Enhanced endogenous epinephrine release from the vascular adrenergic neurons in spontaneously hypertensive rats

This study was performed to investigate the role of endogenous epinephrine in the regulation of vascular tone in hypertension. The release of endogenous epinephrine and norepinephrine from the vascular adrenergic neurons by periarterial nerve stimulation was examined in spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). The isolated mesenteric vasculatures were prepared, and the epinephrine and norepinephrine release during electrical nerve stimulation was determined as the increase in epinephrine and norepinephrine contents in the vascular perfusate. Epinephrine and norepinephrine were measured by high performance liquid chromatography with an electrochemical detector. Vasoconstrictor responses and norepinephrine overflow during electrical nerve stimulation were significantly greater in SHR than in WKY. The amount of stimulation-evoked epinephrine overflow into the perfusate was also increased in SHR compared to that in WKY, especially at low frequency stimulation. These results suggest that epinephrine could be released from the vascular adrenergic neurons as a cotransmitter of norepinephrine and contribute to increased vascular tone in hypertension.     

Effects of ouabain on adrenergic neurotransmission in spontaneously hypertensive rats

The purpose of the present study is to determine the role of Na+,K+-ATPase in adrenergic neurotransmission of hypertension. Isolated perfused mesenteric vasculatures were prepared from spontaneously hypertensive rats (SHR, Okamoto and Aoki, 7-10 weeks old) and age-matched normotensive Wistar Kyoto rats (WKY). The effects of ouabain, a Na+,K+-ATPase inhibitor, on the norepinephrine overflow from the sympathetic nerve endings were examined. Norepinephrine overflow from the nerve endings as well as pressor responses during electrical nerve stimulation were significantly greater in SHR than in WKY. Ouabain increased the norepinephrine overflow evoked by electrical nerve stimulation, even in the presence of an uptake-blocker of norepinephrine. Further, the facilitatory effect of ouabain on stimulation-induced norepinephrine overflow was more prominent in SHR than in WKY. These results suggested that ouabain-sensitive Na+,K+-ATPase on sympathetic nerve terminals could have an important role in the regulation of neurotransmitter release, and that its activity might be enhanced in SHR compared with WKY.     

Neurotransmitter release and vascular reactivity in spontaneously hypertensive rats

This study was designed to investigate neurotransmitter release during the sympathetic nerve stimulation of perfused mesenteric arterial beds of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) at young and adult ages. The role of Ca in neurotransmitter release and vascular responsiveness was also examined by using a Ca-antagonist (verapamil). Pressor responses to electrical nerve stimulation and exogenous noradrenaline were greater in SHR than in WKY. Noradrenaline overflow by electrical nerve stimulation from mesenteric arterial beds was also significantly greater in young SHR than age-matched WKY. However, in adult SHR, the noradrenaline overflow was reduced compared with WKY. After verapamil infusion (5.0 X 10(-7)M approximately 2.5 X 10(-6)M), suppression of the pressor responses and noradrenaline overflow evoked by electrical nerve stimulation was greater in SHR than in WKY at both ages. The pressor responses to exogenous noradrenaline were also inhibited by verapamil more in young SHR than in young WKY. In adult SHR, the inhibition was similar to age-matched WKY. These results suggest that noradrenaline release from sympathetic nerve endings in SHR increase at a young age and decreases in adults, and depends at least partly on Ca-influx at both ages as dose vasoconstrictor reactivity. Therefore, Ca-dependency in SHR at both pre- and post-synaptic sites of neurotransmission may contribute to the pathogenesis of hypertension.     

Age-related decrease of calcitonin gene-related peptide-containing vasodilator innervation in the mesenteric resistance vessel of the spontaneously hypertensive rat

