We evaluated insulin sensitivity in normotensive (blood pressure, BP, less than 135/85 mm Hg) and hypertensive (BP greater than 160/90 mm Hg) elderly subjects over 65 years old who were stratified as normal weight (body mass index, BMI, less than 27) and obese (BMI greater than 27). Obese hypertensive individuals demonstrated marked hyperinsulinemia (P less than .01) and significantly reduced (P less than .05) submaximally stimulated adipocyte 2-deoxyglucose (2-DOG) uptake (abdominal wall fat biopsy). Normal weight hypertensive subjects also demonstrated higher levels of insulinemia and lower insulin-stimulated 2-DOG uptake than nonobese controls. Adipocyte [Ca2+]i levels were elevated in all elderly subjects compared to young individuals (P less than .01). Basal and maximally stimulated 2-DOG uptake were similar in all groups. One month of therapy with a calcium channel blocker, 10 mg nitrendipine twice daily, reduced blood pressure in the hypertensive subjects, reduced plasma insulin to control values during an oral glucose tolerance test in obese hypertensive individuals (P less than .01), and restored adipocyte 2-DOG uptake at submaximally effective insulin concentration to control values in normal weight and obese hypertensive subjects. In summary, older hypertensive, and particularly older obese hypertensive, patients manifest significant insulin resistance accompanied by elevated levels of [Ca2+]i in their adipocytes.

It has been shown that the effects of certain vasoactive substances such as adrenaline and posterior pituitary extracts may be modified by varying the ovarian hormone concentrations in the body (Byrom 1938;Reynolds 1952; Boxill & Brown 1955). Certain practical considerations are implicit in these results, and it was decided to examine further the effects of oestrogens and progesterone on vascular responses to constrictor and dilator substances. Vasopressin was used as the chief exemplar of a constrictor drug. When it was found, as described below, that oxytocin could be either dilator or constrictor according to circumstances, attention was also given to this substance. Some study was also made of the action of acetylcholine, this being a naturally occurring dilator substance. METHODSThe experiments were made on rats, anaesthetized with intraperitoneal sodium pentobarbitone 5 mg/100 g body weight. Animals of approximately 200 g body weight were used, and all doses mentioned are calculated as for this weight. Two experimental methods were used, either singly or together; in the first the arterial blood pressure was recorded on a kymograph from the cannulated carotid artery, and in the second the blood vessels of the mesoappendix were directly observed in the manner described by Chambers & Zweifach (1944). When the first method was used test drugs in 0.3 ml. NaCl solution 0 9 % (w/v) were injected into a cannula inserted in the femoral vein; when the mesoappendix preparation was used drugs were either injected intravenously or applied topically. Ovariectomy was performed aseptically under ether anaesthesia. Vaginal smears were stained with Leishmann stain.The ovarian hormone preparations used were stilboestrol dipropionate and Progestin, both in oil, from British Drug Houses; they were injected subcutaneously 24 hr or more before observations were made. The vasopressin used was du Vigneaud's highly purified natural substance (though Parke Davis's Pitressin was occasionally employed), and the oxytocin was the synthetic brand Syntocinon (Sandoz). RESULTS Normal ratsThe results in this group were intended to provide the control responses with which those of other groups could be compared, but individuals differed widely as to the minimal effective dose, and in some animals the response

In two recent papers (Lloyd, 1959a, b) it was shown that the vascular responses of the rat to oxytocin and vasopressin varied with the concentration of ovarian hormones in the body. For example, oxytocin was dilator in the dioestrous rat, though without effect on the blood pressure, while in the oestrous animal, during late pregnancy, or after ovarian hormone administration, oxytocin was pressor and constrictor. It was not known how far this reversal of effect was due to an altered state of the peripheral vasculature, or how far central mechanisms were involved. Since peripheral vasodilatation is one of the consequences of the administration of oestrogen, it was of interest to test the effect of other dilator substances on the response to oxytocin and vasopressin in the rat, and for this purpose infusions of histamine, acetylcholine, isoprenaline and 5-hydroxytryptamine (5-HT) were used. In addition, procedures such as pithing, decerebration, and the administration of autonomic blocking agents were used to determine whether reduction of vasomotor tone would affect the responses to posterior pituitary hormones, and to discover if any part was played by the central and peripheral nervous systems. METHODSAll experiments were made on rats of approximately 200 g body weight. Anaesthesia, injection of drugs, and recording of blood pressure were effected by the methods previously described (Lloyd, 1959a, b). The stage of the reproductive cycle was checked in all females by vaginal smears stained with Leishmann stain. All drugs were dissolved in NaCl solution 0-9 g/100 ml. Single intravenous injections were made up to a volume of 0-3 ml.; intravenous infusions were made into a cannulated femoral vein, at a rate of 0-05 ml./min. Autonomic blocking agents were either given intravenously during the experiments, or subcutaneously 2-3 hr before observations were begun. In experiments in which rats were pre-treated with an oestrogen, stilboestrol dipropionate was used, given in a dose of 3-5 pg/100 g 24 hr before observations were made.

Papers already published report that in the normal mammals so far examined (man, dog and rat, both sexes) oxytocin dilates a number of vascular beds (Lloyd, 1959a, b;Lloyd & Pickford, 1961; see Haigh, Kitchin & Pickford, 1963). This dilator effect is converted to a constrictor one following chemical blockage of ganglia or peripheral sympathetic nerves, after surgical sympathectomy of the part, and after administration of reserpine. The same change is also induced by subcutaneous or intravenous administration of oestrogens, or when the animal (rat) is in natural oestrus. As a first step towards elucidating the mechanism of the identical change in the response to oxytocin induced by procedures as diverse as oestrogen administration and interference with the sympathetic nervous system, it was decided to attempt restoration of the dilator effect of oxytocin after having caused the appearance of the constrictor one. This paper is chiefly concerned with experiments made to this end on a number of dogs and on two monkeys. Brief reference to some of these results has already been made (Haigh, Lloyd & Pickford, 1964;Pickford, 1964). METHODSThe observations were made on a number of dogs of both sexes and on two female monkeys. All but two of the experiments were acute ones in which the animals were anaesthetized with pentobarbitone, 26 5 mg/kg body weight, given intravenously; the animals also received heparin, 5 mg/kg body weight intravenously. Mean blood pressure was recorded by mercury manometer from the carotid artery. Blood flow through the hind limb was measured by means of a Pavlov (1887) stromuhr inserted between the cut ends of the femoral vein. When preparations were complete a period of 25-40 min was allowed before observations were begun.Chronic observations were made in one female and one male dog and, in these, leg flow was measured by means of venous occlusion plethysmography. The diaphragm of the plethysmograph was specially designed with an irregular ovoid opening shaped like the cross-section of a dog's leg. The leg was inserted through this into a thin rubber bag made of two breadths of 2 in. diameter colostomy tubing sealed together; in the usual way the rubber bag was attached to the rim of the diaphragm across the opening of the plethysmograph. 36-2