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Background Angiotensin II causes hypertension not only by direct constriction of vascular smooth muscle, but also by facilitating the release of noradrenaline from sympathetic terminals and by enhancing vascular noradrenaline sensitivity. AT1 receptor antagonists attenuate all these actions, but display some evidence of substance-related selectivities. Objective The contribution of pre- or postsynaptic impairment of sympathetic transmission to long-term antihypertensive efficacy should be determined for four structurally different, clinically approved AT1 antagonists. Design Spontaneously hypertensive rats were treated with candesartan, eprosartan, irbesartan, or losartan via osmotic minipumps for 4 weeks at doses yielding identical reductions of blood pressure. Maximum efficacy was obtained with a tripled dose of candesartan. Methods In the pithed rat model, stimulus/response dependencies were determined for vasopressor effectivity of preganglionic electrical stimulation, and of intravenous bolus applications of noradrenaline and angiotensin II. Results Losartan, irbesartan, eprosartan, and candesartan at doses of 5, 40, 20, and 0.05 mg/kg per day, were equally effective in reducing basal systolic blood pressure (-42 mmHg), and the vasopressor potency of angiotensin II (approximately 10-fold). The efficacies of preganglionic stimulation and exogenous noradrenaline were unaltered, with the exception of irbesartan, which reduced vascular noradrenaline sensitivity. The tripled dose of candesartan further reduced basal and angiotensin II-stimulated blood pressures, and significantly attenuated vascular noradrenaline sensitivity. Conclusion AT1 antagonists at doses that effectively reduce blood pressure in chronic therapy do not generally suppress peripheral sympathetic function. A potential interaction consists in a reduction of vascular noradrenaline sensitivity, which can be considered as a class effect of AT1 antagonists at high dosage.

Objectives Vasopeptidase inhibitors inhibit neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE). Since angiotensin (ANG) II availability is decreased by ACE inhibition but is increased by NEP inhibition, we evaluated the influence of the vasopeptidase inhibitor omapatrilat on ANG II-dependent noradrenaline (NA) release. Design The functional relevance of ACE-dependent and NEP-dependent generation and degradation of ANG II on NA overflow was determined in pithed rats by applications of ANG I (0.1-100 microg/kg) or ANG II (0.01-10 microg/kg) after single injections of ramipril (1 mg/kg), the NEP inhibitor candoxatril (100 mg/kg), or the vasopeptidase inhibitor omapatrilat (30 mg/kg). Results Blood pressure was equipotently decreased by ramipril and omapatrilat, but not by candoxatril. NA overflow was increased after ANG I infusions in controls (EC50 = 9.0 microg/kgANG I, Emax = 5680 pg/ml), but almost completely suppressed by ramipril and omapatrilat. Candoxatril decreased EC50 (4.1 microg/kg) and increased Emax (7259 pg/ml). NA overflow after ANG II infusions was enhanced by candoxatril or omapatrilat. Ex vivo ACE activity was extensively inhibited by ramipril or omapatrilat, whereas ex vivo NEP activity was reduced by omapatrilat and candoxatril only. In vitro, omapatrilat inhibited NEP and ACE with similar potencies (IC50 NEP/IC50 ACE = 0.4). Conclusions Vasopeptidase inhibitors influence ANG II-related NA release depending on their ability to modulate the availability of ANG II via ACE or NEP. After acute application, the vasopeptidase inhibitor suppresses NA release in response to ANG I due to a predominant reduction of ANG II formation. These results indicate that the ratio of ACE-inhibitory and NEP-inhibitory potencies of vasopeptidase inhibitors may be relevant for sympathetic activation in chronic therapy.

