Effects of a calcium-antagonist on vascular sympathetic nerve activity in salt-dependent hypertension

The purpose of the present study was to investigate the effects of a Ca2(+)-antagonist on vascular sympathetic nerve activity in salt-dependent hypertension. Isolated mesenteric vasculature preparations from reduced renal mass-salt hypertensive and age-matched normotensive control rats were used to examine the effects of diltiazem on vascular responsiveness and norepinephrine release from sympathetic nerve endings. Pressor responses and endogenous norepinephrine release during electrical nerve stimulation were significantly greater in preparations from salt-dependent hypertensive rats than from normotensive control rats. Diltiazem inhibited both stimulation-evoked pressor responses and norepinephrine release in a dose-dependent manner. The attenuation of these responses was more pronounced in preparations from rats with salt-dependent hypertension than in those from control rats. These results indicate that norepinephrine release from vascular adrenergic neurons is enhanced in the mesenteric vasculatures of rats with salt-dependent hypertension. The marked reduction of stimulation-evoked pressor responses and norepinephrine release by diltiazem suggests that enhanced Ca2(+)-dependent adrenergic transmission may contribute to the exaggerated vascular sympathetic tone in salt-dependent hypertension.     

The role of protein kinase C and calcium in the regulation of norepinephrine release from the vascular adrenergic neurons in hypertension

This study was designed to investigate the role of protein kinase C and calcium in vascular adrenergic transmission in hypertension. In perfused mesenteric vasculatures of spontaneously hypertensive rats (SHR, 7 to 10 weeks old) and age-matched Wistar-Kyoto rats (WKY), we have examined the effects of the protein kinase C inhibitor H-7 on endogenous norepinephrine release and vascular responsiveness during nerve stimulation. Endogenous norepinephrine release and pressor responses during periarterial nerve stimulation were significantly greater in SHR than in WKY. The protein kinase C inhibitor H-7 inhibited the stimulation-induced norepinephrine release and pressor responses in a dose-dependent manner. The magnitude of these suppressive responses were more pronounced in SHR than in WKY. Calcium removal from extracellular fluid also reduced the norepinephrine release more strongly in SHR than in WKY. These results demonstrate that the regulation of norepinephrine release might be more dependent on protein kinase C and calcium in the blood vessels of SHR, which could contribute, at least partially, to the pathogenesis of this form of hypertension.     

Effects of a Protein Kinase C Inhibitor (H-7) on Norepinephrine Release from Vascular Adrenergic Neurons in Spontaneously Hypertensive Rats

This study was performed to investigate the effects of a specific protein kinase C inhibitor (H-7) on vascular adrenergic transmission in hypertension. In the isolated mesenteric vasculature of spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY), we have examined the effects of H-7 on norepinephrine (NE) release from vascular adrenergic neurons. Endogenous NE release during periarterial nerve stimulation was inhibited by H-7 in a dose-dependent manner with a concomitant reduction of pressor responses of the preparation. The inhibition of NE release was not affected by an uptake blocker of NE (desipramine). In SHR, the stimulation-evoked NE release and pressor responses were significantly greater than in age-matched WKY. The suppressive magnitude of stimulation-evoked NE release and pressor responses by H-7 were pronounced in SHR compared with WKY. These results demonstrate that endogenous NE release and pressor responses were increased in the mesenteric vasculature of SHR. Furthermore, the marked inhibition of NE release and pressor responses by H-7 in SHR may suggest the presence of enhanced protein kinase C-dependent regulation of vascular adrenergic transmission, which may contribute to the calcium-related abnormalities in this form 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.     

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.     

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.     

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.     

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.     

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.     

The role of dopamine in the regulation of neurotransmitter release in spontaneously hypertensive rats

The purpose of the present study was to analyze the influence of dopamine on norepinephrine release in resistance vessels in spontaneously hypertensive rats (SHR). Perfused mesenteric vasculature preparations from spontaneously hypertensive rats (7-10 weeks old) and age-matched normotensive Wistar Kyoto rats (WKY) were used to compare the effects of dopamine on both pressor responses and norepinephrine release. Both responses to electrical nerve stimulation were significantly greater in SHR than in WKY rats. Dopamine reduced these responses in a dose-dependent manner in WKY. However, this suppression of responses to electrical stimulation was attenuated in SHR. These results suggest that the enhanced adrenergic transmission in SHR may partly reflect impaired dopamine-mediated inhibition of nerve terminals, which would contribute to the pathogenesis of hypertension.     

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.     

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.     

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.     

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.     

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.     

