SYSTEMIC, PULMONARY AND CORONARY HEMODYNAMIC 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 dopamin e receptor agonists in the treatment of hypertension and left ventricu lar dysfunction, we investigated the cardiovascular actions of the nov el mixed D-1/D-2 dopamine receptor agonist Z1046 in awake pigs at rest and during treadmill exercise. 2 Thirteen swine were chronically inst rumented under sterile conditions for measurement of systemic, pulmona ry, and coronary haemodynamics. Regional blood hows were determined wi th the radioactive microsphere technique. 3 Z1046 (1, 10, 100 mu g kg( -1), i.v.) produced dose-dependent reductions in central aortic blood pressure (up to 27+/-3%, P less than or equal to 0.05) in awake restin g pigs which was accompanied by only minimal reflex activation of the sympathetic nervous system, The hypotensive response was principally t he result of peripheral vasodilatation (system vascular resistance dec reased up to 35+/-4%, P less than or equal to 0.05), which was located in the cerebral, coronary, renal, mesenteric, adrenal, splenic and sk eletal muscular vascular beds (vascular resistance decreased up to 30- 40% after the highest dose in these beds). Only in the cerebral and me senteric 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 autoregulat ion as neither coronary blood flow nor myocardial oxygen demand were c hanged significantly by Z1046. The systemic vasodilatation that was ca used by the highest i.v. dose (100 mu g kg(-1)) was accompanied by tra nsient and minor increases in heart rate (15+/-5%, P less than or equa l to 0.05) and cardiac output (15+/-5%, P less than or equal to 0.05) whereas after 10 mu g kg(-1), i.v., a slight decrease in cardiac outpu t also contributed to the hypotension. Z1046 had no effect on pulmonar y vascular resistance. 4 The systemic vasodilator responses to Z1046 ( 100 mu g kg(-1), i.v.) were sustained during treadmill exercise (2-4 k m h(-1) which produced heart rates of up to 233+/-10 beats min(-1)), b ut with increasing treadmill speed attenuation of the exercise-induced increase in heart rate (-11+/-3%, P less than or equal to 0.05) and h ence cardiac output (-10+/-3%, P less than or equal to 0.05) (as strok e volume was not altered by Z1046) contributed significantly to a lowe r aortic blood pressure (-20+/-3%, P less than or equal to 0.05). Z104 6 had no effect on pulmonary vascular resistance during exercise. 5 Or al administration of Z1046 (0.5, 1.5 mg kg(-1)) produced a fall in cen tral aortic blood pressure (up to 15+/-3%, P less than or equal to 0.0 5), 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 alpha- and beta-adrenocepto r blockade, nor selective alpha(2)-adrenoceptor blockade altered the v asodilator actions of Z1046, but non-selective alpha- and beta-adrenoc eptor blockade abolished the cardiac responses to dopamine receptor st imulation, suggesting that its cardiac actions were principally caused by D-2-receptor-mediated inhibition of catecholamine release, whereas the vasodilator response was probably the result of vascular D-1-rece ptor stimulation. 7 In conclusion, the novel dopamine receptor agonist Z1046 is an effective blood pressure lowering agent that elicits mini mal reflex activation of the sympathetic nervous system in awake resti ng pigs. Systemic vasodilatation was not affected by combined alpha- a nd beta-adrenoceptor blockade, which is consistent with a predominantl y D-1 receptor-dependent vasodilator mechanism. The hypotensive effect is maintained during treadmill exercise during which systemic vasodil atation and a lower cardiac output both contribute to the blood pressu re lowering actions of Z1046. The cardiovascular profile of this orall y active compound warrants further investigation of this class of drug s in experimental and clinical hypertension.