Pulmonary vasodilator responses to vasoactive intestinal peptide in the cat

We investigated the effects of vasoactive intestinal peptide (VIP) in the feline pulmonary vascular bed under conditions of controlled pulmonary blood flow when pulmonary vascular tone was at base-line levels and when vascular resistance was elevated. Under base-line conditions, VIP caused small but significant reductions in lobar arterial pressure without affecting left atrial pressure. Decreases in lobar arterial pressure in response to VIP were greater and were dose related when lobar vascular resistance was increased by intralobar infusion of U 46619, a stable prostaglandin endoperoxide analogue. Acetylcholine and isoproterenol also caused significant decreases in lobar arterial pressure under base-line conditions, and responses to these agents were enhanced when lobar vascular tone was elevated. Moreover, when doses of these agents are expressed in nanomoles, acetylcholine and isoproterenol were more potent than VIP in decreasing lobar arterial pressure. Responses to VIP were longer in duration with a slower onset than were responses to acetylcholine or isoproterenol. Pulmonary vasodilator responses to VIP were unchanged by indomethacin, atropine, or propranolol. The present data demonstrate that VIP has vasodilator activity in the pulmonary vascular bed and that responses are dependent on the existing level of vasoconstrictor tone. These studies indicate that this peptide is less potent than acetylcholine or isoproterenol in dilating the feline pulmonary vascular bed and that responses to VIP are not dependent on a muscarinic or beta-adrenergic mechanism or release of a dilator prostaglandin.     

L-Name modulates responses to adrenomedullin in the hindquarters vascular bed of the rat

Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide recently discovered in human pheochromocytoma cells, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the hintquarters vascular bed of the rat. Under conditions of controlled hintquarters blood flow, intraarterial injections of ADM (0.01–0.3 nmol) and of CGRP (0.03–0.3 nmol) caused dose-related decreases in hindquarters perfusion pressure and decreases in systemic arterial pressure. Following administration of the nitric oxide synthase inhibitor, N^ω-nitro-L-arginine methyl ester (L-NAME), hindquarters vasodilator and systemic depressor responses to ADM were significantly decreased, whereas L-NAME did not significantly decrease the vasodilator response to CGRP in either the hindquarters or systemic vascular beds. Following administration of the cyclooxygenase inhibitor, meclofenamate, vasodilator responses to ADM and to CGRP were not significantly decreased. When the relative vasodilator activity of the two peptides was compared on a nmol basis, responses to ADM were similar to responses with CGRP in the hindquarters vascular bed, whereas ADM was 30–100 fold less potent than CGRP in decreasing systemic arterial pressure. The present data demonstrate that ADM has significant vasodilator activity in the hindquarters vascular bed of the rat, that hindquarters vasodilator and systemic vasodepressor responses to ADM, but not to CGRP, are dependent upon the release of nitric oxide from the endothelium.     

Differential effects of endothelin peptides in the systemic and pulmonary vascular beds of the cat

The cardiovascular and pulmonary responses to vasoactive intestinal contractor (VIC) were compared with those of endothelin (ET)-1, ET-2, ET-3 and sarafotoxin 6b (S6b) and the mechanism by which ET-1 alters vascular resistance was investigated in the hindquarters vascular bed of the cat. In a manner similar to ET-1 and ET-2, VIC at a dose of 0.3 nmol/kg i.v. produced increases in pulmonary arterial pressure (PAP) and biphasic changes in systemic arterial pressure (AP), systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR). The biphasic changes were characterized by initial decreases followed by increases. In contrast, ET-3 and S6b at doses of 0.3 nmol/kg i.v. produced mainly decreases in AP and SVR, increases in PAP, and biphasic changes in PVR. A monocyclic ET-1 analog and the ET-1 C-terminal hexapeptide fragment produced no effect on AP, SVR, PAP and PVR at doses of 30–100 nmol/kg i.v. ET-1 at a dose of 0.3 nmol i.a. produced a biphasic change in hindquarters perfusion pressure. The initial vasodilation and secondary vasoconstriction were not modified by a variety of blocking agents, whereas the vasoconstrictor response was significantly reduced by infusion of nimodipine, a calcium entry blocking agent. Results of the present study indicate that VIC, a peptide specific to the mouse gastrointestinal tract, elicits cardiovascular responses that are similar to those elicited by ET-1 and ET-2. The present results indicate that responses to these novel peptides are complex and while the mechanism of action remains uncertain, these data indicate that structural differences among the peptides confer differences in biological activity.     

