Interference by Inhibitors of the Renin-Angiotensin System with Neurogenic Vasoconstriction

In the pithed rat preparation captopril, enalapril, teprotide and saralasin given intravenously attenuated pressor responses to both spinal sympathetic nerve stimulation and exogenous noradrenaline, indicating that angiotensin has a potent adrenergic facilitating action. Bi-lateral nephrectomy abolished the effects of captopril on nerve stimulation but responses to noradrenaline were still inhibited following nephrectomy, indicating that part of the post-junctional actions of captopril might not be angiotensin dependent. Both phenylephrine and clonidine are also inhibited by captopril in the pithed rat. It is thus not clear whether captopril is interacting with post-junctional ×s1- or ×s2- adrenoceptors.

Vasoconstrictor responses to nerve stimulation are greater in SHR than WKY and captopril is more effective at inhibiting responses in the SHR than it is in WKY. These interactions between captopril and the sympathetic nervous system could explain the effectiveness of ACE inhibitors as antihypertensive agents.     

Effect of a monoclonal antibody to angiotensin II on hemodynamic responses to noradrenergic stimulation in pithed rats

A specific angiotensin II monoclonal antibody, KAA8, was used to examine the interaction between sympathetic function and angiotensin II in pithed rats. KAA8, at 5 or 50 mg/kg i.v., did not alter the mean blood pressure, cardiac output, total peripheral resistance, or heart rate responses to sympathetic neural stimulation (0.25-4.0 Hz) or to norepinephrine (0.3-3 micrograms/kg i.v.) but blocked significantly the hemodynamic responses to angiotensin II (0.03-1.0 microgram/kg i.v.) and to angiotensin III (0.3-10 micrograms/kg i.v.). KAA8 treatment also reduced the plasma immunoreactive angiotensin II from 2,880 +/- 475 pg/ml to an undetectable level. In contrast, captopril (5 mg/kg i.v.) and saralasin (10 or 50 micrograms/kg/min i.v.) inhibited the mean blood pressure and total peripheral resistance responses, but not the cardiac output and heart rate responses, to sympathetic neural stimulation and to norepinephrine. These results, which confirm previous findings by Kaufman and Vollmer (Kaufman LJ, Vollmer RR: Endogenous angiotensin II facilitates sympathetically mediated hemodynamic responses in pithed rats. J Pharmacol Exp Ther 1985;235:128-134), demonstrate that angiotensin II selectively potentiates the sympathetic vascular function in the pithed rat. However, our results suggest that circulating angiotensin II does not appear to interact with the sympathetic vascular function. It is speculated that in the pithed rat the sympathetic vascular response is enhanced by vascular-formed angiotensin II.     

Reduced Sympathetic Responsiveness Resulting from a High Dietary Sodium Intake in the Rat

The effects of a high sodium diet on sympathetic nervous function were evaluated in normotensive male Wistar rats maintained on a standard (141 mEq/kg) or high (1400 mEq/kg) sodium chow for 4 weeks. No differences were observed in the blood pressures of conscious catheterized rats on the two diets; nowever, heart rates were significantly lower in rats on the high sodium intake. Hypotensive responses produced in these animals by one minute intravenous infusions of sodium nitroprusside were greater in rats on the high sodium diet, whereas, reflex tachycardia was similar. In pithed rats on either diet, basal blood pressures and heart rates were similar. In contrast, blood pressure responses to electrical stimulation of the spinal sympathetic outflow were significantly attenuated in the high sodium rats but the tachycardic responses were unaltered. In addition, norepinephrine induced blood pressure and heart rate increases were not different between the diets. Similarly, the sensitivity of isolated atria to isoproterenol was not affected by dietary sodium, nor were the responses of isolated aortic strips to phenylephrine altered. The results of this investigation indicate that a chronic high sodium intake may result in an attenuation of vascular sympathetic function.     

Inhibition of angiotensin II-induced facilitation of sympathetic neurotransmission in the pithed rat: a comparison between losartan, irbesartan, telmisartan, and captopril

