Brain Renin Angiotensin System Contributes to the Salt-Induced Enhancement of Hypertension in Shr

The study was performed to determine whether the brain renin angiotensin system may contribute to the acceleration in hypertension following long-term salt loading in spontaneously hypertensive rats(SHR). Five weeks old SHR and normotensive Wistar-Kyoto(WKY) were given 1% NaCl solution or plain tap water as drinking for 7 weeks. The salt treatment exaggerated the development of hypertension in SHR, but did not change the blood pressure (BP) in WKY. The hypotensive actions of intracerebroventricular(ICV) captopril was greater in SHR treated with salt than in those without treatment, whereas ICV All increased BP to a similar degree between salt and control SHR. In WKY, the effects of ICV captopril and All were not altered by the salt loading. The increases in BP induced by ICV hypertonic saline were not different between the rats with and without saline drinking in either SHR or WKY. The intravenous (IV) hexamethonium led to a greater fall in BP in SHR treated with saline than in those without salt, while it tended to produce a smaller decrease in BP in WKY with salt overload than in those without loading. Both duration and magnitude of the depressor effects of IV captopril were reduced by the chronic saline treatment in SHR. The plasma renin concentration (PRC) in both SHR and WKY was significantly suppressed by the salt load. The present results suggest that long-term salt overload may result in the enhanced activity of brain renin angiotensin system, which could be responsible for the exaggerated development of hypertension in SHR. Our observations also provide further evidence that the central renin angiotensin system is independent of the peripheral system.     

Vascular wall renin in spontaneously hypertensive rats. Potential relevance to hypertension maintenance and antihypertensive effect of captopril

Relationships among systolic blood pressure (SBP), plasma renin activity (PRA), arterial renin concentrations (ARC), and venous renin concentrations (VRC) were examined in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats before and after treatment with captopril. The ARC was elevated in SHR relative to WKY whereas VRC was not. Similarly, ARC was related to SBP (r = 0.69, p less than 0.01) whereas PRA was not (r = 0.04). Captopril (100 mg/kg daily by mouth for 8 days) decreased blood pressure significantly in both SHR and WKY. PRA as well as ARC and VRC were all increased by captopril. Bilateral nephrectomy virtually eliminated PRA but ARC was not significantly reduced over a 24-hour period. Bilateral nephrectomy also markedly attenuated the acute antihypertensive effects of captopril in SHR; however, a modest effect was still apparent. It is suggested that ARC in SHR, being higher than in WKY, may play a role in the genesis or maintenance of hypertension in this model. Furthermore, the effects of captopril in both intact and nephrectomized SHR may be related to the ability of captopril to inhibit the vascular formation of angiotensin II. Finally, vascular renin is probably not renal in origin and responds to typical feedback inhibition as unmasked by captopril administration.     

Central and peripheral mechanisms of the enhanced hypertension following long-term salt loading in spontaneously hypertensive rats

We evaluated whether or not increased sodium (Na) concentrations of cerebrospinal fluid (CSF) and stimulated activities of brain renin-angiotensin system (RAS) contribute to an enhanced hypertension by salt overload in spontaneously hypertensive rats (SHR). Long-term salt loading (1% NaCl solution as drinking fluid) accelerated the development of hypertension in SHR, but did not alter the blood pressure (BP) in normotensive Wistar-Kyoto rats (WKY). CSF Na concentration was elevated in uninephrectomized (Nx) group as compared to that in control SHR, while in WKY CSF Na was not influenced by the treatment. A fall in BP by intravenous AVP antagonist or hexamethonium was greater in salt-loaded SHR than in controls. This hypotensive response to the combined blockade of AVP and SNS correlated with CSF Na in SHR but not in WKY. Plasma concentration of AVP and epinephrine tended to increase in relation to the degree of salt loading in SHR but not in WKY. Pressor responses to intracerebroventricular (ICV) angiotensin II (AII) and NaCl were greater in SHR than in WKY, although these responses were not influenced by chronic salt load in either SHR or WKY. The enhanced hypertensive action of ICV NaCl in SHR was abolished by pretreatment with ICV AII antagonist. Chronic saline drinking enhanced the depressor effect of ICV captopril in SHR but not in WKY. These observations suggest that salt overload in SHR may cause an elevated CSF Na concentration and an enhanced activity of brain RAS, which may increase activity of SNS and release of AVP, resulting in an enhanced development of hypertension.     