We previously demonstrated that the mesenteric resistance blood vessels have nonadrenergic, noncholinergic vasodilator innervation in which calcitonin gene-related peptide (CGRP) is a possible neurotransmitter. The role of CGRP-containing vasodilator nerves in hypertension was investigated in perfused mesenteric vascular beds isolated from spontaneously hypertensive rats (SHR). The adrenergic vasoconstrictor responses to perivascular nerve stimulation in both SHR (8-, 15-, and 30-week-old) and age-matched Wistar-Kyoto (WKY) rat preparations increased with aging, but the response was greater in SHR than in WKY rats at all ages. The preparation isolated from SHR and WKY rats was precontracted by continuous perfusion of Krebs' solution containing 7 x 10(-6) M methoxamine plus 5 x 10(-6) M guanethidine. In both SHR and WKY rats, perivascular nerve stimulation (1-8 Hz) produced frequency-dependent vasodilation, which was blocked by 1 x 10(-7) M tetrodotoxin, pretreatment with 5 x 10(-7) M capsaicin, and denervation by cold storage (4 degrees C for 72 hours). The vasodilation induced by perivascular nerve stimulation in SHR greatly decreased with age, whereas a slight decrease in the response with age was found in WKY rats. The neurogenic vasodilation in the young SHR preparation was similar in magnitude to the vasodilation in age-matched WKY rats, whereas the vasodilation in 15- and 30-week-old SHR was significantly smaller than that in age-matched WKY rats. In both SHR and WKY rats, perfusion of rat CGRP (1 x 10(-10) to 3 x 10(-8) M) produced marked vasodilation in a concentration-dependent manner. The CGRP-induced vasodilation in SHR increased with age, whereas an age-related decrease in vasodilation was found in WKY rats. Perivascular nerve stimulation (4 and 8 Hz) of the perfused mesenteric vascular bed evoked an increased release of CGRP-like immunoreactive substance in the perfusate, which was significantly less in 15-week-old SHR than in age-matched WKY rats. Immunohistochemical studies showed an age-related decrease in CGRP-like immunoreactive fibers in SHR but not in WKY rats. These results suggest that CGRP-containing vasodilator innervation is greatly decreased when SHR develop and maintain hypertension. It is also suggested that the decreased vasodilator mechanism by CGRP-containing nerves contributes to the development and maintenance of hypertension.     

Diminished Prostaglandin-Mediated Inhibition of Norepinephrine Release from the Sympathetic Nerve Endings in Spontaneously Hypertensive Rats

This study was performed to investigate prostaglandin(PG)-mediated regulation of norepinephrine release from the sympathetic nerve endings in spontaneously hypertensive rats(SHR). The effects of PGE₂ on the pressor responses and norepinephrine overflow during the periarterial nerve stimulation were examined in the perfused mesenteric vascular beds from SHR and age-matched Wistar Kyoto rats(WKY). In preliminary studies using normotensive Wistar rats, PGE₂ inhibited the overflow of norepinephrine in response to the electrical nerve stimulation. On the contrary, when indomethacin was infused into the preparations, the norepinephrine overflow induced by the nerve stimulation was increased. In SHR, the neurogenic vasoconstriction and norepinephrine overflow during the nerve stimulation were significantly greater than in WKY. PGE₂ in the medium inhibited the pressor responses and norepinephrine overflow during the nerve stimulation dose-dependently in WKY, while the inhibitory effects of PGE₂ in SHR were blunted. These results suggest that PGE₂ is an important hormone in regulating sympathetic vascular tone and that presynaptic inhibition of vascular adrenergic transmission by PGE₂ is attenuated in SHR.     

Inhibition of adrenergic transmission by methionine- and leucine-enkephalins is impaired in the mesenteric vasculatures of spontaneously hypertensive rats

The present study was carried out to investigate the effects of enkephalins (methionine-enkephalin: Met-Enk, leucine-enkephalin: Leu-Enk) on the adrenergic neurotransmission in hypertension. Perfused mesenteric vasculatures were prepared in spontaneously hypertensive rats (SHR, Okamoto and Aoki strain, 7-10 weeks old) and age-matched Wistar Kyoto rats (WKY), and the effects of these peptides on vascular responsiveness as well as norepinephrine release from the sympathetic nerve endings were examined. Pressor responses to electrical nerve stimulation were inhibited in a dose-dependent manner by Met-Enk and Leu-Enk, and the inhibition was antagonized by naloxone. Norepinephrine release during electrical nerve stimulation was also suppressed by these peptides. In SHR, stimulation-evoked pressor responses and norepinephrine release were significantly enhanced compared to those in WKY, while the suppressive magnitudes of the responses by Met-Enk and Leu-Enk were smaller in SHR than in WKY. These results demonstrate that Met-Enk and Leu-Enk affected presynaptic sites of blood vessels and caused a decrease in electrically-stimulated norepinephrine release from the sympathetic nerve endings. The lower reduction in norepinephrine release and vascular responsiveness by Met-Enk and Leu-Enk in SHR suggests an insufficient regulation of the vascular adrenergic neurotransmission by the opioid peptides in this model of hypertension.     

