RESUMO
1. The effect of human alpha-calcitonin gene-related peptide (CGRP) and sodium nitroprusside have been measured on human isolated mesenteric vasculature and on rings of human superior mesenteric artery and saphenous vein. 2. When noradrenaline (10(-5) M) was used as the vasoconstrictor in preparations perfused with Krebs solution at constant flow, human alpha-CGRP was 10 times more potent than sodium nitroprusside in evoking dose-dependent falls in perfusion pressure. 3. Human alpha-CGRP and sodium nitroprusside were about equipotent at relaxing rings of superior mesenteric artery contracted by noradrenaline (10(-6) M). When the tone of saphenous vein rings was raised by noradrenaline (10(-6) M), human alpha-CGRP did not relax the vascular smooth muscle. 4. The results show that human alpha-CGRP is a potent vasodilator in human arterial preparations and may act preferentially on arterioles rather than large arteries.
Assuntos
Neuropeptídeos/farmacologia , Circulação Esplâncnica/efeitos dos fármacos , Vasodilatadores , Idoso , Peptídeo Relacionado com Gene de Calcitonina , Feminino , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/efeitos dos fármacos , Norepinefrina/farmacologia , Veia Safena/efeitos dos fármacosRESUMO
A single gene encodes both calcitonin and the calcitonin gene-related peptide (CGRP). Human and rat alpha-CGRP were compared with sodium nitroprusside in the rat and rabbit isolated mesenteric vascular preparation perfused at constant flow. In the presence of the vasoconstrictor noradrenaline (10(-5) M), rat alpha-CGRP was about 10 times as potent as either human alpha-CGRP or sodium nitroprusside as a vasodilator in the rat mesenteric vasculature. In the rabbit mesenteric vasculature the order of potency was rat alpha-CGRP greater than human alpha-CGRP greater than sodium nitroprusside. Human and salmon calcitonin showed no vasodilator activity at doses 100 times greater than human alpha-CGRP. These results show that human and rat alpha-CGRP are potent vasodilators in the mesenteric vasculature, an effect not mimicked by the alternative gene product, the plasma calcium lowering hormone calcitonin.
Assuntos
Calcitonina/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Circulação Esplâncnica/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Peptídeo Relacionado com Gene de Calcitonina , Humanos , Técnicas In Vitro , Masculino , Proteínas do Tecido Nervoso/fisiologia , Nitroprussiato/farmacologia , Perfusão , Coelhos , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
The effects of the recently described human alpha-calcitonin gene-related peptide (CGRP), human beta-CGRP and rat alpha-CGRP have been compared with those of the vasodilator sodium nitroprusside, on the rat and rabbit isolated heart. Hearts were perfused at constant flow and [Arg8]-vasopressin was used to increase coronary perfusion pressure. In the rat heart, the order of potency for evoking cumulative dose-dependent falls in perfusion pressure was human beta-CGRP greater than rat alpha-CGRP greater than human alpha-CGRP greater than sodium nitroprusside. In the same preparations the three CGRPs (but not sodium nitroprusside) elicited cumulative dose-related increases in heart rate. In the rabbit heart the order of potency for vasodilatation was rat alpha-CGRP greater than human alpha-CGRP greater than sodium nitroprusside. In marked contrast to results from the rat, neither rat alpha-CGRP nor human alpha-CGRP altered heart rate in the rabbit isolated heart. These results show that human alpha- and beta-CGRP and rat alpha-CGRP are vasodilators in the coronary vasculature, but that there is species variation as CGRP had a positive chronotropic effect in the rat heart but not in the rabbit heart.
Assuntos
Coração/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Processamento de Proteína Pós-Traducional , Vasodilatadores , Sequência de Aminoácidos , Animais , Peptídeo Relacionado com Gene de Calcitonina , Relação Dose-Resposta a Droga , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Studies on the structure and expression of the rat and human calcitonin gene provide a remarkable example by which a combination of molecular, immunocytochemical and pharmacological techniques have led to the identification of a novel gene product, the calcitonin gene-related peptide, a peptide of unexpected tissue distribution and biological activity. Future studies at the molecular level will provide insight into post-transcriptional mechanisms by which a single gene can give rise to discrete mRNAs in a tissue-specific manner. The isolation and characterization of the CGRP receptor, and hence the site(s) and mechanism(s) of action of the CGRP family within the vasculature, will also add significantly to our understanding of molecular mechanisms involved in the modulation of cardiovascular function in man. Furthermore, the role and mechanism of action of the CGRP peptide family in the central and peripheral nervous systems remains to be elucidated. It is also apparent that measurement of circulating plasma levels of CGRP may be of diagnostic and prognostic value, providing information concerning the onset and progression of lung and thyroid carcinoma. Our analysis of the structure and expression of the calcitonin/alpha-CGRP gene also demonstrates, for the first time, the molecular basis of large calcitonin secretion by lung carcinoma cells. Whether the expression of this gene in lung carcinoma cell-lines can truly be described as 'ectopic' is however questionable, in the light of recent immunocytochemical evidence which demonstrates that the lung is a major source of CGRP producing cells in the rat (see Springall et al., 1984).
