L-NAME enhances responses to atrial natriuretic peptide in the pulmonary vascular bed of the cat.

This study investigated the hypothesis that atrial natriuretic peptide (ANP) responses are mediated by particulate guanylate cyclase in the pulmonary vascular bed of the cat. When tone in the pulmonary vascular bed was raised to a high steady level with the thromboxane mimic U-46619, injections of ANP caused dose-related decreases in lobar arterial pressure. After administration of HS-142-1, an ANP-A- and ANP-B-receptor antagonist, vasodilator responses to ANP were reduced. The nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) enhanced ANP vasodilator responses, suggesting that inhibition of NO modulates ANP responses. L-NAME administration with constant 8-bromo-cGMP infusion attenuated the increased vasodilator response to ANP, suggesting that supersensitivity to ANP occurs upstream to activation of a cGMP-dependent protein kinase. In pulmonary arterial rings, ANP produced concentration-related vasorelaxant responses with and without endothelium. Methylene blue, L-NAME, or N(omega)-monomethyl-L-arginine did not alter ANP vasorelaxant responses. These data show that ANP supersensitivity observed in the intact pulmonary vascular bed is not seen in isolated pulmonary arterial segments, suggesting that it may only occur in resistance vessel elements. These results suggest that ANP responses occur through activation of ANP-A and/or -B receptors in an endothelium-independent manner and are modulated by NO in resistance vessel elements in the pulmonary vascular bed of the cat.

The effect of prior hypothermia on the physiological response to norepinephrine.

OBJECTIVE: this study determines the effect of prior hypothermia on the cardiovascular responses to norepinephrine (NE) after rewarming. METHODS: the experiment was a 2x2 controlled design with four groups of feline animals. The two variables were the presence or absence of previous cooling, and the use or non-use of NE after rewarming. During the 'cooling' phase, animals were either cooled using an external arterial-venous femoral shunt to 30 degrees C or maintained at 37 degrees C. After 'rewarming' animals were stratified to receive either NE at rates to deliver 0.2, 1.0 or 5 microg/kg per h or normal saline infusions. Animals were instrumented to measure mean arterial pressure (MAP) and cardiac output (CO) and systemic vascular resistance (SVR) was calculated. RESULTS: there were no differences between groups at baseline and low dose NE (0.2 microg/kg per min). At 1.0 microg/kg per min, NE caused a significant increase in CO (P<0.01) and no effect of MAP or SVR in the rewarmed animals when compared with normothermic controls. In rewarmed animals 5.0 microg/kg per min NE caused a significant increase in CO (P<0.01) and no effect on MAP or SVR. In normothermic controls there was a significant increase in SVR (P=0.02) and MAP (P=0.05) and no effect on CO. CONCLUSION: this study shows that the effect of prior hypothermia on cardiovascular responses to moderate and high doses of NE is an improved CO with no affect on SVR and MAP. This could alter the clinical utility of NE in this situation.

Nociceptin receptor activation produces nitric oxide-mediated systemic hypotension.

The purpose of the present study was to investigate the effects of L-N5-(1-iminoethyl)ornithine hydrochloride (L-NIO), an inhibitor of nitric oxide (NO) formation, and [Phe1-psi(CH2NH)-Gly2]Nociceptin(1-13)-NH2 (Phe-NOC), a nociceptin receptor antagonist, on the systemic vasodepressor response to nociceptin in the anesthetized rat. The systemic vasodepressor response to bolus intravenous (i.v.) injections of nociceptin was significantly reduced by L-NIO and Phe-NOC. The present data suggest activation of nociceptin receptors dilates the systemic vascular bed through a NO-dependent pathway. These data also demonstrate Phe-NOC is an efficacious and selective nociceptin receptor antagonist in vivo.

Novel catheterization technique for the in vivo measurement of pulmonary vascular responses in rats.

