Factors affecting endothelin-induced venous tone in conscious rats

There may be a relation between altered venous function, endothelin (ET)-1, and an impairment in the activity of endothelial-derived nitric oxide (NO) and prostanoids in salt-dependent hypertension. The present study examined the effects of salt intake on ET-induced changes in venomotor tone and the effects of blockade of NO synthase with N(G)-nitro-L-arginine methyl ester (L-NAME) and of cyclooxygenase with indomethacin on venomotor tone caused by the ET(B) selective agonist sarafotoxin 6c (S6c) in awake rats. Rats were anesthetized for permanent placement of catheters for measurements of arterial and venous pressures. A silicone balloon catheter was also fixed in the right atrium to produce brief circulatory arrest. Venomotor tone was estimated from measurements of mean circulatory filling pressure (MCFP) in conscious rats. There were no differences in mean arterial pressure, heart rate, or MCFP responses to short-term administration of ET-1 or S6c at different levels of salt intake. L-NAME or indomethacin did not change MCFP or the response of MCFP to short-term injection of S6c. In conclusion, neither basal MCFP nor integrated venomotor responses to short-term injection of ET-1 or S6c were altered by short-term changes in salt intake, blockade of NO synthase or cyclooxygenase. These data do not support the hypothesis that increased salt intake alters reactivity of veins to ET-1, NO, or prostanoids.     

Effects of vasodilator drugs on venous tone in conscious rats

The dose-response effects of vasodilator drugs, nitroglycerin, sodium nitroprusside and hydralazine, on mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP), an index of body venous tone, were investigated in conscious, unrestrained, intact rats as well as in rats treated with the ganglionic blocker, hexamethonium. The effects of these drugs were compared with those of the vehicle, normal saline, in control rats. In intact rats, i.v. infusion of nitroglycerin did not alter MAP while i.v. infusions of nitroprusside or hydralazine caused dose-dependent decreases in MAP. After ganglionic blockade, all three drugs decreased MAP. In intact rats, nitroglycerin and sodium nitroprusside did not affect MCFP but hydralazine increased MCFP. After treatment with hexamethonium, all three drugs decreased MCFP. The decreases in MCFP caused by nitroglycerin and nitroprusside, but not that by hydralazine, were significantly greater than the corresponding changes in control rats. Thus, in intact rats, the direct venodilator actions of nitroprusside and nitroglycerin were masked by endogenous sympathetic tone. When sympathetic nerve activity was attenuated, both nitroprusside and nitroglycerin have venodilator effects. Hydralazine, on the other hand, had insignificant venodilator effect both in the presence and absence of sympathetic reflexes.     

Effect of substance P on venous tone in conscious rats

Substance P is an undecapeptide that belongs to the mammalian tachykinin family. We investigated the effects of substance P on venous tone in conscious rats through measurement of mean circulatory filling pressure. The effects of substance P (10 and 30 nmol/kg, IV) and the vehicle (0.9% NaCl) on mean arterial pressure, heart rate, and mean circulatory filling pressure were examined in 2 groups each of conscious rats: rats without or with ganglionic blockade through pretreatment with mecamylamine (10 mg/kg, IV) and norepinephrine (4 microg/kg/min, IV). In the unblocked rats, both doses of substance P reduced mean arterial pressure (-19 +/- 1 and -35 +/- 2 mm Hg) and increased heart rate (+113 +/- 14 and +115 +/- 23 beats/min). The high dose of substance P also decreased mean circulatory filling pressure (-1.7 +/- 0.3 mm Hg). In the ganglionic-blocked rats, both doses of substance P decreased mean arterial pressure (-48 +/- 6 and -73 +/- 6 mm Hg) and mean circulatory filling pressure (-2.9 +/- 0.4 and -4.2 +/- 0.8 mm Hg) but did not affect HR. In conclusion, substance P is a vasodilator peptide that has a prominent venodilator action.     

Influence of urocortin and corticotropin releasing factor on venous tone in conscious rats

The corticotropin releasing factor (CRF) family includes CRF and urocortin. The effects of urocortin and CRF (0.3, 1, 3 and 10 nmol/kg, i.v.) relative to those of vehicle (0.9% NaCl) on mean arterial pressure and mean circulatory filling pressure (index of venous tone) were examined in conscious, unrestrained rats that were either intact (unblocked) or ganglion-blocked by treatment with mecamylamine (10 mg/kg, i.v.) followed by noradrenaline (4 microg/kg/min, i.v.) to increase vasomotor tone. Both urocortin and CRF dose-dependently decreased mean arterial pressure in intact rats and ganglion-blocked rats. The depressor action of urocortin was greater than that of CRF at all doses. In intact rats, neither compound reduced mean circulatory filling pressure. In ganglion-blocked rats, urocortin and the highest dose of CRF decreased mean circulatory filling pressure. In conclusion, both urocortin and CRF are vasodepressor agents with venodilator action.     

