ObjectiveTo investigate the role of hypercholesterolemia in the regulation of blood pressure.Subjects and methodsWe compared blood pressure responses to arithmetic stress and hand-grip tests in normotensive patients with hypercholesterolemian= 15) and a mean (± SEM) age of 49 ± 3 years, and normal cholesterolemic controls (n= 22) aged 48 ± 1 years. Blood pressure and heart rate were measured throughout the tests. We examined the intracellular Ca2+concentration in platelets with or without low-density-lipoprotein stimulation (2.9 nmol/l, 10 mg/ml). The plasma nitrite plus nitrate and cyclic GMP were determined before and at the end of each test to evaluate nitric oxide production and activity.ResultsBoth tests showed that systolic/diastolic blood pressure was higher in the hypercholesterolemic patients than in the normal controls (stress test: 139 ± 3/91 ± 4 versus 127 ± 2/80 ± 3 mmHg,P< 0.01/P< 0.05; handgrip test: 164 ± 5/106 ± 5 versus 144 ± 3/88 ± 3 mmHg,P< 0.01/P< 0.01). The intracellular Ca2+concentration in platelets and the increase in response to low-densitylipoprotein stimulation were higher in the hypercholesterolemic patients (without stimulation: 72 ± 3 versus 64 ± 3 nmol/l,P< 0.01; with 2.9 nmol/l stimulation: 145 ± 21 versus 89 ± 6 nmol/l,P< 0.01). The increase in Ca2+in response to 2.9 nmol/ml stimulation with lowdensity lipoprotein was positively related to the increase in mean blood pressure in response to the stress test (r= 0.56,P< 0.002). Nitric oxide production appeared to be increased in the hypercholesterolemic patients (65 ± 5 versus 51 ± 4 mmol/l,P< 0.05), and was not affected significantly by the tests. In contrast, cyclic GMP was lower in the patients and was increased significantly in the normal controls by the hand-grip test (P< 0.05). As a result, plasma cyclic GMP was lower in the patients (1.9 ± 0.2 versus 2.5 ± 0.1 nmol/l,P< 0.01). The ratio of plasma cyclic GMP to nitric oxide was also lower in the hypercholesterolemic patients at rest (P< 0.05), and at the end of the mental stress (P< 0.02) and hand-grip (P< 0.001) tests.ConclusionsPatients with hypercholesterolemia showed an exaggerated blood pressure response to both mental stress and exercise, even if resting blood pressure was normal. Increases in the intracellular Ca2+concentration can contribute to these excessive responses. A disproportionately lower level of cyclic GMP to nitric oxide in plasma may also be involved in these abnormal responses.