A novel cardiac catheterization technique was devised to investigate the pulmonary arterial pressure-blood flow relationship in intact spontaneously breathing rats (ISBR) under physiological conditions with constant left atrial pressure and controlled blood flow within the normal range. Observations using this new technique in vivo were contrasted with data derived with isolated perfused rat lungs in vitro. Unlike results in in vitro isolated perfused rat lungs, the pressure-flow curves in vivo were curvilinear, with pulmonary artery pressure increasing more rapidly at low pulmonary blood flows of 4-8 ml/min and less rapidly at higher flow rates. Pressure-flow curves were reproducible and were not altered by 1-1.5 h of arrested perfusion, cyclooxygenase blockade, or perfusion with aortic or mixed venous blood. In contrast to results in in vitro isolated perfused rat lungs, NG-nitro-L-arginine methyl ester (L-NAME) increased pulmonary arterial pressure at all but the lowest flow rates with a slight effect on the curvilinear pressure-flow relationship. L-NAME reversed pulmonary vasodilator responses to acetylcholine and bradykinin and enhanced the pulmonary vasodilator response to nitroglycerin. The present data suggest that actively induced pulmonary hypertension is under greater control by endothelium-derived relaxing factor (EDRF). Unlike previous results in in vitro perfused rat lungs, results in ISBR demonstrate that the pulmonary vasodilator response to adrenomedullin-(13-52) is not mediated by calcitonin gene-related peptide receptors, which are not coupled to the release of EDRF. These results indicate that this novel technique may provide a useful model for the study of the pulmonary circulation in the intact chest rat.

Analysis of responses to adrenomedullin-(13-52) in the pulmonary vascular bed of rats.

The effects of human adrenomedullin-(13-52) [hADM-(13-52)] were investigated in the rat pulmonary vascular bed and in isolated rings from the rat pulmonary artery (PA). Under conditions of controlled blood flow and constant left atrial pressure when tone was increased with U-46619, injection of hADM-(13-52) produced dose-related decreases in lobar arterial pressure. Pulmonary vasodilator responses in the intact rat and vasorelaxant responses to hADM-(13-52) in rat PA rings were inhibited by NG-nitro-L-arginine methyl ester (L-NAME) and L-N5-(1-iminoethyl)-ornithine hydrochloride (L-NIO). Vasorelaxant responses to hADM-(13-52) were also inhibited by methylene blue, endothelium removal, hADM-(26-52), and iberiotoxin, whereas meclofenamate, calcitonin gene-related peptide-(8-37) [CGRP-(8-37)], glibenclamide, and apamin were without effect. Because vasorelaxant responses to NS-1619, a large-conductance Ca(2+)-activated K+ channel agonist, were not altered by L-NAME and vasorelaxant responses to acetylcholine and CGRP were not altered by hADM-(26-52), the present data suggest that ADM-(13-52) acts on a receptor in the pulmonary vascular bed that is coupled to endothelial nitric oxide release. These data suggest that this nitric oxide release may lead to guanosine 3',5'-cyclic monophosphate-dependent K+ channel activation, which produces a pulmonary vasorelaxant response through hyperpolarization of vascular smooth muscle cells. The present data suggest that ADM-(13-52) modulates receptor-mediated, but not voltage-dependent, pulmonary vascular contraction by influencing Ca2+ influx. These results suggest that the ADM fragment, hADM-(13-52), acts as an endothelium-dependent vasodilator agent in the pulmonary vascular bed of the rat.

The physiological response to norepinephrine during hypothermia and rewarming.

Our purpose was to determine if core hypothermia influences physiological responses to norepinephrine (NE); and if rewarming reverses these effects. Animals were instrumented to measure mean arterial pressure (MAP) and cardiac output (CO). Core temperature was manipulated from 37.5 degrees C (normothermia), to 30 degrees C (hypothermia) and the back to 37.5 degrees C (rewarming) using an external arterial-venous femoral shunt. At each of these temperatures, baseline CO and MAP were measured. Norepinephrine (NE) was infused at rates to deliver 0.2, 1.0, or 5 microg kg(-1) per h. At each dose CO and MAP was measured again. Systemic vascular resistance (SVR) was calculated using the formula (SVR = (MAP/CO) x 80). Eight animals underwent all three phases of the protocol. The response to NE during normothermia was a significant increase in MAP to doses of 1 microg kg(-1) per min (P < 0.01) and 5 microg kg(-1) per min (P < 0.01) and SVR to doses of 1 microg kg(-1) per min (P < 0.01) and 5 microg kg(-1) per min (P < 0.01). The response to NE during hypothermia was a significant increase in MAP only at doses of 1 microg kg(-1) per min (P = 0.03) and 5 microg kg(-1) per min (P = 0.01). The response to NE after rewarming was a significant increase in MAP only at a dose of 5 microg kg(-1) per min (P = 0.03). This study shows that core hypothermia causes a change in physiological response to NE that rewarming does not reverse.

