title: Systemic, pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist in awake pigs at rest and during treadmill exercise Z1046.
abstract: 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 micrograms kg-1, i.v.) produced dose-dependent reductions in central aortic blood pressure (up to 27 +/- 3%, P < or = 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 < or = 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 micrograms kg-1) was accompanied by transient and minor increases in heart rate (15 +/- 5%, P < or = 0.05) and cardiac output (15 +/- 5%, P < or = 0.05) whereas after 10 micrograms 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 micrograms 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 < or = 0.05) and hence cardiac output (-10 +/- 3%, P < or = 0.05) (as stroke volume was not altered by Z1046) contributed significantly to a lower aortic blood pressure (-20 +/- 3%, P < or = 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 < or = 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/dtmax. 6. Neither non-selective alpha- and beta-adrenoceptor blockade, nor selective alpha 2-adrenoceptor blockade altered the vasodilator actions of Z1046, but non-selective alpha- and beta-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 alpha- and beta-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.
authors.affiliation: Thoraxcenter, Erasmus University Rotterdam, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: Duncker
authors.forename: D B
authors.initials: DB
authors.lastname: Haitsma
authors.forename: I E
authors.initials: IE
authors.lastname: van der Geest
authors.forename: R
authors.initials: R
authors.lastname: Stubenitsky
authors.forename: J R
authors.initials: JR
authors.lastname: van Meegen
authors.forename: A J
authors.initials: AJ
authors.lastname: Man in't Veld
authors.forename: P D
authors.initials: PD
authors.lastname: Verdouw
mesh_terms: D000284:Administration, Oral; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D018491:Dopamine Agonists / Q000008:administration & dosage*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D009284:Naphthols / Q000008:administration & dosage*; D010646:Phentolamine / Q000494:pharmacology; D005082:Physical Exertion; D011433:Propranolol / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects*; D013552:Swine; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D018674:Adrenergic Antagonists; D018491:Dopamine Agonists; D009284:Naphthols; C105333:Z1046; D015016:Yohimbine; D011433:Propranolol; D010646:Phentolamine