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.     

Inhibitory action on alpha-human atrial natriuretic polypeptide on vascular adrenergic neurotransmission is attenuated in spontaneously hypertensive rats

The purpose of the present study is twofold, firstly to investigate the effects of alpha-human atrial natriuretic polypeptide (alpha-hANP) on norepinephrine overflow from sympathetic nerve endings, and secondly to compare vascular responsiveness in perfused mesenteric preparations in spontaneously hypertensive rats (SHR, Okamoto and Aoki, 7-9 weeks old) and a cohort of Wistar Kyoto rats (WKY). In preliminary studies using normotensive Wistar rats, the pressor responses to electrical nerve stimulation or exogenous norepinephrine application were inhibited by alpha-hANP. Norepinephrine overflow was also suppressed by alpha-hANP, during nerve stimulation. The pressor responses and norepinephrine overflow during nerve stimulation were significantly greater in SHR than in WKY rats. The inhibitory effect of alpha-hANP on these responses was reduced in SHR. These results indicate that alpha-hANP could affect both pre- and post-synaptic sites of the resistance vessels. Further, the reduced inhibition of pressor responses and norepinephrine overflow by alpha-hANP in SHR suggests an insufficient regulation of adrenergic transmission by alpha-hANP in hypertension.     

Norepinephrine overflow in perfused mesenteric arteries of spontaneously hypertensive rats

We examined the overflow of endogenous norepinephrine with electrical stimulation, the associated pressor response, and rate of initial neuronal uptake of [3H]norepinephrine in perfused mesenteric arteries of 7- and 13-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The tissues of two rats, a spontaneously hypertensive and a WKY control rat, were simultaneously processed and subjected to the same electrical stimulation. Both absolute and fractional overflow of endogenous norepinephrine during periarterial nerve stimulation (5 and 10 Hz for 1 minute) in the tissue of 7-week-old SHR was significantly greater whereas overflow of 13-week-old SHR was equivalent as compared with that of the age-matched WKY rats. The tissue content of norepinephrine was 20-25% higher in SHR of both ages. There was significantly enhanced [3H]norepinephrine uptake in the tissues of young SHR, but no difference was observed in the older SHR. The pressor response to periarterial nerve stimulation was significantly enhanced in 7-week-old SHR and much more so at the older age as compared with the WKY control rats. Exogenous norepinephrine dose-response curves in the tissues of 7-week-old SHR exhibited a parallel leftward shift, characteristic of a change in sensitivity, whereas that of 13-week-old SHR showed a much steeper slope as compared with the respective WKY control rats. This finding suggests that in addition to smooth muscle supersensitivity, structural alterations had occurred in vasculature of 13-week-old SHR. These data indicate that in SHR both the exocytotic release of norepinephrine and the responsiveness of the vascular smooth muscle cells are enhanced in the developmental stage of hypertension whereas smooth muscle supersensitivity to norepinephrine and nonspecific structural alterations primarily contribute to the maintenance of hypertension at 13 weeks of age.     

The Role of Calmodulin in Neurotransmitter Release and Vascular Responsiveness in Spontaneously Hypertensive Rats

ABSTRACT

This study was designed to investigate the role of calmodulin in adrenergic transmission in hypertension. In perfused mesenteric vasculature: from spontaneously hypertensive rats(SHR, 7-9 weeks of age) and age-matched Wistar Kyoto rats(WKY), the effects of a specific calmodulin antagonist(W-7) on norepinephrine overflow and vascular responsiveness to endogenous and exogenous norepinephrine were examined.

The vasoconstrictor responses to electrical nerve stimulation and exogenous norepinephrine as well as norepinephrine overflow during electrical nerve stimulation were significantly enhanced in SHR compared with those in age-matched WKY. The calmodulin antagonist, W-7, reduced not only vasoconstrictor responses but also norepinephrine overflow during nerve stimulation. These inhibitory effects of W-7 were significantly greater in SHR than in WKY.

