Increased pressor function of central vasopressinergic system in hypertensive renin transgenic rats

OBJECTIVE: Renin transgenic hypertensive rats [TGR(mRen2)27] have increased contents of angiotensin II and arginine vasopressin (AVP) in the cardiovascular brain regions. The aim of the present study was to evaluate the effects of centrally released AVP on the regulation of baseline blood pressure in TGR(mRen2)27 rats and to determine the interaction between AVP and angiotensin II in the central control of blood pressure in this model of hypertension. DESIGN: Three basic series of experiments were performed on 20 TGR(mRen2)27 and 20 Hannover Sprague-Dawley conscious rats, chronically instrumented with lateral cerebral ventricle (LCV) cannulae and femoral artery catheters. In series 1, blood pressure and heart rate were recorded during an LCV infusion of artificial cerebrospinal fluid before and after LCV administration of angiotensin II. In series 2, the effects of an LCV administration of angiotensin 11 (100 ng) on mean arterial pressure and the heart rate were determined during LCV infusion of a selective AVP receptor (V1) antagonist [1-(1-mercapto-4-methylcyclohexaneacetic acid)-8-arginine vasopressin (MeCAAVP) and d(CH2)5[Tyr(Me)2,Ala-NH2(9)]AVP] or a selective angiotensin II type 1 (AT1) receptor antagonist (losartan) or both. In series 3, mean arterial pressure and the heart rate were determined after an LCV injection of either AVP (10 ng) or AVP together with angiotensin II. RESULTS: The LCV infusions of antagonists to V1 and AT1 receptors caused significant comparable decreases in baseline MAP in TGR(mRen2)27 but not in Sprague-Dawley rats. Angiotensin II elicited significant pressor responses, both in TGR(mRen2)27 and in Sprague-Dawley rats. Blockade of V1 receptors significantly reduced the duration and the maximum amplitude of the central pressor response to angiotensin II in TGR(mRen2)27 rats, whereas in Sprague-Dawley rats the maximum pressor effect was not significantly altered. In both strains, the pressor response to angiotensin II was abolished by blockade of AT1 receptors. CONCLUSIONS: The results indicate that the elevated blood pressure in TGR(mRen2)27 rats is partly caused by increased function of the brain angiotensinergic AT1 and vasopressinergic V1 systems. Centrally released AVP is involved in mediation of the pressor effect exerted by centrally applied angiotensin II in TGR(mRen2)27 rats.     

AT1 receptor-mediated stimulation by angiotensin II of rat aortic fibronectin gene expression in vivo

Fibronectin plays an important role in various vascular diseases. A subpressor (200 ng kg-1 min-1) or pressor (1000 ng kg-1 min-1) dose of angiotensin II was continuously infused into rats by osmotic minipump for various times, to investigate the effects on aortic fibronectin gene expression. In rats infused with a subpressor dose of angiotensin II in which blood pressure was normal for 3 days, aortic fibronectin mRNA levels started to increase by 1.4 fold at 12 h and reached the maximal levels (increased by 3.1 fold) at 3 days. Treatment with TCV-116 (3 mg kg-1 day-1), a non-peptide selective AT1 receptor antagonist, completely inhibited the angiotensin II-induced increase in aortic fibronectin mRNA, while hydralazine (10 mg kg-1 day-1) did not block this effect. Similar results were also obtained for a pressor dose of angiotensin II. Thus, angiotensin II directly stimulates aortic fibronectin gene expression in vivo, which is mediated by the AT1 receptor but not by blood pressure.     

Restoration of blood pressure by choline treatment in rats made hypotensive by haemorrhage

1. Intracerebroventricular (i.c.v.) injection of choline (25-150 micrograms) increased blood pressure in rats made acutely hypotensive by haemorrhage. Intraperitoneal administration of choline (60 mg kg-1) also increased blood pressure, but to a lesser extent. Following i.c.v. injection of 25 micrograms or 50 micrograms of choline, heart rate did not change, while 100 micrograms or 150 micrograms i.c.v. choline produced a slight and short lasting bradycardia. Choline (150 micrograms) failed to alter the circulating residual volume of blood in haemorrhaged rats. 2. The pressor response to i.c.v. choline (50 micrograms) in haemorrhaged rats was abolished by pretreatment with mecamylamine (50 micrograms, i.c.v.) but not atropine (10 micrograms, i.c.v.). The pressor response to choline was blocked by pretreatment with hemicholinium-3 (20 micrograms, i.c.v.). 3. The pressor response to i.c.v. choline (150 micrograms) was associated with a several fold increase in plasma levels of vasopressin and adrenaline but not of noradrenaline and plasma renin. 4. The pressor response to i.c.v. choline (150 micrograms) was not altered by bilateral adrenalectomy, but was attenuated by systemic administration of either phentolamine (10 mg kg-1) or the vasopressin antagonist [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2,Arg8]-vasopressin (10 micrograms kg-1). 5. It is concluded that the precursor of acetylcholine, choline, can increase and restore blood pressure in acutely haemorrhaged rats by increasing central cholinergic neurotransmission. Nicotinic receptor activation and an increase in plasma vasopressin and adrenaline level appear to be involved in this effect of choline.     

