Regional haemodynamic effects of prolonged infusions of human alpha-calcitonin gene-related peptide in conscious, Long Evans rats.

1. Haemodynamic measurements were made in conscious, Long Evans rats chronically instrumented for the assessment of changes in regional blood flows (renal, mesenteric and hindquarters, or internal and common carotid) and systemic arterial blood pressure and heart rate, before, during and after 3 day infusions of vehicle or human alpha-calcitonin gene-related peptide (CGRP) (1.5 or 15 nmol kg-1 h-1). 2. In animals with renal, mesenteric and hindquarters flow probes (n = 8), during the first day of infusion of human alpha-CGRP (1.5 nmol kg-1 h-1) there was sustained tachycardia and hypotension, a sustained reduction in renal flow, a transient reduction in mesenteric flow and a relatively well-maintained increase in hindquarters flow. All these effects were significantly different from the changes seen in vehicle-infused rats (n = 8), but calculation of vascular conductances showed only the late mesenteric vasodilatation and the sustained hindquarters vasodilatation were different from the changes in vehicle-infused rats. However, by the second day of infusion and thereafter cardiovascular variables in the animals receiving vehicle and those receiving human alpha-CGRP were not different. 3. Nine animals instrumented with probes to monitor changes in internal and common carotid haemodynamics initially received human alpha-CGRP infused at a rate of 1.5 nmol kg-1 h-1. Three of these animals still showed some response to the human alpha-CGRP (tachycardia, hypotension, hyperaemic vasodilatation) throughout the second day of infusion and hence were taken through the 3 day infusion protocol. When the infusion was stopped on the fourth day all these animals showed reversal of the effects of human alpha-CGRP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of beta 2-adrenoceptors in the regional haemodynamic responses to bradykinin in conscious rats.

1. Bradykinin can release neuronal calcitonin gene-related peptide (CGRP) and adrenal medullary catecholamines, both of which could contribute to its cardiovascular effects in vivo. Therefore, in the main experiment, regional haemodynamic responses to bolus injections of bradykinin (3 nmol kg-1, i.v.) were assessed in the same chronically-instrumented, conscious, Long Evans rats in the absence and in the presence of human alpha-CGRP [8-37] or ICI 118551, antagonists of CGRP1-receptors and beta 2-adrenoceptors, respectively. The selected doses of these antagonists caused specific inhibition of responses mediated by exogenous human alpha-CGRP and beta 2-adrenoceptor agonists, respectively. 2. Bradykinin administered alone as an i.v. bolus had a slight pressor effect accompanied by a marked tachycardia. There were early (at about 30 s) increases in flow and conductance in the mesenteric vascular bed, and delayed (at about 90 s), but qualitatively similar, changes in the hindquarters vascular bed. There were only slight increases in flow and conductance in the renal vascular bed. 3. Human alpha-CGRP [8-37] had no statistically significant effects on the responses to bolus doses of bradykinin. However, in the presence of ICI 118551, the pressor effect of bradykinin was significantly enhanced while its tachycardic effect was significantly suppressed. The hindquarters vasodilator effect of bradykinin was converted to a vasoconstriction and there was a slight renal vasoconstriction, but the mesenteric vasodilator effect of bradykinin was unchanged by ICI 118551. 4. In subsidiary experiments, in other animals, it was found that infusion of bradykinin (36 nmol kg-1 min-1) elicited a pattern of haemodynamic responses similar to that seen with bolus injections and, as in the latter case, the hindquarters hyperaemic vasodilation was inhibited by ICI 118551. In the presence of mecamylamine (at a dose sufficient to block reflex heart rate responses to rises or falls in arterial blood pressure) bolus injection or infusion of bradykinin still elicited increases in renal, mesenteric and hindquarters blood flow. However, in additional experiments in adrenal demedullated rats (n = 4) the hindquarters hyperaemic effect of bradykinin was absent, although the mesenteric hyperaemic effect remained. 5. The results indicate that the increase in hindquarters blood flow following administration of bradykinin in vivo is largely due to activation of beta 2-adrenoceptors by catecholamines released subsequent to direct stimulation of the adrenal medulla by the peptide. However, the bradykinin-induced increase in mesenteric blood flow does not depend on this mechanism.     

