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Responses to human CGRP, adrenomedullin (ADM), and proadrenomedullin N[H.sub.2]-terminal 20 peptide (PAMP) were studied in small human thymic arteries. CGRP, ADM, and PAMP produced concentration-dependent vasodilator responses in arteries preconstricted with the thromboxane mimic U-46619. Responses to ADM and PAMP were attenuated, whereas responses to CGRP were not altered by endothelial denudation. Inhibitors of nitric oxide synthase and guanylyl cyclase attenuated responses to ADM and PAMP but not to CGRP. The CGRP1 receptor antagonist CGRP(8-37) attenuated responses to CGRP and ADM but not to PAMP. Responses to CGRP were reduced by SQ-22536 and Rp-cAMPS, inhibitors of adenylyl cyclase and PKA. These data suggest that responses to CGRP and ADM are mediated by CGRP(8-37)-sensitive receptors and that the endothelial ADM receptor induces vasodilation by a nitric oxide-guanylyl cyclase mechanism, whereas a smooth muscle CGRP receptor signals by a cAMP-dependent mechanism. A different endothelial receptor recognizes PAMP and signals by a nitric oxide-dependent mechanism. CGRP1 receptor; vascular endothelium; vascular tone; human thymus

Research were performed to determine whether the neuropeptides bombesin/gastrin-releasing polypeptide, vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide can act directly on secretin-producing cells to stimulate secretin release. The murine intestinal neuroendocrine tumor cell line STC-1 was employed as a model. Findings indicated that the neuropeptides and galanin can regulate secretin secretion in secreting-producing cells.

Research shows that vasodilator adrenomedullin controls osteoblast activity and stimulates bone mass production in vivo. Experiments using osteoblasts from fetal rat calvaria are described. The 52-amino acid peptide chain induces bone formation by causing increased phenylalanine incorporation into osteoblast cells. The effects of adrenomedullin treatment on fetal rat osteoblast cells over a 24-hour period are illustrated.

A primary culture system of rat fundic D cells was developed to examine the cellular response of bombesin-like peptides. Epithelial cells were isolated using Sprague-Dawley rats as experimental models. The concentration of somatostatin-like immunoreactivity in the culture system was determined via specific radioimmunoassay. Results indicated that rat fundic D cells play a role in the expression of gastrin-releasing peptide receptors and direct mediation of bombesin-like peptides on somatostatin release.

The biological actions of adrenomedullin in conscious sheep were analyzed to characterize the regulatory activity of the vasodilator peptide on renal performance, renal hemodynamics and endocrine activity. Infusions of adrenomedullin resulted in clear-cut renal hemodynamic effects such as reduced filling pressure and arterial pressure. The blood-pressure lowering effects of adrenomedullin was also coupled with increased cardiac output and renin stimulation in conscious sheep.

The mechanisms that mediate the vasodilatory effects of proadrenomedullin NH2-terminal 20 peptide (PAMP) were analyzed in hindlimb vascular bed of the cat. Administration of PAMP in cat hindlimb vascular beds reduced systemic arterial and hindlimb perfusion pressure due to decreased vascular resistance. Furthermore, the vasodilator activity of PAMP was retained in absence of the first 11 amino acids from the molecule. However, adrenomedullin exhibited more potent vasodilatory activities compared to PAMP.

The mechanisms the mediate vasodilator response to calcitonin gene-related peptide (CGRP) were analyzed in adult cats after the administration of adrenomedullin (ADM) in the cat hindlimb vascular bed. Administration of ADM in cat hindlimb vascular bed inhibited vascular responses to CGRP without altering hindlimb perfusion pressure. However, the inhibitory effects of ADM and the vasodilatory effects of CGRP were mediated by different receptors in the hindlimb vascular bed of cats.

beta-endorphin-like immunoreactivity was measured by radioimmunoassay in the brains of adult rats treated neonatally with beta-endorphin, naloxone, or vehicle. After treatment with beta-endorphin, the decreases observed in beta-endorphin-like immunoreactivity in the hypothalamus, pineal, midbrain, pons-medulla, hippocampus, striatum, frontal cortex, occipital cortex, and posterior cortex were highly significant but the 23% decrease in the thalamus was not significantly different from that of control rats. Neonatal administration of naloxone only resulted in a significant decrease in beta-endorphin-like immunoreactivity in the hypothalamus. In contrast, no differences were discernible in content of either beta-endorphin-like immunoreactivity or ACTH-like immunoreactivity in the pituitary of rats treated with beta-endorphin, naloxone, or vehicle in the neonatal period. These same rats had shown an increased threshold to painful thermal stimulation by the tail-flick test after administration of either beta-endorphin or naloxone at birth. The results suggest that neonatally injected beta-endorphin may alter the levels of beta-endorphin-like immunoreactivity in rat brain as well as the response to pain.

Male and female rat pups were injected with β-endorphin, naloxone or a saline control solution during days 2-7 postnatally. At 90 days of age the rats were tested for analgesia with the tail flick test. Testing was conducted during the first 2 hours of the light and the dark cycle. In both sexes and during both phases of the light cycle rats treated with β-endorphin as infants evidenced a significant elevation in threshold for painful thermal stimuli. Early treatment with naloxone also resulted in elevated threshold for thermal stimuli. Administration of naloxone to these rats as adults did not reverse the analgesic effect. It was concluded that early exposure to β-endorphin results in permanent changes in behavior perhaps by altering the interaction of endogenous opiates with their binding sites during a ciritcal period of opiate receptor development. © 1979.

The role of the pituitary adenylate cyclase-activating polypeptide (PACAP) in the secretion of gastrointestinal hormones was investigated by measuring cholecystokinin (CCK) release from STC-1, a murine intestinal cell line. The results revealed a marked increase in CCK release in cells incubated with PACAP as compared to cells incubated with other stimulants. The increase was time- and dose-dependent, and was accompanied by increased production of cAMP. It is suggested that PACAP-induced increases in CCK release may require the activation of adenylate cyclase.

Gastrin releasing peptides (GRP) found in the mammalian gastrointestinal tract and central nervous system play an important role in the regulation of feeding. In a study of feeding suppression in rats, it was shown that blockade of the GRP receptors abolishes the effects of feeding suppression by peripherally administered GRP. Thus, it was concluded that GRP receptors are necessary to suppress eating in rats.

The role of nitric oxide (NO) in mediating vasodilator responses to adrenomedullin (ADM), a hypotensive peptide derived from human pheochromocytoma cells, and the calcitonin gene-related peptide (CGRP) was investigated. Application of a NO synthase inhibitor on the lungs of rats and cats showed that NO mediate pulmonary vasodilator responses by dilating the pulmonary vascular bed of the rat during NO release, while in the cat, vasodilator responses to ADM and CGRP were independent of NO release. These results suggest that the role of NO in mediating vasodilator responses is species dependent.