Endogenous vasopressin increases acute endotoxin shock-provoked gastrointestinal mucosal injury in the rat

Administration of a low dose of endotoxin (from Escherichia coli, 3 mg kg(-1), i.v.), which does not affect vascular permeability or blood pressure over 1 h, leads to the release of endogenous vasopressin and damage to the mucosal microvasculature. Thus, endogenous vasopressin could be involved in septic shock. In the present study, we investigated the role of endogenous vasopressin in gastrointestinal mucosal injury induced by acute endotoxin shock, which was generated in rats by administering a high dose of E. coli endotoxin (50 mg kg(-1), i.v.). Tissues were removed 15 min after endotoxin. The vasopressin V1 receptor antagonist, d[CH2]5Tyr[Me]arginine-vasopressin (0.2-1 microg kg(-1), i.v.), was injected 10 min before endotoxin. Monastral blue (30 mg kg(-1), i.v.), which stains damaged vasculature, was injected 10 min before autopsy. Endotoxin reduced systemic arterial blood pressure (from 115+/-5 to 42+/-4 mmHg), generated macroscopic and microvascular injury, and elevated plasma vasopressin levels (from 3.4+/-0.2 to 178+/-16 pg ml(-1)). The vasopressin V1 receptor antagonist reduced this macroscopic injury, and in the vasopressin-deficient Brattleboro rat a similar reduction of gastrointestinal mucosal damage was found. Substantial decreases in endotoxin-induced microvascular damage were observed in each tissue, e.g., the gastric Monastral blue staining was reduced by 47+/-3% and 96+/-3% (P < 0.01) after vasopressin V1 receptor antagonist treatment and in Brattleboro rats, respectively. Vasopressin, acting through its V1 receptors, thus appears to be involved in acute endotoxin shock-provoked gastrointestinal injury.     

A micropuncture study of the renal response to haemorrhage in rats: assessment of the role of vasopressin

The acute effects of haemorrhage (15 ml (kg body wt)-1) on renal function at whole-kidney and single-nephron levels were studied in Inactin-anaesthetized rats. In order to assess the role of vasopressin in mediating the haemodynamic effects, responses in untreated Long-Evans rats were compared with those in Brattleboro rats (which lack circulating vasopressin) and in Long-Evans rats treated with a V1 receptor antagonist. In time-control animals, there were no significant changes in mean arterial pressure (MAP), excretion rates, glomerular filtration rate (GFR), superficial-nephron GFR (SNGFR) or fluid reabsorption in the superficial proximal tubules during the course of the experiment. Following haemorrhage, the immediate reduction in MAP was followed in each group by partial recovery for 30 min; thereafter, MAP was stable. In untreated Long-Evans rats, haemorrhage was followed by a 26% reduction in GFR (P < 0.001, measured 60-150 min post-haemorrhage) and a larger reduction (45%, P < 0.001) in SNGFR, so that the SNGFR/GFR ratio fell significantly ((27.9 +/- 1.9) x 10(-6), control period; (20.2 +/- 2.2) x 10(-6) post-haemorrhage, P < 0.01). Slightly greater reductions in GFR and SNGFR were seen in Brattleboro rats and V1 antagonist-treated Long-Evans rats, which corresponded to slightly greater haemorrhage-induced reductions in blood pressure in these groups; the falls in the SNGFR/GFR ratio were similar to that in untreated Long-Evans rats. In all three groups of bled rats, fractional reabsorption by the proximal convoluted tubule increased slightly 30-60 min after haemorrhage, but during the subsequent period (60-150 min) returned to values indistinguishable from those during the control period. The results suggest that the renal haemodynamic changes that follow moderate haemorrhage include a preferential reduction in the GFR of superficial nephrons. Vasopressin appears to play no role in this response. Increases in fractional reabsorption in the proximal tubules are seen only during the immediate post-haemorrhage period.     

