Sex differences in pulmonary vascular control: focus on the nitric oxide pathway

Although the incidence of pulmonary hypertension is higher in females, the severity and prognosis of pulmonary vascular disease in both neonates and adults have been shown to be worse in male subjects. Studies of sex differences in pulmonary hypertension have mainly focused on the role of sex hormones. However, the contribution of sex differences in terms of vascular signaling pathways regulating pulmonary vascular function remains incompletely understood. Consequently, we investigated pulmonary vascular function of male and female swine in vivo, both at rest and during exercise, and in isolated small pulmonary arteries in vitro, with a particular focus on the NO-cGMP-PDE5 pathway. Pulmonary hemodynamics at rest and during exercise were virtually identical in male and female swine. Moreover, NO synthase inhibition resulted in a similar degree of pulmonary vasoconstriction in male and female swine. However, NO synthase inhibition blunted bradykinin-induced vasodilation in pulmonary small arteries to a greater extent in male than in female swine. PDE5 inhibition resulted in a similar degree of vasodilation in male and female swine at rest, while during exercise there was a trend towards a larger effect in male swine. In small pulmonary arteries, PDE5 inhibition failed to augment bradykinin-induced vasodilation in either sex. Finally, in the presence of NO synthase inhibition, the pulmonary vasodilator effect of PDE5 inhibition was significantly larger in female swine both in vivo and in vitro. In conclusion, the present study demonstrated significant sex differences in the regulation of pulmonary vascular tone, which may contribute to understanding sex differences in incidence, treatment response, and prognosis of pulmonary vascular disease

Systemic, pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist in awake pigs at rest and during treadmill exercise Z1046

1. In view of the potential therapeutic application of specific dopamine receptor agonists in the treatment of hypertension and left ventricular dysfunction, we investigated the cardiovascular actions of the novel mixed D1/D2 dopamine receptor agonist Z1046 in awake pigs at rest and during treadmill exercise. 2. Thirteen swine were chronically instrumented under sterile conditions for measurement of systemic, pulmonary, and coronary haemodynamics. Regional blood flows were determined with the radioactive microsphere technique. 3. Z1046 (1, 10, 100 μg kg-1, i.v.) produced dose-dependent reductions in central aortic blood pressure (up to 27 ± 3%, P ≤ 0.05) in awake resting pigs which was accompanied by only minimal reflex activation of the sympathetic nervous system. The hypotensive response was principally the result of peripheral vasodilatation (system vascular resistance decreased up to 35 ± 4%, P ≤ 0.05), which was located in the cerebral, coronary, renal, mesenteric, adrenal, splenic and skeletal muscular vascular beds (vascular resistance decreased up to 30-40% after the highest dose in these beds). Only in the cerebral and mesenteric bed was the vasodilatation sufficiently large to overcome the decrease in blood pressure and result in an increased blood flow; the vasodilatation in the coronary bed was most likely due to autoregulation as neither coronary blood flow nor myocardial oxygen demand were changed significantly by Z1046. The systemic vasodilatation that was caused by the highest i.v. dose (100 μg kg-1) was accompanied by transient and minor increases in heart rate (15 ± 5%, P ≤ 0.05) and cardiac output (15 ± 5%, P ≤ 0.05) whereas after 10 μg kg-1, i.v., a slight decrease in cardiac output also contributed to the hypotension. Z1046 had no effect on pulmonary vascular resistance. 4. The systemic vasodilator responses to Z1046 (100 μg kg-1, i.v.) were sustained during treadmill exercise (2-4 km h-1 which produced heart rates of up to 233 ± 10 beats min-1), but with increasing treadmill speed attenuation of the exercise-induced increase in heart rate (-11 ± 3%, P ≤ 0.05) and hence cardiac output (-10 ± 3%, P ≤ 0.05) (as stroke volume was not altered by Z1046) contributed significantly to a lower aortic blood pressure (-20 ± 3%, P ≤ 0.05). Z1046 had no effect on pulmonary vascular resistance during exercise. 5. Oral administration of Z1046 (0.5, 1.5 mg kg-1) produced a fall in central aortic blood pressure (up to 15 ± 3%, P ≤ 0.05), which developed gradually during the first 90 min and lasted up to 4 h after administration, again with negligible changes in heart rate and LVdP/dt(max). 6. Neither non-selective α- and β-adrenoceptor blockade, nor selective α2-adrenoceptor blockade altered the vasodilator actions of Z1046, but non-selective α- and β-adrenoceptor blockade abolished the cardiac responses to dopamine receptor stimulation, suggesting that its cardiac actions were principally caused by D2-receptor-mediated inhibition of catecholamine release, whereas the vasodilator response was probably the result of vascular D1-receptor stimulation. 7. In conclusion, the novel dopamine receptor agonist Z1046 is an effective blood pressure lowering agent that elicits minimal reflex activation of the sympathetic nervous system in awake resting pigs. Systemic vasodilatation was not affected by combined α- and β-adrenoceptor blockade, which is consistent with a predominantly D1 receptor-dependent vasodilator mechanism. The hypotensive effect is maintained during treadmill exercise during which systemic vasodilatation and a lower cardiac output both contribute to the blood pressure lowering actions of Z1046. The cardiovascular profile of this orally active compound warrants further investigation of this class of drugs in experimental and clinical hypertension.</p