Haemodynamic effects of human alpha-calcitonin gene-related peptide following administration of endothelin-1 or NG-nitro-L-arginine methyl ester in conscious rats.

1 We investigated the peripheral haemodynamic effects of human alpha-calcitonin gene-related peptide (CGRP) following administration of endothelin-1 or NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide production, in conscious, chronically-instrumented, Long Evans rats. 2 Infusion of endothelin-1 (3 nmol kg-1 h-1) caused hypertension, bradycardia and renal, mesenteric and hindquarters vasoconstrictions. Co-infusion of human alpha-CGRP (1.5 nmol kg-1 h-1) reduced the hypertension and abolished the hindquarters vasoconstriction caused by endothelin-1 but the renal and mesenteric vasoconstrictor actions of endothelin-1 were not affected. 3 Infusion of human alpha-CGRP (15 nmol kg-1 h-1) in the presence of endothelin-1 caused hypotension and hyperaemic vasodilatation in the hindquarters; the mesenteric vasoconstrictor effects of endothelin-1 were diminished, but there was only a transient reversal of the renal vasoconstrictor effects of endothelin-1. 4 Pretreatment with the non-peptide angiotensin II receptor antagonist, DuP 753 (10 mg kg-1), caused slight hypotension associated with renal, mesenteric and hindquarters vasodilatations, but DuP 753 did not affect responses to endothelin-1 infusion. However, under these conditions co-infusion of human alpha-CGRP (15 nmol kg-1 h-1) caused a sustained reversal of the renal vasoconstrictor effects of endothelin-1. 5 These results indicate that the failure of human alpha-CGRP to cause sustained reversal of the renal vasoconstrictor effects of endothelin-1 in the absence of DuP 753 was due to activation of the reninangiotensin system (possibly as a consequence of the hypotension).(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional haemodynamic effects of human alpha- and beta-calcitonin gene-related peptide in conscious Wistar rats.

1. A comparative study was carried out to assess the regional haemodynamic effects of intravenous infusion of human alpha- and beta-calcitonin gene-related peptide (CGRP; 0.006, 0.06 and 0.6 nmol h-1) in conscious, unrestrained Wistar rats. 2. With human alpha-CGRP, tachycardia was always accompanied by a fall in mean arterial blood pressure (MBP), but human beta-CGRP at the middle dose caused tachycardia with no significant hypotension. 3. Human alpha- and beta-CGRP both caused dose-dependent falls in MBP accompanied by common carotid and hindquarters vasodilatations and increased flows. The highest dose of alpha- and beta-CGRP caused mesenteric vasoconstriction and renal vasodilatation, but the latter was not associated with an increase in flow. 4. With the intermediate dose, human alpha-CGRP caused more significant haemodynamic changes than did human beta-CGRP. In addition, comparison with previous experiments involving infusion of rat alpha-CGRP indicated that human alpha-CGRP had more potent haemodynamic effects than the former.     

Regional haemodynamic responses to acetylcholine, methoxamine, salbutamol and bradykinin during lipopolysaccharide infusion in conscious rats.