Effect of intermedin/adrenomedullin-2 on venous tone in conscious rats

We investigated the effect of intermedin/adrenomedullin-2 (3 and 10 nmol/kg, i.v.), a member of the calcitonin gene-related peptide family, relative to the vehicle (0.9% NaCl) on mean circulatory filling pressure (index of venous tone) in conscious rats: intact (unblocked) or ganglionic blocked through treatment with mecamylamine (10 mg/kg, i.v.) and noradrenaline (4 μg/kg/min, i.v.). In intact rats, both doses of intermedin/adrenomedullin-2 reduced mean arterial pressure (−14±3, −30±3 mmHg), but did not alter mean circulatory filling pressure; the high dose also increased heart rate. In ganglionic-blocked rats, both doses decreased mean arterial pressure (−22±3, −46±5 mmHg) and the high dose also decreased mean circulatory filling pressure (−2.81±0.82 mmHg), but neither dose affected heart rate. The vehicle did not have any effects in any of the groups. In addition, intermedin/adrenomedullin-2 did not have any effect on blood volume in both intact and ganglion-blocked rats. The results show that intermedin/adrenomedullin-2 is a dilator of arterial resistance and capacitance vessels.     

Effect of nociceptin/orphanin FQ on venous tone in conscious rats

Nociceptin (orphanin FQ) is an endogenous agonist for the opioid receptor-like1 (ORL1) receptor. We investigated the effects of nociceptin on mean circulatory filling pressure, an index of venous tone. The effects of nociceptin (10, 30 nmol/kg, i.v.) and the vehicle (0.9% NaCl) on mean arterial pressure, heart rate and mean circulatory filling pressure were examined in two groups each of conscious rats: rats with, or without, ganglionic blockade through pretreatment with mecamylamine (1 mg/kg, i.v.) and noradrenaline (2 microg/kg min, i.v.). In the unblocked rats, both doses of nociceptin decreased mean arterial pressure and heart rate, and the high dose also decreased mean circulatory filling pressure. In the ganglionic-blocked rats, nociceptin did not alter heart rate but caused greater reductions of mean arterial pressure and mean circulatory filling pressure. The vehicle had no effects in any group. Therefore, nociceptin is a depressor agent with prominent direct venodilator and bradycardic action.     

Effects of endothelin on arterial pressure and venous tone in intact and hexamethonium-treated conscious rats.

The dose-response effects of the potent vasoconstrictor peptide endothelin on mean arterial pressure (MAP), heart rate (HR), and mean circulatory filling pressure (MCFP), an index of body venous tone, were investigated in conscious and unrestrained, intact rats as well as in rats continuously infused with the ganglionic blocker hexamethonium. The dose of hexamethonium selected was that which reduced the reflex tachycardia induced by i.v. injections of acetylcholine by 50%. In intact rats and rats pretreated with hexamethonium, i.v. injections of endothelin caused dose-dependent increases in MAP and decreases in HR. Low doses of endothelin did not affect MCFP while the highest dose in the intact rat, and the two highest doses in hexamethonium-treated rats, caused small but significant increases in MCFP. Our results suggest that endothelin has small effects on body venous tone in contrast to its effectiveness in raising arterial pressure.     

Regional haemodynamic effects of angiotensin II (3-8) in conscious rats.