Blockade of angiotensin II type-1 (AT 1 ) receptors has been shown to reduce the magnitude of the blood pressure response to noradrenaline in pithed rats via an unidentified mechanism. Dose-response curves were established for the noradrenaline-induced (10 −12 to 10 −7 mol/kg) increase of diastolic blood pressure in pithed rats treated with tubocurarine, propranolol, and atropine. Candesartan (1 mg/kg) increased the ED 50 of the noradrenaline response (1.3±0.1 nmol/kg) up to 20-fold. Vasopressor responsiveness to noradrenaline was attenuated specifically, whereas the vasopressin-induced increase in diastolic blood pressure was maintained. Specific involvement of AT 1 receptors was confirmed by equivalent actions of losartan. Blockade of norepinephrine transporter or α 2 -adrenoceptors using desipramine or rauwolscine reduced the losartan-induced shifts in the ED 50 values of noradrenaline by 63% and 21%, respectively. Combined blockade of norepinephrine transporter and α 2 -adrenoceptors eliminated the influence of losartan on noradrenaline sensitivity ( ED 50 5.5±1.3 versus 5.6±1.2 nmol/kg), a result also observed after sympathetic denervation by reserpine ( ED 50 7.1±0.8 versus 7.8±0.8 nmol/kg). Our experiments show that the reduction of vascular noradrenaline sensitivity by AT 1 blockade is dependent on the intact functioning of both neuronal noradrenaline uptake via norepinephrine transporter and presynaptic α 2 -mediated autoinhibition, exclusively provided by the sympathetic innervation. These newly identified mechanisms may contribute to the antihypertensive and protective actions of AT 1 blockers.

Objectives It is well established that angiotensin-converting enzyme (ACE) inhibitors (ACEI) reduce blood pressure (BP) and hypertrophy of the left ventricle and vessels. The aim of our study was to compare chemically different ACEIs regarding their ability to modulate left ventricular and media hypertrophy, ACE activity and plasma endothelin-1 concentrations in spontaneously hypertensive rats (SHRs). Design After establishing equi-effective dose regimes, SHRs were treated (3 months) with captopril, enalapril, fosinopril or ramipril (2 × 25, 10, 20 or 1 mg/kg per day or corresponding 1% doses for studying blood pressure-independent effects). Methods and results Systolic blood pressure was reduced in SHRs receiving high doses of captopril, enalapril, fosinopril or ramipril (−61, −54, −35 and −47 mmHg), whereas low doses were ineffective. Left ventricular weight was decreased in animals treated with high doses (captopril/enalapril/fosinopril/ramipril: −17/−19/−17/−19%), but not low doses of agents. Media thickness of thoracal aorta was reduced by administering high doses (captopril/enalapril/fosinopril/ramipril: −31/−32/−27/−26%) and low doses (−16/−22/−22/−19%) of agents. ACE activity was reduced in heart, aorta and kidney of rats treated with high and low doses of all ACE inhibitors, whereby high doses showed more pronounced effects. Plasma endothelin-1 concentrations were not altered. A blood-pressure-ineffective treatment with an AT1-antagonist revealed similar effects on cardiovascular hypertrophy. Conclusions ACEIs reduce cardiovascular hypertrophy uniformly via an AT1-receptor- mediated mechanism, reinforcing the opinion that ACEI effects are indeed class effects. The significance of local renin–angiotensin systems was confirmed by antihypertrophic effects in the aorta that were apparent in the absence of any blood pressure reduction.

Angiotensin II (ANG) is known to facilitate catecholamine release from peripheral sympathetic neurons by enhancing depolarization-dependent exocytosis. In addition, a direct excitation by ANG of peripheral sympathetic nerve activity has recently been described. This study determined the significance of the latter mechanism for angiotensin-induced catecholamine release in the pithed rat. Rats were anesthetized and instrumented for measuring either hemodynamics and renal sympathetic nerve activity or plasma catecholamine concentrations in response to successively increasing doses of angiotensin infusions. Even during ganglionic blockade by hexamethonium (20 mg/kg), angiotensin dose-dependently elevated sympathetic nerve activity, whereas blood pressure–equivalent doses of phenylephrine were ineffective. Independently of central nervous sympathetic activity and ganglionic transmission, angiotensin (0.1 to 1 μg/kg) also induced an up-to 27-fold increase in plasma norepinephrine levels, reaching 2.65 ng/mL. Preganglionic electrical stimulation (0.5 Hz) raised basal norepinephrine levels 11-fold and further enhanced the angiotensin-induced increase in norepinephrine (4.04 ng/mL at 1 μg/kg ANG). Stimulation of sympathetic nerve activity and norepinephrine release were suppressed by candesartan (1 mg/kg) or tetrodotoxin (100 μg/kg), respectively. Angiotensin enhanced plasma norepinephrine, heart rate, and sympathetic nerve activity at similar threshold doses (0.3 to 1 μg/kg), but raised blood pressure at a significantly lower dose (0.01 μg/kg). It is concluded that direct stimulation of ganglionic angiotensin type 1 (AT 1 ) receptors arouses electrical activity in sympathetic neurons, leading to exocytotic junctional catecholamine release. In both the absence and presence of preganglionic sympathetic activity, this mechanism contributes significantly to ANG-induced enhancement of catecholamine release.