The results demonstrate that norepinephrine overflow from the sympathetic nerve endings and vascular responsiveness were increased in SHR. The marked reduction in norepinephrine overflow and pressor responses by W-7 might suggest the greater calmodulin-dependent adrenergic transmission in this model of hypertension.     

Norepinephrine release and reuptake by hypothalamic synaptosomes of spontaneously hypertensive rats

We compared the overflow of endogenous norepinephrine during electrical field stimulation, the norepinephrine content, and the rate of initial neuronal uptake of [3H]norepinephrine in synaptosomes isolated from hypothalamus and brainstem of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 7 and 13 weeks of age. The synaptosomes of two rats, a SHR and a WKY rat control, were simultaneously processed and subjected to the same electrical field stimulation. The overflow of endogenous norepinephrine during electrical stimulation (2 Hz, 2 minutes) in the hypothalamic synaptosomes of 7-week-old SHR was significantly greater, whereas the overflow of 13-week-old SHR was equivalent to the age-matched WKY rat. The norepinephrine content of synaptosomes was about the same in SHR and age-matched controls. There was also significantly enhanced [3H]norepinephrine uptake in the hypothalamic synaptosomes of young SHR, but neither the hypothalamic nor the brainstem samples of 13-week-old SHR showed any significant difference in their rate of [3H]norepinephrine uptake. These data are similar to those we observed (unpublished observations) in perfused mesenteric artery system in which norepinephrine release was significantly elevated during periarterial nerve stimulation only in young SHR. Thus, these results suggest that a parallel enhancement of norepinephrine release in hypothalamus with that of peripheral nervous system may play an important role during development of hypertension in young SHR.     

Effect of Insulin on Norepinephrine Overflow at Peripheral Sympathetic Nerve Endings in Young Spontaneously Hypertensive Rats

To determine how the effect of insulin is related to the development of salt-induced hypertension, and whether a hyporesponse to insulin exists in the peripheral sympathetic nerves of a hypertensive model rat, we measured norepinephrine overflow from the periarterial nerve of isolated mesenteric arteries exposed to insulin in spontaneously hypertensive rats (SHR) as well as Wistar-Kyoto rats (WKY) fed diets that were high and low in salt. Salt loading (diet containing 8% salt for 4 weeks) accelerated the development of hypertension in young, spontaneously hypertensive rats (SHR) (157 ± 5 mm Hg υ 198 ± 4 mm Hg, P < .01) but did not affect the blood pressure of Wistar-Kyoto rats (WKY) (102 ± 7 mm Hg υ 104 ± 6 mm Hg, P = NS). Basal norepinephrine overflow did not differ in the SHR and WKY rats, but the overflow of norepinephrine after periarterial electrical stimulation (8 Hz 1 min.) was significantly greater in SHR (0.806 ± 0.079 ng/g) than in WKY (0.723 ± 0.022 ng/g P < .01). Although insulin reduced the norepinephrine overflow by periarterial nerve stimulation in both WKY and SHR, the decrease with insulin was significantly greater in the SHR than in WKY (−18.4% ± 4.0% υ −32.0% ± 4.6%, P < .05). The inhibitory effect of insulin on norepinephrine overflow was reduced by salt loading in SHR (−8.8% ± 4.0%, P < .05), but not in WKY (−32.5% ± 4.7%, P = NS). Cocaine and ouabain completely blocked the effect of insulin in all four groups. In contrast to insulin, direct stimulation of Na⁺-K⁺ ATPase with a high-potassium buffer (12 mmol/L) reduced NE overflow to the same extent among the four groups. These findings show that SHR have a blunted response to the suppression by insulin of norepinephrine overflow. Salt loading reduced the insulin response at peripheral sympathetic nerves of young SHR, but did not affect that of age-matched WKY. Thus, hyporeactivity to insulin may play a role in the development of salt-induced hypertension in young SHR, possibly through a reduced suppression of norepinephrine overflow from sympathetic nerve endings. Am J Hypertens 1996;9:1119–1125     

Abnormalities in the Sodium Transport as the Causative Factor for Enhanced Norepinephrine Overflow in the Spontaneously Hypertensive Rat