Contribution of humoral systems to the recovery of blood pressure following severe haemorrhage

1. Profound haemorrhage activates a number of pressor mechanisms, including the release of catecholamines, angiotensin II and arginine-vasopressin, which contribute to the subsequent cardiovascular recovery. Using specific single or combined blockade with prazosin, losartan and Manning compound (AVPX), the aim of this study was to evaluate the involvement of the three pressor systems in blood pressure recovery following severe haemorrhage (20 ml kg-1). 2. Haemorrhage of conscious, unrestrained rats resulted in a significant initial decrease in blood pressure of approximately 60 mmHg, and heart rate of approximately 70 bpm. Then, blood pressure tended to return to the control level within 10 min. The total cardiovascular recovery corresponded to increments of 52 +/- 5 mmHg (81% of the acute fall) for systolic blood pressure, and of 92 +/- 22 bpm (124%) for heart rate at 60 min post-bleeding. Significant falls in haematocrit (-10.5 +/- 1.2%, P < 0.01), in plasma concentrations of proteins (-10.3 +/- 0.9 g l-1, P < 0.01) and haemoglobin (-2.58 +/- 0.72 g 100 ml-1, P < 0.05) were observed at 60 min post-bleeding. 3. Pretreatment with one or two specific antagonists did not exaggerate the initial fall in blood pressure. The initial bradycardia was weakened only by combined blockade with losartan and AVPX. 4. The blood pressure recovery from a haemorrhage was delayed by approximately 25 min by the inhibition of vasopressin activity. The systolic blood pressure recovery in control animals (81% of the acute fall) was blunted by losartan (55% of the acute fall), prazosin (49%), combined losartan and AVPX (36%), prazosin and AVPX (36%), and also by prazosin plus losartan (13%). The diastolic blood pressure recovery was blunted only in the groups where the activity of angiotensin II was inhibited by losartan. 5. In conclusion, we have shown that neither catecholamines, angiotensin II nor vasopressin, although activated, individually compensate the acute hypotensive response to haemorrhage. The contribution of vasopressin to the blood pressure recovery post-bleeding is transient and is rapidly replaced by the pressor activity of the catecholamines and angiotensin II. The full systolic blood pressure recovery from severe haemorrhage requires the combined activity of these two pressor systems, while the diastolic blood pressure recovery seems to be only dependent upon angiotensin II activity.     

Lack of effect of a selective vasopressin V1A receptor antagonist SR 49,059, on potentiation by vasopressin of adrenoceptor-mediated pressor responses in the rat mesenteric arterial bed

The vasopressin receptor subtype involved in the enhancement by vasopressin of adrenoceptor-mediated vasoconstriction was investigated in rat isolated perfused mesenteric arteries. [Arg8]vasopressin (1-10 nM) dose-dependently increased the perfusion pressure and enhanced the pressor response to the adrenoceptor agonist methoxamine (40 nmol) or electrical stimulation of periarterial nerves (16 Hz), at the concentration of 10 nM of [Arg8]vasopressin up to 4 and 3 fold, respectively. During prolonged exposure (45 min) the direct vasoconstrictor effect of [Arg8]vasopressin (10 nM) rapidly declined whereas the potentiation of methoxamine-induced vasoconstriction was maintained. The selective vasopressin V1A receptor antagonist SR 49,059 (1-3 nM) and the non-selective V1A/B and oxytocin receptor antagonist [deamino-Pen1,Tyr(Me)2,Arg8]vasopressin (15-45 nM) inhibited the direct vasoconstrictor action of [Arg8]vasopressin but had no effect on the enhancement of the pressor response to methoxamine or electrical stimulation. The V1B receptor agonist [deamino-Cys1,beta-(3-pyridyl)-D-Ala2,Arg8]vasopressin (100-1000 nM) and the V2 receptor agonist [deamino-Cys1,D-Arg8]vasopressin (1-10 nM) were devoid of any pressor activity and did not potentiate methoxamine-evoked vasoconstriction. In contrast, [1-triglycyl,Lys8]vasopressin (100 - 1000 nM) potentiated the methoxamine responses without per se inducing vasoconstriction. In arteries precontracted with methoxamine (7.5 microM) pressor responses to [Arg8]vasopressin (3-10 nM) were not inhibited by a dose of SR 49,059 (3 nM) which abolished the peptide's vasoconstrictor effect under control conditions. These data show that the direct vasoconstrictor effect of [Arg8]vasopressin is mediated by V1A receptors while the enhancement of adrenoceptor-mediated pressor responses is insensitive to V1A, V1B, and oxytocin receptor antagonists and is not mimicked by selective agonists of V1B and V2 receptors. In conclusion, an unusual interaction of vasopressin with V1A receptors, or even the existence of a novel receptor subtype, has to be considered.     