Comparison of responses to rat and human adrenomedullin in the hindlimb vascular bed of the cat

Responses to rat (r) adrenomedullin (ADM) and human (h) ADM were compared in the hindlimb vascular bed of the cat under conditions of controlled blood flow. Intra-arterial injections of rADM and hADM in doses of 0.03–1 nmol caused dose-related decreases in hindlimb perfusion pressure. In terms of relative vasodilator activity, rADM was similar to hADM. The time course of the vasodilator response and the recovery half times (T_1/2) for the vasodilator response to rADM and hADM were not significantly different. Decreases in hindlimb perfusion pressure in response to rADM and hADM were not altered by the calcitonin gene-related peptide receptor antagonist, rCGRP(8–37), at the same time, vasodilator responses to calcitonin gene-related peptide (CGRP) were significantly reduced. The T_1/2 of the vasodilator response to rADM and hADM were significantly greater after administration of the cAMP-selective, type IV phosphodiesterase inhibitor, rolipram. These data demonstrate that decreases in hindlimb perfusion pressure in response to rADM and hADM are similar and that vasodilator responses to rADM are not dependent on the activation of CGRP receptors in the hindlimb vascular bed of the cat. These data further suggest that decreases in hindlimb perfusion pressure in response to rADM are mediated by smooth muscle increases in cAMP levels.     

In vivo attenuation of endothelium-dependent pulmonary vasodilation by methylene blue.

In vitro evidence suggests that resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation are mediated by changes in vascular smooth muscle concentrations of guanosine 3',5'-cyclic monophosphate (cGMP). We investigated this hypothesis in vivo in 19 mechanically ventilated intact lambs by determining the hemodynamic effects of methylene blue (a guanylate cyclase inhibitor) and then by comparing the hemodynamic response to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimic) or methylene blue. Methylene blue caused a significant time-dependent increase in pulmonary arterial pressure. During U-46619 infusions, acetylcholine, ATP-MgCl2, sodium nitroprusside, isoproterenol, and 8-bromo-cGMP decreased pulmonary arterial pressure. During methylene blue infusions, the decreases in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) and sodium nitroprusside (an endothelium-independent guanylate cyclase-dependent vasodilator) were attenuated by greater than 50%. The decreases in pulmonary arterial pressure caused by isoproterenol and 8-bromo-cGMP (endothelium-independent vasodilators) were unchanged. This study in intact lambs supports the in vitro evidence that changes in vascular smooth muscle cell concentrations of cGMP in part mediate resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation.     

Analysis of responses to endothelins in the rabbit pulmonary and systemic vascular beds

The effects of two isoforms of human endothelin (ET) on the pulmonary and systemic vascular beds were compared in the anesthetized intact-chest rabbit under conditions of constant pulmonary blood flow and left atrial pressure. Intralobar bolus injections of ET-1 (0.1-1 micrograms) and ET-3 (1-3 micrograms) produced modest vasoconstriction in the pulmonary vascular bed, whereas both peptides decreased systemic arterial pressure. The pulmonary vasoconstrictor response to ET-1 and ET-3 was inhibited by intralobar infusion of nitrendipine but was not altered by indomethacin. In contrast to the small effects of ET-1 and ET-3 on intact pulmonary resistance vessels, both peptides markedly contracted isolated pulmonary conductance vessels, with greater activity on venous than on arterial segments. Intravenous bolus injection of ET-1 (0.1-0.3 micrograms) or ET-3 (0.3-1 microgram) decreased systemic arterial pressure, increased cardiac output, and markedly decreased systemic vascular resistance. Higher doses of ET-1 produce a biphasic systemic vascular response with a prominent secondary pressor component. The present data suggest that the pulmonary vasoconstrictor activity of ET-1 is greater than that of ET-3 and their pressor activity depends on an extracellular source of calcium. The pulmonary and systemic hemodynamic effects of ET-1 and ET-3 in the rabbit do not depend on cyclooxygenase products. The systemic vasodilator response to ET-1 is not altered by first-pass lung transit. Furthermore the systemic vasodilator response to both peptides occurs independent of activation of muscarinic, beta 2-adrenergic, and platelet-activating factor receptors. Although ET-1 and ET-3 were initially reported as vasoconstrictor peptides, the present data suggest that, by having unique and potent systemic vasodilator activity, ET-1 and ET-3 act differently in the systemic and pulmonary vascular beds under resting conditions in the rabbit.     

