1 Regional haemodynamic responses to i.v. bolus doses (0.1-10.Omgkg-) of N0-nitro-L-arginine methyl ester (L-NAME) were measured in conscious, Long Evans rats (n = 8) chronically instrumented with renal, mesenteric and hindquarters pulsed Doppler flow probes and intravascular catheters. 2 L-NAME caused dose-dependent pressor effects associated with renal, mesenteric and hindquarters vasoconstrictions. The mesenteric vascular bed showed earlier onset with more rapid, and greater, maximum vasoconstrictions than the renal or hindquarters vascular beds; however, the hindquarters vasoconstriction was more persistent. D-NAME was without significant effects (n = 2).3 Primed infusion of L-arginine (lOOmgkg-1 bolus followed by lOOmgkg-h-' infusion), starting 10min after an i.v. bolus injection of L-NAME (10mgkg-1), caused significant reversal of the pressor responses, and renal and mesenteric vasoconstrictions, but not of the hindquarters vasoconstriction.Primed infusions of L-arginine (100 mg kg 1, 100 mg kg'-h -1) starting 5 min after L-NAME (1 mg kg1 additionally caused some reversal of the hindquarters vasoconstriction, but this effect was transient.4 Primed infusion of L-arginine (lOOmgkg-', lOOmgkg-'h-1) starting 30min before i.v. bolus injection of L-NAME (10mgkg-') caused significant attenuation of the pressor effects and the renal and mesenteric vasoconstrictions but not of the hindquarters vasoconstriction. 5 In a separate group of rats (n = 8) chronically instrumented with thoracic aortic electromagnetic flow probes for the measurement of cardiac haemodynamics, i.v. bolus injection of L-NAME (10mgkg-1) produced significant reductions in total peripheral conductance, cardiac output, stroke volume, peak thoracic aortic flow and the maximum rate of rise of aortic flow; these were coincident with the maximum pressor and vasoconstrictor effects.6 These results, collectively, are consistent with L-NAME interfering with L-arginine-nitric oxide pathways that have important influences on regional vascular conductances in vivo. The pressor effect resulting from L-NAME-induced vasoconstrictions is offset by a substantial reduction in cardiac function that may depend on direct and/or indirect effects of L-NAME on the heart.

The regional hemodynamic consequences of inhibiting vascular endothelial nitric oxide generation with NG-monomethyl-L-arginine (L-NMMA) were studied in conscious Long-Evans rats. Experiments were carried out in groups of chronically instrumented rats with intravascular catheters and pulsed Doppler probes to monitor regional blood flow. L-NMMA (0.3-300 mg/kg) caused a dose-dependent, long-lasting (5-90 minutes), and enantiomerically specific increase in mean blood pressure and also caused bradycardia. The increase in blood pressure was accompanied by a dose-dependent and long-lasting vasoconstriction in the internal carotid, mesenteric, renal, and hindquarters vascular beds that could be attenuated, in a concentration-dependent manner, by L-arginine but not by D-arginine. In contrast, L-arginine did not affect the pressor or vasoconstrictor effects of vasopressin. These results indicate that nitric oxide production by vascular endothelial cells contributes to the maintenance of blood pressure and to the control of the resting tone of different vascular beds in the conscious rat.

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1 Conscious Long Evans rats, chronically instrumented for cardiovascular measurements, were challenged with i.v. bolus doses of glyceryl trinitrate (40 nmol kg-1), acetylcholine (1.2 nmol kg-1), bradykinin (3.2 nmol kg-1), or endothelin-1 (0.25 nmol kg '). Under control conditions these doses produced similar falls in mean arterial blood pressure (glyceryl trinitrate, -20 + 3 mmHg; acetylcholine, -24 + 2 mmHg; bradykinin, -21 + 3 mmHg; endothelin-1, -25 + 3 mmHg), associated with renal, mesenteric and hindquarters vasodilatations (except for endothelin-1 which caused mesenteric vasoconstriction). 2 In the presence of NG-nitro-L-arginine methyl ester (L-NAME, 10 mg kg-1), a potent inhibitor of nitric oxide biosynthesis and endothelium-dependent vasorelaxation in vitro, the hypotensive responses to glyceryl trinitrate, acetylcholine, and endothelin-1 were increased, although that to bradykinin was not. However, comparing the differences between the response to glyceryl trinitrate and that to any other agonist in the absence and presence of L-NAME showed that there were relative attenuations of the hypotensive responses to bradykinin and endothelin-1, but not to acetylcholine, in the presence of L-NAME. 3 This comparative analysis showed that the renal and hindquarters vasodilator responses to bradykinin and endothelin-1 were attenuated in the presence of L-NAME, but the renal, mesenteric and hindquarters vasodilator responses to acetylcholine were not. However, when L-NAME was administered in the presence of pentolinium, captopril and the vasopressin Vj-receptor antagonist, d(CH2)5[Tyr-(Et)]DAVP, (to abolish baroreflex and neurohumoral mechanisms), there was attenuation of the renal and mesenteric vasodilator effects of acetylcholine relative to those seen with glyceryl trinitrate. Under those conditions only the renal vasodilator effects of bradykinin and endothelin-1 were attenuated. 4 In separate experiments in conscious Long Evans rats, direct measurement of cardiac haemodynamics showed that the hypotensive responses to glyceryl trinitrate, acetylcholine, bradykinin and endothelin-l were entirely attributable to rises in total peripheral conductance since both in the absence and presence of L-NAME there were no reductions in cardiac index in response to these substances. 5 The results indicate that measurement of systemic arterial blood pressure alone in conscious rats does not permit reliable quantitation of the influence of L-NAME on regional vasodilator responses to glyceryl trinitrate, acetylcholine, bradykinin or endothelin-1. Furthermore, these substances exert effects in different vascular beds that may be differentially influenced by baroreflex mechanisms, neurohumoral mechanisms, or both. Moreover, except in the case of the renal vasodilator response to endothelin-1 (which was abolished in the presence of L-NAME), even when L-NAME caused attenuation of the vasodilator effects of acetylcholine or bradykinin (relative to glyceryl trinitrate), substantial responses remained. It is feasible that such r...