Differential effects of endotoxaemia on pressor and vasoconstrictor actions of angiotensin II and arginine vasopressin in conscious rats

1. Regional haemodynamic responses to arginine vasopressin (AVP; 0.5, 1.0, 5.0 pmol i.v.) and angiotensin II (AII; 5.0, 10.0, 50.0 pmol i.v.) were measured in conscious Long Evans rats at various times (0, 2, 6 and 24 h) during infusion of lipopolysaccharide (LPS, 150 microg kg(-1) h(-1), i.v., n=9) or saline (n=9). Additional experiments were performed in vasopressin-deficient (Brattleboro) rats infused with LPS (n=7) or saline (n=8) to determine whether or not, in the absence of circulating vasopressin, responses to the exogenous peptides differed from those in Long Evans rats. 2. In the Long Evans rats, during the 24 h infusion of LPS, there was a changing haemodynamic profile with renal vasodilatation from 2 h onwards, additional mesenteric vasodilatation at 6 h, and a modest hypotension (reduction in mean arterial blood pressure (MAP) from 103+/-1 to 98+/-2 mmHg) associated with renal and hindquarters vasodilatation at 24 h. 3. In the Brattleboro rats, the changes in regional haemodynamics during LPS infusion were more profound than in the Long Evans rats. At 2 h and 6 h, there was a marked fall in MAP (from 103+/-3 mmHg; to 65+/-3 mmHg at 2 h, and to 82+/-4 mmHg at 6 h) associated with vasodilatation in all three vascular beds. After 24 h infusion of LPS, the hypotension was less although still significant (from 103+/-3 mmHg; to 93+/-4 mmHg, a change of 10+/-4 mmHg), and there was renal and hindquarters vasodilatation, but mesenteric vasoconstriction. 4. During infusion of LPS, at each time point studied, and in both strains of rat, pressor responses to AII and AVP were reduced, but the changes were less marked at 6 h than at 2 h or 24 h. The reduced pressor responses were not accompanied by generalized reductions in the regional vasoconstrictor responses. Thus, in the Long Evans rats, the renal vasoconstrictor responses to both peptides were enhanced (at 6 h and 24 h for AVP; at all times for AII), whereas the mesenteric vasoconstrictor response to AVP was unchanged at 2 h, enhanced at 6 h and reduced at 24 h. The mesenteric vasoconstrictor response to AII was reduced at 2 h, normal at 6 h and reduced at 24 h. The small hindquarters vasoconstrictor responses to both peptides were reduced at 2 h and 6 h, but normal at 24 h. 5. In the Brattleboro rats, the renal vasoconstrictor responses to both peptides were reduced at 2 h and enhanced at 6 h and 24 h, whereas the mesenteric vasoconstrictor response to AVP was normal at 2 h and 6 h, and reduced at 24 h. The response to AII was reduced at 2 h, normal at 6 h and reduced again at 24 h. There were no reproducible hindquarters vasoconstrictions to AVP in the Brattleboro rats. The small hindquarters vasoconstrictor responses to AII were unchanged at 2 h and enhanced at 6 h and 24 h. 6. In isolated perfused mesenteric vascular beds, removed after 24 h of LPS infusion in vivo, there was an increase in the potency of AVP in both strains (Long Evans, ED50 saline: 56.9+/-15.0 pmol, ED50 LPS: 20.4+/-4.8 pmol, Brattleboro, ED50 saline: 38.6+/-4.2, ED50 LPS: 19.6+/-2.9 pmol), but no change in the responses to AII. 7. These findings indicate that a reduced pressor response to a vasoconstrictor challenge during LPS infusion is not necessarily associated with a reduced regional vasoconstriction. The data obtained in the Brattleboro rats indicate a potentially important role for vasopressin in maintaining haemodynamic status during LPS infusion in Long Evans rats. However, it is unlikely that the responses to exogenous AVP (or AII) are influenced by changes in the background level of endogenous vasopressin, since the patterns of change were similar in Long Evans and Brattleboro rats. 8. The results obtained in isolated perfused mesenteric vascular beds differed from those in vivo, possibly due to the conditions pertaining with in vitro perfusion.     

