Cardiovascular effects of cromakalim (BRL 34915) in healthy volunteers.

Abstract

1 The effect of oral doses of cromakalim 0.5, 1.0, 1.5 and 2.0 mg on several cardiovascular parameters was studied in healthy male volunteers. 2 In the first study, no dose of cromakalim reduced systolic or diastolic blood pressure in the supine or standing position. Reductions of diastolic blood pressure after exercise (P < 0.01) were observed 4 h after administration of 2.0 mg. 3 There was a trend towards increased heart rate after 2.0 mg at all time intervals, and significant changes were observed in supine and standing heart rate at 2 and 4 h (P < 0.01). No significant change was observed in exercise heart rate. 4 In the second study small increases in forearm blood flow were observed from 3 h to 5 h after oral administration of 1.0 and 2.0 mg of cromakalim. Forearm vascular resistance was significantly reduced after 2.0 mg (P < 0.025) when compared with placebo. No change was observed in forearm venous capacitance after either dose of cromakalim, or placebo. Supine heart rate was significantly increased 4 h after 2.0 mg of cromakalim (P < 0.025). 5These results show that oral administration of cromakalim decreases diastolic blood pressure and forearm vascular resistance. A hypotensive effect is probably attenuated by reflex tachycardia.

KATP‐channel activation: effects on myocardial recovery from ischaemia and role in the cardioprotective response to adenosine A1‐receptor stimulation

“…This interaction may have profound implications for the potential of K ATP -channel activators in the clinical management of ischaemic heart disease as high levels of free fatty acids (equivalent to those used in the present study) are present in human plasma following myocardial ischaemia (Lopaschuk et al, 1994). Thus, these results, in combination with those of other studies (Goldberg et al, 1988;Fox et al, 1991) suggest that K ATP -channel activators would be of limited clinical ecacy and prone to marked adverse eects.…”

Levcromakalim, an Adenosine Triphosphate‐Sensitive Potassium Channel Opener, Dilates Extracerebral but not Cerebral Arteries

“…1 K ATP channels are expressed in the cranial arteries, trigeminal ganglion (TG) and trigeminal nucleus caudalis, [2][3][4][5][6][7] and several migraine triggering molecules activate and open K ATP channels. 13,14 Furthermore, intravenous infusion of levcromakalim-induced migraine attacks in migraine patients. 13,14 Furthermore, intravenous infusion of levcromakalim-induced migraine attacks in migraine patients.…”

“…[8][9][10][11][12] In humans, intravenous infusion of synthetic K ATP channel openers, levcromakalim, and pinacidil, were associated with development of headache. 13,14 Furthermore, intravenous infusion of levcromakalim-induced migraine attacks in migraine patients. 15 Underlying mechanisms responsible for headache and migraine induction after levcromakalim infusion are unknown.…”

Hemodynamic and Cardiac Effects of BMS-180448, a Novel KATP Opener, in Anesthetized Dogs and Isolated Rat Hearts

“…It is important to point out that the initial effects of cromakalim were to increase coronary flow [7], Since BMS-180448 has lit tle effect on blood pressure, it should have lit tle adverse effect, unlike other K +At p openers. Thus, one would expect that adverse sideeffects seen with most K+Atp openers, such as hypotension, headache, and reflex tachycar dia, will be minimal with BMS-180448 [24][25][26], It is important to point out that doses of cromakalim that display cardioprotective ef fects cannot be obtained following intrave nous administration due to the severe hypo tensive nature of this compound. Thus, BMS-180448 at cardioprotective doses (2-3 mg/kg i.v.)…”