Blood flow to the immature hip. Ultrasonic measurements in pigs.

We quantitatively analyzed blood flow through the major arteries supplying the pig's femoral head during various hip positions and following ligation of various vessels in order to identify the vascular abnormalities which may be responsible for the development of avascular necrosis during the treatment of developmental dysplasia of the hip. Our findings reveal that a decrease in total blood flow to the femoral head occurs when the hip is held in the frog leg position with ligation of the deep femoral artery and proximal ligation of the lateral femoral circumflex artery, and ligation of the deep femoral artery, together with the lateral femoral circumflex artery proximally. In contrast, neither distal ligation of the medial femoral circumflex artery nor lateral femoral circumflex artery alone nor holding the hip in the Lange position caused a statistically significant decrease in total flow. We also observed a unique steal effect on total proximal femoral blood flow, with the hip held in the frog leg position. In 4 of 7 pigs, we found a reversal of flow in the medial femoral circumflex artery.

Adrenomedullin mediates coronary vasodilation through adenosine receptors and KATP channels.

The following experiments were conducted to determine whether, and the mechanisms through which, endogenous peptides alter coronary artery blood flow. Ultrasonic transit time probes were placed around the ascending aorta and left anterior descending coronary artery in groups of anesthetized, open-chest dogs. A Millar pressure catheter monitored left ventricular developed pressure. Intracoronary artery bolus injections of adenosine (a purinergic receptor activator), pinacidil (a KATP channel activator), calcitonin gene-related peptide (CGRP; which causes vascular smooth muscle relaxation by intracellular increases in cyclic-AMP), and adrenomedullin (mechanism unknown) each significantly (P < 0.05, Student's t test) increased coronary blood flow in a dose-dependent fashion, without altering systemic hemodynamic measurements. Intracoronary artery injection of U37883A (a KATP channel antagonist) significantly (P < 0.05) blocked the coronary vasodilator responses to adenosine, adrenomedullin, and pinacidil. Intracoronary xanthine amine congener (an adenosine receptor antagonist) blocked only the responses to adenosine and adrenomedullin, not pinacidil. Intracoronary CGRP8-37 (CGRP receptor antagonist) blocked only the vasodilator response to CGRP. These data suggest that the coronary vasodilator effect of adrenomedullin is initiated first by activation of adenosine receptors, and subsequently through KATP channels-not by activation of CGRP receptors. That there were no changes in left ventricular developed pressure or in systemic hemodynamics after intracoronary artery infusions of adrenomedullin indicates that this endogenous peptide may have clinical utility in facilitating myocardial protection or preconditioning.

Nociceptin: an endogenous agonist for central opioid like1 (ORL1) receptors possesses systemic vasorelaxant properties.

The purpose of the present study was to investigate the effects of nociceptin on peripheral arterial rings from the cat. When feline renal, mesenteric, carotid and femoral rings with intact endothelium were precontracted with phenylephrine (100 nanomolar), nociceptin (3 x 10(-11)-3 x 10(-6) M) decreased tension in a concentration-dependent manner. The present data suggest nociceptin possesses biologic activity outside the CNS and may contribute to the regulation of systemic blood pressure and regional blood flow.

Diuretic and antinatriuretic responses produced by the endogenous opioid-like peptide, nociceptin (orphanin FQ).

Nociceptin (orphanin FQ) is a novel peptide isolated from brain tissue that has an amino acid sequence most similar to that of the endogenous opioid peptide dynorphin A. Aside from this similarity, the association of nociceptin to the endogenous opioid peptide systems and the functional importance of this new peptide in vivo are not completely known. Here we report that nociceptin is physiologically active in vivo and produces marked changes in the renal excretion of water and sodium. In conscious Sprague-Dawley rats, intravenous infusion of nociceptin produced a profound increase in urine flow rate and decrease in urinary sodium excretion. In further studies, intracerebroventricular (i.c.v.) injection of nociceptin into conscious rats produced a concurrent diuresis (dose-dependent) and antinatriuresis. The magnitude and pattern of the central nociceptin-induced water diuresis was similar to that produced by i.c.v. dynorphin A. Whereas i.c.v. pretreatment with the selective kappa-opioid receptor antagonist, nor-binaltorphimine, completely prevented the renal responses produced by dynorphin A, this antagonist did not alter the diuresis or antinatriuresis produced by central nociceptin. Thus, these results indicate that in conscious rats, nociceptin produces a selective water diuresis via a central nervous system mechanism independent of kappa-opioid receptors. Together, these observations suggest that endogenous nociceptin may be a novel peptide involved in the central control of water balance and ultimately in the regulation of arterial blood pressure. In the future, analogues of nociceptin may prove to be the first clinically useful water diuretics for patients with water-retaining diseases.