Renorenal reflexes present in young and captopril-treated adult spontaneously hypertensive rats

In normotensive Sprague-Dawley rats and Wistar-Kyoto (WKY) rats stimulation of renal mechanoreceptors or chemoreceptors by increasing ureteral pressure or renal pelvic perfusion with 0.9 M NaCl results in a contralateral inhibitory renorenal reflex response with contralateral diuresis and natriuresis. However, in 14-15-week-old spontaneously hypertensive rats (SHR) renal sensory receptor stimulation failed to elicit a contralateral inhibitory renorenal reflex response. The present study was performed to examine whether the lack of a renorenal reflex response in SHR was related to elevated arterial pressure by studying the responses to renal sensory receptor stimulation in 5-6-week-old SHR and in 12-16-week-old SHR that had been treated with captopril from 3 weeks of age to prevent the development of hypertension. In 5-6-week-old SHR, mean arterial pressure was 113 +/- 3 mm Hg. Graded increases of ureteral pressure of 15 and 29 mm Hg resulted in graded increases in ipsilateral afferent renal nerve activity of 57 +/- 22% and 120 +/- 38%. Contralateral urinary sodium excretion increased from 0.26 +/- 0.06 to 0.35 +/- 0.07 mumol/min/g and from 0.36 +/- 0.08 to 0.46 +/- 0.11 mumol/min/g, respectively. In captopril-treated SHR, mean arterial pressure was 109 +/- 3 mm Hg. Increasing ureteral pressure by 34 mm Hg increased ipsilateral afferent renal nerve activity 65 +/- 21% and contralateral urinary sodium excretion from 1.28 +/- 0.24 to 1.53 +/- 0.30 mumol/min/g. Similar results were produced by renal chemoreceptor stimulation. It is concluded that renal sensory receptor stimulation results in a contralateral inhibitory renorenal reflex response in 5-6-week-old SHR and in SHR treated with captopril to prevent the development of hypertension. These results suggest that the previously demonstrated lack of a renorenal reflex response to renal sensory receptor stimulation in hypertensive SHR is related to the maintenance of hypertension.     

Effects of sodium depletion in rats actively immunized against renin

The influence of active immunization against renin on systolic blood pressure in response to a dietary sodium restriction was assessed in normotensive rats (WKY) and spontaneously hypertensive rats (SHR). Immunization was obtained by multiple injections of pure submaxillary murine renin. Animals received a normosalt diet (NS diet) for 6 days. Then sodium was abruptly removed from the diet (LS diet), and rats were maintained for an additional 6 day-period on this salt-free diet. In rats maintained on NS diet, immunization induced a decrease in systolic blood pressure (SBP) about 11 p. 100 and 27 p. 100 respectively in WKY immune and SHR immune groups. SBP was not affected by abrupt dietary sodium removal in non-immunized rats from both strains. However, in immunized rats sodium restriction was accompanied by a significant SBP decrease compared to the value observed during NS period in the same group. The relative variation in SBP was about 10 p. 100 and 14 p. 100 respectively in WKY immune and SHR immune groups. The present study shows that active immunization against renin leads to a reduction in systolic blood pressure regardless to the initial pressure level. When sodium is removed from the diet, systolic blood pressure level is maintained in non-immunized rats, whereas it decreases in immunized rats of both strains. These results confirm the importance of an efficient renin-angiotensin system in the adaptative response to sodium restriction.     

Kidney renin gene expression in spontaneously hypertensive rats

We studied the expression of kidney renin gene in hypertensive animals by measuring the kidney renin messenger (m) RNA. The kidney renin mRNA was quantified by densitometric Northern blot analysis using a 32P-labelled rat renin genomic DNA fragment as a hybridization probe. Spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) were treated with a low-sodium diet plus furosemide, captopril or propranolol for a week. Plasma renin activity (PRA) in SHR and WKY was increased similarly by sodium depletion and by treatment with captopril. PRA in both strains was not decreased significantly by treatment with propranolol. Both sodium depletion and captopril treatment caused significant increases in the kidney renin mRNA in SHR and WKY. However, the increases in the kidney renin mRNA of SHR were greater than those in the corresponding WKY (SHR, 10.0- and 22.1-fold increases; WKY, 6.2- and 7.8-fold increases, respectively). Propranolol had no effect on the kidney renin gene expression in either WKY or SHR. These results indicate that SHR show an enhanced expression of the renin gene in the kidney compared with WKY in response to stimuli that increase renin release.     

