1 This study investigated the cannabinoid receptor, known to inhibit neuronally-evoked contractions of the mouse isolated urinary bladder, in bladder sections isolated from mouse, rat, dog, pig non-human primate or human. 2 The CB 1 -like pharmacology of the cannabinoid receptor in mouse isolated bladder observed previously was con®rmed in this study by the rank order of agonist potencies: CP 559405WIN 55212-24HU 2104JWH 0154anandamide, the high anity of the CB 1 selective antagonist, SR 141716A (apparent pK B 8.7), and the low anity of the CB 2 antagonist, SR 144528 (apparent pK B 56.5). In these studies, SR 141716A (10 ± 100 nM) signi®cantly potentiated electrically-evoked contractions in this tissue by an undetermined mechanism. 3 A similar rank order of agonist potencies was determined in rat isolated bladder sections (CP 55,. In this tissue, the maximal inhibitory eect of all agonists was lower than in the mouse bladder. Indeed, the eects of both HU 210 and anandamide were too modest to quantify potency accurately. 4 In the rat isolated bladder, SR 141716A (30 nM) or SR 144528 (100 nM), reversed the inhibitory eect of WIN 55212-2 (apparent pK B =8.4 and 8.0, respectively) or JWH 015 (apparent pK B =8.2 and 7.4, respectively). These ®ndings may demonstrate pharmacological dierences between the rat and mouse orthologues of the CB 1 receptor. Alternatively, they may be attributed to a mixed population of CB 1 and CB 2 receptors that jointly in¯uence neurogenic contraction of the rat bladder, but cannot be dierentiated without more selective ligands. 5 WIN 55212-2 had no eect on electrically-evoked contractions of bladder sections isolated from dog, pig, cynomolgus monkey and human. These ®ndings suggest that the eect of cannabinoid agonists to inhibit neurogenic contraction of the mouse and rat bladder is not conserved across all mammalian species.

The effects of left ventricular diastolic pressure changes on the values of the time constant (T) of isovolumic pressure fall are controversial. Normally, T is calculated either by linear regression of 1n left ventricular pressure (LVP) vs. time (TL) or by using an exponential model with asymptote (PB, extrapolated base-line pressure to which LVP would fall if decay continued indefinitely). This study, in intact dogs, has been designed to revise the effects that drugs that alter load (angiotensin and nitroprusside, without and with autonomic blockade) and inotropism (isoproterenol and propranolol) might have on the relaxation rate using different numerical methods. We found that 1) the upward or downward translation of the LVP curve had an important effect on the value of TL calculated by the semilogarithmic method; 2) when a model with asymptote was used, the simultaneous changes of T and PB, were not related to the dose of the drug; 3) the values of TL and the -dP/dt values extrapolated to 15 mmHg from a model with PB, were much more sensitive to beta-agonist or antagonist drugs than to others whose action was through load alteration. We feel that some of the earlier studies on relaxation rate determinants should be revised as possibly some of the conclusions have been based on artifacts introduced by the method chosen for the computation of the relaxation parameters.

1 The two peptides calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) produced marked dilatation of the forearm vascular bed when infused via the brachial artery. 2 CGRP relaxed preconstricted segments of human radial, coronary, gastric and cerebral arteries in an endothelium dependent manner. 3 VIP relaxed human gastric and transverse cervical arteries in an endothelium dependent manner, but relaxation of the human pulmonary artery was not dependent on endothelium. 4 The characteristics of the endothelium dependent relaxation of these medium-sized muscular arteries indicated involvement of the endothelium derived relaxing factor in vitro. 5 Caution is expressed in drawing comparisons between the mechanisms involved in the in vivo and in vitro vascular responses.Keywords calcitonin gene related peptide vasoactive intestinal peptide vasodilatation endothelium derived relaxing factor

1 This study was designed to investigate dopaminergic mechanisms in human vasculature using the selective vascular dopamine receptor agonist fenoldopam in vivo and in vitro. In vivo, forearm blood flow was measured plethysmographically and in vitro isolated rings of human blood vessels from a variety of sites were used for tissue bath studies. 2 Intra-arterial fenoldopam markedly increased forearm blood flow, this effect was antagonised by (R) sulpiride, a vascular dopamine (DA1) antagonist, but not by metoclopramide, a neuronal (DA2) antagonist, or by guanethidine, an adrenergic neurone blocking agent. 3 In vitro, fenoldopam relaxed preconstricted human renal, mesenteric and lumbar arteries, but not saphenous vein in a concentration dependent manner. (RS) sulpiride and SCH 23390 competitively antagonised this effect. 4 These studies demonstrate the presence of a vasodilatory vascular dopamine receptor in man both in vivo and in vitro.Keywords dopamine receptor fenoldopam forearm blood flow isolated blood vessels

Eleven patients with moderate to severe hypertension were pre-treated with oral labetalol 800-1200 mg/day for one week, prior to receiving two i.v. infusions of dopamine 1-3 micrograms/kg/min each of 30 min each, before and after the i.v. bolus injection of metoclopramide 30 mg. There were washout periods before and after the metoclopramide administration. Dopamine induced a significant decrease of blood pressure from 172/104 to 153/94 mm Hg without altering heart rate, and it increased the plasma insulin level from 8.3 to 12.1 microU.ml-1. Metoclopramide did not itself affect blood pressure or plasma insulin, but it did block the hypotensive response and rise in plasma insulin due to dopamine. We conclude that the pharmacological actions of intravenous dopamine on the cardiovascular system and on insulin secretion may be mediated by dopaminergic receptor stimulation.