cl-316243 and Hypertension

Previous studies have identified adrenergic receptor sites in the lower esophageal sphincter (LES) of animals and humans. A beta3 adrenoceptor has been identified and cloned. The binding site for this receptor has been found in the rat LES in vitro. The aim of the study was to assess the role of a specific beta3 agonist (CL316243) on LES pressure (LESP) in vivo.. Anesthetized adult opossums were given CL316243 and isoproterenol intravenously as boluses before and after continuous infusion of L748337 (a specific beta3 antagonist), propranolol, and bethanechol. Blood pressure, heart rate, and LESP were continuously recorded.. CL316243 caused a dose-dependent maximal inhibition of LESP of 88.5% +/- 4.8%. The mean duration of inhibition was 62.2 +/- 9.2 minutes with minimal change in cardiovascular parameters. Isoproterenol caused dose-dependent maximal inhibition of 89.4% +/- 4.7% with mean duration of action of 5.1 +/- 0.9 minutes but was associated with significant hypotension and tachycardia. L748337 and propranolol significantly blocked the effects of CL316243 and isoproterenol, respectively. CL316243 and isoproterenol inhibited the bethanechol-mediated hypertensive LES.. (1) A selective beta3 agonist, CL316243, caused significant, prolonged, and dose-dependent inhibition of LESP and, unlike isoproterenol, had minimal effect on heart rate and mean arterial pressure. (2) The beta3 antagonist, L748337, selectively inhibited CL316243 without altering the isoproterenol response. (3) CL316243 and isoproterenol both caused inhibition of cholinergic-mediated hypertensive LESP.

Topics: Adrenergic beta-3 Receptor Antagonists; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Aminophenols; Animals; Bethanechol; Blood Pressure; Dioxoles; Dose-Response Relationship, Drug; Esophagogastric Junction; Heart Rate; Hypertension; Isoproterenol; Opossums; Pressure; Sulfonamides

Cardiovascular function during cold exposure is dependent on effective thermoregulation. This dependence is particularly apparent in infants. For example, we have previously demonstrated that in infant rats during cold exposure, cardiac rate is directly related to their ability to produce heat endogenously. The primary source of endogenous heat production for infant rats is brown adipose tissue (BAT). Because of the dependence of cardiac rate on effective thermoregulation in the cold and because hypertension in spontaneously hypertensive rats (SHR) is influenced by the preweanling environment, in this study we examined the thermoregulatory and cardiac rate responses of infant SHR and Wistar-Kyoto rats (WKY) to varying levels of cold exposure. In experiment 1, 7- to 8-day-old SHR and WKY were acclimated at a thermoneutral air temperature (35 degrees C) and then exposed to successive decreases in ambient temperature (30.5 degrees C, 26.5 degrees C, 23 degrees C, and 17 degrees C) while thermal and metabolic measures were recorded. Although both strains increased BAT thermogenesis and oxygen consumption in response to cold exposure, SHR cooled more than WKY and exhibited lower levels of oxygen consumption at the lowest air temperatures. Experiment 2 was identical to experiment 1 except that cardiac rate was also measured. Again, SHR exhibited substantial thermoregulatory deficits compared with WKY; in addition, they were less able than WKY to maintain cardiac rate at the 2 lowest air temperatures tested. Finally, in experiment 3, infant SHR exhibited diminished BAT thermogenesis in response to a range of doses of a selective beta3-adrenoceptor agonist. We hypothesize that long-term thermoregulatory deficits during the early postnatal period influence cardiovascular function and contribute to the development of hypertension in SHR.

Topics: Acclimatization; Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Body Temperature Regulation; Cold Temperature; Dioxoles; Heart; Heart Rate; Hypertension; Male; Oxygen Consumption; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Species Specificity