Two experiments were carried out in male subjects. In the first experiment heart rate and blood pressures were measured before, during and for 90 min after a 50 min period of intermittent exercise in seven hypertensive subjects. After exercise there was a marked reduction in systolic and diastolic blood pressures; this effect lasted throughout the 90 min observation period and was unaccompanied by tachycardia. In the second experiment heart rate and blood pressures were measured before and during the rest periods in a 50 min session of intermittent exercise in nine hypertensive and nine normotensive subjects. Following the first 10 min bout of exercise, resting blood pressures were significantly reduced in the hypertensive subjects; the reduction in blood pressure progressively increased following successive exercise periods. The normotensive subjects did not show a significant reduction in resting blood pressures until the fifth bout of exercise had been completed. In the second experiment also, the competence of baroreflexes was assessed by measuring cardiovascular responses to lower body subatmospheric pressure ( LBSP ) 30 min before and 30 and 60 min after exercise. The post-exercise reduction in blood pressure was not due to exercise-induced impairment of baroreflex mechanisms since the reduced blood pressure after exercise was well maintained during lower body subatmospheric pressure. Furthermore, after exercise, exposure to lower body subatmospheric pressure elicited greater increases in heart rate and forearm vascular resistance than were seen before exercise.

1 A reproducible model of the hyperdynamic circulatory sequelae of endotoxaemia in conscious, chronically-instrumnted Long Evans rats, was achieved with a continuous infusion of lipopolysaccharide (LPS, 150 pg kg-' h'l) for 32 h. Over the first 2 h of LPS infusion, there was a transient hypotension and tachycardia, accompanied by a marked increase in renal flow and vascular conductance, although there were reductions in cardiac and stroke index. Between 4-8 h after the start of LPS infusion, there was slight hypotension and tachycardia, and a transient rise in mesenteric flow and conductance, but reductions in the hindquarters vascular bed; the hyperaemic vasodilatation in the renal vascular bed was maintained. At this stage, all cardiac haemodynamic variables and total peripheral conductance, were increased, but central venous pressure was reduced. By 24 h after the onset of LPS infusion, there was clear hypotension and tachycardia, accompanied by increases in renal and hindquarters flow and conductance, although mesenteric haemodynamic variables were not different from baseline. At this stage, cardiac and stroke index were substantially elevated, in association with marked increases in peak aortic flow, dF/dtm. and total peripheral conductance; these changes were well-maintained over the following 8 h of LPS infusion. 2 By 2 h after the start of LPS infusion, only lung inducible nitric oxide synthase (iNOS) activity was increased, but at 6 h there were significant increases in iNOS activity in lung, liver, spleen, heart and aorta (43.3±7.8, 28.8±3.3, 50.8±7.2, 3.04±0.29, 3.76±0.94 pmol min' mg -' protein, respectively). However, by 24 h after the start of LPS infusion, iNOS activity was not elevated significantly in any tissue examined, and kidney iNOS activity did not change significantly during LPS infusion. Plasma nitrite/nitrate levels were increased after 2 h infusion of LPS (from 6.07 ± 1.23 to 29.44± 7.08 pmol 1-1), and further by 6 h (228.10±29.20 pmol I-'), but were less 24 h after onset of LPS infusion (74.96±11.34 pmol I-'). Hence, the progressive hypotension, increasing cardiac function and developing hyperaemic vasodilatation in renal and hindquarters vascular beds between 8-24 h after the onset of LPS infusion, occurred when tissue iNOS activity and plasma nitrite/nitrate levels were falling.3 Pretreatment with N0-monomethyl-L-arginine (L-NMMA, 30 mg kg-' bolus, 30mg kg7' h-' infusion) 1 11 before LPS infusion did not prevent the early hypotension, but abolished the initial renal vasodilatation and the later (6-8 h) fall in mean arterial pressure (MAP), and the additional renal vasodilatation. However, under these conditions, mesenteric and hindquarters flows and conductances were substantially decreased. Similar, but less marked, effects were seen with L-NMMA pretreatment at 10 mg kg' bolus, 10 mg kg-' h-' infusion, whereas at a lower dose of 3 mg kg-' bolus, 3 mg kg' h-' infusion, L-NMMA pretreatment had little effect on responses to LPS.4 Delaying treatment with L-NMMA (10 mg kg-' bolus, 10 mg...

The regional haemodynamic eects of rat or human urotensin II (U-II) 3, 30, 300 and 3000 pmol kg 71 , i.v.) were assessed in separate groups of conscious, unrestrained, male, SpragueDawley rats (n=8 in each). Rat and human U-II had similar eects. At a dose of 3 pmol kg 71 , neither peptide had any signi®cant action, while at a dose of 30 pmol kg 71, there was a transient mesenteric vasodilatation (signi®cant only for rat U-II). At doses of 300 and 3000 pmol kg 71, there were dose-dependent tachycardias, and mesenteric and hindquarters hyperaemic vasodilatations. Thus, in conscious rats, the predominant cardiovascular action of rat and human U-II is vasodilatation. This is in contrast to recent ®ndings with human U-II in non-human primates, but is consistent with eects on human isolated resistance vessels.

The reduction in BRS and the resulting aberrant blood pressure response to the physiological stress and volume changes of HD may be important in the further understanding of the pathophysiology of the increased mortality in HD patients with vascular calcification.