The effect of angiotensin AT1 receptor blockade in the brain on the maintenance of blood pressure during haemorrhage in sheep

The effect of systemic or intracerebroventricular (ICV) infusion of the angiotensin AT1 receptor antagonist losartan on blood pressure during hypotensive haemorrhage was investigated in five conscious sheep. Mean arterial pressure (MAP) was measured during haemorrhage (15 mL kg-1 body wt). Losartan (1 or 0.33 mg h-1) was given to sheep by ICV, intravenous or intracarotid administration, beginning 60 min before and continuing during the haemorrhage. During control infusion of ICV artificial cerebrospinal fluid, MAP was maintained until 13.16 +/- 0.84 mL kg-1 blood loss, when a rapid reduction of at least 15 mmHg in arterial pressure occurred (the decompensation phase). ICV infusion of losartan at 1 mg h-1 caused an early onset of the decompensation phase after only 9.8 +/- 0.8 mL kg-1 of blood loss compared with control. Intravenous infusion of losartan (1 mg h-1) also caused an early onset (P < 0.05) of the decompensation phase at 10.2 +/- 1.0 mL kg-1 blood loss. This dose of losartan inhibited the pressor response to ICV angiotensin II, but not to intravenously administered angiotensin II, indicating that only central AT1 receptors were blocked. Bilateral carotid arterial administration of losartan at 0.33 mg h-1 caused an early onset of the decompensation phase during haemorrhage at 11.06 +/- 0.91 mL kg-1 blood loss (P < 0.05), which did not occur when infused by intravenous or ICV routes. The results indicate that an angiotensin AT1-receptor-mediated mechanism is involved in the maintenance of MAP during haemorrhage in sheep. The locus of this mechanism appears to be the brain.     

The influence of perindopril on intrarenal RAS in experimental diabetic rats

OBJECTIVE: To examine the effect of perindopril on the intrarenal renin angiotensin system (RAS) in diabetic rats. METHODS: Diabetes of rats was induced by a single injection of STZ. The rats were treated with perindopril (1 mg.kg-1.d-1) and the controls were given insulin only. Plasma and intrarenal renin activity (PRA, TRA) and angiotensin I (PAT I, TATII) were measured by radioimmunoassay in the diabetic rats at 1, 3, 6 months. Message RNA (mRNA) expression of renal angiotensinogen (TATO) and TATII receptor (TATII R) was assessed by slot blot hybridization. RESULTS: At 6 month, TATII levels in the control group were significantly decreased compared with those of normal controls (P < 0.05), and TATII levels in perindopril treated rats were decreased remarkedly compared with those of the control group (P < 0.01). TRA was not different among the three groups at 3 to 6 months (P > 0.05). In slot blot hybridization TATII R mRNA expression in the control group was markedly increased compared with that of perindopril treated and normal control groups (P < 0.05, P < 0.01). TATO mRNA expression was not different among the three groups (P > 0.05) during the experimental period. CONCLUSION: The abnormalities of intrarenal RAS existed in STZ induced diabetic rats, including the decrement of TATII content and the enhancement of TATII R mRNA expression. Perindopril could further decrease the level of intrarenal TATII, and inhibit its receptor mRNA expression.     

Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade

It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type I (AT1) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8 [angiotensin II] (10 micrograms/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertension.     

Effects of niflumic acid on alpha1-adrenoceptor-induced vasoconstriction in mesenteric artery in vitro and in vivo in two-kidney one-clip hypertensive rats

