CGRP is Protective Against Hypertension Induced End Organ Damage

The results described above in Sections 4 and 4.2 demonstrate that the a-CGRP/CT deficient mice display a significant increase in basal blood pressure and a significant decrease in basal coronary flow rates. Hypertension-induced end organ damage is one of the most severe and common consequences of chronic increased blood pressure. Because CGRP has such potent biological effects on the heart and kidneys, and in light of several lines of indirect evidence suggesting that CGRP is an endogenous organ-protective agent

(42.43), the purpose of this study was to determine whether end organ damage is enhanced in the DOC-salt hypertensive a-CGRP KO mice compared to their hypertensive WT counterparts. After initiation of the DOC-salt protocol, the blood pressure, as determined by long-term telemetric recording, increased rapidly in both groups to final values of 166 ± 5 mmHg for the a-CGRP KO and 147 ± 4 mmHg for the WT mice

(36.44). When normalized to basal blood pressure this represents an approx 35% (and equal) increase in MAP for the two groups. The MAP was unchanged in the two control groups (unpublished observations). Both the a-CGRP KO and WT mice displayed a normal 24 h circadian rhythm, both before and after DOC-salt treatment, with the highest blood pressure and heart rate occurring near midnight and the lowest in the early afternoon.

At the conclusion of the blood pressure measurement studies, the mice were sacrificed and the hearts, kidneys, aortas, and femoral arteries were removed for histopathological examination (44). As before, no changes were seen in the hearts and kidneys between the control a-CGRP KO and WT mice. Furthermore, no significant pathological changes were seen in the hearts and kidneys from the DOC-salt hypertensive WT mice compared to their normotensive controls. The only exception was that heart sections from both the DOC-salt hypertensive a-CGRP KO and WT mice displayed a marked increase in cardiac myocyte size. This result demonstrates left ventricular hypertrophy and is consistent with the increased heart-to-body weight ratios of the heats from the DOC-salt treated mice of both strains. In contrast, extensive damage was evident in the heart and kidney sections from the DOC-salt hypertensive a-CGRP KO mice. Marked (2+, in scale of 1+ to 4+) small vessel disease was seen in the heart sections from DOC-salt treated a-CGRP mice with thickening and inflammation of the vessel walls. Perivascular inflammation was also noted and the endothelial cells were prominent which is consistent with inflammation of this critical cell layer. In the myocardium, there were prominent 2+ myocarditis, myocardial necrosis, and foci of inflammation that extended to the epicardium. The kidneys of these mice showed marked 2+ glomerular changes including congestion of the capillary loops, focal mesangial proliferation, crescentic proliferation, and focal histocytic infiltration. Proteinaceous casts were also noted in a number of tubules.

These data demonstrate that deletion of the a-CGRP gene enhances hypertension-induced end organ damage in the heart and kidney. The mechanism of this increased tissue damage may be through the loss of CGRP-mediated vasodilator activity and/or to an increase in the local tissue production of reactive oxygen species. Indirect mechanisms such as activation of the sympathetic nervous system and/or the RAS system may also be involved. To our knowledge this is the first report of a sensory nerve-mediated cardio- and renal-protective effect against hypertension-induced end organ damage. Traditionally, sensory nerves were defined as purely afferent neurons that monitor changes in their chemical and physical environment and convey this information to the central nervous system. They also have the capacity to act in an efferent manner. This efferent function is mediated by the release of neuropeptides, including CGRP, from their peripheral terminals that regulate vasodilation and other tissue activities independently of sensation. Thus, this organ-protective activity of CGRP may reflect another significant function of the efferent arm of the sensory nervous system.

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Reducing Blood Pressure Naturally

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