1. It has been reported that angiotensin II (AII) (3-8) causes endothelium-dependent renal cortical vasodilatation, in anaesthetized rats, through interaction with a novel receptor that shows no affinity for the AT1-receptor antagonist, losartan. Therefore in order to get a fuller profile of the regional haemodynamic effects of AII (3-8) in conscious rats we assessed its renal, mesenteric and hindquarters vascular effects, and compared them to the responses elicited by AII and AIII. 2. AII and AIII (1.25, 12.5 and 125 pmol kg-1) caused dose-dependent pressor and renal and mesenteric vasoconstrictor effects. At doses up to 125 pmol kg-1, AII (3-8) was without any cardiovascular effects, but with doses of 1.25 and 12.5 nmol kg-1 there were dose-dependent increases in mean arterial blood pressure and reductions in renal and mesenteric flows and vascular conductances. The responses to AII (3-8) (12.5 nmol kg-1) were abolished by losartan (20 mumol kg-1). 3. Since it has been found that pretreatment with L-arginine can reveal a vasodilator effect of AII (3-8) on rabbit pial arterioles, we assessed responses to AII (3-8) (12.5 nmol kg-1) before and 5 min after onset of a primed infusion of L-arginine (1.4 mmol kg-1 bolus, 1.4 mmol kg-1 h-1 infusion). Responses to AII (3-8) were unchanged by L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct positive chronotropic effects of angiotensin II and angiotensin III in pithed rats and in rat isolated atria.

1. The direct positive chronotropic effects of angiotensin II (AII) and its degradation products angiotensin III (AIII) and angiotensin IV (AIV) were established in pithed rats and in rat spontaneously beating right atria. 2. In pithed rats, AII, AIII and AIV caused dose-dependent tachycardia with similar maximal responses (110 beats min-1). The beta-adrenoceptor antagonist propranolol (3.37 x 10(-6) mol kg-1) but not the alpha 1-adrenoceptor antagonist prazosin (2.38 x 10(-7) mol kg-1) significantly reduced these effects (P < 0.05; n = 7-8), but 20-25% of the responses could not be blocked by propranolol. 3. In isolated atria, AII, AIII and AIV caused concentration-dependent increases in beating rate with similar maximal responses to AII and AIII (34.3 +/- 0.4 and 34.7 +/- 0.4 beats min-1; n = 9-10), and a lower maximal response to AIV (26.8 +/- 0.6 beats min-1; P < 0.05; n = 8). AIII was about 9 times less potent than AII, whereas AIV proved approximately 3800 times less potent than AII. Neither propranolol (1 microM) nor prazosin (1 microM) could influence the effects of the angiotensin peptides. 4. In isolated atria, the selective AT1-receptor antagonist, losartan (10, 100 and 300 nM) caused parallel rightward shifts of the concentration-response curves for AII and AIII, whereas the selective AT2- receptor antagonist PD123177 (1 microM) did not influence the effects of AII and AIII. The aminopeptidase-A and -M inhibitor amastatin (10 microM), significantly steepened the slope of the AIII curves and increased the potency of AIII about 6 fold. Amastatin did not influence the responses to AII. 5. Our results indicate that both in vivo and in vitro, exogenous AII and AIII induced a direct dose-dependent chronotropic effect, which is independent of the adrenergic system. This chronotropic effect is mediated by AT1-subtype receptors.     

Differential venous effects of isoprenaline in conscious rats

The role β-adrenoceptors in the control of venous tone is not clear. This study examines the dose-response effects of isoprenaline, a non-selective β-adrenoceptor agonist, on mean circulatory filling pressure (MCFP), an index of body venous tone, in conscious and unrestrained rats. Dose-response curves of isoprenaline were constructed in three groups of rats, namely, I, intact; III, pretreated with the ganglionic blocker hexamethonium; and V, pretreated with noradrenaline. Three additional groups, Groups II, IV and VI, served as time controls and were treated similar to I, III and V, respectively, except that they were given normal saline in place of isoprenaline. The infusion of isoprenaline in intact rats dose dependently decreased mean arterial pressure (MAP) and increased heart rate (HR) and MCFP while in the ganglionic-blocked rat, it caused similar effects on MAP and HR but had no significant effects on MCFP. In rats given noradrenaline, isoprenaline again decreased MAP and increased HR and, in contrast to the other two groups, it decreased MCFP. The results show that isoprenaline has variable venous effects depending on existing venous tone. It causes reflex-mediated venoconstriction under normal conditions due to its hypotensive effects and direct venodilatation when venous tone is elevated by the infusion of noradrenaline.     

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 μg 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.