Systemic, pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist in awake pigs at rest and during treadmill exercise Z1046

1. In view of the potential therapeutic application of specific dopamine receptor agonists in the treatment of hypertension and left ventricular dysfunction, we investigated the cardiovascular actions of the novel mixed D1/D2 dopamine receptor agonist Z1046 in awake pigs at rest and during treadmill exercise. 2. Thirteen swine were chronically instrumented under sterile conditions for measurement of systemic, pulmonary, and coronary haemodynamics. Regional blood flows were determined with the radioactive microsphere technique. 3. Z1046 (1, 10, 100 μg kg-1, i.v.) produced dose-dependent reductions in central aortic blood pressure (up to 27 ± 3%, P ≤ 0.05) in awake resting pigs which was accompanied by only minimal reflex activation of the sympathetic nervous system. The hypotensive response was principally the result of peripheral vasodilatation (system vascular resistance decreased up to 35 ± 4%, P ≤ 0.05), which was located in the cerebral, coronary, renal, mesenteric, adrenal, splenic and skeletal muscular vascular beds (vascular resistance decreased up to 30-40% after the highest dose in these beds). Only in the cerebral and mesenteric bed was the vasodilatation sufficiently large to overcome the decrease in blood pressure and result in an increased blood flow; the vasodilatation in the coronary bed was most likely due to autoregulation as neither coronary blood flow nor myocardial oxygen demand were changed significantly by Z1046. The systemic vasodilatation that was caused by the highest i.v. dose (100 μg kg-1) was accompanied by transient and minor increases in heart rate (15 ± 5%, P ≤ 0.05) and cardiac output (15 ± 5%, P ≤ 0.05) whereas after 10 μg kg-1, i.v., a slight decrease in cardiac output also contributed to the hypotension. Z1046 had no effect on pulmonary vascular resistance. 4. The systemic vasodilator responses to Z1046 (100 μg kg-1, i.v.) were sustained during treadmill exercise (2-4 km h-1 which produced heart rates of up to 233 ± 10 beats min-1), but with increasing treadmill speed attenuation of the exercise-induced increase in heart rate (-11 ± 3%, P ≤ 0.05) and hence cardiac output (-10 ± 3%, P ≤ 0.05) (as stroke volume was not altered by Z1046) contributed significantly to a lower aortic blood pressure (-20 ± 3%, P ≤ 0.05). Z1046 had no effect on pulmonary vascular resistance during exercise. 5. Oral administration of Z1046 (0.5, 1.5 mg kg-1) produced a fall in central aortic blood pressure (up to 15 ± 3%, P ≤ 0.05), which developed gradually during the first 90 min and lasted up to 4 h after administration, again with negligible changes in heart rate and LVdP/dt(max). 6. Neither non-selective α- and β-adrenoceptor blockade, nor selective α2-adrenoceptor blockade altered the vasodilator actions of Z1046, but non-selective α- and β-adrenoceptor blockade abolished the cardiac responses to dopamine receptor stimulation, suggesting that its cardiac actions were principally caused by D2-receptor-mediated inhibition of catecholamine release, whereas the vasodilator response was probably the result of vascular D1-receptor stimulation. 7. In conclusion, the novel dopamine receptor agonist Z1046 is an effective blood pressure lowering agent that elicits minimal reflex activation of the sympathetic nervous system in awake resting pigs. Systemic vasodilatation was not affected by combined α- and β-adrenoceptor blockade, which is consistent with a predominantly D1 receptor-dependent vasodilator mechanism. The hypotensive effect is maintained during treadmill exercise during which systemic vasodilatation and a lower cardiac output both contribute to the blood pressure lowering actions of Z1046. The cardiovascular profile of this orally active compound warrants further investigation of this class of drugs in experimental and clinical hypertension.</p