lower than the MAP in untreated old SHR. Thus, this study indicates that glomerular thrombosis is a significant renal lesion in old SHR and heparin can alter the glomerular thrombosis and arterial blood pressure. Further study, however, would be necessary to elucidate the mechanisms of the above beneficial effects of heparin.     

Effect of capsaicin on plasma and tissue levels of insulin-like growth factor-I in spontaneously hypertensive rats.

OBJECTIVE: Plasma levels of insulin-like growth factor-I (IGF-I), an important substance for maintaining cardiovascular homeostasis, are lower in spontaneously hypertensive rats (SHR) than in normotensive Wistar Kyoto rats (WKY). Calcitonin gene-related peptide (CGRP) increases IGF-I production in vitro and in vivo, suggesting that stimulation of sensory neurons might increase the production of IGF-I in SHR. DESIGN: Levels of CGRP and IGF-I in plasma, kidneys and heart in WKY and SHR and cellular cyclic AMP levels in dorsal root ganglion neurons (DRGs) isolated from WKY and SHR were measured by an ELISA-based method. RESULTS: Levels of CGRP and IGF-I in plasma, kidneys and heart of SHR were about half of those of WKY. Administration of capsaicin significantly increased levels of CGRP and IGF-I in plasma and tissues of SHR to the levels in WKY and these increases were completely reversed by pretreatment with capsazepine, an inhibitor of vanilloid receptor-1 activation. CGRP release and cellular levels of cAMP in DRGs isolated from SHR were significantly lower than those in DRGs isolated from WKY. Capsaicin increased both CGRP release and cellular cAMP levels in DRGs isolated from SHR to the levels in DRGs isolated from WKY. CONCLUSIONS: Sensory neuron activation might be lower in SHR than in WKY probably due to decreased production of cAMP in sensory neurons, explaining why IGF-I levels in plasma and tissues are lower in SHR than in WKY.     

Renal renin-angiotensin system activity in naturally reared and cross-fostered spontaneously hypertensive rats

BACKGROUND: Young (4 week) spontaneously hypertensive rats (SHR) exhibit greater renal responses to angiotensin II (Ang II) than normotensive Wistar Kyoto (WKY) rats. SHR pups cross-fostering to a WKY dam at birth (SHRX) are less sensitive to Ang II and have lower adult blood pressure. The aim of this study was to compare renal renin-angiotensin system activity in young naturally reared and cross-fostered SHR pups. METHODS: SHR and WKY rats were reared either by their natural mothers or by a foster mother of the opposite strain. At 5, 10, and 15 days of age, renal tissue renin activity and Ang II concentration were measured by radioimmunoassay. Renin-secreting cells were identified by in situ hybridization and AT(1) receptor expression was compared using Western blots. Ang II-mediated cAMP generation was measured in isolated proximal tubules. CONCLUSIONS: Tissue renin activity and numbers of renin-secreting cells did not differ, but Ang II was higher in SHRX. The AT(1) receptor expression was significantly lower in SHRX compared with SHR. Basal and Ang II-stimulated cAMP was lower in SHR tubules compared with WKY and SHRX tubules.Cross-fostering reversed the increased renal sensitivity of the SHR to Ang II. These data suggest that renal AT(1) receptor expression can be manipulated during the postnatal period and that this may affect adult blood pressure.     

The role of epinephrine as a neuromodulator in spontaneously hypertensive rats

The present study was carried out to elucidate the role of epinephrine as a neuromodulator in hypertension. The effects of epinephrine on norepinephrine release from the sympathetic nerve endings were examined in isolated perfused mesenteric arteries of spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). Norepinephrine overflow during electrical nerve stimulation (5, 15 Hz) was significantly greater in SHR than in WKY. Low concentration of exogenous epinephrine (5.5 X 10(-9) M) potentiated norepinephrine overflow during nerve stimulation in SHR, and this (at 15 Hz stimulation) was antagonized by propranolol (5.0 x 10(-7) M), whereas, the overflow in WKY was reduced by the same concentration of epinephrine. A higher concentration of epinephrine (1.4 x 10(-8) M) decreased norepinephrine overflow in both SHR and WKY, and this change (at 15 Hz stimulation) was antagonized by yohimbine (1.0 x 10(-7) M). Further, magnitudes of the suppressions were smaller in SHR than in WKY. These results suggest that altered modulations of norepinephrine release by epinephrine through presynaptic beta- and alpha 2-adrenoceptors might induce increased sympathetic nerve activity in SHR.     

Increased norepinephrine sensitive intracellular Ca2+ pool in the caudal artery of spontaneously hypertensive rats

The contractions evoked by norepinephrine (NE) and caffeine in Ca2+-free solution were determined using denervated caudal artery rings from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The magnitude of contractions produced by different concentrations of NE was significantly greater (P less than 0.05) in SHR caudal artery rings compared to WKY. The contractions evoked by NE in Ca2+-free solution were mediated primarily through the activation of postsynaptic alpha 1-adrenoceptors. In addition to alpha 1-adrenoceptor stimulation, caffeine also evoked significantly greater (P less than 0.05) contractions in Ca2+-free solution in SHR caudal arteries compared to WKY. From these observations it is concluded that intracellular Ca2+ pool (presumably sarcoplasmic reticulum, SR) is increased in SHR caudal arteries which, at least in part, may account for the increased contraction observed in response to NE and caffeine stimulation in the absence of extracellular Ca2+.