     

Effects of alpha 1- and alpha 2-adrenoceptor antagonists on venous tone in conscious rats

The dose-response effects of hexamethonium, prazosin and rauwolscine - a ganglionic blocker, alpha 1- and alpha 2-adrenoceptor antagonists, respectively - on mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP), an index of body venous tone, were examined in conscious and unrestrained rats. Prazosin and rauwolscine were also administered to rats after venous tone was elevated by drug-induced hypotension via the infusion of the vasodilator drug hydralazine. The effects of these drugs were compared with those of the vehicle, acidified glucose solution, administered to control rats. In intact rats, i.v. infusions of prazosin and rauwolscine dose dependently decreased MAP; the highest dose of rauwolscine, but not prazosin slightly reduced MCFP. The i.v. infusion of hexamethonium reduced MAP and caused a marked dose-dependent decrease in MCFP. After venous tone was raised by hydralazine, both prazosin and rauwolscine dose dependently decreased MCFP. The decrease in MCFP caused by rauwolscine was significantly greater than that caused by prazosin. Our results show that in the basal condition, the capacitance vessels are somewhat resistant to the effects of alpha-adrenoceptor antagonists in contrast to the effects of ganglionic blockers. After venous tone was raised by reflex mechanisms, both alpha-adrenoceptor antagonists were effective in lowering venous tone, however, the effect of alpha 2-adrenoceptor antagonist is significantly greater than that of alpha 1-adrenoceptor antagonist.     

Effect of genistein on cardiovascular responses to angiotensin II in conscious unrestrained rats

Soybeans contain genistein, a phytoestrogen that may have beneficial effects in coronary artery disease, osteoporosis, and breast cancer. In vitro studies demonstrated that genistein reduced vascular smooth muscle contractions to angiotensin II. We tested the hypothesis that genistein attenuates the overall cardiovascular responses to angiotensin II via nongenomic mechanisms in conscious rats. Mean arterial blood pressure (MAP) was recorded from conscious unrestrained Sprague-Dawley rats (n = 26) approximately 48 hours after surgery. Cumulative dose response curves to angiotensin II (10-200 ng/kg/min) were constructed before and after i.v. treatment with genistein given as a single bolus dose of 160 microg/kg or 1500 microg/kg, or as a loading dose of 160 microg/kg followed by an infusion at a rate of 20 microg/kg. Angiotensin II infusions were associated with graded increases in arterial pressure ranging between 0+/-1 and 35+/-4 mm Hg. These pressor responses were accompanied by significant dose-dependent decreases in heart rate. None of the genistein treatment regimens significantly affected the pressor responses to angiotensin II. Accordingly, we conclude that short-term i.v. treatment with genistein does not depress pressor responsiveness to angiotensin II.     

Does enhanced sympathetic tone contribute to angiotensin II hypertension in rats?

To determine whether enhanced sympathetic tone contributes to the maintenance of chronic angiotensin II (A II, 10 ng/min i.v. for 10 days) hypertension in rats, sympathetic activity was assessed in hypertensive and control rats by measuring norepinephrine (NE) turnover (alpha-methyl-p-tyrosine) in peripheral organs and by measuring depressor responses to ganglionic blockade in conscious rats. Pressor responses to methoxamine (1-8 micrograms/min) and arginine vasopressin (0.5-4 ng/min) were also obtained in rats with ganglionic blockade. Chronic A II infusion produced significant hypertension (mean +/- S.E. tail cuff pressure: 176 +/- 5 vs. 134 +/- 2 mm Hg in controls; n = 23 each group) but there were no significant differences in NE turnover in heart, kidney, skeletal muscle, or intestine in hypertensive rats compared with controls. Ganglionic blockade produced a significantly larger decrease in mean arterial pressure in A II-treated rats when compared with controls (73 +/- 7 vs. 38 +/- 2 mm Hg, n = 18 for each group). Dose-response curves for methoxamine and vasopressin were not significantly different between groups. The results suggest that the maintenance of chronic A II hypertension does not involve postsynaptic interactions between A II and the sympathetic system. The NE turnover data do not support the hypothesis that rats with chronic A II hypertension have enhanced sympathetic tone.     

Regional haemodynamic effects of antagonists of angiotensin II, endothelin and adrenoceptors in conscious, vasopressin-deficient, genetically hypertensive rats.