Structural and functional alterations of mesenteric vascular beds in spontaneously hypertensive rats

The morphology and reactivity of mesenteric arteries from spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY) were investigated. Isolated, perfused mesenteric vascular beds were prepared from 6-, 11- and 18-week-old SHR and WKY. At these ages, the walls and media of large mesenteric arteries were significantly thicker in SHR than in WKY. The number of smooth muscle cell layers in the media was significantly larger in SHR than in WKY. This difference between SHR and WKY increased as rats grew older, in parallel with differences in the blood pressure. Flow rate-perfusion pressure curves indicated that the vascular basal resistance to flow increased more profoundly in SHR preparations than in WKY preparations as rats grew older. This may be related to the structural alterations of the resistance vessel wall in SHR. The pressor responses to KCl were greater in SHR preparations than in WKY preparations as rats grew older. This may be caused partly by the increase of the number of smooth muscle cell layers in the media of SHR resistance vessels. The pressor response to norepinephrine (NE) was significantly higher in SHR preparations than in WKY preparations at all ages investigated. In marked contrast to the vascular basal resistance and the pressor response to KCl, the pressor response to NE was extremely exaggerated in SHR at the age of 6 weeks. This extremely high NE response in younger SHR may not be caused by the structural alteration in resistance vessels. It may be caused by a functional change, which is regulated by the signal transduction process in smooth muscle cells of resistance vessels. These results suggest that the development of hypertension in SHR may be caused by genetic structural and functional abnormalities of resistance vessels. Both abnormalities may be caused by the hyperreactivity to NE through an altered signal transduction process in smooth muscle cells of resistance vessels in SHR.     

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.     

Neurotransmitter release and vascular responsiveness in mesenteric vasculatures from two-kidney, one-clip Goldblatt hypertensive rats

In order to investigate the peripheral neuroeffector functions of renal hypertension, norepinephrine release from the sympathetic nerve endings and vascular responsiveness were evaluated in the mesenteric vasculatures from two-kidney, one-clip Goldblatt hypertensive rats (2K, 1C-HT). Norepinephrine release and pressor responses during periarterial nerve stimulation (40 V, 5 msec rectangular pulses for 1 min, 5, 10 and 15 Hz) were unchanged during the acute phase (3 weeks after surgery), and were rather reduced during the chronic phase (7-8 weeks after surgery) in 2K, 1C-HT compared to sham-operated normotensive control rats. By contrast, the vasoconstrictor responses to exogenously applied norepinephrine were significantly greater in 2K, 1C-HT than in the normotensive controls. From these observations, it seems unlikely that peripheral adrenergic function in the blood vessels plays an important role in the pathogenesis of 2K, 1C-HT. However, the increased sensitivity of vascular smooth muscle cells to norepinephrine may contribute to the maintenance of high blood pressure in the face of reduced vascular sympathetic tone in this form of hypertension.     

Pressor mechanisms linked obligatorily to spontaneous hypertension in the rat

To identify genetic factors linked obligatorily to hypertension in the rat, pithed spontaneously hypertensive rats (SHR) were compared with genetically similar (Wistar-Kyoto rats; WKY) and different (Sprague-Dawley) normotensive strains. The only variables that distinguished SHR from both WKY and Sprague-Dawley rats were a greater maximum pressor response to electrical stimulation of sympathetic outflow and decreased sensitivity to submaximal doses of the alpha 1-adrenergic agonist methoxamine (i.e., higher ED50). SHR had in common with Sprague-Dawley rats basal blood pressure after pithing plus adrenalectomy and the maximum pressor response to methoxamine; both these values were higher than those in WKY. All strains demonstrated equal sensitivity of the vasoconstrictor response to endogenous norepinephrine released by electrical simulation at submaximal frequency, even though sensitivity to the alpha 1-adrenergic receptor agonist was lower in SHR. The alpha 2-adrenergic receptor antagonist rauwolscine attenuated the pressor response to electrical stimulation in SHR and WKY but increased it in Sprague-Dawley rats. The alpha 1-adrenergic receptor antagonist prazosin attenuated the response more in SHR and WKY than in Sprague-Dawley rats. We conclude that 1) sympathetic hyperactivity is linked obligatorily to hypertension in SHR; 2) increased basal blood pressure and noradrenergic vasoconstrictor response are present in SHR, but they are not obligatorily linked to hypertension; 3) feedback inhibition of norepinephrine release is comparable in SHR or WKY and poorly developed compared with that in Sprague-Dawley rats; 4) decreased sensitivity of the pressor response to stimulation of vascular alpha 1-adrenergic receptors in SHR compensates partially for increased sympathetic activity or hyperinnervation, or both.     

Effects of calcium-antagonists on norepinephrine release from sympathetic nerve endings in rat mesenteric vasculature

The present study was designed to investigate whether Ca-antagonists influence norepinephrine release from the sympathetic nerve endings in resistance vessels. Isolated mesenteric vascular preparations of rats, perfused with Ringer-Locke solution, were used to determine the effects of verapamil or diltiazem on norepinephrine release from sympathetic nerve terminals. Pressor responses to exogenous norepinephrine and electrical nerve stimulation were recorded, and the norepinephrine contents of the perfusate were measured before and after the electrical nerve stimulation, using high pressure liquid chromatography with an electrochemical detector. Pressor responses to exogenous norepinephrine and electrical nerve stimulation were depressed dose-dependently by verapamil and diltiazem. The inhibition of the pressor responses for nerve stimulation was greater than exogenous norepinephrine. Both verapamil and diltiazem reduced norepinephrine release from the mesenteric arterial beds after the electrical nerve stimulation. These results indicate that Ca++-antagonists, such as verapamil and diltiazem, have inhibitory effects on norepinephrine release from the sympathetic nerve endings, in addition to their direct actions on the vascular smooth muscle. It is also suggested that the presynaptic inhibitory action of Ca++-antagonists could be due to the blockade of Ca++-channels in nerve cell terminals, which may be important in the clinical use of Ca-antagonists.