Enhanced Vascular Responsiveness to Bay K 8644 in Mineralocorticoid- and N-Nitro Arginine-Induced Hypertension

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Abstract
The present study evaluates the response to the L-type voltage gated calcium channel agonist Bay K 8644 in two forms of experimental hypertension (mineralocorticoid- and hypertension induced by the nitric oxide synthase inhibitor Nw-nitro-L-arginine (N-Nitro arginine)) and under conditions of acute stretch. These studies test the hypothesis that increased L-type calcium channel activity in vasculature is a hallmark or general characteristic of hypertension. Male Sprague-Dawley rats were made hypertensive by subcutaneous implantation of deoxycorticosterone acetate (200 mg/kg DOCA) and given normal or high salt water (1% NaCl + 0.2% KC1); other rats were made hypertensive by ingestion of N-Nitro arginine (2% in water). Systolic blood pressures (SBP) were taken by the standard tail cuff method. Following development of hypertension, rats were anesthetized, and aortae or mesenteric arteries were isolated for measurement of isometric contractile force. Cumulative concentration response curves to Bay K 8644 (110–10 to 10–6M), KC1 (6 to 100 mM), or phenylephrine (10–10–3 × 10–7 M) were evaluated. Isolated mesenteric arteries from rats given both DOCA and salt were most sensitive to BayK 8644 (SBP = 191 ± 6 mm Hg, – log EC50 = 7.78 ± 0.13), followed by rats receiving high salt alone (SBP = 118 ± 6 mm Hg, – log EC50 = 7.30 ± 0.17), DOCA alone (SBP = 152 ± 2 mm Hg, –log EC50 = 7.25 ± 0.15), and finally normal sham rats (SBP = 111 ± 5mm Hg, –log EC50 ± 6.80 ± 0.10). These data indicate that both DOCA and salt intake can independently influence responsiveness to BayK 8644. Bay K 8644 was also significantly more potent and efficacious in aortae from both DOCA-high salt and N-Nitro-arginine (SBP = 153 ± 3mm Hg) hypertensive rats. Aortae from normotensive male Sprague-Dawley rats were removed and maintained at varied passive tensions (100, 1000, and 2000 mg) during experimentation. Threshold responses to Bay K 8644 but not KC1 or phenylephrine were enhanced in those vessels maintained at 2000 mg compared to the lower passive tensions and was not affected by, indomethacin (10–5 M), indicating that cyclooxygenase products were not involved in the change in sensitivty to BayK 8644 seen with increasing preload. Collectively, these data suggest that 1) there is an augmented responsiveness to calcium channel agonists in vessels from animals made hypertensive by mineralocorticoid treatment or by ingestion of N-Nitro-arginine; 2) a portion of this hyperreactivity in mineralocorticoid-treated rats can be attributed to both DOCA and salt intake; and 3) this result is mimicked in vessels from normotensive animals that have been acutely stretched. Thus, these studies suggest that hypertension or acute stretch serve to alter calcium channel reactivity to the dihydropyridine agonist BayK 8644.