Peroxynitrite does not impair pulmonary and systemic vascular responses.

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.     

N omega-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.     

Synthetic human adrenomedullin and adrenomedullin 15-52 have potent short-lived vasodilator activity in the hindlimb vascular bed of the cat

Responses to synthetic human adrenomedullin, a novel hypotensive peptide isolated from human pheochromccytoma cells, and the carboxy terminal 15-52 amino acid fragment of adrenomedullin (ADM15-52) were investigated in the hindlimb vascular bed of the cat under constant flow conditions. Intraarterial injections of the peptides in doses of 0.01–0.3 nmol caused dose-related decreases in hindlimb perfusion pressure. When compared on a nmol basis, adrenomedullin and ADM15-52 were similar to bradykinin in visodilator potency and were approximately 10 fold less potent than acetylcholine. The half-life of the vasodilator response to adrenomedullin and ADM15-52 ranged from 55 to 80 sec and was greater than the half-life of vasodilator responses to bradykinin in doses of 0.01–0.3 nmol and acetylcholine in doses of 0.01–0.3 nmol. The present data demonstrate that synthetic human adrenomedullin and ADM15-52 have potent but relatively short-lasting vasodilator activity in the hindlimb vascular bed of the cat. These data suggest that amino acid residues 15-52 of adrenomedullin are important for the expression of vasodilator activity in the hindlimb vascular bed of the cat.     

THE ENDOGENOUS μ-OPIOID AGONISTS,ENDOMORPHIN 1 AND 2, HAVE VASODILATOR ACTIVITY IN THE HINDQUARTERS VASCULAR BED OF THE RAT

Endomorphin 1 and endomorphin 2 are newly-discovered endogenous ligands for the μ-opioid receptor. In the present study, responses to intra-arterial injections of endomorphin 1 and 2 were investigated in the hindquarters vascular bed of the rat. Under constant-flow conditions, endomorphin 1 and 2 induced dose-dependent decreases in hindquarters perfusion pressure when injected in doses of 3–100 nmol into the hindquarters perfusion circuit. Vasodilator responses to endomorphin 1 and 2 and met-enkephalin were attenuated by the opioid receptor antagonist naloxone (2 mg/kg i.v.) at a time when vasodilator responses to isoproterenol were not altered. In terms of relative vasodilator activity, endomorphin 1 and 2 were similar to ATP, 100-fold less potent than isoproterneol, and 10,000-fold less potent than acetylcholine. These data demonstrate that endomorphin 1 and 2 have significant naloxone-sensitive vasodilator activity in the hindquarters vascular bed of the rat. © 1997 Elsevier Science Inc.     

Influence of cyclooxygenase blockade on responses to isoproterenol, bradykinin and nitroglycerin in the feline pulmonary vascular bed