1. The aim of the study was to assess the regional haemodynamic responsiveness to vasoconstrictor and vasodilator challenges during continuous 24 h infusion of lipopolysaccharide (LPS) in conscious Long Evans rats. 2. Rats were chronically instrumented for the measurement of regional haemodynamics (either internal and common carotid or renal, superior mesenteric and hindquarters) and received 3 min of infusions of acetylcholine (22 nmol min-1), methoxamine (120 nmol min-1), salbutamol (0.83 nmol min-1) and bradykinin (14.4 nmol min-1) at 2, 6 and 24 h after the start of saline or LPS (150 micrograms kg-1 h-1) infusion (rats with carotid probes received only acetylcholine and methoxamine). 3. During infusion of LPS there was a changing haemodynamic profile. After 2 h, there was a modest hypotension and vasodilatation in the internal carotid, renal and hindquarters vascular beds. After 6 h, arterial blood pressure had returned to baseline, there was still vasodilatation in the renal vascular bed but vasoconstriction in the internal and common carotids and the hindquarters. After 24 h, there was hypotension, tachycardia and generalized vasodilatation. 4. Acetylcholine caused a fall in blood pressure, tachycardia and hyperaemic vasodilatation in the carotid and renal vascular beds. Throughout the infusion of LPS, the carotid vasodilator response was enhanced after 2 h, reduced after 6 h and enhanced again after 24 h, whereas the renal vasodilator response to acetylcholine was either reduced (6 h) or absent (2 and 24 h); at this juncture the hypotensive response to acetylcholine was also enhanced and the tachycardia was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of NG-nitro-L-arginine methyl ester on regional haemodynamic responses to MgSO4 in conscious rats.

1. We assessed regional haemodynamic responses to the vasodilator, MgSO4, in the absence and presence of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), in conscious chronically instrumented Long Evans rats (n = 9). 2. MgSO4 (loading dose 220 mumol kg-1 min-1 for 7 min, maintenance dose 56 mumol kg-1 min-1 for 7 min), alone, caused slight bradycardia and hypotension accompanied by reductions in renal and mesenteric flows, but a marked hyperaemic vasodilatation in the hindquarters (flow, delta 54 +/- 6%, vascular conductance, delta 77 +/- 5%). 3. L-NAME (183 nmol kg-1 min-1) caused hypertension (29 +/- 2 mmHg) accompanied by bradycardia (-51 +/- 6 beats min-1) and reductions in flow and vascular conductance in the renal (-18 +/- 4% and -35 +/- 3%, respectively), mesenteric (-35 +/- 3% and -49 +/- 3%, respectively), and hindquarters (-26 +/- 3% and -42 +/- 3%, respectively) vascular beds. In the presence of L-NAME, the hypotensive and bradycardic effects of MgSO4 were still apparent, but its hindquarters hyperaemic vasodilator effect was significantly attenuated. 4. In order to determine if the inhibitory action of L-NAME on the hindquarters hyperaemic vasodilator action of MgSO4 was a non-specific effect, due to the change in baseline conditions caused by L-NAME, we also examined responses to MgSO4 in the presence of endothelin-1 (12.5 pmol kg-1 min-1) or angiotensin II (50 pmol kg-1 min-1). In the presence of either peptide, the overall effects of MgSO4 on hindquarters flow and vascular conductance were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of NG-nitro-L-arginine methyl ester on vasodilator responses to adrenaline or BRL 38227 in conscious rats.

1. Conscious, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, were used to assess responses to 3 min infusions of the potassium channel opener, BRL 38227 (1 and 10 micrograms kg-1 min-1) or adrenaline (0.05 and 0.5 microgram kg-1 min-1) in the absence and in the presence of NG-nitro-L-arginine methyl ester (L-NAME; 3 mg kg-1 h-1), an inhibitor of nitric oxide biosynthesis. 2. In the absence of L-NAME, the low dose of BRL 38227 caused slight hypotension and tachycardia, accompanied by small increases in mesenteric and hindquarters blood flow only. However, there were increases in renal, mesenteric and hindquarters vascular conductances. L-NAME had no effect on any of these responses. 3. The high dose of BRL 38227 caused substantial hypotension and tachycardia. Renal and hindquarters flows did not change significantly, but there was a marked increase in mesenteric flow. There were only modest increases in renal and hindquarters vascular conductances but a substantial mesenteric vasodilatation. In the presence of L-NAME, there was a slight reduction of the latter but no other changes in the responses to BRL 38227. 4. In the absence of L-NAME, the low dose of adrenaline caused slight hypotension but a marked tachycardia. There were no changes in renal or mesenteric blood flow but a clear-cut increase in hindquarters flow. Renal and mesenteric vascular conductances showed only small rises, in contrast to the substantial hindquarters vasodilatation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional haemodynamic responses to pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide in conscious rats.