Background Angiotensin II is known to facilitate the release of catecholamines from peripheral sympathetic neurons by stimulating presynaptically located receptors. Although inhibitor studies have revealed these to be angiotensin II type 1 (AT 1 ) receptors, they do in fact appear to display peculiar susceptibilities to various AT 1 receptor antagonists, which might correspond to different neuronal and vascular receptor subtypes. Objective A direct comparison of the pre- and postsynaptic potencies of four AT 1 antagonists was performed to characterize these receptors further. Design We studied angiotensin II-induced catecholamine release and vasoconstriction in pithed, spontaneously hypertensive rats under the influence of candesartan, eprosartan, EXP 3174, and irbesartan. The effect of AT 1 blockade on postsynaptic vascular sensitivity to noradrenaline (NA) was also determined. Methods Pithed rats received repeated intravenous applications of either angiotensin II or NA, preceded by cumulatively increasing doses of the AT 1 antagonists. Vasoconstriction and catecholamine release were quantified by the measurement of acute increases in blood pressure and plasma NA, respectively. Results All AT 1 antagonists dose-dependently suppressed angiotensin II-induced vasoconstriction and release of NA. Although the antagonists differed greatly in their inhibitory potencies (ID 50 range 7-445 μg/kg), each displayed a similar potency at both neuronal and vascular angiotensin receptors. In a higher dose range, all AT 1 antagonists attenuated the blood pressure increase in response to NA by up to 70%. The order of potencies for all inhibitory effects was: candesartan > eprosartan > EXP 3174 > irbesartan. Conclusion The AT 1 antagonists tested do not discriminate between presynaptic neuronal and postsynaptic vascular angiotensin II receptors - a fact that refutes the existence of tissue-specific AT 1 receptor subtypes. A marked reduction in vascular sensitivity to NA may contribute to the antihypertensive and cardioprotective mechanisms of AT 1 antagonists.

Objectives It has been shown that a diminished sympathetic activity contributes to the hypotensive and cardioprotective actions of angiotensin converting enzyme (ACE) inhibitors (ACEI). Besides an inhibition of central sympathetic tone and peripheral noradrenaline release, we hypothesized that the interactions of ACEI with the sympathetic system may include a modulation of neuronal catecholamine uptake by peripheral nerves. Design We investigated the influence of fosinopril on noradrenergic uptake into cardiac neurones in vitro and in vivo in acute and chronic models. Methods and results Acute administration of fosinoprilat to isolated perfused rat hearts increased the extraction of [3H]-noradrenaline from the perfusate by 39%. Treatment (14 days) of spontaneously hypertensive rats (SHR) with fosinopril (20 mg/kg per day) enhanced the cardiac uptake of i.v. administered [3H]-noradrenaline by 28%. The endogenous left ventricular content of noradrenaline was increased by 49% after an antihypertensive treatment of SHR with fosinopril (20 mg/kg per day). Identical increases in cardiac noradrenaline stores (53%) were observed in SHR treated with a blood pressure ineffective dose of fosinopril (0.2 mg/kg per day). The myocardial content of adrenaline was increased in parallel to noradrenaline after both dose regimes. Conclusions It is concluded that ACEI increases neuronal uptake of catecholamines in SHR in a blood pressure-independent manner. This effect occurs acutely and is independent of central sympathetic activity. Therefore, we hypothesize that ACEI modulate the activity of the cardiac noradrenaline transporter by direct activation. The improved uptake of noradrenaline may contribute to the antihypertensive and cardioprotective effects of ACEI.