ABSTRACT

These studies were designed to investigate whether alterations in the sodium transport could account for the enhanced transmitter release observed during sympathetic nerve stimulation in SHR. In the isolated in vitro perfused rat kidneys, norepinephrine (NE) storage sites were labelled with [³H]-NE and the transmitter overflow was evaluated at various frequencies during the periarterial nerve stimulation. Stimulus-induced transmitter overflow was consistently greater and the maximal overflow was 2-fold higher in the kidneys of SHR when compared to that of normotensive WKY. Addition of ouabain, a selective inhibitor of the sodium pump, (10^?3M in the medium) significantly enhanced stimulus induced overflow in both the groups. However, the magnitude of these changes was significantly greater in WKY than in SHR kidneys suggesting that the membrane Na⁺-pump was functionally less efficient in the SHR. Ouabain virtually eliminated the differences between the two groups in that the transmitter overflow was essentially identical in SHR and WKY in the presence of the Na⁺-pump inhibitor. These observations suggest that a genetic abnormality in the neuronal sodium pump could account for the enhanced sympathetic transmitter overflow and contribute to hypertension in the spontaneously hypertensive rats.     

Enhanced 5-hydroxytryptamine release from vascular adrenergic nerves in spontaneously hypertensive rats

The release of 5-hydroxytryptamine from the vascular adrenergic nerve by periarterial nerve stimulation in spontaneously hypertensive rats (SHR) was compared with that in normotensive Wistar-Kyoto rats (WKY). The isolated mesenteric vascular bed was perfused at a constant flow rate of 5 ml/min. Vasoconstrictor responses to periarterial nerve stimulation (4, 8, 12, and 16 Hz for 30 seconds) and 5-hydroxytryptamine (1 microM), but not norepinephrine (1 nmol), were significantly greater in SHR than in WKY. After treatment with 5-hydroxytryptamine (1 microM) for 15 minutes, vasoconstrictor responses to periarterial nerve stimulation previously reduced by prazosin (50 nM) were restored and a frequency-dependent pressor response reappeared. However, 5-HT treatment did not significantly affect the pressor response to exogenously administered norepinephrine (1 nmol), which was previously inhibited by prazosin. The degree of the restoration in SHR was significantly greater than that in WKY at all frequencies used. The restoration of the pressor response to periarterial nerve stimulation after 5-hydroxytryptamine treatment did not occur in the presence of the selective 5-hydroxytryptamine2 receptor antagonists ketanserin (10 nM) or LY53857 (10 nM). In the perfused mesenteric vascular bed of both WKY and SHR prelabeled with [3H]5-hydroxytryptamine, periarterial nerve stimulation (4-16 Hz) evoked a frequency-dependent increase in tritium efflux that was abolished by Ca2+-free Krebs-Ringer solution or tetrodotoxin (100 nM) and treatment with 6-hydroxydopamine. The tritium efflux evoked by periarterial nerve stimulation was significantly greater in SHR than in WKY at all frequencies used. These results suggest that the release of 5-hydroxytryptamine from adrenergic nerve endings by periarterial nerve stimulation is enhanced in the mesenteric vascular bed of the SHR.     

Effects of Serotonin and Some Other Neurohumoral Agents on Adrenergic Neurotransmission in Spontaneously Hypertensive Rat Vasculature

The effects of serotonin (5HT), acetylcholine (ACh), histamine and dopamine on the pressor responses of the mesenteric vasculature were examined in view of their potential role in neuromodulation. The responses to periarterial sympathetic nerve stimulation (NS, 8 Hz, 2 msec, 30 sec) and to exogenous norepinephrine (NE, 0.2 nmol) were compared between spontaneously hypertensive rats (SHR) and the control Wistar Kyoto rats (WKY). In both WKY and SHR, ACh (3-30 nM), histamine (0.3-3 μM) and dopamine (0.3 μM) attenuated the NS-induced vasoconstrictor response as much as the NE-induced response, indicative of predominance of postsynaptic inhibition. 5HT (10-100 nM) potentiated the vasoconstrictor responses to NS significantly less than that to NE in WKY, suggestive of presynaptic inhibition. Such difference was absent in SHR. These results suggest that the presynaptic inhibition of vascular adrenergic neurotransmission by 5HT is diminished in SHR, and this may contribute to the elevated blood pressure.     

