Omapatrilat in Subtotal Nephrectomy-Salt Hypertension

Abstract

Abstract-Calcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide, plays a counterregulatory role in subtotal nephrectomy-salt (SN-salt)-induced hypertension, reflecting a stimulation of the efferent vasodilator function of perivascular sensory nerves. To determine the effect of omapatrilat, a dual ACE and neutral endopeptidase inhibitor, on blood pressure and the potential antihypertensive role for CGRP, 24 male Sprague-Dawley rats were separated into 4 groups: (1) SN-salt, (2) SN-salt plus omapatrilat (80 mg · kg Ϫ1 · d Ϫ1 in the drinking water), (3) sham-operated plus salt, (4) sham-operated plus salt and omapatrilat. After 11 days the mean arterial pressure was higher in the SN-salt group (174Ϯ10 mm Hg) versus the sham-operated-salt (109Ϯ4 mm Hg) and sham-operated-salt plus omapatrilat (105Ϯ3 mm Hg) groups. Omapatrilat treatment of the SN-salt rats significantly decreased the mean arterial pressure to 123Ϯ7 mm Hg and significantly reduced the heart-to-body weight ratio. Intravenous administration of a specific CGRP receptor antagonist produced a significant 10Ϯ2 mm Hg mean arterial pressure increase in the untreated SN-salt hypertensive rats but was without effect in the other groups. This indicates that CGRP does not contribute to the antihypertensive actions of omapatrilat. In addition, CGRP mRNA and protein content in dorsal root ganglia were decreased Ϸ25% in the SN-salt plus omapatrilat rats. Thus, omapatrilat not only markedly reduces the blood pressure in this model of renal failure-induced hypertension but may also prevent the abnormal compensatory stimulation of the vasodilator activity of the peripheral sensory nervous system. Key Words: nervous system Ⅲ neuropeptides Ⅲ hypertension, experimental Ⅲ antihypertensive agents Ⅲ vasodilator agents C alcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide, participates in the regulation of vascular tone and regional organ blood flows, both under normal physiological conditions and in the pathophysiology of hypertension. 1,2 A prominent site of CGRP synthesis is the dorsal root ganglia (DRG), which contain the cell bodies of sensory nerves that terminate peripherally on blood vessels and centrally in the spinal cord. A dense perivascular CGRP neural network is seen around the blood vessels in virtually every vascular bed. 1,2 Several lines of evidence suggest that the vasodilator activity of CGRP is mediated by the release of this peptide from predominantly capsaicin-sensitive perivascular sensory nerve terminals. 3 We have previously reported that in the deoxycorticosteronesalt 4,5 and subtotal nephrectomy-salt (SN-salt) 6 rat models of acquired hypertension, CGRP acts as a compensatory vasodilator to partially counteract the blood pressure (BP) increase. In deoxycorticosterone-salt rats, the antihypertensive activity of CGRP appears to be mediated through an upregulation in the neuronal (DRG) expression of this peptide. The SN-salt model did not exhibit this increase in CGRP production. We later demonstrated that in thi...

Omapatrilat Induces Profound Renal Vasodilation but Does Not Affect Coronary Hemodynamics

“…Omapatrilat and other ACE/NEP inhibitors have been shown to reduce left ventricular mass (3,7,36,37). Although we demonstrated reduced left ventricular and aortic mass, arterial pressure was not reduced to normotensive levels, further supporting our previous assertion that the nonhemodynamic actions of some pharmacologic agents also participate in the reduction of left ventricular mass (20,38,39).…”

“…Omapatrilat has been shown to be an effective antihypertensive and antihypertrophic agent in experimental hypertension and cardiac failure (2)(3)(4)(5)(6)(7)(8)(9). Moreover, it has improved endothelial function and vascular remodeling in salt-induced hypertension as well as in a malignant form of genetic hypertension (2,5).…”

Pathophysiology and therapeutic possibilities of calcitonin gene-related peptide in hypertension

“…In contrast, in subtotal nephrectomy (SN) salt hypertensive rats, CGRP mRNA accumulation in DRG was similar to that found in normotensive rats and treatment with CGRP 8-37 produced a greater dose-dependent increase in arterial pressure than it did in normotensive rats. These results suggest that sensitivity to CGRP is enhanced in SN salt hypertensive rats (68,70).…”

Role of anandamide transporter in regulating calcitonin gene-related peptide production and blood pressure in hypertension

“…Reports from other laboratories and ours have demonstrated that CGRP is involved in hypertensive diseases [20,33]. It is intriguing that changes in plasma levels of CGRP are dependent on types of hypertension.…”