Treatment of conscious spontaneously hypertensive rats (SHR) with the dopamine D2 receptor agonist quinpirole causes a short-lasting pressor response and apparent desensitisation to the effects of subsequent injections of quinpirole or central antihypertensives such as clonidine. In the present study, a number of aspects of this apparent desensitisation were investigated. Thirty minutes after intravenous injection of quinpirole into spontaneously hypertensive rats, treatment with the dopamine D2 receptors antagonist raclopride caused a significant fall in blood pressure. At this time point, circulating levels of vasopressin were not significantly different compared to controls. In Brattleboro rats, the pressor response to quinpirole was reduced in the first 15 min after injection, but not difference in blood pressure was observed at later time points. In SHR which had been treated with quinpirole, the central antihypertensive effects of rilmenidine or alpha-methyldopa were significantly inhibited. By contrast, the bradycardia induced by these drugs was similar in quinpirole-treated rats and controls. Quinpirole pretreatment caused an enhancement of the hypotension but a reduction of the reflex tachycardia after intravenous treatment with hydralazine. In SHR treated with methylatropine and quinpirole, the upper plateau of the sympathetic baroreceptor-heart rate reflex curve was reduced. These results show that treatment with quinpirole has marked effects on central sympathetic vasomotor mechanisms which are the target of antihypertensive drugs such as rilmenidine and alpha-methyldopa. At least some of these effects may occur at the level of the sympathetic baroreflex. Moreover, while the effects of quinpirole on sympathetic regulation are prolonged, the initial pressor response is counteracted by an as yet unidentified compensatory mechanism which can be unmasked when quinpirole is displaced from its receptor by dopamine D2 receptor antagonist treatment.     

Principal modifications of the Duhamel procedure in the treatment of Hirschsprung''s disease. Analysis based on results of an international retrospective study of 2,430 patients

The present study was undertaken to investigate the effects of losartan, a non-peptide angiotensin II subtype 1 (AT1) receptor antagonist, on both the pressor responses elicited by stimulation of afferent vagal nociceptive fibres and the involvement of the sympathetic nervous system (evaluated by plasma levels of noradrenaline and its co-neurotransmitter neuropeptide Y) in dogs. Electrical stimulation of the afferent fibres of the vagus (1, 5, 10 and 20 Hz) elicited a frequency-dependent increase in blood pressure and heart rate. Plasma noradrenaline levels only increased after stimulation at frequencies of 10 and 20 Hz. Plasma neuropeptide Y levels did not change. Losartan (10 mg/kg i.v.) induced both a decrease in resting blood pressure and an increase in basal plasma levels of noradrenaline and neuropeptide Y. Losartan failed to modify the magnitude of the electrically-evoked pressor and positive chronotropic responses. The angiotensin AT1 receptor antagonist elicited a fall in plasma noradrenaline values after a 1 Hz stimulation and abolished the increase in plasma noradrenaline levels induced by the 10 (but not 20) Hz stimulation. The data suggest that angiotensin AT1 receptors are not directly involved in acute pressor responses induced by stimulation of afferent vagal fibres. Moreover, the results show that, besides its sympatho-inhibitory effect, losartan can exert a sympatho-excitatory action as shown by the increase in the plasma levels of both noradrenaline and its coneurotransmitter, neuropeptide Y.     

Monocyte chemotactic protein 1 regulates oral tolerance induction by inhibition of T helper cell 1-related cytokines

Intracerebroventricular (i.c.v.) choline (50-150 microg) increased blood pressure and decreased heart rate in spinal cord transected, hypotensive rats. Choline administered intraperitoneally (60 mg/kg), also, increased blood pressure, but to a lesser extent. The pressor response to i.c.v. choline was associated with an increase in plasma vasopressin. Mecamylamine pretreatment (50 microg; i.c.v.) blocked the pressor, bradycardic and vasopressin responses to choline (150 microg). Atropine pretreatment (10 microg; i.c.v.) abolished the bradycardia but failed to alter pressor and vasopressin responses. Hemicholinium-3 [HC-3 (20 microg; i.c.v.)] pretreatment attenuated both bradycardia and pressor responses to choline. The vasopressin V1 receptor antagonist, (beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2, Arg8)-vasopressin (10 microg/kg) administered intravenously 5 min after choline abolished the pressor response and attenuated the bradycardia-induced by choline. These data show that choline restores hypotension effectively by activating central nicotinic receptors via presynaptic mechanisms, in spinal shock. Choline-induced bradycardia is mediated by central nicotinic and muscarinic receptors. Increase in plasma vasopressin is involved in cardiovascular effects of choline.     

Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat

BACKGROUND: After myocardial infarction, the noninfarcted left ventricle develops reactive hypertrophy associated with a depressed coronary flow reserve, myocardial interstitial fibrosis, and reduced capillary density. The present study investigated the comparative cardiac effects of chronic angiotensin-converting enzyme (ACE) inhibition and selective angiotensin II type 1 receptor (AT1) blockade in the rat model of myocardial infarction and failure. METHODS AND RESULTS: Seven days after coronary ligation (MI), rats were randomized to enalapril (n = 8; 500 micrograms.kg-1.d-1), losartan (n = 9; 3 mg.kg-1.d-1), or placebo (n = 8) and treated for 6 weeks. Sham-operated rats (n = 10) served as controls. Coronary blood flow was measured with radiolabeled microspheres during baseline and maximal coronary dilation induced by dipyridamole (2 mg.kg-1.min-1 over 10 minutes). Right and left ventricular (LV) weight was increased in infarcted rats compared with sham-operated animals and enalapril- and losartan-treated MI rats. Minimal LV and right ventricular coronary vascular resistance was increased in MI rats but normalized with enalapril and losartan (LV:sham, 8.9; MI-placebo, 12.7; MI-enalapril, 9.2; MI-losartan, 8.8 mm Hg.mL-1.min-1.g-1, all P < .05 versus MI-placebo). Interstitial fibrosis determined from perfusion-fixed hearts was increased in infarcted rats but reduced by both enalapril and losartan. Myocardial capillary density improved with enalapril and losartan. In separate groups treated as above, plasma and tissue ACE activity was determined and demonstrated significantly higher ACE activity in noninfarcted LV tissue of MI-placebo rats compared with sham (0.64 vs 0.27 nmol.mg protein-1.min-1, P < .05). Enalapril and losartan reduced LV ACE activity (0.39 and 0.29 nmol.mg protein-1.min-1, P < .05 versus MI-placebo). CONCLUSIONS: The present study demonstrates that both chronic ACE inhibition and AT1 receptor blockade (1) reduces cardiac hypertrophy, (2) restores minimal coronary vascular resistance in postinfarction reactive hypertrophy, and (3) attenuates the development of myocardial interstitial fibrosis in the noninfarcted LV. These results suggest that inhibition of generation of angiotensin II and AT1 receptor blockade are equally effective in preventing important features of ventricular remodeling after myocardial infarction.     

Mechanisms of the regional hemodynamic effects of a mu-opioid receptor agonist microinjected into the hypothalamic paraventricular nuclei of conscious unrestrained rats

The present study was undertaken to characterize the mechanisms of the hemodynamic responses to microinjection of the selective mu-opioid receptor agonist [D-Ala2,MePhe4,Gly5-ol]enkephalin (DAMGO) into the paraventricular nucleus of the hypothalamus, in conscious rats chronically instrumented with pulsed Doppler flow probes. We found that i.v. pretreatment with phentolamine had no effect on the tachycardia elicited by DAMGO (1 nmol); however, the pressor response was reversed to a state of hypotension, the renal and superior mesenteric vasoconstrictions were attenuated and the hindquarter vasodilation was potentiated. In the presence of propranolol, the pressor response and renal vasoconstriction were unchanged, whereas the superior mesenteric vasoconstriction was reduced and the hindquarter vasodilation was abolished. Moreover, in those animals we observed bradycardia followed by tachycardia. Combined i.v. pretreatment with phentolamine and propranolol abolished the pressor and heart rate responses to DAMGO but had no effect on the renal and superior mesenteric vasoconstrictions, although the hindquarter vasodilation was reduced. Intravenous pretreatment with a vasopressin V1 receptor antagonist or captopril had no effect on the cardiovascular responses to DAMGO. Together, these results indicate that the hypertension observed after injection of DAMGO into the paraventricular nucleus of the hypothalamus was secondary to alpha adrenoceptor-mediated vasoconstrictions in renal and superior mesenteric vascular beds and to beta adrenoceptor-mediated vasodilation in the hindquarter vascular bed, whereas the involvement of circulating vasopressin or angiotensin seems less obvious from the present findings. However, we cannot exclude the possibility that nonadrenergic, nonvasopressinergic and nonangiotensinergic vasoconstrictor mechanisms were acting in the renal and superior mesenteric vascular beds.     