1. Regional haemodynamic responses to the homologous peptides, pituitary adenylate cyclase-activating peptide (1-27) (PACAP27) and vasoactive intestinal polypeptide (VIP) were assessed by giving 20 min infusions (1.5-15 nmol kg-1 h-1) in conscious, chronically-instrumented, Long Evans rats. 2. PACAP27 caused dose-dependent depressor and tachycardic effects associated with renal, mesenteric and hindquarters vasodilatations, although only in the latter vascular bed was there a sustained increase in flow. 3. VIP caused dose-dependent depressor and tachycardic effects that were not significantly different from those caused by equimolar doses of PACAP27. However, the hindquarters vasodilator effects of VIP (at 7.5 and 15 nmol kg-1 h-1) were greater than those of PACAP27 (at the same doses), and accompanied by reductions in renal and mesenteric flows and conductances. 4. In the presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 11 mumol kg-1 h-1), there was significant inhibition of the hindquarters vasodilator effects of PACAP27 and VIP (at 7.5 and 15 nmol kg-1 h-1). Under these circumstances the renal and mesenteric vasoconstrictor effects of VIP were abolished. 5. The beta 2-adrenoceptor antagonist, ICI 118551 (670 nmol kg-1 bolus, 335 nmol kg-1 h-1 infusion), reduced the matched hindquarters vasodilator responses to PACAP27 (15 nmol kg-1 h-1) and VIP (7.5 nmol kg-1 h-1), and also abolished the renal vasoconstrictor effects of VIP. 6. The AT1-receptor antagonist, losartan potassium (20 mumol kg-1), had no significant effect on the haemodynamic response to PACAP27 (15 nmol kg-1 h-1), but augmented the hypotensive action of VIP (7.5 nmol kg-1 h-1). This influence of losartan was associated with conversion of the renal and mesenteric vasoconstrictor effect of VIP to vasodilatation. 7. Our findings show that similar changes in mean systemic arterial blood pressure in response to PACAP27 and VIP conceal substantial differences in their regional haemodynamic actions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional haemodynamic effects of depressor neuropeptides in conscious, unrestrained, Long Evans and Brattleboro rats.

1. The regional haemodynamic effects of i.v. bolus doses of atrial natriuretic peptide (ANP, 1 and 10 nmol), calcitonin gene-related peptide (CGRP, 0.05 and 0.5 nmol) and corticotropin-releasing factor (CRF, 1 and 5 nmol) were assessed in conscious Long Evans and Brattleboro rats chronically instrumented with miniaturized, pulsed Doppler probes. 2. The low dose of ANP was without effect on mean arterial pressure (MAP), but caused tachycardia and hindquarters vasodilatation with vasoconstriction in renal and mesenteric beds in Long Evans rats. With the high doses of ANP these effects were more pronounced and MAP fell. In Brattleboro rats there was a primary renal vasodilatation. 3. The low dose of CGRP caused a slight fall in MAP in Long Evans rats, tachycardia and a renal vasodilatation. The high dose of CGRP caused marked hypotension, tachycardia and renal, mesenteric and hindquarters vasodilatation in both strains of rat. However, only in Long Evans rats were there secondary renal and mesenteric vasoconstrictions. 4. The low dose of CRF caused falls in MAP in both strains of rat, accompanied by renal and, particularly, mesenteric vasodilatation. Administration of the high dose of CRF caused profound, prolonged hypotension, tachycardia and mesenteric vasodilatation. There was also (late onset) hindquarters vasodilatation accompanying renal vasoconstriction that followed the initial vasodilatation in this vascular bed. 5. These results indicate that appropriate doses of particular peptides may be capable of promoting flow through individual peripheral vascular beds.     

