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.
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