OBJECTIVE: Numerous studies have shown that angiotensin II enhances sympathetic nervous transmission. The objective of the present study was to quantify the inhibitory effect of the angiotensin II type 1 (AT1) receptor blockers losartan, irbesartan and telmisartan and the angiotensin converting enzyme (ACE) inhibitor captopril on sympathetic neurotransmission and to compare the potency of these agents both at the presynaptic and the postsynaptic levels. DESIGN: In the male, normotensive pithed rat model, we studied the effect of losartan (1, 3, 10 and 30 mg/kg), irbesartan (3, 10, 30 and 60 mg/kg), telmisartan (0.3, 1, 3 and 10 mg/kg) and captopril (1.5, 5, 15 and 45 mg/kg) on electrical stimulation of the thoraco-lumbar spinal cord. To investigate the interaction between postsynaptic AT1-receptors and alpha-adrenoceptors, the effects of these compounds on pressor responses to exogenous noradrenaline were studied. RESULTS: Stimulation of the thoracolumbar spinal cord caused a stimulation-frequency dependent rise in diastolic blood pressure (DBP) that could be dose-dependently reduced by both AT1 receptor blockade and ACE inhibition. Interestingly, the highest doses of the AT1 antagonists caused less than maximal reduction in the rise in DBP. This phenomenon was not observed after ACE inhibition by captopril. In experiments with exogenous noradrenaline, no effect of AT1 blockade or ACE inhibition on alpha-adrenoceptor-mediated blood pressure responses was seen. CONCLUSION: We conclude that, in the pithed rat model, the effects of stimulation of the thoraco-lumbar spinal cord on DBP are counteracted by blockade of presynaptically located AT1 receptors. The order of potency concerning sympatico-inhibition is telmisartan > losartan > irbesartan. Regarding the inhibition of angiotensin II-induced facilitation of sympathetic neurotransmission, marked differences were observed between selective AT1 blockade and ACE inhibition. The finding that all three AT1 blockers cause less than maximal inhibition in their highest doses, as opposed to captopril, suggests that this is a class effect of the AT1 antagonists.     

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.     

The vascular response to adrenergic stimulation in pithed rats following endotoxin

In vivo and in vitro studies have shown that the vascular response to catecholamine is attenuated during endotoxemia. The mechanism of such attenuation is complex and might involve high catecholamine-induced desensitization of adrenoceptors. The purpose of this study was to assess the vascular response to adrenergic stimulation after endotoxin (ETX) administration in pithed rats. In pithed rats, sympathetic outflow is controlled by stimulation, ETX does not elevate norepinephrine (NE), and there are no compensatory reflexes. Rats were pithed, curarized, and adrenal-demedullated. Preganglionic thoracolumbar nerves were stimulated (3 Hz, 10 V, 0.5 msec) for 1 hr after pithing, at which time the first set of frequency and NE-dose responses were assessed by measuring the peak increase in diastolic blood pressure. Intravenous ETX (1.5 mg/kg or 0.5 mg/kg) or saline was administered immediately after these measurements. A sham group was designed to mimic the falling blood pressure pattern seen in the endotoxin group during 1 hr after ETX was given by gradually decreasing the stimulation frequency. The second set of frequency and NE-dose responses were evaluated 1 hr after ETX, saline, or sham treatment. Plasma NE and epinephrine (EPI) were determined before and 1 hr after ETX (1.5 mg/kg) or saline injection. The results showed that blood pressure response to adrenergic stimulation was markedly attenuated in pithed rats following both high and low doses of ETX compared with the saline and sham groups. Plasma NE was not elevated by ETX insult in pithed rats. We propose that mechanisms other than high-catecholamine-induced adrenergic desensitization or hypotension account for the attenuated adrenergic responsiveness of the vasculature following ETX.     

Comparative effects of captopril and MK 421 on sympathetic function in spontaneously hypertensive rats

The effects of captopril and MK 421, both orally active angiotensin-converting enzyme inhibitors, on sympathetic function in the pithed spontaneously hypertensive rat were examined. Captopril (100 mg/kg orally) signif icantly inhibited pressor responses to sympathetic nerve stimulation and norepinephrine whereas MK 421 (10 and 100 mg/kg orally) was without effect. Both drugs abolished the angiotensin l response without affecting that to angiotensin II. Because these doses of MK 421 are antihypertensive in the Spontaneously hypertensive rat, it is concluded that inhibition of sympathetic function plays no role in its effect. The role of the sympatholytic action of captopril in its antihypertensive action remains unclear.     