Impaired potentiation by endothelin-1 and vasopressin of sympathetic contraction in tail artery from hypertensive rats

OBJECTIVE: To analyse the effects of endothelin-1 and vasopressin on the sympathetic vasoconstriction during hypertension. METHODS: Electrical field stimulation (4 Hz) was applied to isolated, 2 mm segments of the tail artery from spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats prepared for isometric tension recording. RESULTS: The contraction to electrical stimulation was potentiated by endothelin-1 (10(-10)-10(-8) M) in arteries from WKY but not from SHR, and by vasopressin (10(-12)-10(-10) M) more markedly in arteries from WKY than from SHR. The potentiation by endothelin-1 was reduced more markedly by the antagonist of endothelin ETA receptors BQ-123 (10(-5) M) than by the endothelin ETB receptor antagonist BQ-788 (10(-5) M). The potentiation by vasopressin was reduced by the antagonist of vasopressin V1 receptors d(CH2)5Tyr(Me)AVP (10(-7) M), but not by the vasopressin V2 receptor antagonist d(CH2)5D-Ile2, Ile4AVP (10(-7) M). The blocker of L-type calcium channels verapamil (10(-5) M) reduced the potentiation by both endothelin-1 and vasopressin in arteries from WKY rats, and increased the potentiation by vasopressin in arteries from SHR. Noradrenaline (10(-8)-10(-4) M) contraction was not modified by endothelin-1 (3 x 10(-9) M) or vasopressin (3 x 10(-11) M), and contraction to endothelin-1 (10(-9)-10(-7) M) and vasopressin (10(-10)-10(-7) M) was lower in arteries from SHR than from WKY rats. CONCLUSIONS: (1) The potentiation by endothelin-1 and vasopressin of the sympathetic vasoconstriction, probably due to increased release of noradrenaline, is impaired during hypertension, and (2) this potentiation is mediated mainly by endothelin ETA receptors, and by vasopressin V1 receptors, in both WKY and SHR, and for both peptides it is mediated by L-type calcium channels in arteries from normotensive but not in those from hypertensive animals.     

Effects of Captopril on Neurosecretion and Vascular Responsiveness in Hypertension

The purpose of the present study was to investigate the mechanisms of hypotensive action of an angiotensin converting enzyme inhibitor(captopril) in hypertension. In perfused mesenteric vasculatures from spontaneously hypertensive rats(SHR) and normotensive Wistar Kyoto rats(WKY), the effects of captopril on the vascular responsiveness and norepinephrine overflow from the adrenergic nerve endings were examined

The vasoconstrictor responses and norepinephrine overflow during the electrical nerve stimulation was significantly enhanced in SHR compared with WKY. Captopril reduced not only vasoconstrictor responses but also norepinephrine overflow during the nerve stimulation in a dose-dependent fashion. The suppressions of these responses by captopril were significantly greater in SHR than in WKY

These results demonstrate that captopril could affect the presynaptic site of the resistance vessels and cause a decrease in electrically-stimulated norepinephrine overflow from the adrenergic nerve endings. The marked reduction of the pressor responses and norepinephrine overflow to nerve stimulation by captopril in the SHR suggests that the renin-angiotensin system in the vascular beds is enhanced in this model of hypertension.     

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.     

Role of sympathetic nerve inhibition in the vasodepressor effect of bromocriptine in normotensive and hypertensive rats.

This study aimed to elucidate the mechanism of the hypotensive effect of bromocriptine (BRC), and to investigate whether or not the effects of BRC on the sympathetic nervous system are altered in hypertension. BRC was administered intravenously to normotensive and spontaneously hypertensive rats (SHR). It elicited hypotensive effects dose-dependently in urethane-anaesthetized normotensive rats, an effect which was antagonized with metoclopramide. Pretreatment with intravenous hexamethonium attenuated the hypotensive effect of BRC. BRC decreased plasma norepinephrine (NE) without inhibiting the sympathetic nerve spikes recorded from the postganglionic sympathetic nerve bundle. The hypotensive effect of BRC was significantly greater in SHR than in Wistar Kyoto Rats (WKY). Decrease in NE by BRC was also significantly greater in SHR than in WKY. These results suggest that the hypotensive effect of BRC is induced by suppression of NE release, not by inhibition of sympathetic nerve spikes, and that the dopaminergic presynaptic inhibition is attenuated in SHR.