Angiotensin (Ang) II in cardiac, renal and adrenal tissue is known to originate mainly from locally produced Ang I. Experimental evidence and theoretical considerations show that a simple relation between Ang II receptor occupancy, in tissue micromilieu, and the circulating levels of Ang II or renin may not exist. This supports the clinicians' view that the plasma level of renin tells more about the mechanisms regulating its release into the circulation than about the Ang II-dependency of hypertension. ISAs are a welcome addition to clinical studies of renin inhibitors. By comparing the results of ISAs with those of EKAs, the inhibitor-bound forms of renin and prorenin can be distinguished from the unbound forms. ISAs also provide important information on the molecular basis of prorenin activation. We propose a single kinetic model to incorporate the conformational changes of prorenin induced by cryo-activation and acid-activation, and by binding to renin inhibitors. It explains why renin ISAs can overestimate the rise of renin in response to these drugs, and shows how to deal with this artefact.
Background Migraine has been associated with a dysfunctional activation of the trigeminovascular system. Calcitonin gene-related peptide, a neuropeptide released from the trigeminal nerve fibres, has an important role in the pathophysiology of migraine and is a current therapeutic target for migraine treatment. Methods We examined the effects of two novel calcitonin gene-related peptide receptor antagonists, ubrogepant and atogepant, on the relaxations induced by α calcitonin gene-related peptide in human isolated middle meningeal, cerebral and coronary arteries. Furthermore, the contractile responses to atogepant and ubrogepant per se were studied and compared to the responses elicited by zolmitriptan in proximal and distal human coronary arteries. Results In intracranial arteries, both blockers antagonized the calcitonin gene-related peptide-induced relaxations more potently when compared to the inhibition observed in distal human coronary arteries, with atogepant showing a higher potency. When analysing their antagonistic profile in HCA, ubrogepant showed a competitive antagonist profile, while atogepant showed a non-competitive one. Neither of the gepants had vasoconstrictor effect at any of the concentrations studied in human coronary arteries, whereas zolmitriptan elicited concentration-dependent contractions. Conclusion ubrogepant and atogepant differentially inhibit the calcitonin gene-related peptide-dependent vasodilatory responses in intracranial arteries when compared to distal human coronary arteries. Also, both gepants are devoid of vasoconstrictive properties in human coronary arteries.
Although it is tempting to speculate that the (pro)renin receptor is the missing link providing a role for prorenin in tissue angiotensin generation, the discrepant results with handle region peptide and the lack of clinical studies with (pro)renin receptor blockers do not yet firmly support such a role.
Contractions to DHE in distal coronary arteries are smaller than those to sumatriptan, while at clinical concentrations they both induce only slight contractions. In meningeal arteries contractions to DHE and sumatriptan are significantly larger, showing their cranioselectivity. Contractions to DHE in the saphenous vein are higher than those in the arteries, confirming its venous contractile properties.
Introduction: Tryptophan is the precursor of kynurenine pathway (KP) metabolites which regulate immune tolerance, energy metabolism, and vascular tone. Since these processes are important during pregnancy, changes in KP metabolite concentrations may play a role in the pathophysiology of pregnancy complications. We hypothesize that KP metabolites can serve as novel biomarkers and preventive therapeutic targets. This review aimed to provide more insight into associations between KP metabolite concentrations in maternal and fetal blood, and in the placenta, and adverse maternal pregnancy and fetal outcomes. Methods: A systematic search was performed on 18 February 2022 comprising all KP metabolites, and keywords related to maternal pregnancy and fetal outcomes. English-written human studies measuring KP metabolite(s) in maternal or fetal blood or in the placenta in relation to pregnancy complications, were included. Methodological quality was assessed using the ErasmusAGE quality score (QS) (range: 0-10). A meta-analysis of the mean maternal tryptophan and kynurenine concentrations in uncomplicated pregnancies was conducted. Results: Of the 6262 unique records, 37 were included (median QS = 5). Tryptophan was investigated in most studies, followed by kynurenine, predominantly in maternal blood (n = 28/37), and in the second and third trimester of pregnancy (n = 29/37). Compared to uncomplicated pregnancies, decreased tryptophan in maternal blood was associated with an increased prevalence of depression, gestational diabetes mellitus, fetal growth restriction, spontaneous abortion, and preterm birth. Elevated tryptophan was only observed in women with pregnancy-induced hypertension compared to normotensive pregnant women. In women with preeclampsia, only kynurenic acid was altered; elevated in the first trimester of pregnancy, and positively associated with proteinuria in the third trimester of pregnancy. Conclusions: KP metabolite concentrations were altered in a variety of maternal pregnancy and fetal complications. This review implies that physiological pregnancy requires a tight balance of KP metabolites, and that disturbances in either direction are associated with adverse maternal pregnancy and fetal outcomes.
Objective: The aims were (1) to quantitate angiotensin I to II conversion on the endothelial surface and at deeper sites in isolated arteries, (2) to assess whether the angiotensin II that is formed at deeper sites is released into the vascular lumen, and (3) to examine whether enzymes other than angiotensin converting enzyme (ACE) are involved in vascular angiotensin I to II conversion. Methods: Metabolism of [""I]-angiotensin I was studied in isolated perfused porcine coronary and carotid arteries after luminal administration of the labelled peptide (in the perfusion fluid) and after adventitial administration (in the organ bath). Measurements were made both in the presence and in the absence of captopril. Results: ['*'I]-angiotensin II was a major metabolite and its formation was virtually completely blocked by captopril, after both luminal and adventitial administration of ['251]-angiotensin I. In coronary arteries (n = S), the ['251]-angiotensin I to II conversion rate after adventitial administration was about half that after luminal administration. In coronary arteries (n = 6) the conversion rate after adventitial administration was lo-20 times lower than after luminal administration. Degradation of
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