Interaction of angiotensin-converting enzyme inhibitors with the function of the sympathetic nervous system

The effects of the converting enzyme inhibitors captopril and SQ 20881 and the angiotensin II antagonist saralasin were studied on neurogenic vasoconstriction in the rat using both in vivo and in vitro techniques. In the pithed rat the presser response to nerve stimulation at 1 to 30 Hz was reduced by captopril (0.1 and 1 mg/kg), saralasin (4 gmg/kg/min) and SQ 20881 (10 mg/kg). The pressor responses to noradrenaline (10 to 500 ng total dose) were also antagonized by captopril (1 mg/kg only), SQ 20881 and saralasin. In animals bilaterally nephrectomized 18 to 24 hours previously, captopril and saralasin were without effect on responses to nerve stimulation, but captopril still had a small residual effect on responses to noradrenaline.In isolated mesenteric vessels perfused with Krebs solution exogenous angiotensin I and II potentiated vasoconstrictor responses to nerve stimulation in doses that themselves did not have a direct vasoconstrictor effect. This potentiating effect of angiotensin I was antagonized by captopril (6.7 × 10^?8 to 2 × 10^?6mol) and by saralasin (10^?8 mol). The potentiating action of angiotensin II was blocked only by saralasin. These concentrations of the antagonists themselves had no effect on vasoconstrictor responses to nerve stimulation in the absence of angiotensin although higher concentrations of captopril (10^?4 to 3 × 10^?4mol/liter) did antagonize vasoconstrictor responses to both nerve stimulation and noradrenaline.These results indicate that inhibitors of the renin-angiotensin system may impair neurogenic vasoconstriction by interfering with both a preand postjunctional action of angiotensin. In addition, very high concentrations of captopril antagonize neurogenic vasoconstriction by a nonangiotensin-dependent mechanism. This important interaction of angiotensin with the sympathetic nervous system may help to explain the effectiveness of converting enzyme inhibitors as antihypertensive agents.     

Effect of low sodium diet on the facilitatory effect of angiotensin on 3H-norepinephrine release in the rat portal vein

The ability of angiotensin to enhance the field-stimulation induced release of 3H-norepinephrine from the superfused rat portal vein was examined in vessels obtained from animals fed a normal (0.5% Na+) or low sodium diet (0.05% Na+). Angiotensin was seen to enhance the field-stimulation (480 pulses, 2 Hz, 1 ms duration, supramaximal voltage) induced release of 3H-norepinephrine from vessels obtained from Sprague-Dawley, Wistar, Wistar-Kyoto (WKY) and the spontaneously hypertensive rats (SHR) maintained on a normal sodium diet. The effect of angiotensin was attenuated when examined in vessels obtained from animals maintained on the low sodium diet. The selectivity of the low sodium diet for angiotensin was demonstrated by a lack of effect of the low sodium diet in altering the facilitatory effect of isoproterenol on the release of 3H-norepinephrine and an enhanced response to the alpha 2-adrenoceptor-selective antagonist, yohimbine. The simultaneous treatment of rats with a low sodium diet plus captopril (estimated to be approximately 50 mg/kg/day for 7 days) prevented the attenuation of the angiotensin-induced enhancement of the release of 3H-norepinephrine seen by sodium alone. These results are consistent with the hypothesis that low sodium treatment increases circulating angiotensin levels which lead to a down-regulation of the angiotensin receptors located on adrenergic nerve varicosities.     

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.     

Effect of sodium intake on sympathetic and hemodynamic response to thermal receptor stimulation

Low dietary sodium intake increases central nervous system angiotensin activity, which increases basal renal sympathetic nerve activity and shifts its arterial baroreflex control to a higher level of arterial pressure. This results in a higher level of renal sympathetic nerve activity for a given level of arterial pressure during low dietary sodium intake than during either normal or high dietary sodium intake, in which there is less central angiotensin activity. Peripheral thermal receptor stimulation overrides arterial baroreflex control and produces a pressor response, tachycardia, increased renal sympathetic nerve activity, and renal vasoconstriction. To test the hypothesis that increased central angiotensin activity would enhance the responses to peripheral thermal receptor stimulation, anesthetized normal rats in balance on low, normal, and high dietary sodium intake were subjected to acute peripheral thermal receptor stimulation. Low sodium rats had greater increases in renal sympathetic nerve activity, greater decreases in RBF, and greater increases in renal vascular resistance than high sodium rats. Responses of normal sodium rats were between those of low and high sodium rats. Arterial pressure and heart rate responses were not different among dietary groups. Spontaneously hypertensive rats, known to have increased central nervous system angiotensin activity, also had greater renal sympathoexcitatory and vasoconstrictor responses than normotensive Wistar-Kyoto rats. These results support the view that increased central nervous system angiotensin activity alters arterial baroreflex control of renal sympathetic nerve activity such that the renal sympathoexcitatory and vasoconstrictor responses to peripheral thermoreceptor stimulation are enhanced.     

