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

• Published in: British journal of pharmacology 1997-03, Vol.120 (6), p.1101-1113
• Main Authors: Duncker, Dirk J, Haitsma, David B, Geest, Ingeborg E J, Stubenitsky, Rene, Van Meegen, Jan R, Manin't Veld, Arie J, Verdouw, Pieter D
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adrenergic Antagonists - pharmacology; Animals; Antihypertensive agents; awake pig; Biological and medical sciences; Cardiovascular system; Coronary Circulation - drug effects; Dopamine Agonists - administration & dosage; dopamine receptor; exercise; Female; Haemodynamics; Hemodynamics - drug effects; Injections, Intravenous; Male; Medical sciences; Naphthols - administration & dosage; organ blood flows; Pharmacology. Drug treatments; Phentolamine - pharmacology; Physical Exertion; Propranolol - pharmacology; pulmonary circulation; Pulmonary Circulation - drug effects; Space life sciences; Swine; systemic circulation; Yohimbine - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701022

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. 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. Z1046 (1, 10, 100 μg kg−1, i.v.) produced dose‐dependent reductions in central aortic blood pressure (up to 27±3%, P0.05) 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%, P0.05), 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%, P0.05) and cardiac output (15±5%, P0.05) 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. 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%, P0.05) and hence cardiac output (−10±3%, P0.05) (as stroke volume was not altered by Z1046) contributed significantly to a lower aortic blood pressure (−20±3%, P0.05). Z1046 had no effect on pulmonary vascular resistance during exercise. Oral administration of Z1046 (0.5, 1.5 mg kg−1) produced a fall in central aortic blood pressure (up to 15±3%, P0.05), which developed gradually during the first 90 min and lasted up to 4 h