We investigated the effect of indomethacin on responses to isoproterenol, bradykinin and nitroglycerin in the feline pulmonary vascular bed when pulmonary vascular resistance was actively increased by infusion of U46619 in order to determine if vasodilator responses to these agents were dependent on the integrity of the cyclooxygenase pathway. Since pulmonary blood flow left atrial pressure were held constant, changes in lobar arterial pressure directly reflect changes in lobar vascular resistance. Intralobar injections of isoproterenol, bradykinin, and nitroglycerin decreased lobar arterial pressure in a dose-related manner. Pulmonary vasodilator responses to the lower and midrange doses of bradykinin and nitrogylcerin were unchanged in the presence of indomethacin whereas pulmonary responses to the highest doses of nitroglycerin and bradykinin were increased by cyclooxygenase blockade. In contrast, pulmonary vasodilator responses to isoproterenol were significantly attenuated in the presence of propranolol, whereas pulmonary vasodilator responses to bradykinin and nitroglycerin were unchanged after beta blockade. The present data indicate that isoproterenol, bladykinin, and nitroglycerin have significant vasodilator activity in the cat when pulmonary vascular tone is actively increased. These data suggest that the formation of vasodilator cyclooxygenase products such as PGI₂ do not mediate vasodilator responses to isoproterenol, bradykinin, and nitroglycerin in the feline pulmonary vascular bed.     

Influence of cyclooxygenase blockade on responses to isoproterenol, bradykinin and nitroglycerin in the feline pulmonary vascular bed

We investigated the effect of indomethacin on responses to isoproterenol, bradykinin and nitroglycerin in the feline pulmonary vascular bed when pulmonary vascular resistance was actively increased by infusion of U46619 in order to determine if vasodilator responses to these agents were dependent on the integrity of the cyclooxygenase pathway. Since pulmonary blood flow and left atrial pressure were held constant, changes in lobar arterial pressure directly reflect changes in lobar vascular resistance. Intralobar injections of isoproterenol, bradykinin, and nitroglycerin decreased lobar arterial pressure in a dose-related manner. Pulmonary vasodilator responses to the lower and midrange doses of bradykinin and nitroglycerin were unchanged in the presence of indomethacin whereas pulmonary responses to the highest doses of nitroglycerin and bradykinin were increased by cyclooxygenase blockade. In contrast, pulmonary vasodilator responses to isoproterenol were significantly attenuated in the presence of propranolol, whereas pulmonary vasodilator responses to bradykinin and nitroglycerin were unchanged after beta blockade. The present data indicate that isoproterenol, bradykinin, and nitroglycerin have significant vasodilator activity in the cat when pulmonary vascular tone is actively increased. These data suggest that the formation of vasodilator cyclooxygenase products such as PGI2 do not mediate vasodilator responses to isoproterenol, bradykinin, and nitroglycerin in the feline pulmonary vascular bed.     

Methylene blue selectively inhibits pulmonary vasodilator responses in cats

The effects of methylene blue on vascular tone and the responses to pressor and depressor substances were investigated in the constricted feline pulmonary vascular bed under conditions of controlled blood flow and constant left atrial pressure. When tone was elevated with U46619, intralobar injections of acetylcholine, bradykinin, nitroglycerin, isoproterenol, epinephrine, and 8-bromoguanosine-3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intralobar infusions of methylene blue elevated lobar arterial pressure without altering base-line left atrial or aortic pressure, heart rate, or cardiac output. When methylene blue was infused in concentrations that raised lobar arterial pressure to values similar to those attained during U46619 infusion, the pulmonary vasodilator responses to acetylcholine, bradykinin, and nitroglycerin were reduced significantly, whereas vasodilator responses to isoproterenol, epinephrine, and 8-bromo-cGMP were not altered. Moreover, the pressor responses to angiotensin II and BAY K 8644 during U46619 infusion and during methylene blue infusion were similar. The enhancing effects of methylene blue on vascular tone and inhibiting effects of this agent on responses to acetylcholine, bradykinin, and nitroglycerin were reversible. These responses returned to control value when tone was again increased with U46619, 30-45 min after the methylene blue infusion was terminated. The present data are consistent with the hypothesis that cGMP may play a role in the regulation of tone in the feline pulmonary vascular bed and in the mediation of vasodilator responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, and to nitrogen oxide-containing vasodilators such as nitroglycerin.     