Diminished Sympathetic Responsiveness in Nephrectomized Rats-Role of the Renin Angiotensin System

Experiments were conducted in pithed Wistar rats to assess the effects of nephrectomy on the responsiveness of the cardiovascular system to sympathetic neurohumoral stimuli. Blood pressure and heart rate increases produced in response to stimulation of the spinal sympathetic outflow and to norepinephrine were compared in nephrectomized (NXR) and sham operated animals (SOR). Both the blood pressure (BP) and heart rate (HR) increases to nerve stimulation were markedly attenuated in the NXR, however, only the reduction in BP responses could be attributed to the absence of a functional renin angiotensin system. Infusion of angiotensin II (10 ng/kg/min) in NXR enhanced the neurally mediated increments in BP to the extent that the responses were not different from SOR. Angiotensin II administration also enhanced BP responses in SOR but to a lesser extent than in NXR. HR responses were not altered by angiotensin in NXR or SOR. Blockade of the renin angiotensin system in SOR with the converting enzyme inhibitor captopril, reduced BP responses to the same level as NXR. In contrast, HR increments were not altered by captopril. BP but not HR increments to norepinephrine were significantly reduced in NXR. Infusion of angiotensin II restored the BP responses to a level equal to SOR; HR responses were not affected. In addition, captopril reduced the norepinephrine responses of SOR but not NXR. Thus the results of the present study indicate that endogenously formed angiotensin facilitates sympathetically mediated vasoconstrictor activity but does not influence heart rate responses. Therefore, the attenuation of neurally elicited increases in HR observed in NXR does not appear to be acutely related to reduced levels of angiotensin II.     

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.     

Effect of chronic treatment with captopril on reactivity of aortic smooth muscle from normotensive and renal hypertensive rats

Acute administration of the angiotensin I converting enzyme inhibitor, captopril (2 X 10(-4) M), was shown in an earlier study to attenuate the contractile responses of aortic rings of rats to alpha-adrenergic agonists in vitro. The objective of the present study was to determine the effect of chronic treatment with captopril on reactivity of aortic rings from both normotensive and renal hypertensive rats when captopril was no longer present. Four groups of rats were used: (1) normotensive, untreated; (2) normotensive, captopril-treated (48 mg/kg b.w. per day for five weeks); (3) hypertensive (bilateral renal encapsulation for five weeks), untreated and (4) hypertensive, captopril-treated. Renal encapsulation was associated with a significant increase in systolic blood pressure, which was prevented by concomitant treatment with captopril. At the end of the five weeks treatment aortic rings, 4 mm in length, were washed for 2 h to remove the captopril, following which contractile responses to various vasoactive agents were studied in vitro. Chronic treatment with captopril attenuated significantly contractile responses to both norepinephrine (10(-9) to 10(-5) M) and phenylephrine (10(-8) to 10(-4) M) but had no effect on isoproterenol-induced relaxation of KCl-depolarized tissue in the presence of 10(-5) M phentolamine. Contractile responses to angiotension I (10(-10) to 10(-7) M) did not differ statistically among the four groups. Following addition of captopril (2 X 10(-4) m) to the bath for 30 min, contractile responses to angiotensin I were attenuated in all four groups of rings.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal Kallikrein-Kinin System and the Depressor Effect of Angiotensin Converting Enzyme Inhibitors MK 421, SA 446, And Captopril In Rats

Responses in urinary kallikrein and kinin excretion and systolic blood pressure to MK 421, SA 446 or captopril were studied in normotensive rats fed on a regular or a low sodium diet to assess the role of renal kallikrein-kinin system in their hypotensive effect. MK 421, SA 446 or captopril were infused at a rate of 6 mg/kg/day by osmotic minipump implanted intraperito-neally for up to 6 days. The magnitude of fall in systolic blood pressure was greater on a low sodium diet when compared to on a regular diet, whereas the pattern of the fall was similar on both diets. The magnitude of falls in plasma angiotensin II and aldosterone concentration induced by MK 421, SA 446 and captopril was not significantly different between both regular and low sodium diets. Urinary kallikrein and kinin excretion and sodium excretion were increased during infusion of MK 421, SA 446 or captopril on a low sodium diet, however any significant changes were not found in each of them on a regular diet

The present results suggest that on a low sodium diet the augmented hypotensive response to angiotensin converting enzyme inhibitors in the rats might be due to the enhanced renal kallikrein-kinin system in addition to suppressed renin-angiotensin system     

Studies on the Mechanism of the Enhancement of the Antihypertensive Activity of Captopril by A Diuretic in Spontaneously Hypertensive Rats

