Nadal trailed 94th-ranked Damir Dzumhur 2-6 6-4 3-0, with the Bosnian 30-15 up on serve, when he called it a day. It was the first time Nadal had quit during a match since a quarter-final against Murray at the 2010 Australian Open.
"Everything was fine until the end of the first set," Nadal said. "Then I started to feel dizzy, not very good. It was getting worse and worse.
"I wanted to finish the match, but I seriously could not. It was tough, because I felt I was playing well. I stopped because I was concerned for my health."
Nadal twice called for a trainer, and had his blood pressure checked on the second occasion, but resumed play both times after a short break.
Dzumhur was also affected by the heat early in the match and was the first to call a trainer, but he battled on and after a poor first set eventually gained control to post his first career victory against a world top-10 player.
In the night session, Briton Murray had a heated exchange with the chair umpire en route to a 6-3 7-5 victory over Uzbek Denis Istomin.
Murray faced break point at 2-2 in the second set when he noticed that a women's ball had somehow got into the mix. Women use different balls at the Miami Open, and they have a red stamping to differentiate them.
"That’s unbelievable. That’s one of the women’s balls. I could have just hit a shot with it," Murray complained.
Though the rogue ball was removed from play, Murray was clearly flustered and netted a groundstroke in the next rally to lose the game.
Murray then gave the umpire another earful.
"It’s not right. Do you know how different the balls are?" he asked.
The umpire said he was fully aware but could do nothing about what had transpired.
"The point stands. It’s the same for both," he said.
Murray then settled down, immediately broke back and closed out the match without further incident.
Number four Stan Wawrinka was the highest seed to lose on Saturday after the Swiss was sent packing 6-4 6-3 by Russian Andrey Kuznetsov, who saved eight break points.
Sixth seed Kei Nishikori of Japan moved on after beating Pierre-Hugues Herbert 6-2 7-6(4).
(Reporting by Andrew Both in Cary, North Carolina; Editing by Toby Davis/Peter Rutherford)
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