Characterization of alpha-adrenoceptor activity in term-newborn piglet mesentery.

For further characterization of neonatal mesenteric alpha 1-adrenoceptor populations, an extracorporeal perfusion circuit was established to control intestinal blood flow in 0-2 day old piglets. Activation of alpha 1-adrenoceptors was first documented by observing dose-dependent increases in mesenteric perfusion pressure after intra-mesenteric arterial injection of methoxamine and noradrenaline. Peripheral intravenous injections of WB 4101 (a competitive alpha 1A-adrenoceptor antagonist), but not clorethylclonidine (CEC, an alpha 1B-adrenoceptor antagonist), significantly (P < 0.05, analysis of variance) blunted mesenteric vasoconstrictor responses to those agonists. That the mesenteric vasoconstrictor response to mesenteric plexus stimulation was unaltered by CEC, but was muted by both WB 4101 and SK&F 104856 (a post-junctional alpha 1- and alpha 2-adrenoceptor antagonist) suggests that pre- and post-junctional alpha 1A-adrenoceptors are present and functional at birth.

Adrenomedullin dilates rat pulmonary artery rings during hypoxia: role of nitric oxide and vasodilator prostaglandins.

Hypoxia decreases vasorelaxation and leads to pulmonary arterial hypertension. A newly identified 52 amino-acid peptide adrenomedullin (ADM) exerts vasodilator effect in intact animals under normoxic condition. We studied the effect of human ADM on rat pulmonary arterial and aortic rings under normoxic and hypoxic conditions. During normoxia, ADM caused a concentration-dependent relaxation of precontracted aortic and pulmonary arterial rings; the relaxation was much more pronounced in pulmonary arterial rings and was abolished by the nitric oxide (NO) synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and by deendothelialization. A fragment of ADM, ADM13-52, caused a degree of relaxation similar to that induced by ADM in pulmonary arterial rings, but not in the aortic rings, and the relaxation of pulmonary artery caused by ADM13-52 was not affected by the cyclooxygenase inhibitor indomethacin but was abolished by L-NAME and by deendothelialization. During hypoxia, ADM13-52 failed to relax pulmonary arterial rings, whereas ADM caused modest relaxation of pulmonary arterial rings (one third of the relaxation during normoxia), which was abolished by pretreatment with indomethacin. Our results indicate that the vasorelaxant effect of ADM is more pronounced in pulmonary artery than in the aorta; ADM has more potent vasodilator effect than ADM13-52 during hypoxia; ADM relaxes hypoxic pulmonary artery through an indomethacin-sensitive pathway; amino acids 1-12 in ADM must be present for relaxation of chronic hypoxic pulmonary arterial rings; and last, the presence of endothelium is necessary for the expression of ADM-mediated relaxation.

Effects of anti-inflammatory agents on hydrochloric acid-induced pulmonary injury.

To determine the effects of anti-inflammatory agents on hydrochloric acid lung injury, the heart and lungs were harvested from rats, placed in a lung chamber, constant flow perfused with whole blood, and ventilated. The following experiments were conducted: observation alone; intratracheal injection of normal saline; intratracheal hydrochloric acid; and intravenous meclofenamate or indomethacin before intratracheal hydrochloric acid. Wet-to-dry lung weights were measured. Peak airway pressures increased immediately (p < .001 vs. baseline; ANOVA) in all intratracheal groups, hydrochloric acid producing even greater (p < .05) increases than saline-effects unaltered by meclofenamate or indomethacin. The increased (p < .001 vs. baseline) 2-h pulmonary artery pressures in hydrochloric acid-treated groups were unaltered by meclofenamate or indomethacin. All hydrochloric acid-treated groups demonstrated increases (p < .05) in weight that were unchanged by meclofenamate or indomethacin. These data suggest that the beneficial effects of these medications described elsewhere, using a variety of in vivo lung injury experimental models, may be attributed to their experimental design, or to contributions from organs/systems outside the pulmonary circuit.

