Regional blood flow measurements were made using the radioactive microsphere technique of Rudolph and Heymann [13] before Histamine and 3 times after the i.v. infusion of 2 mg/kg morphine in 9 unanesthetized monkeys restrained in horizontally tilted primate chairs. The dose was chosen after response curves established its minimal but consistent hypotensive effects. Although little systemic hemodynamic change was observed, the morphine evoked significant increases in blood flow to the heart, brain and bone, which lasted up to 1¹/₂ h. The changes in regional blood flow outlasted the effects on blood pressure. Initially blood flow to the bronchial arteries was reduced to 50% of baseline. These changes were associated with depressed respiration, decreased pH and PO₂ and an increased PCO₂ of arterial blood. Arterial blood levels of histamine were not significantly changed after the morphine infusion; therefore, histamine cannot be considered the mediator of the changes in regional blood flow.

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A series of 19 congener derivatives and conjugates of histamine was synthesized and tested to determine whether the ligands would alter the conventional histamine activity in various tissues. The derivatives, which contained either branched or unbranched aliphatic groups, aromatic amide groups, or dipeptides, exhibited affinities for histamine type 1 and/or type 2 receptors that were widely different from the progenitor. The p-trifluoromethyl derivative of histamine with an intermediate chain length of four methylenes (compound 13) was the most potent lymphocytes H2 receptor agonist but was inactive on guinea pig myocardium H2 receptors. The deletion of a single methylene chain (compound 12) from this compound resulted in total loss of its H2 activity on lymphocytes and its H1 activity on aorta. Compound 12 became an exclusive H1 agonist on lymphocytes H1 receptors. The dipeptide conjugate (compound 17) and the aliphatic congener derivative (compound 18), both with four methylenes, retained some of the activity on guinea pig myocardium H2 receptors, but lost their activity on lymphocytes H2 receptors. Therefore, histamine can be modified at sites that are at a distance from the imidazole moiety, resulting in tissue selective histamine receptor agonists.

Systemic and regional hemodynamic changes were measured in restrained, conscious rhesus monkeys with indwelling arterial and venous catheters before and after clonidine (5 and 15 mug/kg) was slowly infused intravenously or smaller doses (2 mug/kg) were injected into a lateral cerebral ventricle. Dye-dilution cardiac outputs and the complete distribution of cardiac output were obtained intermittently with the use of the radioactive microsphere method. After the higher intravenous dose and the intraventricular injection, systemic arterial pressure was significantly lowered for 30-45 min. Both of these groups had similar changes in the redistribution of cardiac output and blood flow that outlasted the hypotensive period. Blood flow was maintained or increased in the hepatic and renal arteries at the expense of skin; flow to skeletal muscle and brain also decreased during the first hour. These data support previous studies that indicate that the primary action of clonidine is in the central nervous system and, in addition, add new information about the regional blood flow changes evoked by clonidine.