Selective impairment of hindquarters vasodilator responses to bradykinin in conscious Wistar rats with streptozotocin-induced diabetes mellitus.

1. Male, Wistar rats were treated with streptozotocin (STZ, 70 mg kg-1, i.p.) or saline and chronically instrumented with pulsed Doppler probes and intravascular catheters (implanted under sodium methohexitone anaesthesia) to allow assessment of haemodynamics in the conscious state 28 days later. 2. Control and STZ-treated rats received bolus doses of glyceryl trinitrate (10-80 nmol kg-1), acetylcholine (0.1-5 nmol kg-1) and bradykinin (0.3-30 nmol kg-1). 3. Although, as reported previously, STZ-treated rats had normal mean arterial blood pressure together with renal and mesenteric vasodilatations and hindquarters vasoconstriction relative to control rats, both groups showed similar hypotensive and regional haemodynamic responses to glyceryl trinitrate and acetylcholine. However, while the depressor effects of bradykinin were similar in control and STZ-treated rats, the former showed a hindquarters vasodilator response to bradykinin that was absent in the STZ-treated rats. 4. A loss of bradykinin-mediated vasodilatation in the hindquarters vascular bed in STZ-treated rats in the presence of normal, hindquarters vasodilator responses to other agents and normal bradykinin-mediated vasodilator responses in other vascular beds is consistent with existing evidence that the vasodilatation elicited by bradykinin in the hindquarters vascular bed is particularly dependent on nitric oxide synthesis and that this is impaired selectively in STZ-treated rats.     

Influence of CGRP (8-37), but not adrenomedullin (22-52), on the haemodynamic responses to lipopolysaccharide in conscious rats.

1. The functional involvement of the vasodilator peptides, adrenomedullin (ADM) and calcitonin gene-related peptide (CGRP), in the haemodynamic sequelae of continuous infusion of lipopolysaccharide (LPS) was assessed in conscious, male, Long Evans rats, by the use of peptide antagonists. 2. It was demonstrated that ADM (22-52) at a dose of 500 nmol kg-1 h-1 caused significant inhibition of the effects of ADM (1 nmol kg-1), without affecting responses to CGRP (0.1 or 1 nmol kg-1). 3. Even when the regional vasodilator responses to LPS infusion were enhanced (by pre-treatment with dexamethasone and the endothelin antagonist, SB 209670, or by pretreatment with SB 209670 and the AT1-receptor antagonist, losartan), ADM (22-52) had no significant cardiovascular effects. In contrast, the CGRP1-receptor antagonist, CGRP (8-37), caused small, but significant, inhibitions of the hypotensive and renal and mesenteric vasodilator effects of LPS, but only 6 h after onset of infusion in the presence of dexamethasone and SB 209670. 4. The results indicate that, in this model of endotoxaemia, the marked regional vasodilatations seen in the presence of dexamethasone and SB 209670 do not involve ADM, but do involve CGRP, albeit only to a small extent.     

Involvement of capsaicin-sensitive neurones in the haemodynamic effects of exogenous vasoactive peptides: studies in conscious, adult Long Evans rats treated neonatally with capsaicin.