Significance of brain renin for pathogenesis of hypertension: effect of antihypertensive drugs on active and inactive renins in the brain of spontaneously hypertensive rat

Relationship between blood pressure and brain renin was studied in four groups of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY); as controls (n = 5), administered captopril (n = 5), trichlormethiazide (n = 5) and atenolol (n = 5). 1) Inactive renin in the hypothalamus of captopril-administered SHR was significantly lower than that of control SHR and captopril-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and striatum of captopril-administered SHR was significantly lower than that of control SHR and captopril-administered WKY. 2) Inactive renin in the hypothalamus of trichlormethiazide administered SHR was significantly lower than that of control SHR and trichlormethiazide-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and midbrain of trichlormethiazide-administered SHR was significantly lower than that of control SHR and trichlormethiazide-administered WKY. 3) Inactive renin in the hypothalamus of atenolol-administered SHR was significantly lower than that of control SHR and atenolol-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and midbrain of atenolol-administered SHR was significantly lower than that of control SHR and atenolol-administered WKY. These results suggest that the production and/or activation of renin in the hypothalamus, thalamus, midbrain and striatum play an important role in the initiation and/or development of hypertension of SHR by the local generation of angiotensin II.     

Central and Peripheral Contributions of the Renin-Angiotensin System in Two Models Experimental Hypertension in Rats

To examine the relationships between the central and pepirheral renin angiotensin system in normotensive Wistar Kyoto (WKY) rats, two-kidney, one-clip Goldblatt renovascular hypertension (RVH), spontaneously hypertensive rats (SHR), SQ 14225 (captopril) was administered intraventricularly (IVT and intravenously (IV) in the alternative manner and there combination. Also, the effects of IVT captopril on the peripheral sympathetic nervous system were evaluated using an intravenous injection of prazosin.

IVT captopril induced a significant reduction of blood pressure in both types hypertensive rats but not in normotensive rats. Greater depressor effects of IV captopril not IV prazosin following IVT captopril were observed in RVH. compared to those in SHR.

These results indicate that the pressor action of the brain renin angiotensin system is closely related with the sympathetic nervous system in hypertensive conditions and that these functions are independent from the peripheral renin angiotensin system. Furthermore. their roles were different in different types of experimental hypertension in rats.     

Increases in renal angiotensin II content and tubular angiotensin II receptors in prehypertensive spontaneously hypertensive rats

To examine the role of the intrarenal renin-angiotensin system in the development of hypertension in spontaneously hypertensive rats (SHR), we measured angiotensin II contents and tubular 125I-angiotensin II binding sites in the kidney of SHR and age-matched Wistar-Kyoto rats (WKY). In prehypertensive (4-week-old) SHR, not only the kidney angiotensin II content but also the angiotensin II receptor density in brush border membranes were significantly higher than in the WKY. In contrast, angiotensin II levels in the 20-week-old SHR kidneys were significantly lower than in the WKY. Acceleration of the intrarenal renin-angiotensin system and the increased density of tubular angiotensin II receptors in young SHR may therefore play an important role in the development of high blood pressure in SHR.     

Physiological and immunopathological consequences of active immunization of spontaneously hypertensive and normotensive rats against murine renin