Captopril (30 mg/kg/day orally for two days) in spontaneously hypertensive rats (SHR) inhibited serum angiotensin converting enzyme (ACE) activity 92.3%; increased plasma renin activity (PRA) 18-fold and reduced mean arterial blood pressure (MABP) 19 mm Hg. Hydrochlorothiazide (HCTZ) (100 mg/kg-day 1; 10 mg/kg-day 2, orally) increased PRA 3-fold but did not affect serum ACE or MABP. HCTZ plus captopril inhibited serum ACE 95.2%; increased PRA 38-fold and reduced MABP 47.5 mm Hg. Captopril or HCTZ plus captopril did not alter the responses of isolated aortic strips to norepinephrine (NE), serotonin, angiotensin II (AII) or isoproterenol. Pressor responses of conscious SHR to AII and NE were unaltered by captopril or HCTZ plus captopril although the bradykinin-induced depressor responses were significantly but equally potentiated. These results suggest that the potentiating effect of HCTZ is due to some mechanism that shifts the animal's blood pressure maintenance system to a renin-dependent state and is not due to changes in vascular reactivity.     

Cardiovascular regulation during angiotensin converting enzyme inhibition with captopril in diabetes-associated hypertension

Diabetes-associated hypertension is accompanied by high levels of body sodium and cardiovascular hyper-reactivity to noradrenaline. Captopril, a promising drug for the treatment of hypertension in diabetics, may influence sodium metabolism and adrenergic pathways. This possibility was investigated in 11 patients with non-azotaemic diabetes mellitus and hypertension, studied after a 3-week placebo phase and after an 8-week phase of captopril treatment (50-100 mg/day). Blood pressure, exchangeable body sodium, blood volume, plasma renin activity, angiotensin II (Ang II), aldosterone, catecholamine levels and the pressor reactivity to infused Ang II or noradrenaline were measured. Compared with placebo, captopril caused a significant decrease in arterial pressure and stimulation of plasma renin activity. Exchangeable sodium, blood volume, plasma Ang II, aldosterone, noradrenaline and adrenaline levels, the pressor and aldosterone responsiveness to infused Ang II and the pressor response to infused noradrenaline (alone or combined with atropine) were not modified. These findings suggest that in hypertensive diabetics angiotensin converting enzyme inhibition causes a marked decrease in blood pressure. The mechanism of action is unrelated to changes in body sodium or noradrenergic-dependent pressor reactivity. In the stable phase of therapy, Ang II-dependent pathways are left unaltered when captopril is administered twice a day.     

Effects of Captopril on Sympathetic Control of the Heart and Vasculature in Dogs

ABSTRACT

Experiments were conducted in pentobarbital anesthetized dogs to investigate the effects of captopril on sympathetic neuronal control of the heart and hindlimb vasculature. Captopril, 3.1 mg/kg, i. v. produced marked reductions in blood pressure and hindlimb perfusion pressure, an observation consistent with the high plasma renin activity in the test animals. Increments in hindlimb perfusion pressure elicited by electrical stimulation of the lumbar sympathetic chain were also significantly reduced following Captopril administration (p <. 002). The subsequent administration of a ten fold higher dose of Captopril, 31. 0 mg/kg, produced no further attenuation of the neurally mediated responses. In contrast to the decreased vascular responses to nerve stimulation after captopril, the tachycardia produced by stimulation of pre- or post-ganglionic neurons to the stellate ganglion were not altered. The results of the present study suggest that captopril acts by inhibiting vascular sympathetic neuronal function when the activity of the renin-angiotensin system is elevated. The attenuation of neurally mediated vasoconstriction may be due to the interruption of angiotensin II formation, thereby, preventing the facilitatory effects of angiotensin on sympathetic neurons.     

Dissociation between in vivo and in vitro measurements of converting enzyme activity after chronic oral treatment with captopril in rats

Intravenous administration of captopril (20 micrograms) produced inhibition of angiontensin I pressor responses by 70 percent and of plasma-converting enzyme activity by 72 percent. Oral treatment with captopril (50 mg/kg/day) for 1 week inhibited angiotensin I pressor responses more (84 percent) than plasma-converting enzyme activity (23 percent). Four month oral treatment of normotensive and spontaneously hypertensive rats with captopril (50 mg/kg/day) led to 68 and 71 percent inhibition of angiotensin I pressor responses, but produced increases in plasma-converting enzyme activity of 123 and 94 percent, respectively. In spontaneously hypertensive rats, elevated converting enzyme activity in the medulla oblongata was measured after this treatment. It is concluded that plasma-converting enzyme activity measurements can be dissociated from the in vivo inhibition of converting enzyme. Chronic oral captopril treatment results in an induction of converting enzyme biosynthesis not only in peripheral tissue but also in the brain.     

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.