Lack of involvement of bradykinin in the vascular sympathoinhibitory effects of angiotensin converting enzyme inhibitors in spontaneously hypertensive rats

1. The aim of this study was to investigate the contribution of endogenous bradykinin to the vascular sympathoinhibitory effects exerted by angiotensin I converting enzyme inhibitors (ACEIs) in the spontaneously hypertensive rat (SHR). 2. Adult SHRs were treated daily for 8 days with either perindopril (3 mg kg-1), or a selective angiotensin II AT1 receptor antagonist, losartan (10 mg kg-1) both given orally--these two doses being equipotent in inhibiting angiotensin I (AI)-induced vascular responses--or distilled water (controls). After pithing, the animals were instrumented for determination of blood pressure, heart rate, cardiac output, regional (renal, mesenteric, hindlimb) blood flows (pulsed Doppler technique) and corresponding vascular resistances. Afterwards, half of the animals of each group were given the selective bradykinin B2 receptor antagonist, icatibant, used in a dose (10 micrograms kg-1, i.v.) that achieved B2 receptor blockade, the other half received saline (10 microliters kg-1, i.v.). Haemodynamic responses to increasing frequencies of spinal cord stimulation were then measured. 3. Pressor and vasoconstrictor responses to AI were significantly and similarly reduced in both perindopril- and losartan-treated groups. Perindopril and losartan both decreased to a similar extent the pressor and vasoconstrictor responses to electrical stimulation of the spinal cord. 4. In the dose used, icatibant did not affect any of the investigated haemodynamic parameters in any of the experimental groups. Furthermore, icatibant did not affect the stimulation frequency-response curves in the control animals and did not modify the vascular sympathoinhibitory effects exerted by perindopril and by losartan. 5 Taken together, these results demonstrate that endogenous bradykinin does not, through B2 receptor activation, contribute to the vascular sympathoinhibitory effects of ACEIs in SHRs.     

Circulating angiotensin II and renal sodium handling in man: a dose-response study

1. Animal studies have shown that angiotensin II has a biphasic effect on urinary sodium excretion. To examine whether this is also true in man, we studied seven salt-replete male subjects in a single-blind placebo-controlled manner. 2. While undergoing maximum diuresis, subjects were infused with 0, 1, 2, 5 or 10 ng of angiotensin II min-1 kg-1 over 80 min. Subjects were studied while seated, and stood every 20 min for urine collection. 3. Angiotensin II produced a dose-dependent antidiuretic effect. The urine flow rate, in ml/min expressed as the change from baseline with increasing dose of angiotensin, was: +3.4 +/- 1.77, -1.26 +/- 0.49 (P < 0.05), -2.75 +/- 1.23 (P < 0.05), -4.21 +/- 0.82 (P < 0.05) and -6.51 +/- 1.07 (P < 0.01). 4. In contrast, the effect of angiotensin II on sodium excretion showed a flat dose-response curve beyond 5 ng min-1 kg-1. The urinary sodium excretion, in mumol/min expressed as the change from baseline with increasing dose of angiotensin, was: 9.5 +/- 21.2, -18.9 +/- 29.6, -37.0 +/- 11.6 (P < 0.05), -67.7 +/- 19.6 (P < 0.01) and -63.8 +/- 14.3 (P < 0.01). 5. The fractional distal reabsorption of sodium, determined by using the lithium clearance technique, showed a rise with all doses of angiotensin II used and reached statistical significance with the top two doses. 6. Unlike antidiuresis, antinatriuresis after graded doses of angiotensin II in human subjects showed a flat dose-response curve beyond 5 ng min-1 kg-1. Pressor doses of angiotensin II also have a significant effect on the distal tubule in promoting sodium reabsorption.     

Changes of blood pressure responsiveness in rats exposed in utero and perinatally to a high-salt environment

We tested the hypothesis that the pressor responses to angiotensin II could be influenced by an early salt exposure. Twenty-five adult female rats were pseudorandomly divided in two groups. Twelve animals underwent a partial ligature of their abdominal aorta (PAL). Once polydipsia and sodium appetite developed, these rats were mated. The other group (13 rats) was sham-operated (Sham) and mated. Throughout pregnancy and lactation, water and 2.7% NaCl solution intakes differed between the two groups of mother rats. PAL offspring (PAL-O; n = 14), and Sham-operated offspring (Sh-O; n = 10), were maintained on a solid diet containing 1% NaCl, tap water and a 2.7% NaCl solution. At 90 days of age, pressor responsiveness to intravenous angiotensin II (50, 100 and 200 ng) was assessed in anesthetized rats. The pressor responses to 50 and 200 ng angiotensin II were significantly greater in PAL-O rats than in Sh-O rats. These results support the hypothesis of a modulation of cardiovascular responsiveness or its underlying mechanisms by an early high salt environment.