Mesenteric vasoconstriction and hindquarters vasodilatation accompany the pressor actions of exendin-4 in conscious rats.

The hemodynamic effects of the glucagon-like peptide-1 (GLP-1) receptor agonist, exendin-4, and putative underlying mechanisms were assessed in conscious male Sprague-Dawley rats. At a dose of 25 ng kg(-1) i.v., exendin-4 had little effect, but doses of 250 and 2500 ng kg(-1) had significant tachycardic effects (+66 +/- 9 and +95 +/- 16 beats min(-1) at 5 min, respectively) and pressor actions (+10 +/- 2 and +12 +/- 1 mm Hg), accompanied by substantial falls in mesenteric vascular conductance (-38 +/- 3% and -47 +/- 3%) and increases in hindquarters vascular conductance (+82 +/- 14% and +126 +/- 15%). The latter were likely due to adrenaline-mediated activation of beta(2) adrenoceptors since they were abolished by the beta(2) adrenoceptor antagonist, ICI 118551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol) hydrochloride], or propranolol [(RS)-1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-2-propanol], and absent in adrenal-demedullated rats. In the presence of beta-adrenoceptor antagonism, the tachycardic effects of exendin-4 were suppressed, but the pressor action was enhanced. Enhancement of the pressor action of exendin-4 was not seen in adrenal-demedullated rats or in animals given phentolamine in addition to propranolol, consistent with a component of the pressor action of exendin-4 being due to an adrenaline-mediated positive inotropic effect mediated by alpha-adrenoceptors. The mesenteric vasoconstrictor effect of exendin-4 was unaffected by antagonism of alpha-adrenoceptors, vasopressin receptors, angiotensin receptors, or GLP-1 receptors, although antagonism of the latter substantially inhibited the hindquarter vasodilator effects of exendin-4. These results are consistent with exendin-4 having cardiovascular effects through GLP-1 receptor-dependent and -independent mechanisms, some of which involve sympathoadrenal activation.

Regional heterogeneity in the haemodynamic responses to urotensin II infusion in relation to UT receptor localisation.

The aim of the study was to measure regional haemodynamic responses to 6 h infusions of human urotensin II (hUII), to identify possible mediators of the effects observed, and to relate the findings to the distribution of urotensin II receptors (UT receptors). Male, Sprague-Dawley rats had pulsed Doppler flow probes and intravascular catheters implanted for measurement of regional haemodynamics in the conscious, freely moving state. Infusions of saline (0.4 ml h(-1)) or hUII (30, 300 and 3,000 pmol kg(-1) h(-1)) were given i.v. for 6 h, and the effects of pretreatment with indomethacin (5 mg kg(-1) h(-1)), N(G)-nitro-L-arginine methyl ester (L-NAME, 3 mg kg(-1) h(-1)) or propranolol (1 mg kg(-1); 0.5 mg kg(-1) h(-1)) on responses to hUII (300 pmol kg(-1) h(-1) for 6 h) were assessed. Cellular localisation of UT receptor-like immunoreactivity was determined in relevant tissues. hUII caused dose-dependent tachycardia and hindquarters vasodilatation, accompanied by a slowly developing rise in blood pressure. Haemodynamic effects of hUII were attenuated by propranolol or L-NAME and abolished by indomethacin. UT receptor-like immunoreactivity was detected in skeletal and vascular smooth muscle. The findings indicate that in conscious rats, infusions of hUII cause vasodilatation, which, of the vascular beds monitored, is selective for the hindquarters and dependent on cyclooxygenase products and nitric oxide. The pressor effect of hUII under these conditions is likely to be due to an increase in cardiac output, possibly due to a positive inotropic effect. UT receptor-like immunoreactivity present in skeletal muscle is consistent with the haemodynamic pattern.

Regional hemodynamic actions of selective corticotropin-releasing factor type 2 receptor ligands in conscious rats.

