Abstract-␣-Calcitonin gene-related peptide (␣CGRP) is a pleiotropic neuropeptide implicated in a variety of physiological processes. To better understand the biological functions of ␣CGRP, we developed an ␣CGRP-null mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were significantly higher in both anesthetized and conscious, unrestrained ␣CGRP-null mice than in corresponding wild-type mice. The elevated MAP in ␣CGRP-null mice was shown to be the result of elevated peripheral vascular resistance by ␣-adrenergic blockade with prazosin and by transthoracic echocardiogram, which revealed no significant differences between ␣CGRP-null and wild-type mice in the stroke volume, fractional shortening, and ejection fraction. Moreover, evaluation of autonomic nervous activity by measuring HR after pretreatment of atropine and/or atenolol and by analyzing arterial baroreceptor reflexes showed sympathetic nervous activity to be significantly elevated in ␣CGRP-null mice; elevated levels of urinary catecholamine metabolites and decreased HR variability in mutant mice were also consistent with that finding. These findings suggest that ␣CGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity. Key Words: calcitonin gene-related peptide Ⅲ gene targeting Ⅲ blood pressure Ⅲ autonomic nervous system Ⅲ hypertension C alcitonin gene-related peptide (CGRP) is a 37-amino acid vasoactive neuropeptide produced by tissue-specific alternative splicing of the primary transcript of the calcitonin/ ␣CGRP gene. 1 While calcitonin (CT), which controls calcium homeostasis, is expressed almost exclusively in the C cells of the thyroid gland, ␣CGRP is widely distributed in the central and peripheral nervous systems in mammals. In addition, a second CGRP isoform, ␤CGRP, is encoded by a different gene locus and is expressed almost exclusively in specific neuronal sites. 2 These two CGRP isoforms-␣ and ␤ in rat and I and II in humans-exhibit overlapping biological activities in most vascular beds. 3 Within the nervous system, CGRP immunoreactivity has been detected in spinal cord motor neurons, dorsal root ganglia, and motor nerve endings. 4 Other neuropeptides, the tachykinins, which include substance P (SP) and neurokinin A (NKA), exhibit similar expression patterns to ␣CGRP in several regions of the nervous system. ␣CGRP and tachykinins coexist in primary afferent neurons, forming the part of the so-called nonadrenergic, noncholinergic (NANC) nervous system, 5 and their release from sensory pain fibers has been implicated in the perception of pain.NANC neurons containing ␣CGRP are also widely distributed among autonomic fibers innervating the vasculature; for example, they are found in blood vessels at the junction of the adventitia and the media passing into the muscle layer. 5 Moreover, ␣CGRP is a potent vasodilator, 6 and several investigators have claimed that ␣CGRP may play a key role in regu...

Senile ApoE-deficient mice display aortic valve sclerosis that is similar to that observed in humans. The sclerotic valves displayed frequent apoptotic cell death and chemokine expression. Smooth muscle-like cells observed in degenerative valves might derive, at least in part, from bone marrow.

For multivessel coronary artery disease, simultaneous integrated coronary artery revascularization with bivalirudin is safe and feasible. This approach enables complete multivessel revascularization with decreased surgical trauma and postoperative morbidity. Further studies are necessary to better determine patient selection and long-term outcomes.