Inhibition of periarterial nerve stimulation-induced vasodilation of the mesenteric arterial bed by CGRP (8-37) and CGRP receptor desensitization

We provide the first functional evidence that calcitonin gene-related peptide (8-37) induces a direct vasoconstriction and reversibly antagonizes vasodilation of the mesenteric arterial bed induced by calcitonin gene-related peptide (CGRP) suggesting that CGRP (8-37) is a competitive antagonist of vascular CGRP receptors. Vasodilation induced by periarterial nerve stimulation was inhibited both by CGRP (8-37) and by desensitization of CGRP receptors. These results further support the evidence that the periarterial nerve stimulation-induced nonadrenergic noncholinergic vasodilation of the mesenteric vasculature is mediated by endogenous CGRP and its receptors.     

Pulmonary vasodilation to endothelin isopeptides in vivo is mediated by potassium channel activation

The present study was undertaken to investigate the effects of endothelin (ET) isopeptides on the pulmonary vascular bed of the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of ET-1 (1 microgram), ET-2 (1 microgram), and ET-3 (3 micrograms) produced marked reductions in pulmonary and systemic vascular resistances. The pulmonary vasodilator response to each ET isopeptide was not altered by atropine (1 mg/kg iv), indomethacin (2.5 mg/kg iv), and ICI 118551 (1 mg/kg iv) but was significantly diminished by glybenclamide (5 mg/kg iv). This dose of glybenclamide significantly diminished the decrease in lobar arterial and systemic arterial pressures in response to intralobar injection of pinacidil (30 and 100 micrograms) and cromakalim (10 and 30 micrograms), whereas pulmonary vasodilator responses to acetylcholine (0.03 and 0.1 microgram), prostaglandin I2 (0.1 and 0.3 microgram), and isoproterenol (0.03 and 0.1 microgram) were not altered. The systemic vasodilator response to each ET isopeptide was not changed by glybenclamide or by the other blocking agents studied. The present data comprise the first publication demonstrating that ET-1, ET-2, and ET-3 dilate the pulmonary vascular bed in vivo. The present data further suggest that the pulmonary vasodilator response to ET isopeptides depends, in part, on activation of potassium channels and is mediated differently from the systemic vasodilator response to these substances. Contrary to earlier work, the present data indicate the pulmonary vascular response to ET isopeptides does depend on the preexisting level of pulmonary vasomotor tone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cystic fibrosis, vasoactive intestinal polypeptide, and active cutaneous vasodilation.

The transmitter substance for the active cutaneous vasodilation that accompanies sweating during hyperthermia in humans is unknown. H?kfelt et al. (Nature Lond. 284: 515-521, 180) hypothesized that it is vasoactive intestinal polypeptide (VIP) that is cotransmitted with acetylcholine. Heinz-Erian et al. (Science Wash. DC 229: 1407-1408, 1985) reported that VIP innervation is sparse in the skin of persons with cystic fibrosis (CF). A corresponding attenuation of active vasodilation in these subjects would be evidence that VIP is involved in this effector mechanism of human thermor-regulation. Immunocytochemical analysis of skin biopsies from four men with CF confirmed that VIP innervation was sparse. We also analyzed immunoreactivity for calcitonin gene-related peptide (CGRP; normal), substance P (normal), and neuropeptide Y (low). VIP-immunoreactive Merkel cells were abnormal. Despite sparse VIP-immunoreactive innervation, our CF subjects' cutaneous vascular responses to hyperthermia were normal. Because VIP was not completely absent, this evidence is insufficient to rule out VIP as the vasodilator transmitter. However, the CGRP and substance P innervation we observed could mean that release of one or both of these peptides was the mechanism of the fully developed active cutaneous vasodilation.     