1. The regional haemodynamic effects of i.v. bolus injections of bradykinin (0.05 or 0.5 nmol), cholecystokinin (0.175 or 1.75 nmol), substance P (0.01 or 0.1 nmol) and calcitonin gene-related peptide (0.05 or 0.5 nmol) were assessed in conscious, adult Long Evans rats that had been treated neonatally with either capsaicin (50 mg kg-1, s.c.) or vehicle. 2. In vehicle-treated rats, both doses of bradykinin were without effect on blood pressure, but caused tachycardia and hindquarters vasodilatation. Moreover, after the higher dose there were dilatations in the renal and superior mesenteric vascular beds. In capsaicin-treated rats the hindquarters vasodilator effects elicited by both doses of bradykinin were significantly reduced, while the tachycardia and responses in the renal and superior mesenteric vascular beds were unchanged. 3. In vehicle-treated rats, cholecystokinin caused dose-dependent increases in blood pressure accompanied by renal, superior mesenteric and hindquarters vasoconstriction followed, after the higher dose, by a hindquarters vasodilatation. The lower dose produced a tachycardia, while there was a bradycardia followed by a tachycardia after the higher dose. In capsaicin-treated rats, the pressor response, as well as the renal vasoconstrictor effects of cholecystokinin, were greater than in vehicle-treated rats, while the heart rate, superior mesenteric or hindquarters responses were not different. 4. In vehicle-treated rats, substance P produced a dose-dependent depressor response and tachycardia accompanied by dilatations in the renal and hindquarters vascular beds and constriction in the superior mesenteric vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of phosphoramidon on the regional haemodynamic responses to human proendothelin [1-38] in conscious rats.

1. Cardiovascular responses to human proendothelin [1-38], in the absence and presence of phosphoramidon, were studied in conscious Long Evans rats, chronically instrumented for the continuous recording of heart rate, systemic arterial blood pressure and renal, mesenteric and hindquarters blood flows. 2. A dose of 0.1 nmol kg-1 human proendothelin [1-38] caused a slight pressor effect (maximum 5 +/- 2 mmHg), but a clear bradycardia (maximum -29 +/- 7 beats min-1). Renal haemodynamics were unchanged but there was mesenteric vasoconstriction and a vasodilation followed by a vasoconstriction in the hindquarters. 3. A dose of 1.0 nmol kg-1 human proendothelin [1-38] caused a gradual hypertension (maximum 42 +/- 4 mmHg at 10 min) and a profound bradycardia (-149 +/- 10 beats min-1 at 30 min). There were gradual but marked, renal and hindquarters vasoconstrictions, whereas there was a substantial mesenteric vasoconstriction that was relatively rapid in onset. 4. In 2 animals, administration of human proendothelin [1-38] at a dose of 10 nmol kg-1 caused an initial hypotension followed by a rapidly-developing pressor effect; there were renal and mesenteric vasoconstrictions and vasodilatation followed by vasoconstriction in the hindquarters. These changes were very similar to those seen following injection of endothelin-1 (0.1 nmol kg-1). 5. Phosphoramidon (2 mumol kg-1) had no cardiovascular effects itself and it did not affect significantly the pressor or mesenteric vasoconstrictor effects of human proendothelin [1-38], but it reduced the bradycardia and renal and hindquarters vasoconstrictor responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Bolus injection of human UII in conscious rats evokes a biphasic haemodynamic response

A biphasic cardiovascular response to bolus i.v. injection of human urotensin II (hUII, 3 nmol kg(-1)) in conscious, male, Sprague-Dawley (SD) rats was identified and underlying mechanisms were explored. Initially (0-5 min) there was tachycardia, hypotension and mesenteric and hindquarters vasodilatation; later (30-120 min), tachycardia, hindquarters vasodilatation and a modest rise in blood pressure occurred. Pretreatment with indomethacin or N(G) nitro-l-arginine methylester (l-NAME) reduced the mesenteric vasodilator response to hUII, and abolished the late tachycardia and hindquarters vasodilatation. Indomethacin also abolished the hypotension and early hindquarters vasodilatation, and substantially reduced the initial tachycardia. Indomethacin and l-NAME together prevented all haemodynamic responses to hUII. Inhibition of inducible NOS had no effect on responses to hUII, whereas inhibition of neuronal NOS reduced the delayed tachycardic response to hUII but did not significantly affect the vasodilatation. Only the initial tachycardic response to hUII was antagonised by propranolol. In spontaneously hypertensive rats (SHR), the initial haemodynamic responses to hUII were qualitatively similar to those in SD rats, although there was also a modest renal vasodilatation. The secondary response comprised a smaller tachycardia and a small rise in blood pressure, with no significant hindquarters vasodilatation. Haemodynamic responses to hUII were not enhanced by endothelin and angiotensin receptor antagonism in either SD rats or in SHRs. One interpretation of these results is that the primary response to bolus injection of hUII is prostanoid- or prostanoid- and NO-mediated (mesenteric vasodilatation) and that this triggers secondary events, which are dependent on eNOS (hindquarters vasodilatation) and neuronal NOS (tachycardia).     