Spontaneously hypertensive Okamoto-strain rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were actively immunized with mouse renin to investigate the effect on blood pressure of blocking the renin-angiotensinogen reaction. Ten male SHR and 10 male WKY rats were immunized with purified mouse submandibular gland renin. Control rats were immunized with bovine serum albumin. Antirenin antibodies were produced by both SHR and WKY rats, but renin-immunized SHR had higher titers of circulating renin antibodies after three injections. The increase in renin antibody in renin-immunized SHR was associated with a significant drop in blood pressure (tail-cuff method) that became similar to that of the WKY control rats after four injections. The blockade by antirenin immunoglobulins of the renin-angiotensinogen reaction also decreased the blood pressure of normotensive rats. Perfusion of renin-immunized rats with mouse submandibular renin (10 micrograms) in vivo caused no increase in blood pressure. Perfusion of renin-immunized, salt-depleted SHR with converting enzyme inhibitor caused no further decrease in blood pressure but significantly decreased blood pressure in salt-depleted control rats. The presence of circulating renin antibodies was associated with low plasma renin activity (0.31 +/- 0.23 ng angiotensin I [Ang I]/ml/hr). Plasma renin activity was unchanged in control animals (13.1 +/- 3.9 ng Ang I/ml/hr in control SHR, 13.9 +/- 3.2 ng Ang I/ml/hr in control WKY rats). Renin antibody-rich serum produced a dose-dependent inhibition of rat renin enzymatic activity in vitro. The chronic blockade of the renin-angiotensinogen reaction in renin-immunized SHR produced an almost-complete disappearance of Ang II (0.8 %/- 7 fmol/ml; control SHR, 30.6 +/- 15.7 fmol/ml) and a 50% reduction in urinary aldosterone. Renin immunization was never associated with a detectable loss of sodium after either 10 or 24 weeks. The glomerular filtration rate was not decreased 10 weeks after renin immunization, whereas blood pressure was significantly decreased, plasma renin activity was blocked, and renal plasma flow was increased. The ratio of left ventricular weight to body weight after 24 weeks was significantly below control levels in renin-immunized WKY rats and SHR. Histological examination of the kidney of renin-immunized SHR showed a chronic autoimmune interstitial nephritis characterized by the presence of immunoglobulins, mononuclear cell infiltration, and fibrosis around the juxtaglomerular apparatus. These experiments demonstrate that chronic specific blockade of renin decreases blood pressure in a genetic model of hypertension in which the renin-angiotensin system is not directly involved.(ABSTRACT TRUNCATED AT 400 WORDS)     

Participation of the renin-angiotensin system in the maintenance of blood pressure during changes in posture in patients with essential hypertension

To assess whether and how the activation of the renin-angiotensin system that occurs in response to changes in posture contributes to the maintenance of blood pressure, we measured blood pressure, heart rate, plasma noradrenaline and plasma active and inactive renin in patients with essential hypertension in the supine, sitting and standing positions, (each sustained for 30 min), before and after administration of captopril. These studies were performed before and after a brief period of diuretic therapy. Both in the normal and in the sodium depleted state captopril reduced the normal adaptive response of blood pressure to changes in body position, whereas the responses of heart rate and plasma noradrenaline to these stimuli were unaffected by captopril. In contrast, the postural increases in active renin were magnified after captopril while inactive renin was unchanged throughout these acute studies. Our results indicate that during mild but rather prolonged postural stresses the generation of angiotensin by active renin supports blood pressure either through its direct vasoconstrictive effect and/or by potentiating the activity of the sympathetic nervous system. It is unlikely that the changes in active renin depend upon conversion from the inactive form.     

Blood pressure responses of conscious normotensive and spontaneously hypertensive rats to intracerebroventricular and peripheral administration of captopril

In conscious spontaneously hypertensive rats, intraxerebroventricular injection of captopril (2 mg/kg) resulted in a rapid hypotensive response that lasted several hours. The same dose given by intracerebroventricular injection had no significant effect on blood pressure (BP) of normotensive Wistar-Kyoto (WK) rats over 7 hours. There was no significant change in BP of conscious spontaneously hpertensive rats (SHR) in response to intracerebroventricular injection of vehicle and only a transitory fall in BP in response to intravenous injection of captopril (2 mg/kg). There was no significant differences between plasma renin activity (PRA) of conscious normotensive WKY rats and the PRA of SHR. These results suggest biochemical differences between the brains of SHR and normotensive WKY control rats. These differences could involve the brain renin-angiotensin system or other neuropeptides.     

Endogenous brain angiotensin II-mediated sympathetic nerve responses are not augmented in mature spontaneously hypertensive rats

Conjugated estrogens injected into the lateral brain ventricle in awake rats elicited behavioral excitation and vasopressor responses. Magnitude of pressor responses was greater in spontaneously hypertensive rats (SHR) than in normotensive Kyoto Wistar rats (WKY). Pressor responses in SHR were abolished by central pretreatments of either captopril or angiotensin II analog. Under urethane anesthesia, conjugated estrogens still produced greater pressor responses in SHR, but accompanying increases in sympathetic nerve firings were the same in both WKY and SHR. These results suggest that while centrally-administered estrogens may activate the brain renin-angiotensin system to increase sympathetic nerve firing and thereby elevated blood pressure, SHR have larger pressor responses only because peripheral vascular reactivity has been increased.     