Adrenomedullin is inactivated in the lungs of neonatal piglets.

Adrenomedullin, a novel 52 amino acid peptide normally present in adult human plasma, has been shown to induce systemic hypotension in the adult rat, pig and cat, and in the new-born piglet. Little is known about the site (s) of adrenomedullin inactivation in adults or neonates. Groups of five 0-2-day old and 2-week old anaesthetized piglets were prepared to enable continuous monitoring of cardiac output, mean systemic arterial pressure, mean pulmonary artery pressure, mean systemic vascular resistance and mean pulmonary vascular resistance. In both age groups, injections of human adrenomedullin1-52 into the left atrium produced significant (P < 0.05) reductions in mean systemic arterial pressure and mean pulmonary artery pressure. Although injections of similar doses of human adrenomedullin1-52 into the right atrium produced significant (P < 0.05) decreases in mean pulmonary artery pressure, there were no appreciable alterations in mean systemic arterial pressure in either age group. These results suggest that the systemic vasodilator properties of human adrenomedullin1-52 are reduced upon first pass through the pulmonary circulation in 2-week old piglets, a phenomenon that is present at birth.

Effect of maturation on alpha-adrenoceptor activity in newborn piglet mesentery.

To characterize the mesenteric alpha1- and alpha2-adrenoceptor populations in newborn piglets, an extracorporeal circuit was established to control intestinal blood flow in 0- to 2-day old and 10- to 14-day old animals. In both groups, alpha-adrenoceptor activation was first documented by observing dose-dependent increases in mesenteric perfusion pressure after intramesenteric arterial injection of alpha-adrenoceptor agonists. In the 10- to 14-day old piglets, mesenteric vasoconstrictor responses to alpha1-adrenoceptor agonists (methoxamine and norepinephrine) and an alpha2-adrenoceptor agonist (BHT-933) were each blunted (P < 0.05, analysis of variance) by peripheral intravenous injections of prazosin (an alpha1-adrenoceptor antagonist) and yohimbine (an alpha2-adrenoceptor antagonist), respectively. The mesenteric vasoconstrictor responses to those agonists were not significantly attenuated by prazosin or yohimbine in 0- to 2-day old animals, nor were they blunted by YM-12617 (alpha1-adrenoceptor antagonist) or idazoxan (alpha2-adrenoceptor antagonist)--compounds that are structurally unrelated to prazosin and yohimbine, respectively. In addition, mesenteric vasoconstrictor responses to other known vasoconstrictor agents--angiotensin II, neuropeptide Y, and a thromboxane A2 mimic (U-46619)--were not effected in either age group by prazosin or yohimbine, implying these agents act independently of alpha-adrenoceptor mechanisms. These data suggest that (1) there exists functional mesenteric alpha1- and alpha2-adrenoceptor-like activity in 10- to 14-day old piglets that, in 0- to 2-day old animals, is not specifically expressed; and (2) mesenteric alpha-adrenoceptor function becomes more selective as newborn piglets mature.

Burn edema reduction by methysergide is not due to control of regional vasodilation.

To determine the extent to which edema modulation by methysergide is due to a blunting of the regional vasodilator response to scald and/or local reduction of transvascular fluid flux, a canine hind limb lymphatic was cannulated. Femoral blood flow (Qa; ml/min), lymph flow (QL; microliter/min/100 g), and lymph-to-plasma protein ratios (CL/CP) were monitored in groups of five dogs before and 4 hr after 5-sec, 100 degrees C foot paw scald; high (1.0 mg/kg) or low (.5 mg/kg) dose of methysergide 30 min before scald. The compression on a clamp placed around the femoral artery in other dogs was adjusted after scald to simulate the blunting effect on Qa observed in methysergide treated dogs. Hind leg venous pressure was elevated to approximately = 40 mm Hg before experimentation until steady state QL and (CL/CP)min were reached. Protein reflection coefficient (sigma d; 1-C1/ CP) and fluid filtration coefficient (Kf) were calculated. Compared to preburn values, all groups showed significant (P < 0.002, analysis of variance) increases in CL/CP and Kf. Contrasted with the burn only group, methysergide blunted increases in Qa, Kf and paw weight gain in a dose-dependent fashion, with no effect on the reflection coefficient. Compression clamp control of femoral Qa caused no effects on permeability. Methysergide limits burn edema in a dose-related fashion, though not due to a blunting of the regional vasodilator response. Local, not regional, mechanism(s) likely mediate this response.