Tone-dependent responses to acetylcholine in the feline pulmonary vascular bed

The effects of an increase in base-line tone on pulmonary vascular responses to acetylcholine were investigated in the pulmonary vascular bed of the intact-chest cat. Under conditions of controlled blood flow and constant left atrial pressure, intralobar injections of acetylcholine under low-tone base-line conditions increased lobar arterial pressure in a dose-related manner. When tone was increased moderately by alveolar hypoxia, acetylcholine elicited dose-dependent decreases in lobar arterial pressure, and at the highest dose studied, acetylcholine produced a biphasic response. When tone was raised to a high steady level with the prostaglandin analogue, U46619, acetylcholine elicited marked dose-related decreases in lobar arterial pressure. Atropine blocked both vasoconstrictor responses at low tone and vasodilator responses at high tone, whereas meclofenamate and BW 755C had no effect on responses to acetylcholine at low or high tone. The vasoconstrictor response at low tone was blocked by pirenzepine (20 and 50 micrograms/kg iv) but not gallamine (10 mg/kg iv). The vasodilator response at high tone was not blocked by pirenzepine (50 micrograms/kg iv) or gallamine or pancuronium (10 mg/kg iv). The present data support the concept that pulmonary vascular responses to acetylcholine are tone dependent and suggest that the vasoconstrictor response under low-tone conditions is mediated by a high-affinity muscarinic (M1)-type receptor. These data also suggest that vasodilator responses under high-tone conditions are mediated by muscarinic receptors that are neither M1 nor M2 low-affinity muscarinic-type receptor and that responses to acetylcholine are not dependent on the release of cyclooxygenase or lipoxygenase products.     

Vascular effects of pituitary adenylate cyclase activating peptide: a comparison with vasoactive intestinal peptide

The effects of pituitary adenylate cyclase activating peptide (PACAP) on the blood pressure of the anesthetized rat and on the isolated rat tail artery were investigated and compared to those of vasoactive intestinal peptide (VIP). PACAP-38, PACAP-27 and the C-terminal fragment 16–38 caused a dose-dependent decrease in the systemic blood pressure. PACAP-27 and PACAP-38 were equipotent with VIP. The C-terminal fragment 16–38 was much less potent than VIP. The duration of action was longer for equimolar doses of PACAP-38 and PACAP-27 than for VIP and much longer than for PACAP 16–38. PACAP-27 and the phosphodiesterase inhibitor rolipram given in combination produced additive vasodepressive responses. In vitro PACAP-38, PACAP-27, VIP and PACAP 16–38 relaxed the phenylephrine-precontracted rat tail artery. PACAP-38 and PACAP-27 were equipotent with VIP. PACAP 16–38 was much less potent than the full-length peptides. The responses were resistant to atropine and propranolol. Addition of VIP 1 μM to preparations exposed to 1 μM PACAP-38 or -27 did not produce a further relaxation. VIP-like peptides, PACAP in particular, are known to activate adenylate cyclase and to elevate the plasma cyclic AMP (cAMP) concentration. cAMP was found to be a potent vasodepressor in the anaesthetized rat and a potent vasodilator of precontracted blood vessels. On the basis of these results it cannot be excluded that the vascular effects of PACAP are secondary to the effect of elevated levels of extracellular cAMP.     

Comparative effects of adrenomedullin,an adrenomedullin analog,and CGRP in the pulmonary vascular bed of the cat and rat

Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide initially isolated from human pheochromocytoma cells, an ADM analog (ADM_15–52), and a structurally related peptide, calcitonin gene-related peptide (CGRP), were compared in the pulmonary vascular bed of the cat and rat under constant flow conditions. When tone was increased with U46619, intraarterial injections of ADM (0.03–0.3 nmol), ADM_15–52 (0.03–0.3 nmol), and of CGRP (0.03–0.3 nmol) caused dose-related decreases in pulmonary arterial perfusion pressure. When the relative vasodilator activity of the peptides was compared on a nmol basis, ADM was approximately 10-fold more potent in the cat than in the rat, whereas vasodilator responses to CGRP were very similar in both species. CGRP was slightly more potent than ADM in the rat, whereas ADM was slightly more potent than CGRP in the cat. ADM and ADM_15–52 had similar pulmonary vasodiltor activity in the cat, whereas the full sequence peptide was slightly more potent than ADM_15–52 in the rat. The present data demonstrate that ADM has significant vasodilator activity in the pulmonary vascular beds of the cat and of the rat, and that the relative potency of the vasodilator effects of ADM and ADM_15–52 are different in the two species.