1. Male, vasopressin-deficient, normotensive (DI/N) and hypertensive (DI/H) rats were chronically instrumented (all surgery under sodium methohexitone anaesthesia) to allow assessment of resting haemodynamic status and responses to antagonism of AT1-receptors (Experiment 1), ET(A-) and ET(B-) receptors (Experiment 2) or adrenoceptors (Experiment 3). 2. Before any treatment, mean arterial blood pressure (MAP) was higher, and hindquarters vascular conductance was consistently lower in all groups of DI/H rats than in DI/N rats. 3. In Experiment 1, losartan (10 mg kg-1 i.v.), an AT1-receptor antagonist, was given 5 h after s.c. injection of saline, (DI/N, n = 8; DI/H, n = 8) or hyperoncotic polyethylene glycol, (DI/N, n = 9; DI/H, n = 9) to induce isosmotic hypovolaemia. In the volume-replete state, losartan caused similar small falls in MAP in the two groups (maximum delta MAP; DI/N, -9 +/- 2; DI/H, -15 +/- 5 mmHg), but the mesenteric and hindquarters vasodilatations were greater in DI/N rats. In the volume-depleted state the effects of losartan were augmented (delta MAP; DI/N, -32 +/- 3; DI/H. -31 +/- 3 mmHg), but its vasodilator effects were still greater in DI/N than in DI/H rats. 4. In Experiment 2, infusion of the ET(A-)ET(B-)receptor antagonist, SB 209670 (600 micrograms kg-1 h-1; DI/N, n = 8; DI/H, n = 9), had haemodynamic effects that were not different from those during saline infusion in DI/N (n = 7) and DI/H rats (n = 8). 5. In Experiment 3, sequential administration of the beta 2-adrenoceptor antagonist, ICI 118551 (0.2 mg kg-1 bolus, 0.1 mg kg-1 h-1 infusion), the alpha 2-adrenoceptor antagonist, idazoxan (0.75 mg kg-1 bolus, 1 mg kg-1 h-1 infusion), and losartan (10 mg kg-1 bolus) had only slight haemodynamic effects in DI/N (n = 8) and DI/H (n = 9) rats. Subsequent administration of the alpha 1-adrenoceptor antagonist, prazosin (0.5 mg kg-1 bolus, 0.8 mg kg-1 h-1 infusion) caused marked hypotension, although MAP was still higher in DI/H (95 +/- 4 mmHg) than in DI/N (75 +/- 4 mmHg) rats. However, in this circumstance there were no significant differences between renal, or mesenteric, or hindquarters vascular conductances in the two groups. 6. The results indicate that the hypertension and hindquarters vasoconstriction in DI/H rats is not dependent on AII or endothelin. Moreover, the relative elevation in MAP in DI/H persists in the presence of antagonism of beta 2, alpha 2- and alpha 1-adrenoceptors, in spite of no significant difference in regional vascular conductances.     

Differential effects of captopril on regional haemodynamic responses to angiotensin I and bradykinin in conscious rats.

1. Conscious, Long Evans rats were chronically instrumented with pulsed Doppler flow probes and intravascular catheters to allow regional haemodynamic (coeliac, mesenteric and hindquarters vascular beds) responses to i.v. bradykinin to be assessed in the absence and presence of captopril and of ganglion blockade (with mecamylamine). 2. Bradykinin (3 nmol kg-1, i.v. bolus) had no effect on mean arterial blood pressure, although it caused hyperaemic vasodilatation in the coeliac, mesenteric and hindquarters vascular beds. Following administration of captopril at a dose (28 nmol kg-1) which had no effect on responses to angiotensin I, the hypotensive and coeliac and mesenteric vasodilator responses to bradykinin were enhanced. However, there was a temporal dissociation between these events indicating that changes in cardiac output must have been contributing to the changes in mean arterial blood pressure. 3. Captopril at a higher dose (280 nmol kg-1) caused reversible inhibition of the pressor and coeliac and mesenteric vasoconstrictor effects of angiotensin I, but the inhibition of the mesenteric vascular responses was significantly less than that of the coeliac vascular responses. Under the same conditions, the mesenteric vasodilator effects of bradykinin were less enhanced than the coeliac vasodilator effects, consistent with greater inhibition of angiotensin-converting enzyme (i.e., kininase II) in the coeliac than in the mesenteric vascular bed. But, since the hypotensive action of bradykinin was markedly enhanced in these circumstances, the possibility existed that baroreflex responses influenced the haemodynamic effects of bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of noradrenaline, B-HT 920, methoxamine, angiotensin II and vasopressin on mean circulatory filling pressure in conscious rats.