In conscious male Sprague-Dawley rats, we compared regional hemodynamic actions of the selective corticotropin-releasing factor type 2 (CRF(2)) receptor ligands human and mouse urocortin 2 (hUCN2 and mUCN2, respectively) with those of CRF. Bolus i.v. doses of 3 and 30 pmol kg(-1) hUCN2, mUCN2, or CRF had no significant hemodynamic actions, but at doses of 300 and 3000 pmol kg(-1), all three peptides caused dose-dependent tachycardia and hypotension, with rapid-onset, short-duration, mesenteric vasodilatation and slower-onset, more prolonged hindquarters vasodilatation but little or no change in renal vascular conductance. Pretreatment with the nonselective CRF receptor antagonist astressin or the selective CRF(2) receptor antagonist antisauvagine 30 abolished all the cardiovascular actions of all three peptides. Indomethacin had no effect on responses to hUCN2, and there was no evidence for any involvement of nitric oxide (NO) in the vasodilator actions of hUCN2. There was no evidence that recruitment of angiotensin- and endothelin-mediated vasoconstrictor mechanisms counteracted the vascular actions of hUCN2. The results indicate that the hemodynamic effects of i.v. hUCN2, mUCN2, and CRF depend on activation of CRF(2) receptors and do not involve NO or prostanoids.

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).

Haemodynamic effects of the selective phosphodiesterase 5 inhibitor, UK-357,903, in conscious SHR.

1. Regional haemodynamic responses to a continuous, 4-day infusion of the selective phosphodiesterase type 5 inhibitor, UK-357,903 (0.133 or 1.33 mg x kg(-1) h(-1)) were measured in conscious spontaneously hypertensive rats, and compared with those of enalapril (1 mg x kg(-1) h(-1)). 2. Both doses of UK-357,903 caused modest reductions in mean blood pressure that were not dose-dependent and only significantly different from the vehicle effects on Day 1 of the study (mean -11.8 and -15.3 mmHg for low and high doses, respectively). UK-357,903 had mesenteric and hindquarters vasodilator effects, which were, again, similar for both dose levels and only significantly different from vehicle on Day 1. Neither dose of UK-357,903 affected renal vascular conductance or heart rate. 3. Although the haemodynamic effects of UK-357,903 were not clearly dose-related and some appeared to wane with time, geometric mean plasma levels of UK-357,903 increased in proportion to dose, and were sustained throughout the infusion period. Furthermore, plasma cyclic guanosine monophosphate, a biomarker of phosphodiesterase 5 inhibition, was persistently elevated, and increased with increasing dose. 4. Enalapril caused a fall in mean blood pressure on day 1 (-14.1 mmHg) that was associated with dilatation in renal, mesenteric and hindquarters vascular beds. The haemodynamic effects of enalapril were sustained or increased over the 4-day infusion, although plasma free drug levels were stable. 5. In conclusion, we have shown regional and temporal changes in the haemodynamic effects of UK-357,903, which may be due to activation of compensatory mechanisms, but there were no signs of functional compensation to the cardiovascular effects of enalapril.

Comparative regional haemodynamic effects of the nitric oxide synthase inhibitors, S-methyl-L-thiocitrulline and L-NAME, in conscious rats.

1. The regional haemodynamic effects of the putative nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), were compared with those of the nonselective NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), in conscious, male Sprague-Dawley rats. 2. SMTC (0.3 mg kg(-1) bolus) produced a significant, short-lived, pressor effect associated with renal, mesenteric and hindquarters vasoconstriction; the same dose of L-NAME did not affect mean blood pressure (BP), although it caused bradycardia and mesenteric vasoconstriction. 3. At the highest dose tested (10 mg kg(-1)), L-NAME produced a significantly greater bradycardia and fall in mesenteric vascular conductance than SMTC, although the initial pressor response to SMTC was greater, but less sustained, than that to L-NAME. 4. Infusion of SMTC or L-NAME (3 mg kg(-1) h(-1)) induced rises in BP and falls in renal, mesenteric and hindquarters vascular conductances, but the effects of L-NAME were greater than those of SMTC, and L-NAME also caused bradycardia. 5. The renal vasodilator response to acetylcholine was markedly attenuated by infusion of L-NAME, but unaffected by SMTC. The hindquarters vasodilatation induced by salbutamol was attenuated by L-NAME, but not by SMTC. The mesenteric vasodilator response to bradykinin was modestly enhanced by SMTC, but not by L-NAME. The depressor and renal, mesenteric and hindquarters vasodilator responses to sodium nitroprusside were enhanced by L-NAME, whereas SMTC modestly enhanced the hypotensive and renal vasodilator effects of sodium nitroprusside, but attenuated the accompanying tachycardia. 6. The results are consistent with the cardiovascular effects of low doses of SMTC being attributable to nNOS inhibition.