Dietary sodium restriction, blood pressure and sympathetic activity in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were started at birth on sodium diets ranging from severely deficient (9 mumol) to a regular intake (101 mumol Na+/g food). Blood pressure and sympathetic activity were assessed at 6 and 16 weeks of age. At either age, SHR on 9 mumol Na+ failed to develop hypertension. Spontaneously hypertensive rats on 17 mumol Na+ exhibited significant blunting of the hypertension; SHR on 26 mumol showed a small amelioration. At 6 weeks, basal plasma noradrenaline was similar in SHR and WKY on 9 and 101 mumol Na+, whereas plasma adrenaline was increased in SHR at the lowest sodium level. At 16 weeks, both catecholamines were significantly increased in SHR on the 9 and 17 mumol sodium diet versus SHR on the control diet. Blood pressure responsiveness to noradrenaline was significantly decreased on 9 mumol Na+, but to a similar extent in both strains. In contrast, the blood pressure lowering effect of ganglionic blockade was markedly blunted in SHR on 9 mumol Na+ and to a lesser extent on 17 mumol Na+ (both for percentage and absolute decrease) and 26 mumol Na+ (only for absolute fall); however, this did not occur in WKY over the diet-range used. We conclude that a sodium-deficient diet from birth prevents/blunts the development of hypertension in SHR, at least partly by decreasing the pressor effect of the sympathetic nervous system.     

Corticosteroid Modulation of the Renin System and Blood Pressure in the Spontaneously Hypertensive Rat

This study examines the role of gluco- and mineralcorticoids in the regulation of the renin-angiotensin system and blood pressure in the spontaneously hypertensive rat (SHR). Effects of adrenalectomy and selective treatment with either aldosterone (30 μg/kg/day) or dexamethasone (60 μg/kg/day) on plasma renin substrate, active renin (PRA), total renin and blood pressure were studied in 10 week old SHR and control WKY rats. Systolic blood pressure was moderately lower in adrenalectomized rats (129±2 mm Hg vs 137±4 mm Hg in control WKY and 145±4 mm Hg vs 160±3 mm Hg in control SHR) but could be restored to the control range by aldosterone. Dexamethasone repletion induced substantial increments of systolic blood pressure to comparable levels in both species (202±8 mm Hg in WKY and 192±6 mm Hg in SHR). Renin substrate was markedly lower in adrenalectomized, saline repleted rats. This could be reversed by dexamethasone in both species and by aldosterone in WKY rats only. Both PRA and total renin were higher (p<0.01) in the adrenalectomized, saline repleted state. This increase was not observed in aldosterone repleted rats. However, dexamethasone inhibited the adrenalectomy associated increase of PRA and total renin in SHR but not in WKY rats. Differences in blood pressure between SHR and WKY persist even in adrenalectomized state despite comparable stimulation of the renin system. Conversely, while blood pressure of both species responds similarly to selective corticosteroids therapy, the response of the renin-angiotensin system in SHR and WKY rats is distinct. Therefore factors other than the adrenal gland and the renin system must be involved in the determination of the high blood pressure in SHR.     

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.     

Differential Regulation of Brain Angiotensin II in Genetically Hypertensive and Normotensive Rats after Nephrectomy

To investigate the role of tissue angiotensin II (Ang II) in the maintenance of hypertension after nephrectomy in spontaneously hypertensive rats (SHR), Ang II levels were measured in various tissues of both 12-week-old SHR and normotensive control, Wistar-Kyoto rats (WKY), 48 h after nephrectomy or sham operation. Ang II was determined by radioimmunoassay coupled with high performance liquid chromatography. Nephrectomy caused a decrease of plasma renin activity and plasma Ang II concentration in both SHR and WKY. Aortic Ang II levels were significantly lowered by nephrectomy only in WKY, and not in SHR. Ang II levels in hypothalamic block, brainstem and cerebellum of SHR increased after nephrectomy, whereas those of WKY were unchanged. Intracerebroventricular administration of ceronapril, an angiotensin converting enzyme inhibitor, significantly decreased sustained high blood pressure in SHR 48 h after nephrectomy compared with vehicle administration, whereas intravenous administration had no effect. These results suggest that in spite of the important role of the renal renin-angiotensin system in maintenance of high blood pressure in SHR, control mechanisms may switch to other systems after nephrectomy, and that the increased brain Ang II levels after nephrectomy may be related to these mechanisms.     

Dietary sodium restriction and pressor responsiveness to tyramine in spontaneously hypertensive rats.