The effects of vasoactive substances on mean circulatory filling pressure (MCFP), an index of total body venous tone, were determined in conscious rats. Cumulative doses of saline (0.9% w/v NaCl solution), methoxamine (alpha 1-adrenoceptor agonist), B-HT920 (alpha 2-adrenoceptor agonist) noradrenaline and vasopressin, and individual doses of angiotensin II (AII), were infused into the rats. Mean arterial pressure (MAP), MCFP and heart rate (HR) were determined before and during the plateau responses to infusions of the vasoactive substances. The infusions of all the agonists caused a dose-dependent increase in MAP and a decrease in HR. The infusion of saline affected neither MAP nor HR. The infusions of saline and methoxamine did not affect MCFP while the infusions of B-HT 920, noradrenaline and AII increased MCFP. MCFP was slightly increased during the infusion of high doses of vasopressin. It was concluded that receptors for the alpha 2-adrenoceptor agonist and AII are involved in the control of venous tone. Receptors for the alpha 1-adrenoceptor agonist and vasopressin are not important for the control of venous tone.     

Peripherally applied candesartan inhibits central responses to angiotensin II in conscious rats

In the brain, angiotensin II (Ang II) induces various effects such as blood pressure increase, the release of arginine vasopressin (AVP) and drinking behaviour. In the present study, we investigated the ability of the angiotensin II type-I (AT(1)) receptor antagonist, candesartan, administered peripherally, to block the central effects of Ang II.Experiments were performed in conscious rats instrumented with an intracerebroventricular (i.c.v.) cannula or a guide cannula into the paraventricular nucleus (PVN) and arterial and femoral catheters. Candesartan was administered intravenously (i.v.) at doses of 0.01, 0.1, 1 or 10 mg/kg. Controls received vehicle (0.05 N Na(2)CO(3)). The drinking response ( n=10-11 per group), the pressor response ( n=7-8) and the release of AVP into the circulation ( n=10-11) following i.c.v. Ang II (100 ng) were measured 0.5, 2, 4 and 24 h following i.v. drug application. Candesartan inhibited the central responses to i.c.v. injected Ang II dose- and time-dependently. At the highest dose (10 mg/kg), the drinking and pressor responses and the release of AVP in response to i.c.v. Ang II were completely blocked at 4 h and still markedly inhibited 24 h after the antagonist application (by 85%, 48% and 86%, respectively). The lowest dose of the antagonist was without effect. In a further experiment, the release of AVP induced by microinjection of Ang II (100 ng) into the PVN was determined before and 4 h after administration of vehicle or candesartan (1 mg/kg, i.v.). Candesartan completely blocked the AVP release into the circulation induced by Ang II microinjection into the PVN.Our results demonstrate that candesartan administered peripherally effectively inhibits responses mediated by AT(1) receptors localised in periventricular brain regions as well as inside the blood-brain-barrier.     

Hypotensive effects of angiotensin II analogues and angiotensin converting enzyme inhibitors in water-deprived Brattleboro rats.

The hypotensive effects of three different angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril, and lisinopril) and two angiotensin II (AII) analogues ([Sar1Ile5Ala8]AII and [Sar1Ile5Thr8]AII) were compared in conscious, freely-moving Brattleboro rats after 14 h of water deprivation. There was no difference between the hypotensive effects of the three ACE inhibitors. Neither was there any difference between the hypotensive effects of the two AII antagonists, although when administered following ACE inhibition, [Sar1Ile5Thr8]AII caused a transient pressor effect that was significantly less than that caused by [Sar1Ile5Ala8]AII. ACE inhibition caused a greater fall in blood pressure (BP) than AII antagonism and caused an additional fall in BP during AII antagonism. These results indicate an additional hypotensive effect of ACE inhibitors, over that of AII antagonists, that is not readily accounted for in terms of nonspecific effects of the former or agonistic properties of the latter.     

Mechanisms of the angiotensin II effects on the exploratory behavior of rats in open field. II. Interaction of angiotensin II with yohimbine

The effects of the octapeptide angiotensin II (AT II) and its interaction with yohimbine, an alpha 2-adrenoceptor antagonist, on the exploratory behavior of male rats in open field were studied. AT II (0.1 and 0.5 microgram intracerebroventricularly, i.c.v) increased the open field behavior, mainly ambulation and rearing. Yohimbine (1 and 3 mg/kg) significantly reduced the stimulatory effects of AT II, mainly on ambulation. It is suggested that the augmented release of noradrenaline (NA) resulting from alpha 2-adrenoceptor blockade decreases the exploratory behavior effects of AT II. An interaction between AT II receptors and NA-ergic neurotransmission in the brain might be taken into consideration as an explanation of the influence of yohimbine on AT II effects in open field behavior.