Factors affecting the regional haemodynamic responses to glyceryl trinitrate and molsidomine in conscious rats.

1. A series of experiments was performed in conscious, unrestrained, male, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics. 2. Infusion of glyceryl trinitrate (GTN, 0.1 mg kg-1 min-1, i.v.) for 10 min elicited tachycardia, but no sustained change in mean arterial blood pressure. Renal haemodynamics were unaffected, but there were reductions in hindquarters flow and vascular conductance together with substantial increases in flow and conductance in the mesenteric vascular bed. 3. In the presence of captopril (2 mg kg-1 bolus, and 1 mg kg-1 h-1 infusion, i.v.) GTN elicited significant hypotension and increases in renal blood flow and vascular conductance, indicating that activation of the renin-angiotension system opposed the dilator effects of GTN in this vascular bed. However, the mesenteric and hindquarters haemodynamic effects of GTN were not affected by captopril. In contrast, in the presence of enalaprilat (2 mg kg-1 bolus, and 1 mg kg-1 h-1 infusion, i.v.) there was significant enhancement of the mesenteric, as well as renal, haemodynamic effects of GTN. Hence, these results provide no evidence for the sulphydryl groups in captopril exerting a specific effect to enhance the haemodynamic actions of GTN in our experimental protocols. 4. Administration of molsidomine alone (1 mg kg-1, i.v. bolus) elicited tachycardia and hypotension; there were no changes in mesenteric or hindquarters haemodynamics, but renal flow and vascular conductance fell. Thus, the hypotensive effect of molsidomine was probably due to a reduction in cardiac output, consequent upon venodilatation.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Effects of NG-nitro-L-arginine methyl ester on vasodilator responses to acetylcholine, 5''-N-ethylcarboxamidoadenosine or salbutamol in conscious rats.

1. Conscious, Long Evans rats (n = 16), chronically instrumented for the measurement of regional haemodynamics were given 3 min, randomized infusions of two doses of sodium nitroprusside (1.5 and 15 micrograms min-1), acetylcholine (0.4 and 4 micrograms min-1), 5'-N-ethylcarboxamidoadenosine (NECA; 45 and 450 ng min-1), and salbutamol (24 and 240 ng min-1) in the absence and in the presence of NG-nitro-L-arginine methyl ester (L-NAME; 1 mg kg-1 h-1), a potent inhibitor of nitric oxide biosynthesis. 2. Sodium nitroprusside caused hyperaemic vasodilatation in the mesenteric, and common carotid vascular beds. These effects were enhanced in the presence of L-NAME, as was the hypotension. 3. Acetylcholine caused hyperaemic vasodilation inp6he renal, internal carotid and common carotid vascular beds. These effects were attenuated in the presence of L-NAME, but the hypotension was unaffected. 4. NECA caused hyperaemic vasodiltation in the renal, mesenteric, hindquarters, internal carotid and common carotid vascular beds. However, only the hindquarters and internal carotid responses were diminished in the presence of L-NAME and the hypotension was unchanged. 5. Salbutamol caused hyperaemic vasodilatation in the hindquarters vascular bed only. This effect was reduced in the presence of L-NAME, but the hypotension was unchanged. 6. The results indicate marked regional variations in the sensitivity of vasodilator responses to L-NAME that can depend on the vasodilator agent chosen and the dose employed. It is clear from these findings also that measurement of mean arterial blood pressure alone cannot provide adequate information on which to judge the involvement of L-NAME-sensitive mechanisms in vasodilator responses in vivo.     