Adrenotensin: an adrenomedullin gene product contracts pulmonary blood vessels.

The purpose of the present study was to determine the effects of adrenotensin, a newly described product of the ADM gene, on cat pulmonary arterial (PA) rings. Under resting conditions, adrenotensin increased tension of PA rings in a concentration-dependent manner. Although addition of diphenhydramine, ONO-3708, phentolamine, methysergide, atropine, and meclofenamate did not alter the contractile response to adrenotensin, removal of the endothelial cell layer significantly reduced this response. Moreover, precontraction of PA rings with adrenotensin selectively attenuated the pulmonary vasorelaxant response to ADM but not to other vasodilator substances, including isoproterenol, pinacidil, nifedipine, and adenosine. The present data suggest that adrenotensin acts in an endothelium-dependent manner to contract PA rings. Moreover, the present data suggest that adrenotensin may act in a modulatory manner to influence vasorelaxation in response to ADM, a sister proADM product.

Positive end-expiratory pressure decreases mesenteric blood flow despite normalization of cardiac output.

Positive end-expiratory pressure (PEEP) is a commonly used adjunct to mechanical ventilation and is known to have deleterious effects on cardiac output (CO). Its effects on regional blood flow are not well known. We evaluated the effect of PEEP on the mesenteric microcirculation and CO. Sprague-Dawley rats were treated with mechanical ventilation and either no PEEP (Control) or increasing levels of PEEP (PEEP). Using in vivo video-microscopy, mesenteric A1 arteriolar optical Doppler velocities and A1 and A3 (the first- and third-order arterioles branching off the feeding mesenteric arcade) intraluminal diameters were measured (n = 6/group). In a separate set of experimental animals, CO was determined by thermodilution technique (n = 5/group). Additionally, after the PEEP group attained a PEEP level of 20-cm H2O PEEP, two boluses of 2 mL 0.9 normal saline (NS) were given intravenously. The Control groups had the same determinations performed over the same time course as the PEEP group but were not exposed to any PEEP. Mesenteric blood flow (MBF) was calculated from vessel diameter and red blood cell velocity. The MBF and CO fell progressively as PEEP was increased from 10- to 15- to 20-cm H2O pressure. MBF was reduced 75% (p < 0.05) and the CO was reduced 31% (p < 0.05) from baseline at 20-cm H2O pressure PEEP. After 4 mL normal saline, the MBF was still 45% below baseline (p < 0.05) while the CO had returned to baseline. In conclusion, both MBF and CO are decreased significantly with increasing PEEP.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasodilator effect of human adrenomedullin(13-52) on hypertensive rats.

Human adrenomedullin (hADM) is a newly isolated peptide with hypotensive activity in normotensive rats. The objective of this study was to investigate the effect of hADM(13-52) on hypertensive animals. hADM(13-52) induced a dose-dependent decrease in the blood pressure of spontaneously hypertensive rats and renal hypertensive rats. This result suggests that hADM is a novel antihypertensive peptide. In isolated rat aortic arteries, hADM(13-52) produced nitric oxide dependent relaxation and inhibited endothelin 1 and angiotensin II release. These in vitro effects may represent the molecular mechanisms underlying the hypotensive action of hADM in vivo.

Rat adrenomedullin induces a selective arterial vasodilation via CGRP1 receptors in the double-perfused mesenteric bed of the rat.

The present work was undertaken to study the effect of rat adrenomedullin (rADM (1-50) and its C-terminal fragment (11-50)) in the endothelium-intact arterial and venous vasculatures of the rat perfused mesenteric bed. rADM (1-50) and the fragment rADM (11-50)(1-1000 pmol) induced a dose-dependent and endothelium-independent vasodilation on the arterial mesenteric vasculature. However, both peptides were inactive on the venous side of this vascular bed. The CGRP1 receptor antagonist, hCGRP8-37 (1 microM), markedly reduced the vasodilation caused by rADM (1-50) in the arterial mesenteric vasculature. Thus, our results show that rADM (1-50) in the arterial mesenteric vasculature. Thus, our results show that rADM (1-50) and its C-terminal fragment rADM(11-50) share properties similar to those of hCGRP. The blocking effect of hCGRP8-37 supports a role for CGRP1 receptor activation by adrenomedullin in this vascular preparation.