OBJECTIVE: To determine in vivo whether in young spontaneously hypertensive rats (SHR) dietary sodium restriction decreases adrenergic transmitter release from the sympathetic nerve terminal. DESIGN: Dietary sodium restriction was initiated in young and mature SHR and Wistar-Kyoto (WKY) rats, and subsequently changes in pressor responsiveness to norepinephrine and to the indirectly acting sympathomimetic tyramine were determined in relation to their effects upon plasma catecholamines. RESULTS: In young SHR sodium restriction for 3-6 weeks prevented the development of hypertension, whereas in mature SHR sodium restriction did not affect blood pressure. Sodium restriction caused modest decreases in pressor responsiveness to the exogenous alpha-agonist, not different in young and mature SHR compared with WKY rats. In contrast, sodium restriction markedly inhibited pressor-responses to tyramine in young SHR and WKY rats, but not at all in mature rats. Tyramine increased plasma norepinephrine 5-10-fold. However, sodium restriction did not affect this response. The pressor response to tyramine was related to increases in total peripheral resistance, with minimal changes in cardiac output, and could be blocked by alpha 1-receptor blockade in rats on either control or low-sodium diets. CONCLUSIONS: These results show that sodium restriction causes only a small decrease in the pressor response to norepinephrine, but a more marked inhibition of the pressor response to tyramine in young SHR and WKY rats without affecting the plasma norepinephrine response to tyramine. These results suggest that dietary sodium can indeed affect presynaptic functions in vivo, but that plasma norepinephrine responses to tyramine may not reflect changes in arterial norepinephrine release, or that sodium restriction affects a co-transmitter rather than norepinephrine release per se.     

Inhibitory actions of captopril on norepinephrine release from adrenergic nerve endings in spontaneously hypertensive rats

The purpose of the present study was to investigate the mechanisms of the hypotensive actions of an angiotensin converting enzyme inhibitor of the hypotensive actions of an angiotensin converting enzyme inhibitor (captopril) in hypertension. In perfused mesenteric vasculatures from spontaneously hypertensive rats (SHR, Okamoto and Aoki strain, 10-13 weeks of age) and age-matched normotensive Wistar Kyoto rats (WKY), the effects of captopril on vascular responsiveness and norepinephrine release from the adrenergic nerve endings were examined. The vasoconstrictor responses and norepinephrine release during the electrical nerve stimulation were significantly enhanced in SHR compared to those in age-matched WKY. Captopril reduced both vasoconstrictor responses and norepinephrine release during the electrical nerve stimulation, dose-dependently. These inhibitory effects of captopril were significantly greater in SHR than in WKY. The results demonstrate that captopril affects presynaptic sites on the resistance vessels and causes a decrease in electrically-stimulated norepinephrine release from the adrenergic nerve endings. The marked reduction of both pressor responses and norepinephrine release by captopril in SHR suggests an enhanced renin-angiotensin system in the vascular walls of hypertension.     

Effects of captopril on vascular noradrenergic transmission in SHR

The effects of captopril, 3 and 10 mg/kg, on vascular noradrenergic transmission were examined in vivo in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). These experiments were performed on mesenteric vascular beds perfused in situ. In WKY, 3 mg/kg captopril failed to significantly lower mean arterial blood pressure (MAP) and also failed to have a significant effect on the frequency-response curve to sympathetic nerve stimulation or dose-response curve to norepinephrine (NE) in the mesentery of WKY. In SHR mesentery, 3 mg/kg captopril failed to alter the frequency response curve or NE dose-response curve, while it significantly lowered MAP. The higher dose of captopril, 10 mg/kg, also failed to lower MAP in WKY mesentery, although it caused some reduction in pressor responses to sympathetic nerve stimulation and NE. In SHR mesentery, 10 mg/kg captopril significantly lowered MAP and reduced pressor responses to both nerve stimulation and NE. It should be noted, however, that captopril lowered responses to nerve stimulation and NE to a similar degree in both SHR and WKY, and there was no indication of a prejunctional action on vascular noradrenergic transmission. In conclusion, although captopril was more effective in lowering MAP in SHR than in WKY, no evidence was found for significantly greater facilitation of vascular sympathetic neurotransmission by endogenous angiotensin II in SHR than in WKY, and most of the actions of captopril on vascular neurotransmission appeared to be postjunctional in nature and unrelated to either the renin-angiotensin system or the kallikrein-kinin system.