Differential effects of (+/-)-dobutamine and human alpha-CGRP on cardiac and on regional haemodynamics in conscious Long Evans rats.

1. Comparisons were made of the full haemodynamic profiles of the known cardiostimulant, (+/-)-dobutamine, and the putative inotropic peptide, human alpha-calcitonin gene-related peptide (human alpha-CGRP), in conscious, chronically-instrumented Long Evans rats. Both substances were administered continuously i.v. for 60 min at two doses ((+/-)-dobutamine, 2 and 10 mumol kg-1 h-1; human alpha-CGRP, 0.15 and 1.5 nmol kg-1 h-1). 2. In spite of their similar (small) effects on mean arterial blood pressure, the low doses of (+/-)-dobutamine and human alpha-CGRP influenced cardiac haemodynamics differently. Thus, (+/-)-dobutamine caused an increase in cardiac index (due to a tachycardia), accompanied by rises in peak aortic flow, maximum rate of rise of aortic flow (dF/dtmax) and total peripheral conductance. However, the latter waned during the infusion, and after the infusion there was a significant systemic vasoconstriction and reductions in peak aortic flow, dF/dtmax and stroke index. Such 'off' effects following dobutamine infusion have not been described previously. The infusion of the lower dose of human alpha-CGRP caused only a transient fall in central venous pressure. 3. The rise in total peripheral conductance during infusion of the lower dose of (+/-)-dobutamine was associated with increases in hindquarters and common and internal carotid vascular conductances. The fall in total peripheral conductance after infusion was associated with renal vasoconstriction. Although there was no significant change in total peripheral conductance during the infusion of the lower dose of human alpha-CGRP there were hindquarters and carotid vasodilatations together with mesenteric vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the neutral endopeptidase inhibitor, SQ 28,603, on regional haemodynamic responses to atrial natriuretic peptide or proendothelin-1 [1-38] in conscious rats.

1. Regional haemodynamic responses to atrial natriuretic peptide (ANP, 0.5 nmol kg-1) or proendothelin-1 [1-38] (1.0 nmol kg-1) were assessed in the same conscious Long Evans rats before and 20 min after administration of the novel neutral endopeptidase (NEP) inhibitor, SQ 28,603 (50 mg kg-1, i.v.). In a separate experiment, responses to endothelin-1 (0.5 nmol kg-1), angiotensin I (0.25 nmol kg-1) and angiotensin II (0.12 nmol kg-1) were measured before and after administration of SQ 28,603. 2. SQ 28,603 alone had no significant cardiovascular effects but caused significant prolongation of the hypotensive, tachycardic and renal and mesenteric vasoconstrictor effects of ANP. However, the early vasodilator and late vasoconstrictor responses in the hindquarters were not affected significantly. 3. SQ 28,603 caused significant attenuation of the pressor effects of proendothelin-1 [1-38] but the associated bradycardia was unchanged. SQ 28,603 caused a significant inhibition of the renal and mesenteric vasoconstrictor effects of proendothelin-1 and also inhibited the initial vasodilator and subsequent vasoconstrictor responses in the hindquarters vascular bed. 4. SQ 28,603 had no significant effects on the haemodynamic responses to endothelin-1, angiotensin I, or angiotensin II. 5. The results are consistent with SQ 28,603 not only inhibiting NEP that is involved in the degradation of ANP, but also suppressing activity of the enzyme involved in the conversion of proendothelin-1 [1-38] to endothelin-1.